WorldWideScience

Sample records for genome-wide genetic analysis

  1. Genetics of Obesity Traits: A Bivariate Genome-Wide Association Analysis

    DEFF Research Database (Denmark)

    Wu, Yili; Duan, Haiping; Tian, Xiaocao

    2018-01-01

    Previous genome-wide association studies on anthropometric measurements have identified more than 100 related loci, but only a small portion of heritability in obesity was explained. Here we present a bivariate twin study to look for the genetic variants associated with body mass index and waist......-hip ratio, and to explore the obesity-related pathways in Northern Han Chinese. Cholesky decompositionmodel for 242monozygotic and 140 dizygotic twin pairs indicated a moderate genetic correlation (r = 0.53, 95%CI: 0.42–0.64) between body mass index and waist-hip ratio. Bivariate genome-wide association.......05. Expression quantitative trait loci analysis identified rs2242044 as a significant cis-eQTL in both the normal adipose-subcutaneous (P = 1.7 × 10−9) and adipose-visceral (P = 4.4 × 10−15) tissue. These findings may provide an important entry point to unravel genetic pleiotropy in obesity traits....

  2. A review of genome-wide approaches to study the genetic basis for spermatogenic defects.

    Science.gov (United States)

    Aston, Kenneth I; Conrad, Donald F

    2013-01-01

    Rapidly advancing tools for genetic analysis on a genome-wide scale have been instrumental in identifying the genetic bases for many complex diseases. About half of male infertility cases are of unknown etiology in spite of tremendous efforts to characterize the genetic basis for the disorder. Advancing our understanding of the genetic basis for male infertility will require the application of established and emerging genomic tools. This chapter introduces many of the tools available for genetic studies on a genome-wide scale along with principles of study design and data analysis.

  3. Genome wide characterization of simple sequence repeats in watermelon genome and their application in comparative mapping and genetic diversity analysis.

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    Zhu, Huayu; Song, Pengyao; Koo, Dal-Hoe; Guo, Luqin; Li, Yanman; Sun, Shouru; Weng, Yiqun; Yang, Luming

    2016-08-05

    Microsatellite markers are one of the most informative and versatile DNA-based markers used in plant genetic research, but their development has traditionally been difficult and costly. The whole genome sequencing with next-generation sequencing (NGS) technologies provides large amounts of sequence data to develop numerous microsatellite markers at whole genome scale. SSR markers have great advantage in cross-species comparisons and allow investigation of karyotype and genome evolution through highly efficient computation approaches such as in silico PCR. Here we described genome wide development and characterization of SSR markers in the watermelon (Citrullus lanatus) genome, which were then use in comparative analysis with two other important crop species in the Cucurbitaceae family: cucumber (Cucumis sativus L.) and melon (Cucumis melo L.). We further applied these markers in evaluating the genetic diversity and population structure in watermelon germplasm collections. A total of 39,523 microsatellite loci were identified from the watermelon draft genome with an overall density of 111 SSRs/Mbp, and 32,869 SSR primers were designed with suitable flanking sequences. The dinucleotide SSRs were the most common type representing 34.09 % of the total SSR loci and the AT-rich motifs were the most abundant in all nucleotide repeat types. In silico PCR analysis identified 832 and 925 SSR markers with each having a single amplicon in the cucumber and melon draft genome, respectively. Comparative analysis with these cross-species SSR markers revealed complicated mosaic patterns of syntenic blocks among the genomes of three species. In addition, genetic diversity analysis of 134 watermelon accessions with 32 highly informative SSR loci placed these lines into two groups with all accessions of C.lanatus var. citorides and three accessions of C. colocynthis clustered in one group and all accessions of C. lanatus var. lanatus and the remaining accessions of C. colocynthis

  4. Genome-wide association analysis reveals distinct genetic architectures for single and combined stress responses in Arabidopsis thaliana

    NARCIS (Netherlands)

    Davila Olivas, Nelson H.; Kruijer, Willem; Gort, Gerrit; Wijnen, Cris L.; Loon, van Joop J.A.; Dicke, Marcel

    2017-01-01

    Plants are commonly exposed to abiotic and biotic stresses. We used 350 Arabidopsis thaliana accessions grown under controlled conditions. We employed genome-wide association analysis to investigate the genetic architecture and underlying loci involved in genetic variation in resistance to: two

  5. Genome-wide analysis of adolescent psychotic-like experiences shows genetic overlap with psychiatric disorders.

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    Pain, Oliver; Dudbridge, Frank; Cardno, Alastair G; Freeman, Daniel; Lu, Yi; Lundstrom, Sebastian; Lichtenstein, Paul; Ronald, Angelica

    2018-03-31

    This study aimed to test for overlap in genetic influences between psychotic-like experience traits shown by adolescents in the community, and clinically-recognized psychiatric disorders in adulthood, specifically schizophrenia, bipolar disorder, and major depression. The full spectra of psychotic-like experience domains, both in terms of their severity and type (positive, cognitive, and negative), were assessed using self- and parent-ratings in three European community samples aged 15-19 years (Final N incl. siblings = 6,297-10,098). A mega-genome-wide association study (mega-GWAS) for each psychotic-like experience domain was performed. Single nucleotide polymorphism (SNP)-heritability of each psychotic-like experience domain was estimated using genomic-relatedness-based restricted maximum-likelihood (GREML) and linkage disequilibrium- (LD-) score regression. Genetic overlap between specific psychotic-like experience domains and schizophrenia, bipolar disorder, and major depression was assessed using polygenic risk score (PRS) and LD-score regression. GREML returned SNP-heritability estimates of 3-9% for psychotic-like experience trait domains, with higher estimates for less skewed traits (Anhedonia, Cognitive Disorganization) than for more skewed traits (Paranoia and Hallucinations, Parent-rated Negative Symptoms). Mega-GWAS analysis identified one genome-wide significant association for Anhedonia within IDO2 but which did not replicate in an independent sample. PRS analysis revealed that the schizophrenia PRS significantly predicted all adolescent psychotic-like experience trait domains (Paranoia and Hallucinations only in non-zero scorers). The major depression PRS significantly predicted Anhedonia and Parent-rated Negative Symptoms in adolescence. Psychotic-like experiences during adolescence in the community show additive genetic effects and partly share genetic influences with clinically-recognized psychiatric disorders, specifically schizophrenia and

  6. GWAMA: software for genome-wide association meta-analysis

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    Mägi Reedik

    2010-05-01

    Full Text Available Abstract Background Despite the recent success of genome-wide association studies in identifying novel loci contributing effects to complex human traits, such as type 2 diabetes and obesity, much of the genetic component of variation in these phenotypes remains unexplained. One way to improving power to detect further novel loci is through meta-analysis of studies from the same population, increasing the sample size over any individual study. Although statistical software analysis packages incorporate routines for meta-analysis, they are ill equipped to meet the challenges of the scale and complexity of data generated in genome-wide association studies. Results We have developed flexible, open-source software for the meta-analysis of genome-wide association studies. The software incorporates a variety of error trapping facilities, and provides a range of meta-analysis summary statistics. The software is distributed with scripts that allow simple formatting of files containing the results of each association study and generate graphical summaries of genome-wide meta-analysis results. Conclusions The GWAMA (Genome-Wide Association Meta-Analysis software has been developed to perform meta-analysis of summary statistics generated from genome-wide association studies of dichotomous phenotypes or quantitative traits. Software with source files, documentation and example data files are freely available online at http://www.well.ox.ac.uk/GWAMA.

  7. FGWAS: Functional genome wide association analysis.

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    Huang, Chao; Thompson, Paul; Wang, Yalin; Yu, Yang; Zhang, Jingwen; Kong, Dehan; Colen, Rivka R; Knickmeyer, Rebecca C; Zhu, Hongtu

    2017-10-01

    Functional phenotypes (e.g., subcortical surface representation), which commonly arise in imaging genetic studies, have been used to detect putative genes for complexly inherited neuropsychiatric and neurodegenerative disorders. However, existing statistical methods largely ignore the functional features (e.g., functional smoothness and correlation). The aim of this paper is to develop a functional genome-wide association analysis (FGWAS) framework to efficiently carry out whole-genome analyses of functional phenotypes. FGWAS consists of three components: a multivariate varying coefficient model, a global sure independence screening procedure, and a test procedure. Compared with the standard multivariate regression model, the multivariate varying coefficient model explicitly models the functional features of functional phenotypes through the integration of smooth coefficient functions and functional principal component analysis. Statistically, compared with existing methods for genome-wide association studies (GWAS), FGWAS can substantially boost the detection power for discovering important genetic variants influencing brain structure and function. Simulation studies show that FGWAS outperforms existing GWAS methods for searching sparse signals in an extremely large search space, while controlling for the family-wise error rate. We have successfully applied FGWAS to large-scale analysis of data from the Alzheimer's Disease Neuroimaging Initiative for 708 subjects, 30,000 vertices on the left and right hippocampal surfaces, and 501,584 SNPs. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. A novel statistic for genome-wide interaction analysis.

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    Xuesen Wu

    2010-09-01

    Full Text Available Although great progress in genome-wide association studies (GWAS has been made, the significant SNP associations identified by GWAS account for only a few percent of the genetic variance, leading many to question where and how we can find the missing heritability. There is increasing interest in genome-wide interaction analysis as a possible source of finding heritability unexplained by current GWAS. However, the existing statistics for testing interaction have low power for genome-wide interaction analysis. To meet challenges raised by genome-wide interactional analysis, we have developed a novel statistic for testing interaction between two loci (either linked or unlinked. The null distribution and the type I error rates of the new statistic for testing interaction are validated using simulations. Extensive power studies show that the developed statistic has much higher power to detect interaction than classical logistic regression. The results identified 44 and 211 pairs of SNPs showing significant evidence of interactions with FDR<0.001 and 0.001genome-wide interaction analysis is a valuable tool for finding remaining missing heritability unexplained by the current GWAS, and the developed novel statistic is able to search significant interaction between SNPs across the genome. Real data analysis showed that the results of genome-wide interaction analysis can be replicated in two independent studies.

  9. Chapter 10: Mining genome-wide genetic markers.

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    Xiang Zhang

    Full Text Available Genome-wide association study (GWAS aims to discover genetic factors underlying phenotypic traits. The large number of genetic factors poses both computational and statistical challenges. Various computational approaches have been developed for large scale GWAS. In this chapter, we will discuss several widely used computational approaches in GWAS. The following topics will be covered: (1 An introduction to the background of GWAS. (2 The existing computational approaches that are widely used in GWAS. This will cover single-locus, epistasis detection, and machine learning methods that have been recently developed in biology, statistic, and computer science communities. This part will be the main focus of this chapter. (3 The limitations of current approaches and future directions.

  10. Genome-wide analysis of disease progression in age-related macular degeneration.

    Science.gov (United States)

    Yan, Qi; Ding, Ying; Liu, Yi; Sun, Tao; Fritsche, Lars G; Clemons, Traci; Ratnapriya, Rinki; Klein, Michael L; Cook, Richard J; Liu, Yu; Fan, Ruzong; Wei, Lai; Abecasis, Gonçalo R; Swaroop, Anand; Chew, Emily Y; Weeks, Daniel E; Chen, Wei

    2018-03-01

    Family- and population-based genetic studies have successfully identified multiple disease-susceptibility loci for Age-related macular degeneration (AMD), one of the first batch and most successful examples of genome-wide association study. However, most genetic studies to date have focused on case-control studies of late AMD (choroidal neovascularization or geographic atrophy). The genetic influences on disease progression are largely unexplored. We assembled unique resources to perform a genome-wide bivariate time-to-event analysis to test for association of time-to-late-AMD with ∼9 million variants on 2721 Caucasians from a large multi-center randomized clinical trial, the Age-Related Eye Disease Study. To our knowledge, this is the first genome-wide association study of disease progression (bivariate survival outcome) in AMD genetic studies, thus providing novel insights to AMD genetics. We used a robust Cox proportional hazards model to appropriately account for between-eye correlation when analyzing the progression time in the two eyes of each participant. We identified four previously reported susceptibility loci showing genome-wide significant association with AMD progression: ARMS2-HTRA1 (P = 8.1 × 10-43), CFH (P = 3.5 × 10-37), C2-CFB-SKIV2L (P = 8.1 × 10-10) and C3 (P = 1.2 × 10-9). Furthermore, we detected association of rs58978565 near TNR (P = 2.3 × 10-8), rs28368872 near ATF7IP2 (P = 2.9 × 10-8) and rs142450006 near MMP9 (P = 0.0006) with progression to choroidal neovascularization but not geographic atrophy. Secondary analysis limited to 34 reported risk variants revealed that LIPC and CTRB2-CTRB1 were also associated with AMD progression (P < 0.0015). Our genome-wide analysis thus expands the genetics in both development and progression of AMD and should assist in early identification of high risk individuals.

  11. Significant Locus and Metabolic Genetic Correlations Revealed in Genome-Wide Association Study of Anorexia Nervosa.

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    Duncan, Laramie; Yilmaz, Zeynep; Gaspar, Helena; Walters, Raymond; Goldstein, Jackie; Anttila, Verneri; Bulik-Sullivan, Brendan; Ripke, Stephan; Thornton, Laura; Hinney, Anke; Daly, Mark; Sullivan, Patrick F; Zeggini, Eleftheria; Breen, Gerome; Bulik, Cynthia M

    2017-09-01

    The authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes. Following uniform quality control and imputation procedures using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3,495 anorexia nervosa cases and 10,982 controls, the authors performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression was used to calculate genome-wide common variant heritability (single-nucleotide polymorphism [SNP]-based heritability [h 2 SNP ]), partitioned heritability, and genetic correlations (r g ) between anorexia nervosa and 159 other phenotypes. Results were obtained for 10,641,224 SNPs and insertion-deletion variants with minor allele frequencies >1% and imputation quality scores >0.6. The h 2 SNP of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. The authors identified one genome-wide significant locus on chromosome 12 (rs4622308) in a region harboring a previously reported type 1 diabetes and autoimmune disorder locus. Significant positive genetic correlations were observed between anorexia nervosa and schizophrenia, neuroticism, educational attainment, and high-density lipoprotein cholesterol, and significant negative genetic correlations were observed between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes. Anorexia nervosa is a complex heritable phenotype for which this study has uncovered the first genome-wide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. The study results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology.

  12. Data analysis in the post-genome-wide association study era

    Directory of Open Access Journals (Sweden)

    Qiao-Ling Wang

    2016-12-01

    Full Text Available Since the first report of a genome-wide association study (GWAS on human age-related macular degeneration, GWAS has successfully been used to discover genetic variants for a variety of complex human diseases and/or traits, and thousands of associated loci have been identified. However, the underlying mechanisms for these loci remain largely unknown. To make these GWAS findings more useful, it is necessary to perform in-depth data mining. The data analysis in the post-GWAS era will include the following aspects: fine-mapping of susceptibility regions to identify susceptibility genes for elucidating the biological mechanism of action; joint analysis of susceptibility genes in different diseases; integration of GWAS, transcriptome, and epigenetic data to analyze expression and methylation quantitative trait loci at the whole-genome level, and find single-nucleotide polymorphisms that influence gene expression and DNA methylation; genome-wide association analysis of disease-related DNA copy number variations. Applying these strategies and methods will serve to strengthen GWAS data to enhance the utility and significance of GWAS in improving understanding of the genetics of complex diseases or traits and translate these findings for clinical applications. Keywords: Genome-wide association study, Data mining, Integrative data analysis, Polymorphism, Copy number variation

  13. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

    NARCIS (Netherlands)

    Lee, S.H.; Ripke, S.; Neale, B.; Faraone, S.V.; Purcell, S.M.; Perlis, R.H.; Mowry, B. J.; Thapar, A.; Goddard, M.E.; Witte, J.S.; Absher, D.; Agartz, I.; Akil, H.; Amin, F.; Andreassen, O.A.; Anjorin, A.; Anney, R.; Anttila, V.; Arking, D.E.; Asherson, P.; Azevedo, M.H.; Backlund, L.; Badner, J.A.; Bailey, A.J.; Banaschewski, T.; Barchas, J.D.; Barnes, M.R.; Barrett, T.B.; Bass, N.; Battaglia, A.; Bauer, M.; Bayés, M.; Bellivier, F.; Bergen, S.E.; Berrettini, W.; Betancur, C.; Bettecken, T.; Biederman, J; Binder, E.B.; Black, D.W.; Blackwood, D.H.; Bloss, C.S.; Boehnke, M.; Boomsma, D.I.; Breen, G.; Breuer, R.; Bruggeman, R.; Cormican, P.; Buccola, N.G.; Buitelaar, J.K.; Bunney, W.E.; Buxbaum, J.D.; Byerley, W. F.; Byrne, E.M.; Caesar, S.; Cahn, W.; Cantor, R.M.; Casas, M.; Chakravarti, A.; Chambert, K.; Choudhury, K.; Cichon, S.; Cloninger, C. R.; Collier, D.A.; Cook, E.H.; Coon, H.; Corman, B.; Corvin, A.; Coryell, W.H.; Craig, D.W.; Craig, I.W.; Crosbie, J.; Cuccaro, M.L.; Curtis, D.; Czamara, D.; Datta, S.; Dawson, G.; Day, R.; de Geus, E.J.C.; Degenhardt, F.; Djurovic, S.; Donohoe, G.; Doyle, A.E.; Duan, J.; Dudbridge, F.; Duketis, E.; Ebstein, R.P.; Edenberg, H.J.; Elia, J.; Ennis, S.; Etain, B.; Fanous, A.; Farmer, A.E.; Ferrier, I.N.; Flickinger, M.; Fombonne, E.; Foroud, T.; Frank, J.; Franke, B.; Fraser, C.; Freedman, R.; Freimer, N.B.; Freitag, C.; Friedl, M.; Frisén, L.; Gallagher, L.; Gejman, P.V.; Georgieva, L.; Gershon, E.S.; Geschwind, D.H.; Giegling, I.; Gill, M.; Gordon, S.D.; Gordon-Smith, K.; Green, E.K.; Greenwood, T.A.; Grice, D.E.; Gross, M.; Grozeva, D.; Guan, W.; Gurling, H.; de Haan, L.; Haines, J.L.; Hakonarson, H.; Hallmayer, J.; Hamilton, S.P.; Hamshere, M.L.; Hansen, T.F.; Hartmann, A.M.; Hautzinger, M.; Heath, A.C.; Henders, A.K.; Herms, S.; Hickie, I.B.; Hipolito, M.; Hoefels, S.; Holmans, P.A.; Holsboer, F.; Hoogendijk, W.J.G.; Hottenga, J.J.; Hultman, C. M.; Hus, V.; Ingason, A.; Ising, M.; Jamain, S.; Jones, E.G.; Jones, I.; Jones, L.; Tzeng, J.Y.; Kähler, A.K.; Kahn, R.S.; Kandaswamy, R.; Keller, M.C.; Kennedy, J.L.; Kenny, E.; Kent, L.; Kim, Y.; Kirov, G. K.; Klauck, S.M.; Klei, L.; Knowles, J.A.; Kohli, M.A.; Koller, D.L.; Konte, B.; Korszun, A.; Krabbendam, L.; Krasucki, R.; Kuntsi, J.; Kwan, P.; Landén, M.; Langstrom, N.; Lathrop, M.; Lawrence, J.; Lawson, W.B.; Leboyer, M.; Ledbetter, D.H.; Lee, P.H.; Lencz, T.; Lesch, K.P.; Levinson, D.F.; Lewis, C.M.; Li, J.; Lichtenstein, P.; Lieberman, J. A.; Lin, D.Y.; Linszen, D.H.; Liu, C.; Lohoff, F.W.; Loo, S.K.; Lord, C.; Lowe, J.K.; Lucae, S.; MacIntyre, D.J.; Madden, P.A.F.; Maestrini, E.; Magnusson, P.K.E.; Mahon, P.B.; Maier, W.; Malhotra, A.K.; Mane, S.M.; Martin, C.L.; Martin, N.G.; Mattheisen, M.; Matthews, K.; Mattingsdal, M.; McCarroll, S.A.; McGhee, K.A.; McGough, J.J.; McGrath, P.J.; McGuffin, P.; McInnis, M.G.; McIntosh, A.; McKinney, R.; McLean, A.W.; McMahon, F.J.; McMahon, W.M.; McQuillin, A.; Medeiros, H.; Medland, S.E.; Meier, S.; Melle, I.; Meng, F.; Meyer, J.; Middeldorp, C.M.; Middleton, L.; Milanova, V.; Miranda, A.; Monaco, A.P.; Montgomery, G.W.; Moran, J.L.; Moreno-De Luca, D.; Morken, G.; Morris, D.W.; Morrow, E.M.; Moskvina, V.; Muglia, P.; Mühleisen, T.W.; Muir, W.J.; Müller-Myhsok, B.; Murtha, M.; Myers, R.M.; Myin-Germeys, I.; Neale, M.C.; Nelson, S.F.; Nievergelt, C.M.; Nikolov, I.; Nimgaonkar, V.L.; Nolen, W.A.; Nöthen, M.M.; Nurnberger, J.I.; Nwulia, E.A.; Nyholt, DR; O'Dushlaine, C.; Oades, R.D.; Olincy, A.; Oliveira, G.; Olsen, L.; Ophoff, R.A.; Osby, U.; Owen, M.J.; Palotie, A.; Parr, J.R.; Paterson, A.D.; Pato, C.N.; Pato, M.T.; Penninx, B.W.J.H.; Pergadia, M.L.; Pericak-Vance, M.A.; Pickard, B.S.; Pimm, J.; Piven, J.; Posthuma, D.; Potash, J.B.; Poustka, F.; Propping, P.; Puri, V.; Quested, D.; Quinn, E.M.; Ramos-Quiroga, J.A.; Rasmussen, H.B.; Raychaudhuri, S.; Rehnström, K.; Reif, A.; Ribasés, M.; Rice, J.P.; Rietschel, M.; Roeder, K.; Roeyers, H.; Rossin, L.; Rothenberger, A.; Rouleau, G.; Ruderfer, D.; Rujescu, D.; Sanders, A.R.; Sanders, S.J.; Santangelo, S.; Sergeant, J.A.; Schachar, R.; Schalling, M.; Schatzberg, A.F.; Scheftner, W.A.; Schellenberg, G.D.; Scherer, S.W.; Schork, N.J.; Schulze, T.G.; Schumacher, J.; Schwarz, M.; Scolnick, E.; Scott, L.J.; Shi, J.; Shilling, P.D.; Shyn, S.I.; Silverman, J.M.; Slager, S.L.; Smalley, S.L.; Smit, J.H.; Smith, E.N.; Sonuga-Barke, E.J.; St Clair, D.; State, M.; Steffens, M; Steinhausen, H.C.; Strauss, J.; Strohmaier, J.; Stroup, T.S.; Sutcliffe, J.; Szatmari, P.; Szelinger, S.; Thirumalai, S.; Thompson, R.C.; Todorov, A.A.; Tozzi, F.; Treutlein, J.; Uhr, M.; van den Oord, E.J.C.G.; Grootheest, G.; van Os, J.; Vicente, A.; Vieland, V.; Vincent, J.B.; Visscher, P.M.; Walsh, C.A.; Wassink, T.H.; Watson, S.J.; Weissman, M.M.; Werge, T.; Wienker, T.F.; Wijsman, E.M.; Willemsen, G.; Williams, N.; Willsey, A.J.; Witt, S.H.; Xu, W.; Young, A.H.; Yu, T.W.; Zammit, S.; Zandi, P.P.; Zhang, P.; Zitman, F.G.; Zöllner, S.; Devlin, B.; Kelsoe, J.; Sklar, P.; Daly, M.J.; O'Donovan, M.C.; Craddock, N.; Sullivan, P.F.; Smoller, J.W.; Kendler, K.S.; Wray, N.R.

    2013-01-01

    Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases

  14. Systems genetics of obesity in an F2 pig model by genome-wide association, genetic network and pathway analyses

    DEFF Research Database (Denmark)

    Kogelman, Lisette; Pant, Sameer Dinkar; Fredholm, Merete

    2014-01-01

    .g. metabolic processes. WISH networks based on genotypic correlations allowed further identification of various gene ontology terms and pathways related to obesity and related traits, which were not identified by the GWA study. In conclusion, this is the first study to develop a (genetic) obesity index...... investigations focusing on single genetic variants have achieved limited success, and the importance of including genetic interactions is becoming evident. Here, the aim was to perform an integrative genomic analysis in an F2 pig resource population that was constructed with an aim to maximize genetic variation...... of obesity-related phenotypes and genotyped using the 60K SNP chip. Firstly, Genome Wide Association (GWA) analysis was performed on the Obesity Index to locate candidate genomic regions that were further validated using combined Linkage Disequilibrium Linkage Analysis and investigated by evaluation...

  15. Meta-analysis and genome-wide interpretation of genetic susceptibility to drug addiction

    Science.gov (United States)

    2011-01-01

    Background Classical genetic studies provide strong evidence for heritable contributions to susceptibility to developing dependence on addictive substances. Candidate gene and genome-wide association studies (GWAS) have sought genes, chromosomal regions and allelic variants likely to contribute to susceptibility to drug addiction. Results Here, we performed a meta-analysis of addiction candidate gene association studies and GWAS to investigate possible functional mechanisms associated with addiction susceptibility. From meta-data retrieved from 212 publications on candidate gene association studies and 5 GWAS reports, we linked a total of 843 haplotypes to addiction susceptibility. We mapped the SNPs in these haplotypes to functional and regulatory elements in the genome and estimated the magnitude of the contributions of different molecular mechanisms to their effects on addiction susceptibility. In addition to SNPs in coding regions, these data suggest that haplotypes in gene regulatory regions may also contribute to addiction susceptibility. When we compared the lists of genes identified by association studies and those identified by molecular biological studies of drug-regulated genes, we observed significantly higher participation in the same gene interaction networks than expected by chance, despite little overlap between the two gene lists. Conclusions These results appear to offer new insights into the genetic factors underlying drug addiction. PMID:21999673

  16. Estimating additive and non-additive genetic variances and predicting genetic merits using genome-wide dense single nucleotide polymorphism markers.

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    Guosheng Su

    Full Text Available Non-additive genetic variation is usually ignored when genome-wide markers are used to study the genetic architecture and genomic prediction of complex traits in human, wild life, model organisms or farm animals. However, non-additive genetic effects may have an important contribution to total genetic variation of complex traits. This study presented a genomic BLUP model including additive and non-additive genetic effects, in which additive and non-additive genetic relation matrices were constructed from information of genome-wide dense single nucleotide polymorphism (SNP markers. In addition, this study for the first time proposed a method to construct dominance relationship matrix using SNP markers and demonstrated it in detail. The proposed model was implemented to investigate the amounts of additive genetic, dominance and epistatic variations, and assessed the accuracy and unbiasedness of genomic predictions for daily gain in pigs. In the analysis of daily gain, four linear models were used: 1 a simple additive genetic model (MA, 2 a model including both additive and additive by additive epistatic genetic effects (MAE, 3 a model including both additive and dominance genetic effects (MAD, and 4 a full model including all three genetic components (MAED. Estimates of narrow-sense heritability were 0.397, 0.373, 0.379 and 0.357 for models MA, MAE, MAD and MAED, respectively. Estimated dominance variance and additive by additive epistatic variance accounted for 5.6% and 9.5% of the total phenotypic variance, respectively. Based on model MAED, the estimate of broad-sense heritability was 0.506. Reliabilities of genomic predicted breeding values for the animals without performance records were 28.5%, 28.8%, 29.2% and 29.5% for models MA, MAE, MAD and MAED, respectively. In addition, models including non-additive genetic effects improved unbiasedness of genomic predictions.

  17. Genetic link between family socioeconomic status and children's educational achievement estimated from genome-wide SNPs.

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    Krapohl, E; Plomin, R

    2016-03-01

    One of the best predictors of children's educational achievement is their family's socioeconomic status (SES), but the degree to which this association is genetically mediated remains unclear. For 3000 UK-representative unrelated children we found that genome-wide single-nucleotide polymorphisms could explain a third of the variance of scores on an age-16 UK national examination of educational achievement and half of the correlation between their scores and family SES. Moreover, genome-wide polygenic scores based on a previously published genome-wide association meta-analysis of total number of years in education accounted for ~3.0% variance in educational achievement and ~2.5% in family SES. This study provides the first molecular evidence for substantial genetic influence on differences in children's educational achievement and its association with family SES.

  18. A genome wide survey of SNP variation reveals the genetic structure of sheep breeds.

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    James W Kijas

    Full Text Available The genetic structure of sheep reflects their domestication and subsequent formation into discrete breeds. Understanding genetic structure is essential for achieving genetic improvement through genome-wide association studies, genomic selection and the dissection of quantitative traits. After identifying the first genome-wide set of SNP for sheep, we report on levels of genetic variability both within and between a diverse sample of ovine populations. Then, using cluster analysis and the partitioning of genetic variation, we demonstrate sheep are characterised by weak phylogeographic structure, overlapping genetic similarity and generally low differentiation which is consistent with their short evolutionary history. The degree of population substructure was, however, sufficient to cluster individuals based on geographic origin and known breed history. Specifically, African and Asian populations clustered separately from breeds of European origin sampled from Australia, New Zealand, Europe and North America. Furthermore, we demonstrate the presence of stratification within some, but not all, ovine breeds. The results emphasize that careful documentation of genetic structure will be an essential prerequisite when mapping the genetic basis of complex traits. Furthermore, the identification of a subset of SNP able to assign individuals into broad groupings demonstrates even a small panel of markers may be suitable for applications such as traceability.

  19. Genome-Wide Association Uncovers Shared Genetic Effects Among Personality Traits and Mood States

    NARCIS (Netherlands)

    Luciano, Michelle; Huffman, Jennifer E.; Arias-Vásquez, Alejandro; Vinkhuyzen, Anna A. E.; Middeldorp, Christel M.; Giegling, Ina; Payton, Antony; Davies, Gail; Zgaga, Lina; Janzing, Joost; Ke, Xiayi; Galesloot, Tessel; Hartmann, Annette M.; Ollier, William; Tenesa, Albert; Hayward, Caroline; Verhagen, Maaike; Montgomery, Grant W.; Hottenga, Jouke-Jan; Konte, Bettina; Starr, John M.; Vitart, Veronique; Vos, Pieter E.; Madden, Pamela A. F.; Willemsen, Gonneke; Konnerth, Heike; Horan, Michael A.; Porteous, David J.; Campbell, Harry; Vermeulen, Sita H.; Heath, Andrew C.; Wright, Alan; Polasek, Ozren; Kovacevic, Sanja B.; Hastie, Nicholas D.; Franke, Barbara; Boomsma, Dorret I.; Martin, Nicholas G.; Rujescu, Dan; Wilson, James F.; Buitelaar, Jan; Pendleton, Neil; Rudan, Igor; Deary, Ian J.

    2012-01-01

    Measures of personality and psychological distress are correlated and exhibit genetic covariance. We conducted univariate genome-wide SNP (similar to 2.5 million) and gene-based association analyses of these traits and examined the overlap in results across traits, including a prediction analysis of

  20. The genetic aetiology of cannabis use initiation: A meta-analysis of genome-wide association studies and a SNP-based heritability estimation

    NARCIS (Netherlands)

    Verweij, K.J.H.; Vinkhuyzen, A.A.E.; Benyamin, B.; Lynskey, M.T.; Quaye, L.; Agrawal, A.; Gordon, S.D.; Montgomery, G.W.; Madden, P.A.F.; Heath, A.C.; Spector, T.D.; Martin, N.G.; Medland, S.E.

    2013-01-01

    While initiation of cannabis use is around 40% heritable, not much is known about the underlying genetic aetiology. Here, we meta-analysed two genome-wide association studies of initiation of cannabis use with >10000 individuals. None of the genetic variants reached genome-wide significance. We also

  1. The genetic etiology of cannabis use initiation: a meta-analysis of genome-wide association studies, and a SNP-based heritability estimation.

    NARCIS (Netherlands)

    Verweij, K.J.H.; Vinkhuyzen, A.A.E.; Benyamin, B.; Lynskey, M.T.; Quaye, L.; Agrawal, A.; Gordon, S.D.; Montgomery, G.W.; Madden, P.A.F.; Heath, A.C.; Spector, T.D.; Martin, N.G.; Medland, S.E.

    2013-01-01

    While initiation of cannabis use is around 40% heritable, not much is known about the underlying genetic aetiology. Here, we meta-analysed two genome-wide association studies of initiation of cannabis use with > 10 000 individuals. None of the genetic variants reached genome-wide significance. We

  2. A genome-wide survey of transgenerational genetic effects in autism.

    Directory of Open Access Journals (Sweden)

    Kathryn M Tsang

    Full Text Available Effects of parental genotype or parent-offspring genetic interaction are well established in model organisms for a variety of traits. However, these transgenerational genetic models are rarely studied in humans. We have utilized an autism case-control study with 735 mother-child pairs to perform genome-wide screening for maternal genetic effects and maternal-offspring genetic interaction. We used simple models of single locus parent-child interaction and identified suggestive results (P<10(-4 that cannot be explained by main effects, but no genome-wide significant signals. Some of these maternal and maternal-child associations were in or adjacent to autism candidate genes including: PCDH9, FOXP1, GABRB3, NRXN1, RELN, MACROD2, FHIT, RORA, CNTN4, CNTNAP2, FAM135B, LAMA1, NFIA, NLGN4X, RAPGEF4, and SDK1. We attempted validation of potential autism association under maternal-specific models using maternal-paternal comparison in family-based GWAS datasets. Our results suggest that further study of parental genetic effects and parent-child interaction in autism is warranted.

  3. Genome-Wide Association Analysis of Ischemic Stroke in Young Adults

    OpenAIRE

    Cheng, Yu-Ching; O’Connell, Jeffrey R.; Cole, John W.; Stine, O. Colin; Dueker, Nicole; McArdle, Patrick F.; Sparks, Mary J.; Shen, Jess; Laurie, Cathy C.; Nelson, Sarah; Doheny, Kimberly F.; Ling, Hua; Pugh, Elizabeth W.; Brott, Thomas G.; Brown, Robert D.

    2011-01-01

    Ischemic stroke (IS) is among the leading causes of death in Western countries. There is a significant genetic component to IS susceptibility, especially among young adults. To date, research to identify genetic loci predisposing to stroke has met only with limited success. We performed a genome-wide association (GWA) analysis of early-onset IS to identify potential stroke susceptibility loci. The GWA analysis was conducted by genotyping 1 million SNPs in a biracial population of 889 IS cases...

  4. Genetic Simulation Tools for Post-Genome Wide Association Studies of Complex Diseases

    Science.gov (United States)

    Amos, Christopher I.; Bafna, Vineet; Hauser, Elizabeth R.; Hernandez, Ryan D.; Li, Chun; Liberles, David A.; McAllister, Kimberly; Moore, Jason H.; Paltoo, Dina N.; Papanicolaou, George J.; Peng, Bo; Ritchie, Marylyn D.; Rosenfeld, Gabriel; Witte, John S.

    2014-01-01

    Genetic simulation programs are used to model data under specified assumptions to facilitate the understanding and study of complex genetic systems. Standardized data sets generated using genetic simulation are essential for the development and application of novel analytical tools in genetic epidemiology studies. With continuing advances in high-throughput genomic technologies and generation and analysis of larger, more complex data sets, there is a need for updating current approaches in genetic simulation modeling. To provide a forum to address current and emerging challenges in this area, the National Cancer Institute (NCI) sponsored a workshop, entitled “Genetic Simulation Tools for Post-Genome Wide Association Studies of Complex Diseases” at the National Institutes of Health (NIH) in Bethesda, Maryland on March 11-12, 2014. The goals of the workshop were to: (i) identify opportunities, challenges and resource needs for the development and application of genetic simulation models; (ii) improve the integration of tools for modeling and analysis of simulated data; and (iii) foster collaborations to facilitate development and applications of genetic simulation. During the course of the meeting the group identified challenges and opportunities for the science of simulation, software and methods development, and collaboration. This paper summarizes key discussions at the meeting, and highlights important challenges and opportunities to advance the field of genetic simulation. PMID:25371374

  5. Genome-Wide Association Study of the Genetic Determinants of Emphysema Distribution.

    Science.gov (United States)

    Boueiz, Adel; Lutz, Sharon M; Cho, Michael H; Hersh, Craig P; Bowler, Russell P; Washko, George R; Halper-Stromberg, Eitan; Bakke, Per; Gulsvik, Amund; Laird, Nan M; Beaty, Terri H; Coxson, Harvey O; Crapo, James D; Silverman, Edwin K; Castaldi, Peter J; DeMeo, Dawn L

    2017-03-15

    Emphysema has considerable variability in the severity and distribution of parenchymal destruction throughout the lungs. Upper lobe-predominant emphysema has emerged as an important predictor of response to lung volume reduction surgery. Yet, aside from alpha-1 antitrypsin deficiency, the genetic determinants of emphysema distribution remain largely unknown. To identify the genetic influences of emphysema distribution in non-alpha-1 antitrypsin-deficient smokers. A total of 11,532 subjects with complete genotype and computed tomography densitometry data in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]; non-Hispanic white and African American), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), and GenKOLS (Genetics of Chronic Obstructive Lung Disease) studies were analyzed. Two computed tomography scan emphysema distribution measures (difference between upper-third and lower-third emphysema; ratio of upper-third to lower-third emphysema) were tested for genetic associations in all study subjects. Separate analyses in each study population were followed by a fixed effect metaanalysis. Single-nucleotide polymorphism-, gene-, and pathway-based approaches were used. In silico functional evaluation was also performed. We identified five loci associated with emphysema distribution at genome-wide significance. These loci included two previously reported associations with COPD susceptibility (4q31 near HHIP and 15q25 near CHRNA5) and three new associations near SOWAHB, TRAPPC9, and KIAA1462. Gene set analysis and in silico functional evaluation revealed pathways and cell types that may potentially contribute to the pathogenesis of emphysema distribution. This multicohort genome-wide association study identified new genomic loci associated with differential emphysematous destruction throughout the lungs. These findings may point to new biologic pathways on which to expand diagnostic and therapeutic

  6. Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies

    DEFF Research Database (Denmark)

    Leu, Costin; de Kovel, Carolien G F; Zara, Federico

    2012-01-01

    Purpose: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) ...

  7. Genome-Wide Interaction Analyses between Genetic Variants and Alcohol Consumption and Smoking for Risk of Colorectal Cancer.

    Directory of Open Access Journals (Sweden)

    Jian Gong

    2016-10-01

    Full Text Available Genome-wide association studies (GWAS have identified many genetic susceptibility loci for colorectal cancer (CRC. However, variants in these loci explain only a small proportion of familial aggregation, and there are likely additional variants that are associated with CRC susceptibility. Genome-wide studies of gene-environment interactions may identify variants that are not detected in GWAS of marginal gene effects. To study this, we conducted a genome-wide analysis for interaction between genetic variants and alcohol consumption and cigarette smoking using data from the Colon Cancer Family Registry (CCFR and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO. Interactions were tested using logistic regression. We identified interaction between CRC risk and alcohol consumption and variants in the 9q22.32/HIATL1 (Pinteraction = 1.76×10-8; permuted p-value 3.51x10-8 region. Compared to non-/occasional drinking light to moderate alcohol consumption was associated with a lower risk of colorectal cancer among individuals with rs9409565 CT genotype (OR, 0.82 [95% CI, 0.74-0.91]; P = 2.1×10-4 and TT genotypes (OR,0.62 [95% CI, 0.51-0.75]; P = 1.3×10-6 but not associated among those with the CC genotype (p = 0.059. No genome-wide statistically significant interactions were observed for smoking. If replicated our suggestive finding of a genome-wide significant interaction between genetic variants and alcohol consumption might contribute to understanding colorectal cancer etiology and identifying subpopulations with differential susceptibility to the effect of alcohol on CRC risk.

  8. Genetic diversity and structure of elite cotton germplasm (Gossypium hirsutum L.) using genome-wide SNP data.

    Science.gov (United States)

    Ai, XianTao; Liang, YaJun; Wang, JunDuo; Zheng, JuYun; Gong, ZhaoLong; Guo, JiangPing; Li, XueYuan; Qu, YanYing

    2017-10-01

    Cotton (Gossypium spp.) is the most important natural textile fiber crop, and Gossypium hirsutum L. is responsible for 90% of the annual cotton crop in the world. Information on cotton genetic diversity and population structure is essential for new breeding lines. In this study, we analyzed population structure and genetic diversity of 288 elite Gossypium hirsutum cultivar accessions collected from around the world, and especially from China, using genome-wide single nucleotide polymorphisms (SNP) markers. The average polymorphsim information content (PIC) was 0.25, indicating a relatively low degree of genetic diversity. Population structure analysis revealed extensive admixture and identified three subgroups. Phylogenetic analysis supported the subgroups identified by STRUCTURE. The results from both population structure and phylogenetic analysis were, for the most part, in agreement with pedigree information. Analysis of molecular variance revealed a larger amount of variation was due to diversity within the groups. Establishment of genetic diversity and population structure from this study could be useful for genetic and genomic analysis and systematic utilization of the standing genetic variation in upland cotton.

  9. Polygenic analysis of genome-wide SNP data identifies common variants on allergic rhinitis

    DEFF Research Database (Denmark)

    Mohammadnejad, Afsaneh; Brasch-Andersen, Charlotte; Haagerup, Annette

    Background: Allergic Rhinitis (AR) is a complex disorder that affects many people around the world. There is a high genetic contribution to the development of the AR, as twins and family studies have estimated heritability of more than 33%. Due to the complex nature of the disease, single SNP...... analysis has limited power in identifying the genetic variations for AR. We combined genome-wide association analysis (GWAS) with polygenic risk score (PRS) in exploring the genetic basis underlying the disease. Methods: We collected clinical data on 631 Danish subjects with AR cases consisting of 434...... sibling pairs and unrelated individuals and control subjects of 197 unrelated individuals. SNP genotyping was done by Affymetrix Genome-Wide Human SNP Array 5.0. SNP imputation was performed using "IMPUTE2". Using additive effect model, GWAS was conducted in discovery sample, the genotypes...

  10. A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip

    DEFF Research Database (Denmark)

    Evangelou, Evangelos; Kerkhof, Hanneke J; Styrkarsdottir, Unnur

    2014-01-01

    Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects.......Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects....

  11. Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study.

    Science.gov (United States)

    Kasperaviciūte, Dalia; Catarino, Claudia B; Heinzen, Erin L; Depondt, Chantal; Cavalleri, Gianpiero L; Caboclo, Luis O; Tate, Sarah K; Jamnadas-Khoda, Jenny; Chinthapalli, Krishna; Clayton, Lisa M S; Shianna, Kevin V; Radtke, Rodney A; Mikati, Mohamad A; Gallentine, William B; Husain, Aatif M; Alhusaini, Saud; Leppert, David; Middleton, Lefkos T; Gibson, Rachel A; Johnson, Michael R; Matthews, Paul M; Hosford, David; Heuser, Kjell; Amos, Leslie; Ortega, Marcos; Zumsteg, Dominik; Wieser, Heinz-Gregor; Steinhoff, Bernhard J; Krämer, Günter; Hansen, Jörg; Dorn, Thomas; Kantanen, Anne-Mari; Gjerstad, Leif; Peuralinna, Terhi; Hernandez, Dena G; Eriksson, Kai J; Kälviäinen, Reetta K; Doherty, Colin P; Wood, Nicholas W; Pandolfo, Massimo; Duncan, John S; Sander, Josemir W; Delanty, Norman; Goldstein, David B; Sisodiya, Sanjay M

    2010-07-01

    Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio<1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.

  12. Meta-analysis of 32 genome-wide linkage studies of schizophrenia

    Science.gov (United States)

    Ng, MYM; Levinson, DF; Faraone, SV; Suarez, BK; DeLisi, LE; Arinami, T; Riley, B; Paunio, T; Pulver, AE; Irmansyah; Holmans, PA; Escamilla, M; Wildenauer, DB; Williams, NM; Laurent, C; Mowry, BJ; Brzustowicz, LM; Maziade, M; Sklar, P; Garver, DL; Abecasis, GR; Lerer, B; Fallin, MD; Gurling, HMD; Gejman, PV; Lindholm, E; Moises, HW; Byerley, W; Wijsman, EM; Forabosco, P; Tsuang, MT; Hwu, H-G; Okazaki, Y; Kendler, KS; Wormley, B; Fanous, A; Walsh, D; O’Neill, FA; Peltonen, L; Nestadt, G; Lasseter, VK; Liang, KY; Papadimitriou, GM; Dikeos, DG; Schwab, SG; Owen, MJ; O’Donovan, MC; Norton, N; Hare, E; Raventos, H; Nicolini, H; Albus, M; Maier, W; Nimgaonkar, VL; Terenius, L; Mallet, J; Jay, M; Godard, S; Nertney, D; Alexander, M; Crowe, RR; Silverman, JM; Bassett, AS; Roy, M-A; Mérette, C; Pato, CN; Pato, MT; Roos, J Louw; Kohn, Y; Amann-Zalcenstein, D; Kalsi, G; McQuillin, A; Curtis, D; Brynjolfson, J; Sigmundsson, T; Petursson, H; Sanders, AR; Duan, J; Jazin, E; Myles-Worsley, M; Karayiorgou, M; Lewis, CM

    2009-01-01

    A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (PSR) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for ‘aggregate’ genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies. PMID:19349958

  13. Genome-Wide Interaction Analyses between Genetic Variants and Alcohol Consumption and Smoking for Risk of Colorectal Cancer

    Science.gov (United States)

    Newcomb, Polly A.; Campbell, Peter T.; Baron, John A.; Berndt, Sonja I.; Bezieau, Stephane; Brenner, Hermann; Casey, Graham; Chan, Andrew T.; Chang-Claude, Jenny; Du, Mengmeng; Figueiredo, Jane C.; Gallinger, Steven; Giovannucci, Edward L.; Haile, Robert W.; Harrison, Tabitha A.; Hayes, Richard B.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Jeon, Jihyoun; Jenkins, Mark A.; Küry, Sébastien; Le Marchand, Loic; Lin, Yi; Lindor, Noralane M.; Nishihara, Reiko; Ogino, Shuji; Potter, John D.; Rudolph, Anja; Schoen, Robert E.; Seminara, Daniela; Slattery, Martha L.; Thibodeau, Stephen N.; Thornquist, Mark; Toth, Reka; Wallace, Robert; White, Emily; Jiao, Shuo; Lemire, Mathieu; Hsu, Li; Peters, Ulrike

    2016-01-01

    Genome-wide association studies (GWAS) have identified many genetic susceptibility loci for colorectal cancer (CRC). However, variants in these loci explain only a small proportion of familial aggregation, and there are likely additional variants that are associated with CRC susceptibility. Genome-wide studies of gene-environment interactions may identify variants that are not detected in GWAS of marginal gene effects. To study this, we conducted a genome-wide analysis for interaction between genetic variants and alcohol consumption and cigarette smoking using data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Interactions were tested using logistic regression. We identified interaction between CRC risk and alcohol consumption and variants in the 9q22.32/HIATL1 (Pinteraction = 1.76×10−8; permuted p-value 3.51x10-8) region. Compared to non-/occasional drinking light to moderate alcohol consumption was associated with a lower risk of colorectal cancer among individuals with rs9409565 CT genotype (OR, 0.82 [95% CI, 0.74–0.91]; P = 2.1×10−4) and TT genotypes (OR,0.62 [95% CI, 0.51–0.75]; P = 1.3×10−6) but not associated among those with the CC genotype (p = 0.059). No genome-wide statistically significant interactions were observed for smoking. If replicated our suggestive finding of a genome-wide significant interaction between genetic variants and alcohol consumption might contribute to understanding colorectal cancer etiology and identifying subpopulations with differential susceptibility to the effect of alcohol on CRC risk. PMID:27723779

  14. Genetically contextual effects of smoking on genome wide DNA methylation.

    Science.gov (United States)

    Dogan, Meeshanthini V; Beach, Steven R H; Philibert, Robert A

    2017-09-01

    Smoking is the leading cause of death in the United States. It exerts its effects by increasing susceptibility to a variety of complex disorders among those who smoke, and if pregnant, to their unborn children. In prior efforts to understand the epigenetic mechanisms through which this increased vulnerability is conveyed, a number of investigators have conducted genome wide methylation analyses. Unfortunately, secondary to methodological limitations, these studies were unable to examine methylation in gene regions with significant amounts of genetic variation. Using genome wide genetic and epigenetic data from the Framingham Heart Study, we re-examined the relationship of smoking status to genome wide methylation status. When only methylation status is considered, smoking was significantly associated with differential methylation in 310 genes that map to a variety of biological process and cellular differentiation pathways. However, when SNP effects on the magnitude of smoking associated methylation changes are also considered, cis and trans-interaction effects were noted at a total of 266 and 4353 genes with no marked enrichment for any biological pathways. Furthermore, the SNP variation participating in the significant interaction effects is enriched for loci previously associated with complex medical illnesses. The enlarged scope of the methylome shown to be affected by smoking may better explicate the mediational pathways linking smoking with a myriad of smoking related complex syndromes. Additionally, these results strongly suggest that combined epigenetic and genetic data analyses may be critical for a more complete understanding of the relationship between environmental variables, such as smoking, and pathophysiological outcomes. © 2017 Wiley Periodicals, Inc.

  15. Unraveling the genetic etiology of adult antisocial behavior: a genome-wide association study.

    Directory of Open Access Journals (Sweden)

    Jorim J Tielbeek

    Full Text Available Crime poses a major burden for society. The heterogeneous nature of criminal behavior makes it difficult to unravel its causes. Relatively little research has been conducted on the genetic influences of criminal behavior. The few twin and adoption studies that have been undertaken suggest that about half of the variance in antisocial behavior can be explained by genetic factors. In order to identify the specific common genetic variants underlying this behavior, we conduct the first genome-wide association study (GWAS on adult antisocial behavior. Our sample comprised a community sample of 4816 individuals who had completed a self-report questionnaire. No genetic polymorphisms reached genome-wide significance for association with adult antisocial behavior. In addition, none of the traditional candidate genes can be confirmed in our study. While not genome-wide significant, the gene with the strongest association (p-value = 8.7×10(-5 was DYRK1A, a gene previously related to abnormal brain development and mental retardation. Future studies should use larger, more homogeneous samples to disentangle the etiology of antisocial behavior. Biosocial criminological research allows a more empirically grounded understanding of criminal behavior, which could ultimately inform and improve current treatment strategies.

  16. Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes

    OpenAIRE

    Ng, Maggie C. Y.; Shriner, Daniel; Chen, Brian H.; Li, Jiang; Chen, Wei-Min; Guo, Xiuqing; Liu, Jiankang; Bielinski, Suzette J.; Yanek, Lisa R.; Nalls, Michael A.; Comeau, Mary E.; Rasmussen-Torvik, Laura J.; Jensen, Richard A.; Evans, Daniel S.; Sun, Yan V.

    2014-01-01

    Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 case...

  17. Genetics of Genome-Wide Recombination Rate Evolution in Mice from an Isolated Island.

    Science.gov (United States)

    Wang, Richard J; Payseur, Bret A

    2017-08-01

    Recombination rate is a heritable quantitative trait that evolves despite the fundamentally conserved role that recombination plays in meiosis. Differences in recombination rate can alter the landscape of the genome and the genetic diversity of populations. Yet our understanding of the genetic basis of recombination rate evolution in nature remains limited. We used wild house mice ( Mus musculus domesticus ) from Gough Island (GI), which diverged recently from their mainland counterparts, to characterize the genetics of recombination rate evolution. We quantified genome-wide autosomal recombination rates by immunofluorescence cytology in spermatocytes from 240 F 2 males generated from intercrosses between GI-derived mice and the wild-derived inbred strain WSB/EiJ. We identified four quantitative trait loci (QTL) responsible for inter-F 2 variation in this trait, the strongest of which had effects that opposed the direction of the parental trait differences. Candidate genes and mutations for these QTL were identified by overlapping the detected intervals with whole-genome sequencing data and publicly available transcriptomic profiles from spermatocytes. Combined with existing studies, our findings suggest that genome-wide recombination rate divergence is not directional and its evolution within and between subspecies proceeds from distinct genetic loci. Copyright © 2017 by the Genetics Society of America.

  18. A genome-wide association study demonstrates significant genetic variation for fracture risk in Thoroughbred racehorses

    Science.gov (United States)

    2014-01-01

    Background Thoroughbred racehorses are subject to non-traumatic distal limb bone fractures that occur during racing and exercise. Susceptibility to fracture may be due to underlying disturbances in bone metabolism which have a genetic cause. Fracture risk has been shown to be heritable in several species but this study is the first genetic analysis of fracture risk in the horse. Results Fracture cases (n = 269) were horses that sustained catastrophic distal limb fractures while racing on UK racecourses, necessitating euthanasia. Control horses (n = 253) were over 4 years of age, were racing during the same time period as the cases, and had no history of fracture at the time the study was carried out. The horses sampled were bred for both flat and National Hunt (NH) jump racing. 43,417 SNPs were employed to perform a genome-wide association analysis and to estimate the proportion of genetic variance attributable to the SNPs on each chromosome using restricted maximum likelihood (REML). Significant genetic variation associated with fracture risk was found on chromosomes 9, 18, 22 and 31. Three SNPs on chromosome 18 (62.05 Mb – 62.15 Mb) and one SNP on chromosome 1 (14.17 Mb) reached genome-wide significance (p fracture than cases, p = 1 × 10-4), while a second haplotype increases fracture risk (cases at 3.39 times higher risk of fracture than controls, p = 0.042). Conclusions Fracture risk in the Thoroughbred horse is a complex condition with an underlying genetic basis. Multiple genomic regions contribute to susceptibility to fracture risk. This suggests there is the potential to develop SNP-based estimators for genetic risk of fracture in the Thoroughbred racehorse, using methods pioneered in livestock genetics such as genomic selection. This information would be useful to racehorse breeders and owners, enabling them to reduce the risk of injury in their horses. PMID:24559379

  19. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

    DEFF Research Database (Denmark)

    Mahajan, Anubha; Go, Min Jin; Zhang, Weihua

    2014-01-01

    To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We obs...... and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry....... observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls...

  20. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index

    NARCIS (Netherlands)

    J.F. Felix (Janine); J.P. Bradfield (Jonathan); C. Monnereau; R.J.P. van der Valk (Ralf); E. Stergiakouli (Evie); A. Chesi (Alessandra); R. Gaillard (Romy); B. Feenstra (Bjarke); E. Thiering (Elisabeth); E. Kreiner-Møller (Eskil); A. Mahajan (Anubha); Niina Pitkänen; R. Joro (Raimo); A. Cavadino (Alana); V. Huikari (Ville); S. Franks (Steve); M. Groen-Blokhuis (Maria); D.L. Cousminer (Diana); J.A. Marsh (Julie); T. Lehtimäki (Terho); J.A. Curtin (John); J. Vioque (Jesus); T.S. Ahluwalia (Tarunveer Singh); R. Myhre (Ronny); T.S. Price (Thomas); Natalia Vilor-Tejedor; L. Yengo (Loic); N. Grarup (Niels); I. Ntalla (Ioanna); W.Q. Ang (Wei); M. Atalay (Mustafa); H. Bisgaard (Hans); A.I.F. Blakemore (Alexandra); A. Bonnefond (Amélie); L. Carstensen (Lisbeth); J.G. Eriksson (Johan G.); C. Flexeder (Claudia); L. Franke (Lude); F. Geller (Frank); M. Geserick (Mandy); A.L. Hartikainen; C.M.A. Haworth (Claire M.); J.N. Hirschhorn (Joel N.); A. Hofman (Albert); J.-C. Holm (Jens-Christian); M. Horikoshi (Momoko); J.J. Hottenga (Jouke Jan); J. Huang (Jian); H.N. Kadarmideen (Haja N.); M. Kähönen (Mika); W. Kiess (Wieland); T.A. Lakka (Timo); T.A. Lakka (Timo); A. Lewin (Alex); L. Liang (Liming); L.-P. Lyytikäinen (Leo-Pekka); B. Ma (Baoshan); P. Magnus (Per); S.E. McCormack (Shana E.); G. Mcmahon (George); F.D. Mentch (Frank); C.M. Middeldorp (Christel); C.S. Murray (Clare S.); K. Pahkala (Katja); T.H. Pers (Tune); R. Pfäffle (Roland); D.S. Postma (Dirkje); C. Power (Christine); A. Simpson (Angela); V. Sengpiel (Verena); C. Tiesler (Carla); M. Torrent (Maties); A.G. Uitterlinden (André); J.B.J. van Meurs (Joyce); R. Vinding (Rebecca); J. Waage (Johannes); J. Wardle (Jane); E. Zeggini (Eleftheria); B.S. Zemel (Babette S.); G.V. Dedoussis (George); O. Pedersen (Oluf); P. Froguel (Philippe); J. Sunyer (Jordi); R. Plomin (Robert); B. Jacobsson (Bo); T. Hansen (Torben); J.R. Gonzalez (Juan R.); A. Custovic; O.T. Raitakari (Olli T.); C.E. Pennell (Craig); Elisabeth Widén; D.I. Boomsma (Dorret); G.H. Koppelman (Gerard); S. Sebert (Sylvain); M.-R. Jarvelin (Marjo-Riitta); E. Hypponen (Elina); M.I. McCarthy (Mark); V. Lindi (Virpi); N. Harri (Niinikoski); A. Körner (Antje); K. Bønnelykke (Klaus); J. Heinrich (Joachim); M. Melbye (Mads); F. Rivadeneira Ramirez (Fernando); H. Hakonarson (Hakon); S.M. Ring (Susan); G.D. Smith; T.I.A. Sørensen (Thorkild I.A.); N.J. Timpson (Nicholas); S.F.A. Grant (Struan); V.W.V. Jaddoe (Vincent); H.J. Kalkwarf (Heidi J.); J.M. Lappe (Joan M.); V. Gilsanz (Vicente); S.E. Oberfield (Sharon E.); J.A. Shepherd (John A.); A. Kelly (Andrea)

    2016-01-01

    textabstractA large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown.We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation

  1. Large meta-analysis of genome-wide association studies identifies five loci for lean body mass

    DEFF Research Database (Denmark)

    Zillikens, M Carola; Demissie, Serkalem; Hsu, Yi-Hsiang

    2017-01-01

    Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorpt...... a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.......-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p 

  2. Genetic predictors of response to serotonergic and noradrenergic antidepressants in major depressive disorder: a genome-wide analysis of individual-level data and a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Katherine E Tansey

    Full Text Available It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way.The NEWMEDS consortium, an academia-industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies (three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study. After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants (genome-wide significance p<5×10(-8. No biological pathways were significantly overrepresented in the results. No significant associations (genome-wide significance p<5×10(-8 were detected in a meta-analysis of NEWMEDS and another large sample (STAR*D, with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D.No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study. Please see later in the article for the

  3. Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies.

    Science.gov (United States)

    Leu, Costin; de Kovel, Carolien G F; Zara, Federico; Striano, Pasquale; Pezzella, Marianna; Robbiano, Angela; Bianchi, Amedeo; Bisulli, Francesca; Coppola, Antonietta; Giallonardo, Anna Teresa; Beccaria, Francesca; Trenité, Dorothée Kasteleijn-Nolst; Lindhout, Dick; Gaus, Verena; Schmitz, Bettina; Janz, Dieter; Weber, Yvonne G; Becker, Felicitas; Lerche, Holger; Kleefuss-Lie, Ailing A; Hallman, Kerstin; Kunz, Wolfram S; Elger, Christian E; Muhle, Hiltrud; Stephani, Ulrich; Møller, Rikke S; Hjalgrim, Helle; Mullen, Saul; Scheffer, Ingrid E; Berkovic, Samuel F; Everett, Kate V; Gardiner, Mark R; Marini, Carla; Guerrini, Renzo; Lehesjoki, Anna-Elina; Siren, Auli; Nabbout, Rima; Baulac, Stephanie; Leguern, Eric; Serratosa, Jose M; Rosenow, Felix; Feucht, Martha; Unterberger, Iris; Covanis, Athanasios; Suls, Arvid; Weckhuysen, Sarah; Kaneva, Radka; Caglayan, Hande; Turkdogan, Dilsad; Baykan, Betul; Bebek, Nerses; Ozbek, Ugur; Hempelmann, Anne; Schulz, Herbert; Rüschendorf, Franz; Trucks, Holger; Nürnberg, Peter; Avanzini, Giuliano; Koeleman, Bobby P C; Sander, Thomas

    2012-02-01

    Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type-related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. Meta-analysis of three genome-wide linkage datasets was carried out in 379 GGE-multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type-related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE-multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome-wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31

  4. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

    DEFF Research Database (Denmark)

    Lee, S Hong; Ripke, Stephan; Neale, Benjamin M

    2013-01-01

    Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases...... and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17......-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD...

  5. Genetic Variance Partitioning and Genome-Wide Prediction with Allele Dosage Information in Autotetraploid Potato.

    Science.gov (United States)

    Endelman, Jeffrey B; Carley, Cari A Schmitz; Bethke, Paul C; Coombs, Joseph J; Clough, Mark E; da Silva, Washington L; De Jong, Walter S; Douches, David S; Frederick, Curtis M; Haynes, Kathleen G; Holm, David G; Miller, J Creighton; Muñoz, Patricio R; Navarro, Felix M; Novy, Richard G; Palta, Jiwan P; Porter, Gregory A; Rak, Kyle T; Sathuvalli, Vidyasagar R; Thompson, Asunta L; Yencho, G Craig

    2018-05-01

    As one of the world's most important food crops, the potato ( Solanum tuberosum L.) has spurred innovation in autotetraploid genetics, including in the use of SNP arrays to determine allele dosage at thousands of markers. By combining genotype and pedigree information with phenotype data for economically important traits, the objectives of this study were to (1) partition the genetic variance into additive vs. nonadditive components, and (2) determine the accuracy of genome-wide prediction. Between 2012 and 2017, a training population of 571 clones was evaluated for total yield, specific gravity, and chip fry color. Genomic covariance matrices for additive ( G ), digenic dominant ( D ), and additive × additive epistatic ( G # G ) effects were calculated using 3895 markers, and the numerator relationship matrix ( A ) was calculated from a 13-generation pedigree. Based on model fit and prediction accuracy, mixed model analysis with G was superior to A for yield and fry color but not specific gravity. The amount of additive genetic variance captured by markers was 20% of the total genetic variance for specific gravity, compared to 45% for yield and fry color. Within the training population, including nonadditive effects improved accuracy and/or bias for all three traits when predicting total genotypic value. When six F 1 populations were used for validation, prediction accuracy ranged from 0.06 to 0.63 and was consistently lower (0.13 on average) without allele dosage information. We conclude that genome-wide prediction is feasible in potato and that it will improve selection for breeding value given the substantial amount of nonadditive genetic variance in elite germplasm. Copyright © 2018 by the Genetics Society of America.

  6. Susceptibility to Childhood Pneumonia: A Genome-Wide Analysis.

    Science.gov (United States)

    Hayden, Lystra P; Cho, Michael H; McDonald, Merry-Lynn N; Crapo, James D; Beaty, Terri H; Silverman, Edwin K; Hersh, Craig P

    2017-01-01

    Previous studies have indicated that in adult smokers, a history of childhood pneumonia is associated with reduced lung function and chronic obstructive pulmonary disease. There have been few previous investigations using genome-wide association studies to investigate genetic predisposition to pneumonia. This study aims to identify the genetic variants associated with the development of pneumonia during childhood and over the course of the lifetime. Study subjects included current and former smokers with and without chronic obstructive pulmonary disease participating in the COPDGene Study. Pneumonia was defined by subject self-report, with childhood pneumonia categorized as having the first episode at pneumonia (843 cases, 9,091 control subjects) and lifetime pneumonia (3,766 cases, 5,659 control subjects) were performed separately in non-Hispanic whites and African Americans. Non-Hispanic white and African American populations were combined in the meta-analysis. Top genetic variants from childhood pneumonia were assessed in network analysis. No single-nucleotide polymorphisms reached genome-wide significance, although we identified potential regions of interest. In the childhood pneumonia analysis, this included variants in NGR1 (P = 6.3 × 10 -8 ), PAK6 (P = 3.3 × 10 -7 ), and near MATN1 (P = 2.8 × 10 -7 ). In the lifetime pneumonia analysis, this included variants in LOC339862 (P = 8.7 × 10 -7 ), RAPGEF2 (P = 8.4 × 10 -7 ), PHACTR1 (P = 6.1 × 10 -7 ), near PRR27 (P = 4.3 × 10 -7 ), and near MCPH1 (P = 2.7 × 10 -7 ). Network analysis of the genes associated with childhood pneumonia included top networks related to development, blood vessel morphogenesis, muscle contraction, WNT signaling, DNA damage, apoptosis, inflammation, and immune response (P ≤ 0.05). We have identified genes potentially associated with the risk of pneumonia. Further research will be required to confirm these

  7. Genome-wide association study of handedness excludes simple genetic models

    Science.gov (United States)

    Armour, J AL; Davison, A; McManus, I C

    2014-01-01

    Handedness is a human behavioural phenotype that appears to be congenital, and is often assumed to be inherited, but for which the developmental origin and underlying causation(s) have been elusive. Models of the genetic basis of variation in handedness have been proposed that fit different features of the observed resemblance between relatives, but none has been decisively tested or a corresponding causative locus identified. In this study, we applied data from well-characterised individuals studied at the London Twin Research Unit. Analysis of genome-wide SNP data from 3940 twins failed to identify any locus associated with handedness at a genome-wide level of significance. The most straightforward interpretation of our analyses is that they exclude the simplest formulations of the ‘right-shift' model of Annett and the ‘dextral/chance' model of McManus, although more complex modifications of those models are still compatible with our observations. For polygenic effects, our study is inadequately powered to reliably detect alleles with effect sizes corresponding to an odds ratio of 1.2, but should have good power to detect effects at an odds ratio of 2 or more. PMID:24065183

  8. A Genome-Wide mQTL Analysis in Human Adipose Tissue Identifies Genetic Variants Associated with DNA Methylation, Gene Expression and Metabolic Traits

    DEFF Research Database (Denmark)

    Volkov, Petr; Olsson, Anders H; Gillberg, Linn

    2016-01-01

    Little is known about the extent to which interactions between genetics and epigenetics may affect the risk of complex metabolic diseases and/or their intermediary phenotypes. We performed a genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human adipose tissue of 119 men, w...... and epigenetic variation in both cis and trans positions influencing gene expression in adipose tissue and in vivo (dys)metabolic traits associated with the development of obesity and diabetes.......Little is known about the extent to which interactions between genetics and epigenetics may affect the risk of complex metabolic diseases and/or their intermediary phenotypes. We performed a genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human adipose tissue of 119 men......, where 592,794 single nucleotide polymorphisms (SNPs) were related to DNA methylation of 477,891 CpG sites, covering 99% of RefSeq genes. SNPs in significant mQTLs were further related to gene expression in adipose tissue and obesity related traits. We found 101,911 SNP-CpG pairs (mQTLs) in cis and 5...

  9. Meta-analysis for genome-wide association studies using case-control design: application and practice.

    Science.gov (United States)

    Shim, Sungryul; Kim, Jiyoung; Jung, Wonguen; Shin, In-Soo; Bae, Jong-Myon

    2016-01-01

    This review aimed to arrange the process of a systematic review of genome-wide association studies in order to practice and apply a genome-wide meta-analysis (GWMA). The process has a series of five steps: searching and selection, extraction of related information, evaluation of validity, meta-analysis by type of genetic model, and evaluation of heterogeneity. In contrast to intervention meta-analyses, GWMA has to evaluate the Hardy-Weinberg equilibrium (HWE) in the third step and conduct meta-analyses by five potential genetic models, including dominant, recessive, homozygote contrast, heterozygote contrast, and allelic contrast in the fourth step. The 'genhwcci' and 'metan' commands of STATA software evaluate the HWE and calculate a summary effect size, respectively. A meta-regression using the 'metareg' command of STATA should be conducted to evaluate related factors of heterogeneities.

  10. Generation of Mouse Haploid Somatic Cells by Small Molecules for Genome-wide Genetic Screening

    Directory of Open Access Journals (Sweden)

    Zheng-Quan He

    2017-08-01

    Full Text Available The recent success of derivation of mammalian haploid embryonic stem cells (haESCs has provided a powerful tool for large-scale functional analysis of the mammalian genome. However, haESCs rapidly become diploidized after differentiation, posing challenges for genetic analysis. Here, we show that the spontaneous diploidization of haESCs happens in metaphase due to mitotic slippage. Diploidization can be suppressed by small-molecule-mediated inhibition of CDK1 and ROCK. Through ROCK inhibition, we can generate haploid somatic cells of all three germ layers from haESCs, including terminally differentiated neurons. Using piggyBac transposon-based insertional mutagenesis, we generated a haploid neural cell library harboring genome-wide mutations for genetic screening. As a proof of concept, we screened for Mn2+-mediated toxicity and identified the Park2 gene. Our findings expand the applications of mouse haploid cell technology to somatic cell types and may also shed light on the mechanisms of ploidy maintenance.

  11. Meta-analysis of genome-wide association studies of HDL cholesterol response to statins

    NARCIS (Netherlands)

    Postmus, Iris; Warren, Helen R.; Trompet, Stella; Arsenault, Benoit J.; Avery, Christy L.; Bis, Joshua C.; Chasman, Daniel I.; de Keyser, Catherine E.; Deshmukh, Harshal A.; Evans, Daniel S.; Feng, QiPing; Li, Xiaohui; Smit, Roelof A. J.; Smith, Albert V.; Sun, Fangui; Taylor, Kent D.; Arnold, Alice M.; Barnes, Michael R.; Barratt, Bryan J.; Betteridge, John; Boekholdt, S. Matthijs; Boerwinkle, Eric; Buckley, Brendan M.; Chen, Y.-D. Ida; de Craen, Anton J. M.; Cummings, Steven R.; Denny, Joshua C.; Dubé, Marie Pierre; Durrington, Paul N.; Eiriksdottir, Gudny; Ford, Ian; Guo, Xiuqing; Harris, Tamara B.; Heckbert, Susan R.; Hofman, Albert; Hovingh, G. Kees; Kastelein, John J. P.; Launer, Leonore J.; Liu, Ching-Ti; Liu, Yongmei; Lumley, Thomas; McKeigue, Paul M.; Munroe, Patricia B.; Neil, Andrew; Nickerson, Deborah A.; Nyberg, Fredrik; O'Brien, Eoin; O'Donnell, Christopher J.; Post, Wendy; Poulter, Neil; Vasan, Ramachandran S.; Rice, Kenneth; Rich, Stephen S.; Rivadeneira, Fernando; Sattar, Naveed; Sever, Peter; Shaw-Hawkins, Sue; Shields, Denis C.; Slagboom, P. Eline; Smith, Nicholas L.; Smith, Joshua D.; Sotoodehnia, Nona; Stanton, Alice; Stott, David J.; Stricker, Bruno H.; Stürmer, Til; Uitterlinden, André G.; Wei, Wei-Qi; Westendorp, Rudi G. J.; Whitsel, Eric A.; Wiggins, Kerri L.; Wilke, Russell A.; Ballantyne, Christie M.; Colhoun, Helen M.; Cupples, L. Adrienne; Franco, Oscar H.; Gudnason, Vilmundur; Hitman, Graham; Palmer, Colin N. A.; Psaty, Bruce M.; Ridker, Paul M.; Stafford, Jeanette M.; Stein, Charles M.; Tardif, Jean-Claude; Caulfield, Mark J.; Jukema, J. Wouter; Rotter, Jerome I.; Krauss, Ronald M.

    2016-01-01

    In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation. We performed a meta-analysis of genome-wide

  12. A mega-analysis of genome-wide association studies for major depressive disorder.

    Science.gov (United States)

    Ripke, Stephan; Wray, Naomi R; Lewis, Cathryn M; Hamilton, Steven P; Weissman, Myrna M; Breen, Gerome; Byrne, Enda M; Blackwood, Douglas H R; Boomsma, Dorret I; Cichon, Sven; Heath, Andrew C; Holsboer, Florian; Lucae, Susanne; Madden, Pamela A F; Martin, Nicholas G; McGuffin, Peter; Muglia, Pierandrea; Noethen, Markus M; Penninx, Brenda P; Pergadia, Michele L; Potash, James B; Rietschel, Marcella; Lin, Danyu; Müller-Myhsok, Bertram; Shi, Jianxin; Steinberg, Stacy; Grabe, Hans J; Lichtenstein, Paul; Magnusson, Patrik; Perlis, Roy H; Preisig, Martin; Smoller, Jordan W; Stefansson, Kari; Uher, Rudolf; Kutalik, Zoltan; Tansey, Katherine E; Teumer, Alexander; Viktorin, Alexander; Barnes, Michael R; Bettecken, Thomas; Binder, Elisabeth B; Breuer, René; Castro, Victor M; Churchill, Susanne E; Coryell, William H; Craddock, Nick; Craig, Ian W; Czamara, Darina; De Geus, Eco J; Degenhardt, Franziska; Farmer, Anne E; Fava, Maurizio; Frank, Josef; Gainer, Vivian S; Gallagher, Patience J; Gordon, Scott D; Goryachev, Sergey; Gross, Magdalena; Guipponi, Michel; Henders, Anjali K; Herms, Stefan; Hickie, Ian B; Hoefels, Susanne; Hoogendijk, Witte; Hottenga, Jouke Jan; Iosifescu, Dan V; Ising, Marcus; Jones, Ian; Jones, Lisa; Jung-Ying, Tzeng; Knowles, James A; Kohane, Isaac S; Kohli, Martin A; Korszun, Ania; Landen, Mikael; Lawson, William B; Lewis, Glyn; Macintyre, Donald; Maier, Wolfgang; Mattheisen, Manuel; McGrath, Patrick J; McIntosh, Andrew; McLean, Alan; Middeldorp, Christel M; Middleton, Lefkos; Montgomery, Grant M; Murphy, Shawn N; Nauck, Matthias; Nolen, Willem A; Nyholt, Dale R; O'Donovan, Michael; Oskarsson, Högni; Pedersen, Nancy; Scheftner, William A; Schulz, Andrea; Schulze, Thomas G; Shyn, Stanley I; Sigurdsson, Engilbert; Slager, Susan L; Smit, Johannes H; Stefansson, Hreinn; Steffens, Michael; Thorgeirsson, Thorgeir; Tozzi, Federica; Treutlein, Jens; Uhr, Manfred; van den Oord, Edwin J C G; Van Grootheest, Gerard; Völzke, Henry; Weilburg, Jeffrey B; Willemsen, Gonneke; Zitman, Frans G; Neale, Benjamin; Daly, Mark; Levinson, Douglas F; Sullivan, Patrick F

    2013-04-01

    Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 × 10(-8)), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083-53 822 102, minimum P=5.9 × 10(-9) at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.

  13. Genome-Wide DNA Copy Number Analysis of Acute Lymphoblastic Leukemia Identifies New Genetic Markers Associated with Clinical Outcome.

    Directory of Open Access Journals (Sweden)

    Maribel Forero-Castro

    Full Text Available Identifying additional genetic alterations associated with poor prognosis in acute lymphoblastic leukemia (ALL is still a challenge.To characterize the presence of additional DNA copy number alterations (CNAs in children and adults with ALL by whole-genome oligonucleotide array (aCGH analysis, and to identify their associations with clinical features and outcome. Array-CGH was carried out in 265 newly diagnosed ALLs (142 children and 123 adults. The NimbleGen CGH 12x135K array (Roche was used to analyze genetic gains and losses. CNAs were analyzed with GISTIC and aCGHweb software. Clinical and biological variables were analyzed. Three of the patients showed chromothripsis (cth6, cth14q and cth15q. CNAs were associated with age, phenotype, genetic subtype and overall survival (OS. In the whole cohort of children, the losses on 14q32.33 (p = 0.019 and 15q13.2 (p = 0.04 were related to shorter OS. In the group of children without good- or poor-risk cytogenetics, the gain on 1p36.11 was a prognostic marker independently associated with shorter OS. In adults, the gains on 19q13.2 (p = 0.001 and Xp21.1 (p = 0.029, and the loss of 17p (p = 0.014 were independent markers of poor prognosis with respect to OS. In summary, CNAs are frequent in ALL and are associated with clinical parameters and survival. Genome-wide DNA copy number analysis allows the identification of genetic markers that predict clinical outcome, suggesting that detection of these genetic lesions will be useful in the management of patients newly diagnosed with ALL.

  14. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

    OpenAIRE

    Okbay, Aysu; Baselmans, B.M.L. (Bart M.L.); Neve, Jan-Emmanuel; Turley, Patrick; Nivard, Michel; Fontana, M.A. (Mark Alan); Meddens, S.F.W. (S. Fleur W.); Linnér, R.K. (Richard Karlsson); Rietveld, C.A. (Cornelius A); Derringer, J.; Gratten, Jacob; Lee, James J.; Liu, J.Z. (Jimmy Z); Vlaming, Ronald; SAhluwalia, T. (Tarunveer)

    2016-01-01

    textabstractVery few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associ...

  15. Meta-analysis for genome-wide association studies using case-control design: application and practice

    Directory of Open Access Journals (Sweden)

    Sungryul Shim

    2016-12-01

    Full Text Available This review aimed to arrange the process of a systematic review of genome-wide association studies in order to practice and apply a genome-wide meta-analysis (GWMA. The process has a series of five steps: searching and selection, extraction of related information, evaluation of validity, meta-analysis by type of genetic model, and evaluation of heterogeneity. In contrast to intervention meta-analyses, GWMA has to evaluate the Hardy–Weinberg equilibrium (HWE in the third step and conduct meta-analyses by five potential genetic models, including dominant, recessive, homozygote contrast, heterozygote contrast, and allelic contrast in the fourth step. The ‘genhwcci’ and ‘metan’ commands of STATA software evaluate the HWE and calculate a summary effect size, respectively. A meta-regression using the ‘metareg’ command of STATA should be conducted to evaluate related factors of heterogeneities.

  16. Novel genetic loci underlying human intracranial volume identified through genome-wide association

    Science.gov (United States)

    Adams, Hieab HH; Hibar, Derrek P; Chouraki, Vincent; Stein, Jason L; Nyquist, Paul A; Rentería, Miguel E; Trompet, Stella; Arias-Vasquez, Alejandro; Seshadri, Sudha; Desrivières, Sylvane; Beecham, Ashley H; Jahanshad, Neda; Wittfeld, Katharina; Van der Lee, Sven J; Abramovic, Lucija; Alhusaini, Saud; Amin, Najaf; Andersson, Micael; Arfanakis, Konstantinos; Aribisala, Benjamin S; Armstrong, Nicola J; Athanasiu, Lavinia; Axelsson, Tomas; Beiser, Alexa; Bernard, Manon; Bis, Joshua C; Blanken, Laura ME; Blanton, Susan H; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brickman, Adam M; Carmichael, Owen; Chakravarty, M Mallar; Chauhan, Ganesh; Chen, Qiang; Ching, Christopher RK; Cuellar-Partida, Gabriel; Den Braber, Anouk; Doan, Nhat Trung; Ehrlich, Stefan; Filippi, Irina; Ge, Tian; Giddaluru, Sudheer; Goldman, Aaron L; Gottesman, Rebecca F; Greven, Corina U; Grimm, Oliver; Griswold, Michael E; Guadalupe, Tulio; Hass, Johanna; Haukvik, Unn K; Hilal, Saima; Hofer, Edith; Hoehn, David; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kasperaviciute, Dalia; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Liao, Jiemin; Liewald, David CM; Lopez, Lorna M; Luciano, Michelle; Macare, Christine; Marquand, Andre; Matarin, Mar; Mather, Karen A; Mattheisen, Manuel; Mazoyer, Bernard; McKay, David R; McWhirter, Rebekah; Milaneschi, Yuri; Mirza-Schreiber, Nazanin; Muetzel, Ryan L; Maniega, Susana Muñoz; Nho, Kwangsik; Nugent, Allison C; Olde Loohuis, Loes M; Oosterlaan, Jaap; Papmeyer, Martina; Pappa, Irene; Pirpamer, Lukas; Pudas, Sara; Pütz, Benno; Rajan, Kumar B; Ramasamy, Adaikalavan; Richards, Jennifer S; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rommelse, Nanda; Rose, Emma J; Royle, Natalie A; Rundek, Tatjana; Sämann, Philipp G; Satizabal, Claudia L; Schmaal, Lianne; Schork, Andrew J; Shen, Li; Shin, Jean; Shumskaya, Elena; Smith, Albert V; Sprooten, Emma; Strike, Lachlan T; Teumer, Alexander; Thomson, Russell; Tordesillas-Gutierrez, Diana; Toro, Roberto; Trabzuni, Daniah; Vaidya, Dhananjay; Van der Grond, Jeroen; Van der Meer, Dennis; Van Donkelaar, Marjolein MJ; Van Eijk, Kristel R; Van Erp, Theo GM; Van Rooij, Daan; Walton, Esther; Westlye, Lars T; Whelan, Christopher D; Windham, Beverly G; Winkler, Anderson M; Woldehawariat, Girma; Wolf, Christiane; Wolfers, Thomas; Xu, Bing; Yanek, Lisa R; Yang, Jingyun; Zijdenbos, Alex; Zwiers, Marcel P; Agartz, Ingrid; Aggarwal, Neelum T; Almasy, Laura; Ames, David; Amouyel, Philippe; Andreassen, Ole A; Arepalli, Sampath; Assareh, Amelia A; Barral, Sandra; Bastin, Mark E; Becker, Diane M; Becker, James T; Bennett, David A; Blangero, John; van Bokhoven, Hans; Boomsma, Dorret I; Brodaty, Henry; Brouwer, Rachel M; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Bulayeva, Kazima B; Cahn, Wiepke; Calhoun, Vince D; Cannon, Dara M; Cavalleri, Gianpiero L; Chen, Christopher; Cheng, Ching-Yu; Cichon, Sven; Cookson, Mark R; Corvin, Aiden; Crespo-Facorro, Benedicto; Curran, Joanne E; Czisch, Michael; Dale, Anders M; Davies, Gareth E; De Geus, Eco JC; De Jager, Philip L; de Zubicaray, Greig I; Delanty, Norman; Depondt, Chantal; DeStefano, Anita L; Dillman, Allissa; Djurovic, Srdjan; Donohoe, Gary; Drevets, Wayne C; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Espeseth, Thomas; Evans, Denis A; Fedko, Iryna O; Fernández, Guillén; Ferrucci, Luigi; Fisher, Simon E; Fleischman, Debra A; Ford, Ian; Foroud, Tatiana M; Fox, Peter T; Francks, Clyde; Fukunaga, Masaki; Gibbs, J Raphael; Glahn, David C; Gollub, Randy L; Göring, Harald HH; Grabe, Hans J; Green, Robert C; Gruber, Oliver; Gudnason, Vilmundur; Guelfi, Sebastian; Hansell, Narelle K; Hardy, John; Hartman, Catharina A; Hashimoto, Ryota; Hegenscheid, Katrin; Heinz, Andreas; Le Hellard, Stephanie; Hernandez, Dena G; Heslenfeld, Dirk J; Ho, Beng-Choon; Hoekstra, Pieter J; Hoffmann, Wolfgang; Hofman, Albert; Holsboer, Florian; Homuth, Georg; Hosten, Norbert; Hottenga, Jouke-Jan; Hulshoff Pol, Hilleke E; Ikeda, Masashi; Ikram, M Kamran; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Jönsson, Erik G; Jukema, J Wouter; Kahn, René S; Kanai, Ryota; Kloszewska, Iwona; Knopman, David S; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Lemaître, Hervé; Liu, Xinmin; Longo, Dan L; Longstreth, WT; Lopez, Oscar L; Lovestone, Simon; Martinez, Oliver; Martinot, Jean-Luc; Mattay, Venkata S; McDonald, Colm; McIntosh, Andrew M; McMahon, Katie L; McMahon, Francis J; Mecocci, Patrizia; Melle, Ingrid; Meyer-Lindenberg, Andreas; Mohnke, Sebastian; Montgomery, Grant W; Morris, Derek W; Mosley, Thomas H; Mühleisen, Thomas W; Müller-Myhsok, Bertram; Nalls, Michael A; Nauck, Matthias; Nichols, Thomas E; Niessen, Wiro J; Nöthen, Markus M; Nyberg, Lars; Ohi, Kazutaka; Olvera, Rene L; Ophoff, Roel A; Pandolfo, Massimo; Paus, Tomas; Pausova, Zdenka; Penninx, Brenda WJH; Pike, G Bruce; Potkin, Steven G; Psaty, Bruce M; Reppermund, Simone; Rietschel, Marcella; Roffman, Joshua L; Romanczuk-Seiferth, Nina; Rotter, Jerome I; Ryten, Mina; Sacco, Ralph L; Sachdev, Perminder S; Saykin, Andrew J; Schmidt, Reinhold; Schofield, Peter R; Sigurdsson, Sigurdur; Simmons, Andy; Singleton, Andrew; Sisodiya, Sanjay M; Smith, Colin; Smoller, Jordan W; Soininen, Hilkka; Srikanth, Velandai; Steen, Vidar M; Stott, David J; Sussmann, Jessika E; Thalamuthu, Anbupalam; Tiemeier, Henning; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Turner, Jessica A; Tzourio, Christophe; Uitterlinden, Andre G; Valdés Hernández, Maria C; Van der Brug, Marcel; Van der Lugt, Aad; Van der Wee, Nic JA; Van Duijn, Cornelia M; Van Haren, Neeltje EM; Van 't Ent, Dennis; Van Tol, Marie-Jose; Vardarajan, Badri N; Veltman, Dick J; Vernooij, Meike W; Völzke, Henry; Walter, Henrik; Wardlaw, Joanna M; Wassink, Thomas H; Weale, Michael E; Weinberger, Daniel R; Weiner, Michael W; Wen, Wei; Westman, Eric; White, Tonya; Wong, Tien Y; Wright, Clinton B; Zielke, H Ronald; Zonderman, Alan B; Deary, Ian J; DeCarli, Charles; Schmidt, Helena; Martin, Nicholas G; De Craen, Anton JM; Wright, Margaret J; Launer, Lenore J; Schumann, Gunter; Fornage, Myriam; Franke, Barbara; Debette, Stéphanie; Medland, Sarah E; Ikram, M Arfan; Thompson, Paul M

    2016-01-01

    Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth. PMID:27694991

  17. Genomic selection: genome-wide prediction in plant improvement.

    Science.gov (United States)

    Desta, Zeratsion Abera; Ortiz, Rodomiro

    2014-09-01

    Association analysis is used to measure relations between markers and quantitative trait loci (QTL). Their estimation ignores genes with small effects that trigger underpinning quantitative traits. By contrast, genome-wide selection estimates marker effects across the whole genome on the target population based on a prediction model developed in the training population (TP). Whole-genome prediction models estimate all marker effects in all loci and capture small QTL effects. Here, we review several genomic selection (GS) models with respect to both the prediction accuracy and genetic gain from selection. Phenotypic selection or marker-assisted breeding protocols can be replaced by selection, based on whole-genome predictions in which phenotyping updates the model to build up the prediction accuracy. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis.

    Science.gov (United States)

    Peters, Ulrike; Jiao, Shuo; Schumacher, Fredrick R; Hutter, Carolyn M; Aragaki, Aaron K; Baron, John A; Berndt, Sonja I; Bézieau, Stéphane; Brenner, Hermann; Butterbach, Katja; Caan, Bette J; Campbell, Peter T; Carlson, Christopher S; Casey, Graham; Chan, Andrew T; Chang-Claude, Jenny; Chanock, Stephen J; Chen, Lin S; Coetzee, Gerhard A; Coetzee, Simon G; Conti, David V; Curtis, Keith R; Duggan, David; Edwards, Todd; Fuchs, Charles S; Gallinger, Steven; Giovannucci, Edward L; Gogarten, Stephanie M; Gruber, Stephen B; Haile, Robert W; Harrison, Tabitha A; Hayes, Richard B; Henderson, Brian E; Hoffmeister, Michael; Hopper, John L; Hudson, Thomas J; Hunter, David J; Jackson, Rebecca D; Jee, Sun Ha; Jenkins, Mark A; Jia, Wei-Hua; Kolonel, Laurence N; Kooperberg, Charles; Küry, Sébastien; Lacroix, Andrea Z; Laurie, Cathy C; Laurie, Cecelia A; Le Marchand, Loic; Lemire, Mathieu; Levine, David; Lindor, Noralane M; Liu, Yan; Ma, Jing; Makar, Karen W; Matsuo, Keitaro; Newcomb, Polly A; Potter, John D; Prentice, Ross L; Qu, Conghui; Rohan, Thomas; Rosse, Stephanie A; Schoen, Robert E; Seminara, Daniela; Shrubsole, Martha; Shu, Xiao-Ou; Slattery, Martha L; Taverna, Darin; Thibodeau, Stephen N; Ulrich, Cornelia M; White, Emily; Xiang, Yongbing; Zanke, Brent W; Zeng, Yi-Xin; Zhang, Ben; Zheng, Wei; Hsu, Li

    2013-04-01

    Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10(-8): an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10(-8)). We also found evidence for 3 additional loci with P values less than 5.0 × 10(-7): a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10(-8)), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10(-8)), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10(-7)). In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further

  19. Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans.

    Science.gov (United States)

    Carty, Cara L; Keene, Keith L; Cheng, Yu-Ching; Meschia, James F; Chen, Wei-Min; Nalls, Mike; Bis, Joshua C; Kittner, Steven J; Rich, Stephen S; Tajuddin, Salman; Zonderman, Alan B; Evans, Michele K; Langefeld, Carl D; Gottesman, Rebecca; Mosley, Thomas H; Shahar, Eyal; Woo, Daniel; Yaffe, Kristine; Liu, Yongmei; Sale, Michèle M; Dichgans, Martin; Malik, Rainer; Longstreth, W T; Mitchell, Braxton D; Psaty, Bruce M; Kooperberg, Charles; Reiner, Alexander; Worrall, Bradford B; Fornage, Myriam

    2015-08-01

    The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African Americans, despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations. Using METAL, we conducted meta-analyses of GWAS in 14 746 African Americans (1365 ischemic and 1592 total stroke cases) from COMPASS, and tested genetic variants with Pstroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations. The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613; P=3.9×10(-8)) in African Americans. Nominal associations (Pstroke were observed for 18 variants in or near genes implicated in cell cycle/mRNA presplicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, and IL1F10-IL1RN), and histone modification (HDAC9). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 (P=0.03), and 1p31.1 (P=0.018). Four of 7 previously reported ischemic stroke loci (PITX2, HDAC9, CDKN2A/CDKN2B, and ZFHX3) were nominally associated (Pstroke in COMPASS. We identified a novel genetic variant associated with total stroke in African Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations. © 2015 American Heart Association, Inc.

  20. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia

    NARCIS (Netherlands)

    Berndt, Sonja I; Camp, Nicola J; Skibola, Christine F; Vijai, Joseph; Wang, Zhaoming; Gu, Jian; Nieters, Alexandra; Kelly, Rachel S; Smedby, Karin E; Monnereau, Alain; Cozen, Wendy; Cox, Angela; Wang, Sophia S; Lan, Qing; Teras, Lauren R; Machado, Moara; Yeager, Meredith; Brooks-Wilson, Angela R; Hartge, Patricia; Purdue, Mark P; Birmann, Brenda M; Vajdic, Claire M; Cocco, Pierluigi; Zhang, Yawei; Giles, Graham G; Zeleniuch-Jacquotte, Anne; Lawrence, Charles; Montalvan, Rebecca; Burdett, Laurie; Hutchinson, Amy; Ye, Yuanqing; Call, Timothy G; Shanafelt, Tait D; Novak, Anne J; Kay, Neil E; Liebow, Mark; Cunningham, Julie M; Allmer, Cristine; Hjalgrim, Henrik; Adami, Hans-Olov; Melbye, Mads; Glimelius, Bengt; Chang, Ellen T; Glenn, Martha; Curtin, Karen; Cannon-Albright, Lisa A; Diver, W Ryan; Link, Brian K; Weiner, George J; Conde, Lucia; Bracci, Paige M; Riby, Jacques; Arnett, Donna K; Zhi, Degui; Leach, Justin M; Holly, Elizabeth A; Jackson, Rebecca D; Tinker, Lesley F; Benavente, Yolanda; Sala, Núria; Casabonne, Delphine; Becker, Nikolaus; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; McKay, James; Staines, Anthony; Chaffee, Kari G; Achenbach, Sara J; Vachon, Celine M; Goldin, Lynn R; Strom, Sara S; Leis, Jose F; Weinberg, J Brice; Caporaso, Neil E; Norman, Aaron D; De Roos, Anneclaire J; Morton, Lindsay M; Severson, Richard K; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolph; Masala, Giovanna; Weiderpass, Elisabete; Chirlaque, María-Dolores; Vermeulen, Roel C H|info:eu-repo/dai/nl/216532620; Travis, Ruth C; Southey, Melissa C; Milne, Roger L; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Clavel, Jacqueline; Zheng, Tongzhang; Holford, Theodore R; Villano, Danylo J; Maria, Ann; Spinelli, John J; Gascoyne, Randy D; Connors, Joseph M; Bertrand, Kimberly A; Giovannucci, Edward; Kraft, Peter; Kricker, Anne; Turner, Jenny; Ennas, Maria Grazia; Ferri, Giovanni M; Miligi, Lucia; Liang, Liming; Ma, Baoshan; Huang, Jinyan; Crouch, Simon; Park, Ju-Hyun; Chatterjee, Nilanjan; North, Kari E; Snowden, John A; Wright, Josh; Fraumeni, Joseph F; Offit, Kenneth; Wu, Xifeng; de Sanjose, Silvia; Cerhan, James R; Chanock, Stephen J; Rothman, Nathaniel; Slager, Susan L

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and

  1. Genome-wide association study of pathological gambling.

    Science.gov (United States)

    Lang, M; Leménager, T; Streit, F; Fauth-Bühler, M; Frank, J; Juraeva, D; Witt, S H; Degenhardt, F; Hofmann, A; Heilmann-Heimbach, S; Kiefer, F; Brors, B; Grabe, H-J; John, U; Bischof, A; Bischof, G; Völker, U; Homuth, G; Beutel, M; Lind, P A; Medland, S E; Slutske, W S; Martin, N G; Völzke, H; Nöthen, M M; Meyer, C; Rumpf, H-J; Wurst, F M; Rietschel, M; Mann, K F

    2016-08-01

    Pathological gambling is a behavioural addiction with negative economic, social, and psychological consequences. Identification of contributing genes and pathways may improve understanding of aetiology and facilitate therapy and prevention. Here, we report the first genome-wide association study of pathological gambling. Our aims were to identify pathways involved in pathological gambling, and examine whether there is a genetic overlap between pathological gambling and alcohol dependence. Four hundred and forty-five individuals with a diagnosis of pathological gambling according to the Diagnostic and Statistical Manual of Mental Disorders were recruited in Germany, and 986 controls were drawn from a German general population sample. A genome-wide association study of pathological gambling comprising single marker, gene-based, and pathway analyses, was performed. Polygenic risk scores were generated using data from a German genome-wide association study of alcohol dependence. No genome-wide significant association with pathological gambling was found for single markers or genes. Pathways for Huntington's disease (P-value=6.63×10(-3)); 5'-adenosine monophosphate-activated protein kinase signalling (P-value=9.57×10(-3)); and apoptosis (P-value=1.75×10(-2)) were significant. Polygenic risk score analysis of the alcohol dependence dataset yielded a one-sided nominal significant P-value in subjects with pathological gambling, irrespective of comorbid alcohol dependence status. The present results accord with previous quantitative formal genetic studies which showed genetic overlap between non-substance- and substance-related addictions. Furthermore, pathway analysis suggests shared pathology between Huntington's disease and pathological gambling. This finding is consistent with previous imaging studies. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  2. Significant Locus and Metabolic Genetic Correlations Revealed in Genome-Wide Association Study of Anorexia Nervosa

    NARCIS (Netherlands)

    Duncan, Laramie; Yilmaz, Zeynep; Gaspar, Helena; Walters, Raymond K.; Goldstein, Jackie; Anttila, Verneri; Bulik-Sullivan, Brendan; Ripke, Stephan; Thornton, Laura M.; Hinney, Anke; Daly, Mark J.; Sullivan, Patrick F; Zeggini, Eleftheria; Breen, Gerome; Bulik, Cynthia M.; Adan, RAH

    2017-01-01

    Objective: The authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes. Method: Following uniformquality control and imputation procedures using the 1000 Genomes Project (phase 3) in

  3. Significant locus and metabolic genetic correlations revealed in genome-wide association study of anorexia nervosa

    NARCIS (Netherlands)

    Duncan, Laramie; Yilmaz, Zeynep; Gaspar, Helena; Walters, Raymond; Goldstein, Jackie; Anttila, Verneri; Bulik-Sullivan, Brendan; Ripke, Stephan; Thornton, Laura; Hinney, Anke; Daly, Mark; Sullivan, Patrick F; Zeggini, Eleftheria; Breen, Gerome; Bulik, Cynthia M; Kas, Martinus J.H.

    2017-01-01

    OBJECTIVE: The authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes. METHOD: Following uniform quality control and imputation procedures using the 1000 Genomes Project (phase 3)

  4. Genome-Wide Analysis of Grain Yield Stability and Environmental Interactions in a Multiparental Soybean Population

    Directory of Open Access Journals (Sweden)

    Alencar Xavier

    2018-02-01

    Full Text Available Genetic improvement toward optimized and stable agronomic performance of soybean genotypes is desirable for food security. Understanding how genotypes perform in different environmental conditions helps breeders develop sustainable cultivars adapted to target regions. Complex traits of importance are known to be controlled by a large number of genomic regions with small effects whose magnitude and direction are modulated by environmental factors. Knowledge of the constraints and undesirable effects resulting from genotype by environmental interactions is a key objective in improving selection procedures in soybean breeding programs. In this study, the genetic basis of soybean grain yield responsiveness to environmental factors was examined in a large soybean nested association population. For this, a genome-wide association to performance stability estimates generated from a Finlay-Wilkinson analysis and the inclusion of the interaction between marker genotypes and environmental factors was implemented. Genomic footprints were investigated by analysis and meta-analysis using a recently published multiparent model. Results indicated that specific soybean genomic regions were associated with stability, and that multiplicative interactions were present between environments and genetic background. Seven genomic regions in six chromosomes were identified as being associated with genotype-by-environment interactions. This study provides insight into genomic assisted breeding aimed at achieving a more stable agronomic performance of soybean, and documented opportunities to exploit genomic regions that were specifically associated with interactions involving environments and subpopulations.

  5. Genome-wide association study and genetic diversity analysis on nitrogen use efficiency in a Central European winter wheat (Triticum aestivum L. collection.

    Directory of Open Access Journals (Sweden)

    István Monostori

    Full Text Available To satisfy future demands, the increase of wheat (Triticum aestivum L. yield is inevitable. Simultaneously, maintaining high crop productivity and efficient use of nutrients, especially nitrogen use efficiency (NUE, are essential for sustainable agriculture. NUE and its components are inherently complex and highly influenced by environmental factors, nitrogen management practices and genotypic variation. Therefore, a better understanding of their genetic basis and regulation is fundamental. To investigate NUE-related traits and their genetic and environmental regulation, field trials were evaluated in a Central European wheat collection of 93 cultivars at two nitrogen input levels across three seasons. This elite germplasm collection was genotyped on DArTseq® genotypic platform to identify loci affecting N-related complex agronomic traits. To conduct robust genome-wide association mapping, the genetic diversity, population structure and linkage disequilibrium were examined. Population structure was investigated by various methods and two subpopulations were identified. Their separation is based on the breeding history of the cultivars, while analysis of linkage disequilibrium suggested that selective pressures had acted on genomic regions bearing loci with remarkable agronomic importance. Besides NUE, genetic basis for variation in agronomic traits indirectly affecting NUE and its components, moreover genetic loci underlying response to nitrogen fertilisation were also determined. Altogether, 183 marker-trait associations (MTA were identified spreading over almost the entire genome. We found that most of the MTAs were environmental-dependent. The present study identified several associated markers in those genomic regions where previous reports had found genes or quantitative trait loci influencing the same traits, while most of the MTAs revealed new genomic regions. Our data provides an overview of the allele composition of bread wheat

  6. Genome-wide DNA polymorphism analyses using VariScan

    Directory of Open Access Journals (Sweden)

    Vilella Albert J

    2006-09-01

    Full Text Available Abstract Background DNA sequence polymorphisms analysis can provide valuable information on the evolutionary forces shaping nucleotide variation, and provides an insight into the functional significance of genomic regions. The recent ongoing genome projects will radically improve our capabilities to detect specific genomic regions shaped by natural selection. Current available methods and software, however, are unsatisfactory for such genome-wide analysis. Results We have developed methods for the analysis of DNA sequence polymorphisms at the genome-wide scale. These methods, which have been tested on a coalescent-simulated and actual data files from mouse and human, have been implemented in the VariScan software package version 2.0. Additionally, we have also incorporated a graphical-user interface. The main features of this software are: i exhaustive population-genetic analyses including those based on the coalescent theory; ii analysis adapted to the shallow data generated by the high-throughput genome projects; iii use of genome annotations to conduct a comprehensive analyses separately for different functional regions; iv identification of relevant genomic regions by the sliding-window and wavelet-multiresolution approaches; v visualization of the results integrated with current genome annotations in commonly available genome browsers. Conclusion VariScan is a powerful and flexible suite of software for the analysis of DNA polymorphisms. The current version implements new algorithms, methods, and capabilities, providing an important tool for an exhaustive exploratory analysis of genome-wide DNA polymorphism data.

  7. Genome-wide association scan meta-analysis identifies three loci influencing adiposity and fat distribution

    NARCIS (Netherlands)

    C.M. Lindgren (Cecilia); I.M. Heid (Iris); J.C. Randall (Joshua); C. Lamina (Claudia); V. Steinthorsdottir (Valgerdur); L. Qi (Lu); E.K. Speliotes (Elizabeth); G. Thorleifsson (Gudmar); C.J. Willer (Cristen); B.M. Herrera (Blanca); A.U. Jackson (Anne); N. Lim (Noha); P. Scheet (Paul); N. Soranzo (Nicole); N. Amin (Najaf); Y.S. Aulchenko (Yurii); J.C. Chambers (John); A. Drong (Alexander); J. Luan; H.N. Lyon (Helen); F. Rivadeneira Ramirez (Fernando); S. Sanna (Serena); N.J. Timpson (Nicholas); M.C. Zillikens (Carola); H.Z. Jing; P. Almgren (Peter); S. Bandinelli (Stefania); A.J. Bennett (Amanda); R.N. Bergman (Richard); L.L. Bonnycastle (Lori); S. Bumpstead (Suzannah); S.J. Chanock (Stephen); L. Cherkas (Lynn); P.S. Chines (Peter); L. Coin (Lachlan); C. Cooper (Charles); G. Crawford (Gabe); A. Doering (Angela); A. Dominiczak (Anna); A.S.F. Doney (Alex); S. Ebrahim (Shanil); P. Elliott (Paul); M.R. Erdos (Michael); K. Estrada Gil (Karol); L. Ferrucci (Luigi); G. Fischer (Guido); N.G. Forouhi (Nita); C. Gieger (Christian); H. Grallert (Harald); C.J. Groves (Christopher); S.M. Grundy (Scott); C. Guiducci (Candace); D. Hadley (David); A. Hamsten (Anders); A.S. Havulinna (Aki); A. Hofman (Albert); R. Holle (Rolf); J.W. Holloway (John); T. Illig (Thomas); B. Isomaa (Bo); L.C. Jacobs (Leonie); K. Jameson (Karen); P. Jousilahti (Pekka); F. Karpe (Fredrik); J. Kuusisto (Johanna); J. Laitinen (Jaana); G.M. Lathrop (Mark); D.A. Lawlor (Debbie); M. Mangino (Massimo); W.L. McArdle (Wendy); T. Meitinger (Thomas); M.A. Morken (Mario); A.P. Morris (Andrew); P. Munroe (Patricia); N. Narisu (Narisu); A. Nordström (Anna); B.A. Oostra (Ben); C.N.A. Palmer (Colin); F. Payne (Felicity); J. Peden (John); I. Prokopenko (Inga); F. Renström (Frida); A. Ruokonen (Aimo); V. Salomaa (Veikko); M.S. Sandhu (Manjinder); L.J. Scott (Laura); A. Scuteri (Angelo); K. Silander (Kaisa); K. Song (Kijoung); X. Yuan (Xin); H.M. Stringham (Heather); A.J. Swift (Amy); T. Tuomi (Tiinamaija); M. Uda (Manuela); P. Vollenweider (Peter); G. Waeber (Gérard); C. Wallace (Chris); G.B. Walters (Bragi); M.N. Weedon (Michael); J.C.M. Witteman (Jacqueline); C. Zhang (Cuilin); M. Caulfield (Mark); F.S. Collins (Francis); G.D. Smith; I.N.M. Day (Ian); P.W. Franks (Paul); A.T. Hattersley (Andrew); F.B. Hu (Frank); M.-R. Jarvelin (Marjo-Riitta); A. Kong (Augustine); J.S. Kooner (Jaspal); M. Laakso (Markku); E. Lakatta (Edward); V. Mooser (Vincent); L. Peltonen (Leena Johanna); N.J. Samani (Nilesh); T.D. Spector (Timothy); D.P. Strachan (David); T. Tanaka (Toshiko); J. Tuomilehto (Jaakko); A.G. Uitterlinden (André); P. Tikka-Kleemola (Päivi); N.J. Wareham (Nick); H. Watkins (Hugh); D. Waterworth (Dawn); M. Boehnke (Michael); P. Deloukas (Panagiotis); L. Groop (Leif); D.J. Hunter (David); U. Thorsteinsdottir (Unnur); D. Schlessinger (David); H.E. Wichmann (Erich); T.M. Frayling (Timothy); G.R. Abecasis (Gonçalo); J.N. Hirschhorn (Joel); R.J.F. Loos (Ruth); J-A. Zwart (John-Anker); K.L. Mohlke (Karen); I.E. Barroso (Inês); M.I. McCarthy (Mark)

    2009-01-01

    textabstractTo identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the

  8. Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility

    NARCIS (Netherlands)

    Yin, Xianyong; Low, Hui Qi; Wang, Ling; Li, Yonghong; Ellinghaus, Eva; Han, Jiali; Estivill, Xavier; Sun, Liangdan; Zuo, Xianbo; Shen, Changbing; Zhu, Caihong; Zhang, Anping; Sanchez, Fabio; Padyukov, Leonid; Catanese, Joseph J; Krueger, Gerald G; Duffin, Kristina Callis; Mucha, Sören; Weichenthal, Michael; Weidinger, Stephan; Lieb, Wolfgang; Foo, Jia Nee; Li, Yi; Sim, Karseng; Liany, Herty; Irwan, Ishak; Teo, Yikying; Theng, Colin T S; Gupta, Rashmi; Bowcock, Anne; De Jager, Philip L; Qureshi, Abrar A; de Bakker, Paul I W; Seielstad, Mark; Liao, Wilson; Ståhle, Mona; Franke, Andre; Zhang, Xuejun; Liu, Jianjun

    2015-01-01

    Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here we present the largest trans-ethnic genome-wide meta-analysis (GWMA) of psoriasis in 15,369 cases and 19,517 controls of Caucasian and Chinese ancestries. We

  9. Harnessing the sorghum genome sequence:development of a genome-wide microsattelite (SSR) resource for swift genetic mapping and map based cloning in sorghum

    Science.gov (United States)

    Sorghum is the second cereal crop to have a full genome completely sequenced (Nature (2009), 457:551). This achievement is widely recognized as a scientific milestone for grass genetics and genomics in general. However, the true worth of genetic information lies in translating the sequence informa...

  10. High-resolution genetic map for understanding the effect of genome-wide recombination rate on nucleotide diversity in watermelon.

    Science.gov (United States)

    Reddy, Umesh K; Nimmakayala, Padma; Levi, Amnon; Abburi, Venkata Lakshmi; Saminathan, Thangasamy; Tomason, Yan R; Vajja, Gopinath; Reddy, Rishi; Abburi, Lavanya; Wehner, Todd C; Ronin, Yefim; Karol, Abraham

    2014-09-15

    We used genotyping by sequencing to identify a set of 10,480 single nucleotide polymorphism (SNP) markers for constructing a high-resolution genetic map of 1096 cM for watermelon. We assessed the genome-wide variation in recombination rate (GWRR) across the map and found an association between GWRR and genome-wide nucleotide diversity. Collinearity between the map and the genome-wide reference sequence for watermelon was studied to identify inconsistency and chromosome rearrangements. We assessed genome-wide nucleotide diversity, linkage disequilibrium (LD), and selective sweep for wild, semi-wild, and domesticated accessions of Citrullus lanatus var. lanatus to track signals of domestication. Principal component analysis combined with chromosome-wide phylogenetic study based on 1563 SNPs obtained after LD pruning with minor allele frequency of 0.05 resolved the differences between semi-wild and wild accessions as well as relationships among worldwide sweet watermelon. Population structure analysis revealed predominant ancestries for wild, semi-wild, and domesticated watermelons as well as admixture of various ancestries that were important for domestication. Sliding window analysis of Tajima's D across various chromosomes was used to resolve selective sweep. LD decay was estimated for various chromosomes. We identified a strong selective sweep on chromosome 3 consisting of important genes that might have had a role in sweet watermelon domestication. Copyright © 2014 Reddy et al.

  11. Genome-wide association identifies genetic variants associated with lentiform nucleus volume in N = 1345 young and elderly subjects.

    Science.gov (United States)

    Hibar, Derrek P; Stein, Jason L; Ryles, April B; Kohannim, Omid; Jahanshad, Neda; Medland, Sarah E; Hansell, Narelle K; McMahon, Katie L; de Zubicaray, Greig I; Montgomery, Grant W; Martin, Nicholas G; Wright, Margaret J; Saykin, Andrew J; Jack, Clifford R; Weiner, Michael W; Toga, Arthur W; Thompson, Paul M

    2013-06-01

    Deficits in lentiform nucleus volume and morphometry are implicated in a number of genetically influenced disorders, including Parkinson's disease, schizophrenia, and ADHD. Here we performed genome-wide searches to discover common genetic variants associated with differences in lentiform nucleus volume in human populations. We assessed structural MRI scans of the brain in two large genotyped samples: the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 706) and the Queensland Twin Imaging Study (QTIM; N = 639). Statistics of association from each cohort were combined meta-analytically using a fixed-effects model to boost power and to reduce the prevalence of false positive findings. We identified a number of associations in and around the flavin-containing monooxygenase (FMO) gene cluster. The most highly associated SNP, rs1795240, was located in the FMO3 gene; after meta-analysis, it showed genome-wide significant evidence of association with lentiform nucleus volume (P MA  = 4.79 × 10(-8)). This commonly-carried genetic variant accounted for 2.68 % and 0.84 % of the trait variability in the ADNI and QTIM samples, respectively, even though the QTIM sample was on average 50 years younger. Pathway enrichment analysis revealed significant contributions of this gene to the cytochrome P450 pathway, which is involved in metabolizing numerous therapeutic drugs for pain, seizures, mania, depression, anxiety, and psychosis. The genetic variants we identified provide replicated, genome-wide significant evidence for the FMO gene cluster's involvement in lentiform nucleus volume differences in human populations.

  12. Genome-wide association analyses of expression phenotypes.

    Science.gov (United States)

    Chen, Gary K; Zheng, Tian; Witte, John S; Goode, Ellen L; Gao, Lei; Hu, Pingzhao; Suh, Young Ju; Suktitipat, Bhoom; Szymczak, Silke; Woo, Jung Hoon; Zhang, Wei

    2007-01-01

    A number of issues arise when analyzing the large amount of data from high-throughput genotype and expression microarray experiments, including design and interpretation of genome-wide association studies of expression phenotypes. These issues were considered by contributions submitted to Group 1 of the Genetic Analysis Workshop 15 (GAW15), which focused on the association of quantitative expression data. These contributions evaluated diverse hypotheses, including those relevant to cancer and obesity research, and used various analytic techniques, many of which were derived from information theory. Several observations from these reports stand out. First, one needs to consider the genetic model of the trait of interest and carefully select which single nucleotide polymorphisms and individuals are included early in the design stage of a study. Second, by targeting specific pathways when analyzing genome-wide data, one can generate more interpretable results than agnostic approaches. Finally, for datasets with small sample sizes but a large number of features like the Genetic Analysis Workshop 15 dataset, machine learning approaches may be more practical than traditional parametric approaches. (c) 2007 Wiley-Liss, Inc.

  13. Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity

    DEFF Research Database (Denmark)

    Joshi, Peter K; Pirastu, Nicola; Kentistou, Katherine A

    2017-01-01

    Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE...... that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic...

  14. Integrating molecular QTL data into genome-wide genetic association analysis: Probabilistic assessment of enrichment and colocalization.

    Directory of Open Access Journals (Sweden)

    Xiaoquan Wen

    2017-03-01

    Full Text Available We propose a novel statistical framework for integrating the result from molecular quantitative trait loci (QTL mapping into genome-wide genetic association analysis of complex traits, with the primary objectives of quantitatively assessing the enrichment of the molecular QTLs in complex trait-associated genetic variants and the colocalizations of the two types of association signals. We introduce a natural Bayesian hierarchical model that treats the latent association status of molecular QTLs as SNP-level annotations for candidate SNPs of complex traits. We detail a computational procedure to seamlessly perform enrichment, fine-mapping and colocalization analyses, which is a distinct feature compared to the existing colocalization analysis procedures in the literature. The proposed approach is computationally efficient and requires only summary-level statistics. We evaluate and demonstrate the proposed computational approach through extensive simulation studies and analyses of blood lipid data and the whole blood eQTL data from the GTEx project. In addition, a useful utility from our proposed method enables the computation of expected colocalization signals using simple characteristics of the association data. Using this utility, we further illustrate the importance of enrichment analysis on the ability to discover colocalized signals and the potential limitations of currently available molecular QTL data. The software pipeline that implements the proposed computation procedures, enloc, is freely available at https://github.com/xqwen/integrative.

  15. Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.

    Directory of Open Access Journals (Sweden)

    Maggie C Y Ng

    2014-08-01

    Full Text Available Type 2 diabetes (T2D is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1 and two novel loci (HLA-B and INS-IGF2 at genome-wide significance (4.15 × 10(-94wide P<0.05. These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.

  16. Genome-Wide Association Mapping for Intelligence in Military Working Dogs: Canine Cohort, Canine Intelligence Assessment Regimen, Genome-Wide Single Nucleotide Polymorphism (SNP) Typing, and Unsupervised Classification Algorithm for Genome-Wide Association Data Analysis

    Science.gov (United States)

    2011-09-01

    SNP Array v2. A ‘proof-of-concept’ advanced data mining algorithm for unsupervised analysis of genome-wide association study (GWAS) dataset was... Opal F AUS Yes U141 Peggs F AUS Yes U142 Taxi F AUS Yes U143 Riso MI MAL Yes U144 Szarik MI GSD Yes U145 Astor MI MAL Yes U146 Roy MC MAL Yes... mining of genetic studies in general, and especially GWAS. As a proof-of-concept, a classification analysis of the WG SNP typing dataset of a

  17. Genome-Wide Association Study (GWAS) and Genome-Wide Environment Interaction Study (GWEIS) of Depressive Symptoms in African American and Hispanic/Latina Women

    Science.gov (United States)

    Dunn, Erin C.; Wiste, Anna; Radmanesh, Farid; Almli, Lynn M.; Gogarten, Stephanie M.; Sofer, Tamar; Faul, Jessica D.; Kardia, Sharon L.R.; Smith, Jennifer A.; Weir, David R.; Zhao, Wei; Soare, Thomas W.; Mirza, Saira S.; Hek, Karin; Tiemeier, Henning W.; Goveas, Joseph S.; Sarto, Gloria E.; Snively, Beverly M.; Cornelis, Marilyn; Koenen, Karestan C.; Kraft, Peter; Purcell, Shaun; Ressler, Kerry J.; Rosand, Jonathan; Wassertheil-Smoller, Sylvia; Smoller, Jordan W.

    2016-01-01

    Background Genome-wide association studies (GWAS) have been unable to identify variants linked to depression. We hypothesized that examining depressive symptoms and considering gene-environment interaction (G×E) might improve efficiency for gene discovery. We therefore conducted a GWAS and genome-wide environment interaction study (GWEIS) of depressive symptoms. Methods Using data from the SHARe cohort of the Women’s Health Initiative, comprising African Americans (n=7179) and Hispanics/Latinas (n=3138), we examined genetic main effects and G×E with stressful life events and social support. We also conducted a heritability analysis using genome-wide complex trait analysis (GCTA). Replication was attempted in four independent cohorts. Results No SNPs achieved genome-wide significance for main effects in either discovery sample. The top signals in African Americans were rs73531535 (located 20kb from GPR139, p=5.75×10−8) and rs75407252 (intronic to CACNA2D3, p=6.99×10−7). In Hispanics/Latinas, the top signals were rs2532087 (located 27kb from CD38, p=2.44×10−7) and rs4542757 (intronic to DCC, p=7.31×10−7). In the GWEIS with stressful life events, one interaction signal was genome-wide significant in African Americans (rs4652467; p=4.10×10−10; located 14kb from CEP350). This interaction was not observed in a smaller replication cohort. Although heritability estimates for depressive symptoms and stressful life events were each less than 10%, they were strongly genetically correlated (rG=0.95), suggesting that common variation underlying depressive symptoms and stressful life event exposure, though modest on their own, were highly overlapping in this sample. Conclusions Our results underscore the need for larger samples, more GWEIS, and greater investigation into genetic and environmental determinants of depressive symptoms in minorities. PMID:27038408

  18. Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.

    Science.gov (United States)

    Zillikens, M Carola; Demissie, Serkalem; Hsu, Yi-Hsiang; Yerges-Armstrong, Laura M; Chou, Wen-Chi; Stolk, Lisette; Livshits, Gregory; Broer, Linda; Johnson, Toby; Koller, Daniel L; Kutalik, Zoltán; Luan, Jian'an; Malkin, Ida; Ried, Janina S; Smith, Albert V; Thorleifsson, Gudmar; Vandenput, Liesbeth; Hua Zhao, Jing; Zhang, Weihua; Aghdassi, Ali; Åkesson, Kristina; Amin, Najaf; Baier, Leslie J; Barroso, Inês; Bennett, David A; Bertram, Lars; Biffar, Rainer; Bochud, Murielle; Boehnke, Michael; Borecki, Ingrid B; Buchman, Aron S; Byberg, Liisa; Campbell, Harry; Campos Obanda, Natalia; Cauley, Jane A; Cawthon, Peggy M; Cederberg, Henna; Chen, Zhao; Cho, Nam H; Jin Choi, Hyung; Claussnitzer, Melina; Collins, Francis; Cummings, Steven R; De Jager, Philip L; Demuth, Ilja; Dhonukshe-Rutten, Rosalie A M; Diatchenko, Luda; Eiriksdottir, Gudny; Enneman, Anke W; Erdos, Mike; Eriksson, Johan G; Eriksson, Joel; Estrada, Karol; Evans, Daniel S; Feitosa, Mary F; Fu, Mao; Garcia, Melissa; Gieger, Christian; Girke, Thomas; Glazer, Nicole L; Grallert, Harald; Grewal, Jagvir; Han, Bok-Ghee; Hanson, Robert L; Hayward, Caroline; Hofman, Albert; Hoffman, Eric P; Homuth, Georg; Hsueh, Wen-Chi; Hubal, Monica J; Hubbard, Alan; Huffman, Kim M; Husted, Lise B; Illig, Thomas; Ingelsson, Erik; Ittermann, Till; Jansson, John-Olov; Jordan, Joanne M; Jula, Antti; Karlsson, Magnus; Khaw, Kay-Tee; Kilpeläinen, Tuomas O; Klopp, Norman; Kloth, Jacqueline S L; Koistinen, Heikki A; Kraus, William E; Kritchevsky, Stephen; Kuulasmaa, Teemu; Kuusisto, Johanna; Laakso, Markku; Lahti, Jari; Lang, Thomas; Langdahl, Bente L; Launer, Lenore J; Lee, Jong-Young; Lerch, Markus M; Lewis, Joshua R; Lind, Lars; Lindgren, Cecilia; Liu, Yongmei; Liu, Tian; Liu, Youfang; Ljunggren, Östen; Lorentzon, Mattias; Luben, Robert N; Maixner, William; McGuigan, Fiona E; Medina-Gomez, Carolina; Meitinger, Thomas; Melhus, Håkan; Mellström, Dan; Melov, Simon; Michaëlsson, Karl; Mitchell, Braxton D; Morris, Andrew P; Mosekilde, Leif; Newman, Anne; Nielson, Carrie M; O'Connell, Jeffrey R; Oostra, Ben A; Orwoll, Eric S; Palotie, Aarno; Parker, Stephen C J; Peacock, Munro; Perola, Markus; Peters, Annette; Polasek, Ozren; Prince, Richard L; Räikkönen, Katri; Ralston, Stuart H; Ripatti, Samuli; Robbins, John A; Rotter, Jerome I; Rudan, Igor; Salomaa, Veikko; Satterfield, Suzanne; Schadt, Eric E; Schipf, Sabine; Scott, Laura; Sehmi, Joban; Shen, Jian; Soo Shin, Chan; Sigurdsson, Gunnar; Smith, Shad; Soranzo, Nicole; Stančáková, Alena; Steinhagen-Thiessen, Elisabeth; Streeten, Elizabeth A; Styrkarsdottir, Unnur; Swart, Karin M A; Tan, Sian-Tsung; Tarnopolsky, Mark A; Thompson, Patricia; Thomson, Cynthia A; Thorsteinsdottir, Unnur; Tikkanen, Emmi; Tranah, Gregory J; Tuomilehto, Jaakko; van Schoor, Natasja M; Verma, Arjun; Vollenweider, Peter; Völzke, Henry; Wactawski-Wende, Jean; Walker, Mark; Weedon, Michael N; Welch, Ryan; Wichmann, H-Erich; Widen, Elisabeth; Williams, Frances M K; Wilson, James F; Wright, Nicole C; Xie, Weijia; Yu, Lei; Zhou, Yanhua; Chambers, John C; Döring, Angela; van Duijn, Cornelia M; Econs, Michael J; Gudnason, Vilmundur; Kooner, Jaspal S; Psaty, Bruce M; Spector, Timothy D; Stefansson, Kari; Rivadeneira, Fernando; Uitterlinden, André G; Wareham, Nicholas J; Ossowski, Vicky; Waterworth, Dawn; Loos, Ruth J F; Karasik, David; Harris, Tamara B; Ohlsson, Claes; Kiel, Douglas P

    2017-07-19

    Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

  19. A genome-wide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

    Science.gov (United States)

    Chaste, Pauline; Klei, Lambertus; Sanders, Stephan J; Hus, Vanessa; Murtha, Michael T; Lowe, Jennifer K; Willsey, A Jeremy; Moreno-De-Luca, Daniel; Yu, Timothy W; Fombonne, Eric; Geschwind, Daniel; Grice, Dorothy E; Ledbetter, David H; Mane, Shrikant M; Martin, Donna M; Morrow, Eric M; Walsh, Christopher A; Sutcliffe, James S; Lese Martin, Christa; Beaudet, Arthur L; Lord, Catherine; State, Matthew W; Cook, Edwin H; Devlin, Bernie

    2015-05-01

    Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD. Genome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup. Association analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups. In genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  20. Genome-Wide Analysis Reveals Novel Regulators of Growth in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Sibylle Chantal Vonesch

    2016-01-01

    Full Text Available Organismal size depends on the interplay between genetic and environmental factors. Genome-wide association (GWA analyses in humans have implied many genes in the control of height but suffer from the inability to control the environment. Genetic analyses in Drosophila have identified conserved signaling pathways controlling size; however, how these pathways control phenotypic diversity is unclear. We performed GWA of size traits using the Drosophila Genetic Reference Panel of inbred, sequenced lines. We find that the top associated variants differ between traits and sexes; do not map to canonical growth pathway genes, but can be linked to these by epistasis analysis; and are enriched for genes and putative enhancers. Performing GWA on well-studied developmental traits under controlled conditions expands our understanding of developmental processes underlying phenotypic diversity.

  1. Genome-wide analysis identifies 12 loci influencing human reproductive behavior

    Science.gov (United States)

    Barban, Nicola; Jansen, Rick; de Vlaming, Ronald; Vaez, Ahmad; Mandemakers, Jornt J.; Tropf, Felix C.; Shen, Xia; Wilson, James F.; Chasman, Daniel I.; Nolte, Ilja M.; Tragante, Vinicius; van der Laan, Sander W.; Perry, John R. B.; Kong, Augustine; Ahluwalia, Tarunveer; Albrecht, Eva; Yerges-Armstrong, Laura; Atzmon, Gil; Auro, Kirsi; Ayers, Kristin; Bakshi, Andrew; Ben-Avraham, Danny; Berger, Klaus; Bergman, Aviv; Bertram, Lars; Bielak, Lawrence F.; Bjornsdottir, Gyda; Bonder, Marc Jan; Broer, Linda; Bui, Minh; Barbieri, Caterina; Cavadino, Alana; Chavarro, Jorge E; Turman, Constance; Concas, Maria Pina; Cordell, Heather J.; Davies, Gail; Eibich, Peter; Eriksson, Nicholas; Esko, Tõnu; Eriksson, Joel; Falahi, Fahimeh; Felix, Janine F.; Fontana, Mark Alan; Franke, Lude; Gandin, Ilaria; Gaskins, Audrey J.; Gieger, Christian; Gunderson, Erica P.; Guo, Xiuqing; Hayward, Caroline; He, Chunyan; Hofer, Edith; Huang, Hongyan; Joshi, Peter K.; Kanoni, Stavroula; Karlsson, Robert; Kiechl, Stefan; Kifley, Annette; Kluttig, Alexander; Kraft, Peter; Lagou, Vasiliki; Lecoeur, Cecile; Lahti, Jari; Li-Gao, Ruifang; Lind, Penelope A.; Liu, Tian; Makalic, Enes; Mamasoula, Crysovalanto; Matteson, Lindsay; Mbarek, Hamdi; McArdle, Patrick F.; McMahon, George; Meddens, S. Fleur W.; Mihailov, Evelin; Miller, Mike; Missmer, Stacey A.; Monnereau, Claire; van der Most, Peter J.; Myhre, Ronny; Nalls, Mike A.; Nutile, Teresa; Panagiota, Kalafati Ioanna; Porcu, Eleonora; Prokopenko, Inga; Rajan, Kumar B.; Rich-Edwards, Janet; Rietveld, Cornelius A.; Robino, Antonietta; Rose, Lynda M.; Rueedi, Rico; Ryan, Kathy; Saba, Yasaman; Schmidt, Daniel; Smith, Jennifer A.; Stolk, Lisette; Streeten, Elizabeth; Tonjes, Anke; Thorleifsson, Gudmar; Ulivi, Sheila; Wedenoja, Juho; Wellmann, Juergen; Willeit, Peter; Yao, Jie; Yengo, Loic; Zhao, Jing Hua; Zhao, Wei; Zhernakova, Daria V.; Amin, Najaf; Andrews, Howard; Balkau, Beverley; Barzilai, Nir; Bergmann, Sven; Biino, Ginevra; Bisgaard, Hans; Bønnelykke, Klaus; Boomsma, Dorret I.; Buring, Julie E.; Campbell, Harry; Cappellani, Stefania; Ciullo, Marina; Cox, Simon R.; Cucca, Francesco; Daniela, Toniolo; Davey-Smith, George; Deary, Ian J.; Dedoussis, George; Deloukas, Panos; van Duijn, Cornelia M.; de Geus, Eco JC.; Eriksson, Johan G.; Evans, Denis A.; Faul, Jessica D.; Felicita, Sala Cinzia; Froguel, Philippe; Gasparini, Paolo; Girotto, Giorgia; Grabe, Hans-Jörgen; Greiser, Karin Halina; Groenen, Patrick J.F.; de Haan, Hugoline G.; Haerting, Johannes; Harris, Tamara B.; Heath, Andrew C.; Heikkilä, Kauko; Hofman, Albert; Homuth, Georg; Holliday, Elizabeth G; Hopper, John; Hypponen, Elina; Jacobsson, Bo; Jaddoe, Vincent W. V.; Johannesson, Magnus; Jugessur, Astanand; Kähönen, Mika; Kajantie, Eero; Kardia, Sharon L.R.; Keavney, Bernard; Kolcic, Ivana; Koponen, Päivikki; Kovacs, Peter; Kronenberg, Florian; Kutalik, Zoltan; La Bianca, Martina; Lachance, Genevieve; Iacono, William; Lai, Sandra; Lehtimäki, Terho; Liewald, David C; Lindgren, Cecilia; Liu, Yongmei; Luben, Robert; Lucht, Michael; Luoto, Riitta; Magnus, Per; Magnusson, Patrik K.E.; Martin, Nicholas G.; McGue, Matt; McQuillan, Ruth; Medland, Sarah E.; Meisinger, Christa; Mellström, Dan; Metspalu, Andres; Michela, Traglia; Milani, Lili; Mitchell, Paul; Montgomery, Grant W.; Mook-Kanamori, Dennis; de Mutsert, Renée; Nohr, Ellen A; Ohlsson, Claes; Olsen, Jørn; Ong, Ken K.; Paternoster, Lavinia; Pattie, Alison; Penninx, Brenda WJH; Perola, Markus; Peyser, Patricia A.; Pirastu, Mario; Polasek, Ozren; Power, Chris; Kaprio, Jaakko; Raffel, Leslie J.; Räikkönen, Katri; Raitakari, Olli; Ridker, Paul M.; Ring, Susan M.; Roll, Kathryn; Rudan, Igor; Ruggiero, Daniela; Rujescu, Dan; Salomaa, Veikko; Schlessinger, David; Schmidt, Helena; Schmidt, Reinhold; Schupf, Nicole; Smit, Johannes; Sorice, Rossella; Spector, Tim D.; Starr, John M.; Stöckl, Doris; Strauch, Konstantin; Stumvoll, Michael; Swertz, Morris A.; Thorsteinsdottir, Unnur; Thurik, A. Roy; Timpson, Nicholas J.; Tönjes, Anke; Tung, Joyce Y.; Uitterlinden, André G.; Vaccargiu, Simona; Viikari, Jorma; Vitart, Veronique; Völzke, Henry; Vollenweider, Peter; Vuckovic, Dragana; Waage, Johannes; Wagner, Gert G.; Wang, Jie Jin; Wareham, Nicholas J.; Weir, David R.; Willemsen, Gonneke; Willeit, Johann; Wright, Alan F.; Zondervan, Krina T.; Stefansson, Kari; Krueger, Robert F.; Lee, James J.; Benjamin, Daniel J.; Cesarini, David; Koellinger, Philipp D.; den Hoed, Marcel; Snieder, Harold; Mills, Melinda C.

    2017-01-01

    The genetic architecture of human reproductive behavior – age at first birth (AFB) and number of children ever born (NEB) – has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified and the underlying mechanisms of AFB and NEB are poorly understood. We report the largest genome-wide association study to date of both sexes including 251,151 individuals for AFB and 343,072 for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study, and four additional loci in a gene-based effort. These loci harbor genes that are likely to play a role – either directly or by affecting non-local gene expression – in human reproduction and infertility, thereby increasing our understanding of these complex traits. PMID:27798627

  2. A genome-wide association study of social genetic effects in Landrace pigs.

    Science.gov (United States)

    Hong, Joon Ki; Jeong, Yong Dae; Cho, Eun Seok; Choi, Tae Jeong; Kim, Yong Min; Cho, Kyu Ho; Lee, Jae Bong; Lim, Hyun Tae; Lee, Deuk Hwan

    2018-06-01

    The genetic effects of an individual on the phenotypes of its social partners, such as its pen mates, are known as social genetic effects. This study aims to identify the candidate genes for social (pen-mates') average daily gain (ADG) in pigs by using the genome-wide association approach. Social ADG (sADG) was the average ADG of unrelated pen-mates (strangers). We used the phenotype data (16,802 records) after correcting for batch (week), sex, pen, number of strangers (1 to 7 pigs) in the pen, full-sib rate (0% to 80%) within pen, and age at the end of the test. A total of 1,041 pigs from Landrace breeds were genotyped using the Illumina PorcineSNP60 v2 BeadChip panel, which comprised 61,565 single nucleotide polymorphism (SNP) markers. After quality control, 909 individuals and 39,837 markers remained for sADG in genome-wide association study. We detected five new SNPs, all on chromosome 6, which have not been associated with social ADG or other growth traits to date. One SNP was inside the prostaglandin F2α receptor ( PTGFR ) gene, another SNP was located 22 kb upstream of gene interferon-induced protein 44 ( IFI44 ), and the last three SNPs were between 161 kb and 191 kb upstream of the EGF latrophilin and seven transmembrane domain-containing protein 1 ( ELTD1 ) gene. PTGFR, IFI44, and ELTD1 were never associated with social interaction and social genetic effects in any of the previous studies. The identification of several genomic regions, and candidate genes associated with social genetic effects reported here, could contribute to a better understanding of the genetic basis of interaction traits for ADG. In conclusion, we suggest that the PTGFR, IFI44, and ELTD1 may be used as a molecular marker for sADG, although their functional effect was not defined yet. Thus, it will be of interest to execute association studies in those genes.

  3. Genome-wide analysis reveals novel regulators of growth in Drosophila melanogaster

    OpenAIRE

    Vonesch, Sibylle; Mackay, Trudy; Lamparter, David; Hafen, Ernst; Bergmann, Sven

    2015-01-01

    Organismal size depends on the interplay between genetic and environmental factors. Genome-wide association (GWA) analyses in humans have implied many genes in the control of height but suffer from the inability to control the environment. Genetic analyses in Drosophila have identified conserved signaling pathways controlling size; however, how these pathways control phenotypic diversity is unclear. We performed GWA of size traits using the Drosophila Genetic Reference Panel of inbred, sequen...

  4. Protein Interaction-Based Genome-Wide Analysis of Incident Coronary Heart Disease

    DEFF Research Database (Denmark)

    Jensen, Majken Karoline; Pers, Tune Hannes; Dworzynski, Piotr

    2011-01-01

    in genes associated with risk of coronary heart disease (CHD). Methods and Results-Genome-wide association analyses of approximately approximate to 700 000 single-nucleotide polymorphisms in 899 incident CHD cases and 1823 age-and sex-matched controls within the Nurses' Health and the Health Professionals...... complex. Conclusions-The integration of a GWA study with PPI data successfully identifies a set of candidate susceptibility genes for incident CHD that would have been missed in single-marker GWA analysis. (Circ Cardiovasc Genet. 2011; 4:549-556.)...

  5. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits

    DEFF Research Database (Denmark)

    Speliotes, Elizabeth K; Yerges-Armstrong, Laura M; Wu, Jun

    2011-01-01

    steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (~26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n¿=¿880 to 3,070). By carrying out a fixed-effects meta......-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ~2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome......Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic...

  6. Gene ontology analysis of pairwise genetic associations in two genome-wide studies of sporadic ALS

    Directory of Open Access Journals (Sweden)

    Kim Nora

    2012-07-01

    Full Text Available Abstract Background It is increasingly clear that common human diseases have a complex genetic architecture characterized by both additive and nonadditive genetic effects. The goal of the present study was to determine whether patterns of both additive and nonadditive genetic associations aggregate in specific functional groups as defined by the Gene Ontology (GO. Results We first estimated all pairwise additive and nonadditive genetic effects using the multifactor dimensionality reduction (MDR method that makes few assumptions about the underlying genetic model. Statistical significance was evaluated using permutation testing in two genome-wide association studies of ALS. The detection data consisted of 276 subjects with ALS and 271 healthy controls while the replication data consisted of 221 subjects with ALS and 211 healthy controls. Both studies included genotypes from approximately 550,000 single-nucleotide polymorphisms (SNPs. Each SNP was mapped to a gene if it was within 500 kb of the start or end. Each SNP was assigned a p-value based on its strongest joint effect with the other SNPs. We then used the Exploratory Visual Analysis (EVA method and software to assign a p-value to each gene based on the overabundance of significant SNPs at the α = 0.05 level in the gene. We also used EVA to assign p-values to each GO group based on the overabundance of significant genes at the α = 0.05 level. A GO category was determined to replicate if that category was significant at the α = 0.05 level in both studies. We found two GO categories that replicated in both studies. The first, ‘Regulation of Cellular Component Organization and Biogenesis’, a GO Biological Process, had p-values of 0.010 and 0.014 in the detection and replication studies, respectively. The second, ‘Actin Cytoskeleton’, a GO Cellular Component, had p-values of 0.040 and 0.046 in the detection and replication studies, respectively. Conclusions Pathway

  7. Genome-Wide Gene Set Analysis for Identification of Pathways Associated with Alcohol Dependence

    Science.gov (United States)

    Biernacka, Joanna M.; Geske, Jennifer; Jenkins, Gregory D.; Colby, Colin; Rider, David N.; Karpyak, Victor M.; Choi, Doo-Sup; Fridley, Brooke L.

    2013-01-01

    It is believed that multiple genetic variants with small individual effects contribute to the risk of alcohol dependence. Such polygenic effects are difficult to detect in genome-wide association studies that test for association of the phenotype with each single nucleotide polymorphism (SNP) individually. To overcome this challenge, gene set analysis (GSA) methods that jointly test for the effects of pre-defined groups of genes have been proposed. Rather than testing for association between the phenotype and individual SNPs, these analyses evaluate the global evidence of association with a set of related genes enabling the identification of cellular or molecular pathways or biological processes that play a role in development of the disease. It is hoped that by aggregating the evidence of association for all available SNPs in a group of related genes, these approaches will have enhanced power to detect genetic associations with complex traits. We performed GSA using data from a genome-wide study of 1165 alcohol dependent cases and 1379 controls from the Study of Addiction: Genetics and Environment (SAGE), for all 200 pathways listed in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results demonstrated a potential role of the “Synthesis and Degradation of Ketone Bodies” pathway. Our results also support the potential involvement of the “Neuroactive Ligand Receptor Interaction” pathway, which has previously been implicated in addictive disorders. These findings demonstrate the utility of GSA in the study of complex disease, and suggest specific directions for further research into the genetic architecture of alcohol dependence. PMID:22717047

  8. Genome-wide association genetics of an adaptive trait in lodgepole pine.

    Science.gov (United States)

    Parchman, Thomas L; Gompert, Zachariah; Mudge, Joann; Schilkey, Faye D; Benkman, Craig W; Buerkle, C Alex

    2012-06-01

    Pine cones that remain closed and retain seeds until fire causes the cones to open (cone serotiny) represent a key adaptive trait in a variety of pine species. In lodgepole pine, there is substantial geographical variation in serotiny across the Rocky Mountain region. This variation in serotiny has evolved as a result of geographically divergent selection, with consequences that extend to forest communities and ecosystems. An understanding of the genetic architecture of this trait is of interest owing to the wide-reaching ecological consequences of serotiny and also because of the repeated evolution of the trait across the genus. Here, we present and utilize an inexpensive and time-effective method for generating population genomic data. The method uses restriction enzymes and PCR amplification to generate a library of fragments that can be sequenced with a high level of multiplexing. We obtained data for more than 95,000 single nucleotide polymorphisms across 98 serotinous and nonserotinous lodgepole pines from three populations. We used a Bayesian generalized linear model (GLM) to test for an association between genotypic variation at these loci and serotiny. The probability of serotiny varied by genotype at 11 loci, and the association between genotype and serotiny at these loci was consistent in each of the three populations of pines. Genetic variation across these 11 loci explained 50% of the phenotypic variation in serotiny. Our results provide a first genome-wide association map of serotiny in pines and demonstrate an inexpensive and efficient method for generating population genomic data. © 2012 Blackwell Publishing Ltd.

  9. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

    NARCIS (Netherlands)

    A. Okbay (Aysu); Baselmans, B.M.L. (Bart M.L.); J.E. de Neve (Jan-Emmanuel); P. Turley (Patrick); M. Nivard (Michel); Fontana, M.A. (Mark Alan); Meddens, S.F.W. (S. Fleur W.); Linnér, R.K. (Richard Karlsson); Rietveld, C.A. (Cornelius A); J. Derringer; J. Gratten (Jacob); J.J. Lee (James J.); Liu, J.Z. (Jimmy Z); R. de Vlaming (Ronald); SAhluwalia, T. (Tarunveer); Buchwald, J. (Jadwiga); A. Cavadino (Alana); A.C. Frazier-Wood (Alexis C.); Furlotte, N.A. (Nicholas A); Garfield, V. (Victoria); Geisel, M.H. (Marie Henrike); J.R. Gonzalez (Juan R.); Haitjema, S. (Saskia); R. Karlsson (Robert); Der Laan, S.W. (Sander Wvan); K.-H. Ladwig (Karl-Heinz); J. Lahti (Jari); S.J. van der Lee (Sven); P.A. Lind (Penelope); Liu, T. (Tian); Matteson, L. (Lindsay); E. Mihailov (Evelin); M. Miller (Mike); CMinica, C. (Camelia); MNolte, I. (Ilja); D.O. Mook-Kanamori (Dennis); P.J. van der Most (Peter); C. Oldmeadow (Christopher); Y. Qian (Yong); O. Raitakari (Olli); R. Rawal (R.); A. Realo; Rueedi, R. (Rico); Schmidt, B. (Börge); A.V. Smith (Albert Vernon); E. Stergiakouli (Evangelia); T. Tanaka (Toshiko); K.D. Taylor (Kent); Wedenoja, J. (Juho); Wellmann, J. (Juergen); H.J. Westra (Harm-Jan); MWillems, S. (Sara); Zhao, W. (Wei); L.C. Study (LifeLines Cohort); N. Amin (Najaf); Bakshi, A. (Andrew); P.A. Boyle (Patricia); Cherney, S. (Samantha); Cox, S.R. (Simon R); G. Davies (Gail); O.S.P. Davis (Oliver S.); J. Ding (Jun); N. Direk (Nese); Eibich, P. (Peter); R. Emeny (Rebecca); Fatemifar, G. (Ghazaleh); J.D. Faul; L. Ferrucci (Luigi); A.J. Forstner (Andreas); C. Gieger (Christian); Gupta, R. (Richa); T.B. Harris (Tamara); J.M. Harris (Juliette); E.G. Holliday (Elizabeth); J.J. Hottenga (Jouke Jan); P.L. de Jager (Philip); M. Kaakinen (Marika); E. Kajantie (Eero); Karhunen, V. (Ville); I. Kolcic (Ivana); M. Kumari (Meena); L.J. Launer (Lenore); L. Franke (Lude); Li-Gao, R. (Ruifang); Koini, M. (Marisa); A. Loukola (Anu); P. Marques-Vidal; G.W. Montgomery (Grant); M. Mosing (Miriam); L. Paternoster (Lavinia); A. Pattie (Alison); K. Petrovic (Katja); Pulkki-R'back, L. (Laura); L. Quaye (Lydia); R'ikkönen, K. (Katri); I. Rudan (Igor); R. Scott (Rodney); J.A. Smith (Jennifer A); A.R. Sutin; Trzaskowski, M. (Maciej); Vinkhuyze, A.E. (Anna E.); L. Yu (Lei); D. Zabaneh (Delilah); J. Attia (John); D.A. Bennett (David A.); Berger, K. (Klaus); L. Bertram (Lars); D.I. Boomsma (Dorret); H. Snieder (Harold); Chang, S.-C. (Shun-Chiao); F. Cucca (Francesco); I.J. Deary (Ian J.); C.M. van Duijn (Cornelia); K. Hagen (Knut); U. Bültmann (Ute); E.J.C. de Geus (Eco); P.J.F. Groenen (Patrick); V. Gudnason (Vilmundur); T. Hansen (T.); Hartman, C.A. (Catharine A); C.M.A. Haworth (Claire M.); C. Hayward (Caroline); A.C. Heath (Andrew C.); D.A. Hinds (David A.); E. Hypponen (Elina); W.G. Iacono (William); M.-R. Jarvelin (Marjo-Riitta); K.-H. JöCkel (Karl-Heinz); J. Kaprio (Jaakko); S.L.R. Kardia (Sharon); Keltikangas-J'rvinen, L. (Liisa); P. Kraft (Peter); Kubzansky, L.D. (Laura D.); Lehtim'ki, T. (Terho); P.K. Magnusson (Patrik); N.G. Martin (Nicholas); M. McGue (Matt); A. Metspalu (Andres); M. Mills (Melinda); R. de Mutsert (Reneé); A.J. Oldehinkel (Albertine); G. Pasterkamp (Gerard); N.L. Pedersen (Nancy); R. Plomin (Robert); O. Polasek (Ozren); C. Power (Christopher); S.S. Rich (Stephen); F.R. Rosendaal (Frits); H.M. den Ruijter (Hester ); Schlessinger, D. (David); R. Schmidt (Reinhold); R. Svento (Rauli); R. Schmidt (Reinhold); B.Z. Alizadeh (Behrooz); T.I.A. Sørensen (Thorkild); DSpector, T. (Tim); Steptoe, A. (Andrew); A. Terracciano; A.R. Thurik (Roy); N.J. Timpson (Nicholas); H.W. Tiemeier (Henning); A.G. Uitterlinden (André); P. Vollenweider (Peter); Wagner, G.G. (Gert G.); D.R. Weir (David); J. Yang (Joanna); Conley, D.C. (Dalton C.); G.D. Smith; Hofman, A. (Albert); M. Johannesson (Magnus); D. Laibson (David); S.E. Medland (Sarah Elizabeth); M.N. Meyer (Michelle N.); Pickrell, J.K. (Joseph K.); Esko, T. (T'nu); R.F. Krueger; J.P. Beauchamp (Jonathan); Ph.D. Koellinger (Philipp); D.J. Benjamin (Daniel J.); M. Bartels (Meike); D. Cesarini (David)

    2016-01-01

    textabstractVery few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data.

  10. Genome-Wide Meta-Analysis of Longitudinal Alcohol Consumption Across Youth and Early Adulthood.

    Science.gov (United States)

    Adkins, Daniel E; Clark, Shaunna L; Copeland, William E; Kennedy, Martin; Conway, Kevin; Angold, Adrian; Maes, Hermine; Liu, Youfang; Kumar, Gaurav; Erkanli, Alaattin; Patkar, Ashwin A; Silberg, Judy; Brown, Tyson H; Fergusson, David M; Horwood, L John; Eaves, Lindon; van den Oord, Edwin J C G; Sullivan, Patrick F; Costello, E J

    2015-08-01

    The public health burden of alcohol is unevenly distributed across the life course, with levels of use, abuse, and dependence increasing across adolescence and peaking in early adulthood. Here, we leverage this temporal patterning to search for common genetic variants predicting developmental trajectories of alcohol consumption. Comparable psychiatric evaluations measuring alcohol consumption were collected in three longitudinal community samples (N=2,126, obs=12,166). Consumption-repeated measurements spanning adolescence and early adulthood were analyzed using linear mixed models, estimating individual consumption trajectories, which were then tested for association with Illumina 660W-Quad genotype data (866,099 SNPs after imputation and QC). Association results were combined across samples using standard meta-analysis methods. Four meta-analysis associations satisfied our pre-determined genome-wide significance criterion (FDR<0.1) and six others met our 'suggestive' criterion (FDR<0.2). Genome-wide significant associations were highly biological plausible, including associations within GABA transporter 1, SLC6A1 (solute carrier family 6, member 1), and exonic hits in LOC100129340 (mitofusin-1-like). Pathway analyses elaborated single marker results, indicating significant enriched associations to intuitive biological mechanisms, including neurotransmission, xenobiotic pharmacodynamics, and nuclear hormone receptors (NHR). These findings underscore the value of combining longitudinal behavioral data and genome-wide genotype information in order to study developmental patterns and improve statistical power in genomic studies.

  11. Genome-Wide Association Analysis Reveals Genetic Heterogeneity of Sjögren's Syndrome According to Ancestry

    DEFF Research Database (Denmark)

    Taylor, Kimberly E; Wong, Quenna; Levine, David M

    2017-01-01

    common protocol-directed methods. The aim of this study was to examine the genetic etiology of Sjögren's syndrome (SS) across ancestry and disease subsets. METHODS: We performed genome-wide association study analyses using SICCA subjects and external controls obtained from dbGaP data sets, one using all......OBJECTIVE: The Sjögren's International Collaborative Clinical Alliance (SICCA) is an international data registry and biorepository derived from a multisite observational study of participants in whom genotyping was performed on the Omni2.5M platform and who had undergone deep phenotyping using...... subphenotype distributions differ by ethnicity, and whether this contributes to the heterogeneity of genetic associations. RESULTS: We observed significant associations in established regions of the major histocompatibility complex (MHC), IRF5, and STAT4 (P = 3 × 10(-42) , P = 3 × 10(-14) , and P = 9 × 10...

  12. Connecting the dots, genome-wide association studies in substance use

    NARCIS (Netherlands)

    Nivard, M.G.; Verweij, K.J.H.; Minica, C.C.; Treur, J.L.; Vink, J.M.; Boomsma, D.I.

    2016-01-01

    The recent genome-wide association (GWA) meta-analysis of lifetime cannabis use by the International Cannabis Consortium marks a milestone in the study of the genetics of cannabis use. Similar milestones for the genetics of substance use were the GWA meta-analyses of four smoking related traits, of

  13. Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis

    KAUST Repository

    Coll, Francesc; Phelan, Jody; Hill-Cawthorne, Grant A.; Nair, Mridul; Mallard, Kim; Ali, Shahjahan; Abdallah, Abdallah; Alghamdi, Saad; Alsomali, Mona; Ahmed, Abdallah O.; Portelli, Stephanie; Oppong, Yaa; Alves, Adriana; Bessa, Theolis Barbosa; Campino, Susana; Caws, Maxine; Chatterjee, Anirvan; Crampin, Amelia C.; Dheda, Keertan; Furnham, Nicholas; Glynn, Judith R.; Grandjean, Louis; Minh Ha, Dang; Hasan, Rumina; Hasan, Zahra; Hibberd, Martin L.; Joloba, Moses; Jones-Ló pez, Edward C.; Matsumoto, Tomoshige; Miranda, Anabela; Moore, David J.; Mocillo, Nora; Panaiotov, Stefan; Parkhill, Julian; Penha, Carlos; Perdigã o, Joã o; Portugal, Isabel; Rchiad, ‍ Zineb; Robledo, Jaime; Sheen, Patricia; Shesha, Nashwa Talaat; Sirgel, Frik A.; Sola, Christophe; Oliveira Sousa, Erivelton; Streicher, Elizabeth M.; Helden, Paul Van; Viveiros, Miguel; Warren, Robert M.; McNerney, Ruth; Pain, Arnab; Clark, Taane G.

    2018-01-01

    To characterize the genetic determinants of resistance to antituberculosis drugs, we performed a genome-wide association study (GWAS) of 6,465 Mycobacterium tuberculosis clinical isolates from more than 30 countries. A GWAS approach within a mixed

  14. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

    NARCIS (Netherlands)

    Okbay, Aysu; Baselmans, Bart M L; De Neve, Jan-Emmanuel; Turley, Patrick; Nivard, Michel G; Fontana, Mark Alan; Meddens, S Fleur W; Linnér, Richard Karlsson; Rietveld, Cornelius A; Derringer, Jaime; Gratten, Jacob; Lee, James J; Liu, Jimmy Z; de Vlaming, Ronald; Ahluwalia, Tarunveer S; Buchwald, Jadwiga; Cavadino, Alana; Frazier-Wood, Alexis C; Furlotte, Nicholas A; Garfield, Victoria; Geisel, Marie Henrike; Gonzalez, Juan R; Haitjema, Saskia; Karlsson, Robert; van der Laan, Sander W; Ladwig, Karl-Heinz; Lahti, Jari; van der Lee, Sven J; Lind, Penelope A; Liu, Tian; Matteson, Lindsay; Mihailov, Evelin; Miller, Michael B; Minica, Camelia C; Nolte, Ilja M; Mook-Kanamori, Dennis; van der Most, Peter J; Oldmeadow, Christopher; Qian, Yong; Raitakari, Olli; Rawal, Rajesh; Realo, Anu; Rueedi, Rico; Schmidt, Börge; Smith, Albert V; Stergiakouli, Evie; Tanaka, Toshiko; Taylor, Kent; Wedenoja, Juho; Wellmann, Juergen; Westra, Harm-Jan; Willems, Sara M; Zhao, Wei; Amin, Najaf; Bakshi, Andrew; Boyle, Patricia A; Cherney, Samantha; Cox, Simon R; Davies, Gail; Davis, Oliver S P; Ding, Jun; Direk, Nese; Eibich, Peter; Emeny, Rebecca T; Fatemifar, Ghazaleh; Faul, Jessica D; Ferrucci, Luigi; Forstner, Andreas; Gieger, Christian; Gupta, Richa; Harris, Tamara B; Harris, Juliette M; Holliday, Elizabeth G; Hottenga, Jouke-Jan; De Jager, Philip L; Kaakinen, Marika A; Kajantie, Eero; Karhunen, Ville; Kolcic, Ivana; Kumari, Meena; Launer, Lenore J; Franke, Lude; Li-Gao, Ruifang; Koini, Marisa; Loukola, Anu; Marques-Vidal, Pedro; Montgomery, Grant W; Mosing, Miriam A; Paternoster, Lavinia; Pattie, Alison; Petrovic, Katja E; Pulkki-Råback, Laura; Quaye, Lydia; Räikkönen, Katri; Rudan, Igor; Scott, Rodney J; Smith, Jennifer A; Sutin, Angelina R; Trzaskowski, Maciej; Vinkhuyzen, Anna E; Yu, Lei; Zabaneh, Delilah; Attia, John R; Bennett, David A; Berger, Klaus; Bertram, Lars; Boomsma, Dorret I; Snieder, Harold; Chang, Shun-Chiao; Cucca, Francesco; Deary, Ian J; van Duijn, Cornelia M; Eriksson, Johan G; Bültmann, Ute; de Geus, Eco J C; Groenen, Patrick J F; Gudnason, Vilmundur; Hansen, Torben; Hartman, Catharine A; Haworth, Claire M A; Hayward, Caroline; Heath, Andrew C; Hinds, David A; Hyppönen, Elina; Iacono, William G; Järvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L R; Keltikangas-Järvinen, Liisa; Kraft, Peter; Kubzansky, Laura D; Lehtimäki, Terho; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; Metspalu, Andres; Mills, Melinda; de Mutsert, Renée; Oldehinkel, Albertine J; Pasterkamp, Gerard; Pedersen, Nancy L; Plomin, Robert; Polasek, Ozren; Power, Christine; Rich, Stephen S; Rosendaal, Frits R; den Ruijter, Hester M; Schlessinger, David; Schmidt, Helena; Svento, Rauli; Schmidt, Reinhold; Alizadeh, Behrooz Z; Sørensen, Thorkild I A; Spector, Tim D; Steptoe, Andrew; Terracciano, Antonio; Thurik, A Roy; Timpson, Nicholas J; Tiemeier, Henning; Uitterlinden, André G; Vollenweider, Peter; Wagner, Gert G; Weir, David R; Yang, Jian; Conley, Dalton C; Smith, George Davey; Hofman, Albert; Johannesson, Magnus; Laibson, David I; Medland, Sarah E; Meyer, Michelle N; Pickrell, Joseph K; Esko, Tõnu; Krueger, Robert F; Beauchamp, Jonathan P; Koellinger, Philipp D; Benjamin, Daniel J; Bartels, Meike; Cesarini, David

    Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted

  15. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses.

    NARCIS (Netherlands)

    Okbay, A.; Baselmans, B.M.L.; de Neve, J.E.; Turley, P.; Nivard, M.G.; Fontana, M.A.; Meddens, S.F.W.; Karlsson Linnér, R.; Rietveld, C.A.; Derringer, J.; de Vlaming, R.; Minica, C.C.; Hottenga, J.J.; Vinkhuyzen, A.A.E.; Boomsma, D.I.; de Geus, E.J.C.; Medland, S.E.; Meyer, M.N.; Pickrell, J.K.; Esko, T.; Krueger, R.F.; Beauchamp, J.; Koellinger, P.D.; Benjamin, D.J.; Bartels, M.; Cesarini, D.

    2016-01-01

    Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted

  16. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process

    NARCIS (Netherlands)

    Springelkamp, Henriët; Höhn, René; Mishra, Aniket; Hysi, Pirro G; Khor, Chiea-Chuen; Loomis, Stephanie J; Bailey, Jessica N Cooke; Gibson, Jane; Thorleifsson, Gudmar; Janssen, Sarah F; Luo, Xiaoyan; Ramdas, Wishal D; Vithana, Eranga; Nongpiur, Monisha E; Montgomery, Grant W; Xu, Liang; Mountain, Jenny E; Gharahkhani, Puya; Lu, Yi; Amin, Najaf; Karssen, Lennart C; Sim, Kar-Seng; van Leeuwen, Elisabeth M; Iglesias, Adriana I; Verhoeven, Virginie J M; Hauser, Michael A; Loon, Seng-Chee; Despriet, Dominiek D G; Nag, Abhishek; Venturini, Cristina; Sanfilippo, Paul G; Schillert, Arne; Kang, Jae H; Landers, John; Jonasson, Fridbert; Cree, Angela J; van Koolwijk, Leonieke M E; Rivadeneira, Fernando; Souzeau, Emmanuelle; Jonsson, Vesteinn; Menon, Geeta; Weinreb, Robert N; de Jong, Paulus T V M; Oostra, Ben A; Uitterlinden, André G; Hofman, Albert; Ennis, Sarah; Thorsteinsdottir, Unnur; Burdon, Kathryn P; Spector, Timothy D; Mirshahi, Alireza; Saw, Seang-Mei; Vingerling, Johannes R; Teo, Yik-Ying; Haines, Jonathan L; Wolfs, Roger C W; Lemij, Hans G; Tai, E-Shyong; Jansonius, Nomdo M; Jonas, Jost B; Cheng, Ching-Yu; Aung, Tin; Viswanathan, Ananth C; Klaver, Caroline C W; Craig, Jamie E; Macgregor, Stuart; Mackey, David A; Lotery, Andrew J; Stefansson, Kari; Bergen, Arthur A B; Young, Terri L; Wiggs, Janey L; Pfeiffer, Norbert; Wong, Tien-Yin; Pasquale, Louis R; Hewitt, Alex W; van Duijn, Cornelia M; Hammond, Christopher J

    2014-01-01

    Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important

  17. Genome-wide association study of swine farrowing traits. Part I: genetic and genomic parameter estimates.

    Science.gov (United States)

    Schneider, J F; Rempel, L A; Rohrer, G A

    2012-10-01

    The primary objective of this study was to determine genetic and genomic parameters among swine (Sus scrofa) farrowing traits. Genetic parameters were obtained using MTDFREML. Genomic parameters were obtained using GENSEL. Genetic and residual variances obtained from MTDFREML were used as priors for the Bayes C analysis of GENSEL. Farrowing traits included total number born (TNB), number born alive (NBA), number born dead (NBD), number stillborn (NSB), number of mummies (MUM), litter birth weight (LBW), and average piglet birth weight (ABW). Statistically significant heritabilities included TNB (0.09, P = 0.048), NBA (0.09, P = 0.041), LBW (0.20, P = 0.002), and ABW (0.26, P NBA (0.97, P NBA-LBW (0.56, P NBA (0.06), NBD (0.00), NSB (0.01), MUM (0.00), LBW (0.11), and ABW (0.31). Limited information is available in the literature about genomic parameters. Only the GP estimate for NSB is significantly lower than what has been published. The GP estimate for ABW is greater than the estimate for heritability found in this study. Other traits with significant heritability had GP estimates half the value of heritability. This research indicates that significant genetic markers will be found for TNB, NBA, LBW, and ABW that will have either immediate use in industry or provide a roadmap to further research with fine mapping or sequencing of areas of significance. Furthermore, these results indicate that genomic selection implemented at an early age would have similar annual progress as traditional selection, and could be incorporated along with traditional selection procedures to improve genetic progress of litter traits.

  18. Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

    Science.gov (United States)

    Moayyeri, Alireza; Hsu, Yi-Hsiang; Karasik, David; Estrada, Karol; Xiao, Su-Mei; Nielson, Carrie; Srikanth, Priya; Giroux, Sylvie; Wilson, Scott G.; Zheng, Hou-Feng; Smith, Albert V.; Pye, Stephen R.; Leo, Paul J.; Teumer, Alexander; Hwang, Joo-Yeon; Ohlsson, Claes; McGuigan, Fiona; Minster, Ryan L.; Hayward, Caroline; Olmos, José M.; Lyytikäinen, Leo-Pekka; Lewis, Joshua R.; Swart, Karin M.A.; Masi, Laura; Oldmeadow, Chris; Holliday, Elizabeth G.; Cheng, Sulin; van Schoor, Natasja M.; Harvey, Nicholas C.; Kruk, Marcin; del Greco M, Fabiola; Igl, Wilmar; Trummer, Olivia; Grigoriou, Efi; Luben, Robert; Liu, Ching-Ti; Zhou, Yanhua; Oei, Ling; Medina-Gomez, Carolina; Zmuda, Joseph; Tranah, Greg; Brown, Suzanne J.; Williams, Frances M.; Soranzo, Nicole; Jakobsdottir, Johanna; Siggeirsdottir, Kristin; Holliday, Kate L.; Hannemann, Anke; Go, Min Jin; Garcia, Melissa; Polasek, Ozren; Laaksonen, Marika; Zhu, Kun; Enneman, Anke W.; McEvoy, Mark; Peel, Roseanne; Sham, Pak Chung; Jaworski, Maciej; Johansson, Åsa; Hicks, Andrew A.; Pludowski, Pawel; Scott, Rodney; Dhonukshe-Rutten, Rosalie A.M.; van der Velde, Nathalie; Kähönen, Mika; Viikari, Jorma S.; Sievänen, Harri; Raitakari, Olli T.; González-Macías, Jesús; Hernández, Jose L.; Mellström, Dan; Ljunggren, Östen; Cho, Yoon Shin; Völker, Uwe; Nauck, Matthias; Homuth, Georg; Völzke, Henry; Haring, Robin; Brown, Matthew A.; McCloskey, Eugene; Nicholson, Geoffrey C.; Eastell, Richard; Eisman, John A.; Jones, Graeme; Reid, Ian R.; Dennison, Elaine M.; Wark, John; Boonen, Steven; Vanderschueren, Dirk; Wu, Frederick C.W.; Aspelund, Thor; Richards, J. Brent; Bauer, Doug; Hofman, Albert; Khaw, Kay-Tee; Dedoussis, George; Obermayer-Pietsch, Barbara; Gyllensten, Ulf; Pramstaller, Peter P.; Lorenc, Roman S.; Cooper, Cyrus; Kung, Annie Wai Chee; Lips, Paul; Alen, Markku; Attia, John; Brandi, Maria Luisa; de Groot, Lisette C.P.G.M.; Lehtimäki, Terho; Riancho, José A.; Campbell, Harry; Liu, Yongmei; Harris, Tamara B.; Akesson, Kristina; Karlsson, Magnus; Lee, Jong-Young; Wallaschofski, Henri; Duncan, Emma L.; O'Neill, Terence W.; Gudnason, Vilmundur; Spector, Timothy D.; Rousseau, François; Orwoll, Eric; Cummings, Steven R.; Wareham, Nick J.; Rivadeneira, Fernando; Uitterlinden, Andre G.; Prince, Richard L.; Kiel, Douglas P.; Reeve, Jonathan; Kaptoge, Stephen K.

    2014-01-01

    Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10−8) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10−14). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10−6 also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology. PMID:24430505

  19. Genome-Wide Approaches to Drosophila Heart Development

    Directory of Open Access Journals (Sweden)

    Manfred Frasch

    2016-05-01

    Full Text Available The development of the dorsal vessel in Drosophila is one of the first systems in which key mechanisms regulating cardiogenesis have been defined in great detail at the genetic and molecular level. Due to evolutionary conservation, these findings have also provided major inputs into studies of cardiogenesis in vertebrates. Many of the major components that control Drosophila cardiogenesis were discovered based on candidate gene approaches and their functions were defined by employing the outstanding genetic tools and molecular techniques available in this system. More recently, approaches have been taken that aim to interrogate the entire genome in order to identify novel components and describe genomic features that are pertinent to the regulation of heart development. Apart from classical forward genetic screens, the availability of the thoroughly annotated Drosophila genome sequence made new genome-wide approaches possible, which include the generation of massive numbers of RNA interference (RNAi reagents that were used in forward genetic screens, as well as studies of the transcriptomes and proteomes of the developing heart under normal and experimentally manipulated conditions. Moreover, genome-wide chromatin immunoprecipitation experiments have been performed with the aim to define the full set of genomic binding sites of the major cardiogenic transcription factors, their relevant target genes, and a more complete picture of the regulatory network that drives cardiogenesis. This review will give an overview on these genome-wide approaches to Drosophila heart development and on computational analyses of the obtained information that ultimately aim to provide a description of this process at the systems level.

  20. Genome-wide genetic diversity and differentially selected regions among Suffolk, Rambouillet, Columbia, Polypay, and Targhee sheep.

    Directory of Open Access Journals (Sweden)

    Lifan Zhang

    Full Text Available Sheep are among the major economically important livestock species worldwide because the animals produce milk, wool, skin, and meat. In the present study, the Illumina OvineSNP50 BeadChip was used to investigate genetic diversity and genome selection among Suffolk, Rambouillet, Columbia, Polypay, and Targhee sheep breeds from the United States. After quality-control filtering of SNPs (single nucleotide polymorphisms, we used 48,026 SNPs, including 46,850 SNPs on autosomes that were in Hardy-Weinberg equilibrium and 1,176 SNPs on chromosome × for analysis. Phylogenetic analysis based on all 46,850 SNPs clearly separated Suffolk from Rambouillet, Columbia, Polypay, and Targhee, which was not surprising as Rambouillet contributed to the synthesis of the later three breeds. Based on pair-wise estimates of F(ST, significant genetic differentiation appeared between Suffolk and Rambouillet (F(ST = 0.1621, while Rambouillet and Targhee had the closest relationship (F(ST = 0.0681. A scan of the genome revealed 45 and 41 differentially selected regions (DSRs between Suffolk and Rambouillet and among Rambouillet-related breed populations, respectively. Our data indicated that regions 13 and 24 between Suffolk and Rambouillet might be good candidates for evaluating breed differences. Furthermore, ovine genome v3.1 assembly was used as reference to link functionally known homologous genes to economically important traits covered by these differentially selected regions. In brief, our present study provides a comprehensive genome-wide view on within- and between-breed genetic differentiation, biodiversity, and evolution among Suffolk, Rambouillet, Columbia, Polypay, and Targhee sheep breeds. These results may provide new guidance for the synthesis of new breeds with different breeding objectives.

  1. Genome-wide association analysis of young onset stroke identifies a locus on chromosome 10q25 near HABP2

    Science.gov (United States)

    Cheng, Yu-Ching; Stanne, Tara M.; Giese, Anne-Katrin; Ho, Weang Kee; Traylor, Matthew; Amouyel, Philippe; Holliday, Elizabeth G.; Malik, Rainer; Xu, Huichun; Kittner, Steven J.; Cole, John W.; O’Connell, Jeffrey R.; Danesh, John; Rasheed, Asif; Zhao, Wei; Engelter, Stefan; Grond-Ginsbach, Caspar; Kamatani, Yoichiro; Lathrop, Mark; Leys, Didier; Thijs, Vincent; Metso, Tiina M.; Tatlisumak, Turgut; Pezzini, Alessandro; Parati, Eugenio A.; Norrving, Bo; Bevan, Steve; Rothwell, Peter M; Sudlow, Cathie; Slowik, Agnieszka; Lindgren, Arne; Walters, Matthew R; Jannes, Jim; Shen, Jess; Crosslin, David; Doheny, Kimberly; Laurie, Cathy C.; Kanse, Sandip M.; Bis, Joshua C.; Fornage, Myriam; Mosley, Thomas H.; Hopewell, Jemma C.; Strauch, Konstantin; Müller-Nurasyid, Martina; Gieger, Christian; Waldenberger, Melanie; Peters, Annette; Meisinger, Christine; Ikram, M. Arfan; Longstreth, WT; Meschia, James F.; Seshadri, Sudha; Sharma, Pankaj; Worrall, Bradford; Jern, Christina; Levi, Christopher; Dichgans, Martin; Boncoraglio, Giorgio B.; Markus, Hugh S.; Debette, Stephanie; Rolfs, Arndt; Saleheen, Danish; Mitchell, Braxton D.

    2015-01-01

    Background and Purpose Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a two-stage meta-analysis of genome-wide association studies (GWAS), focusing on stroke cases with an age of onset genetic variants at loci with association Pstroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the Discovery and Follow-up Stages (rs11196288, OR=1.41, P=9.5×10−9). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that two SNPs in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2. Conclusions HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke. PMID:26732560

  2. Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2.

    Science.gov (United States)

    Cheng, Yu-Ching; Stanne, Tara M; Giese, Anne-Katrin; Ho, Weang Kee; Traylor, Matthew; Amouyel, Philippe; Holliday, Elizabeth G; Malik, Rainer; Xu, Huichun; Kittner, Steven J; Cole, John W; O'Connell, Jeffrey R; Danesh, John; Rasheed, Asif; Zhao, Wei; Engelter, Stefan; Grond-Ginsbach, Caspar; Kamatani, Yoichiro; Lathrop, Mark; Leys, Didier; Thijs, Vincent; Metso, Tiina M; Tatlisumak, Turgut; Pezzini, Alessandro; Parati, Eugenio A; Norrving, Bo; Bevan, Steve; Rothwell, Peter M; Sudlow, Cathie; Slowik, Agnieszka; Lindgren, Arne; Walters, Matthew R; Jannes, Jim; Shen, Jess; Crosslin, David; Doheny, Kimberly; Laurie, Cathy C; Kanse, Sandip M; Bis, Joshua C; Fornage, Myriam; Mosley, Thomas H; Hopewell, Jemma C; Strauch, Konstantin; Müller-Nurasyid, Martina; Gieger, Christian; Waldenberger, Melanie; Peters, Annette; Meisinger, Christine; Ikram, M Arfan; Longstreth, W T; Meschia, James F; Seshadri, Sudha; Sharma, Pankaj; Worrall, Bradford; Jern, Christina; Levi, Christopher; Dichgans, Martin; Boncoraglio, Giorgio B; Markus, Hugh S; Debette, Stephanie; Rolfs, Arndt; Saleheen, Danish; Mitchell, Braxton D

    2016-02-01

    Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset genetic variants at loci with association Pstroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2. HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke. © 2016 American Heart Association, Inc.

  3. Genome-wide association study identifies genetic loci associated with iron deficiency.

    Directory of Open Access Journals (Sweden)

    Christine E McLaren

    2011-03-01

    Full Text Available The existence of multiple inherited disorders of iron metabolism in man, rodents and other vertebrates suggests genetic contributions to iron deficiency. To identify new genomic locations associated with iron deficiency, a genome-wide association study (GWAS was performed using DNA collected from white men aged≥25 y and women≥50 y in the Hemochromatosis and Iron Overload Screening (HEIRS Study with serum ferritin (SF≤12 µg/L (cases and iron replete controls (SF>100 µg/L in men, SF>50 µg/L in women. Regression analysis was used to examine the association between case-control status (336 cases, 343 controls and quantitative serum iron measures and 331,060 single nucleotide polymorphism (SNP genotypes, with replication analyses performed in a sample of 71 cases and 161 controls from a population of white male and female veterans screened at a US Veterans Affairs (VA medical center. Five SNPs identified in the GWAS met genome-wide statistical significance for association with at least one iron measure, rs2698530 on chr. 2p14; rs3811647 on chr. 3q22, a known SNP in the transferrin (TF gene region; rs1800562 on chr. 6p22, the C282Y mutation in the HFE gene; rs7787204 on chr. 7p21; and rs987710 on chr. 22q11 (GWAS observed P<1.51×10(-7 for all. An association between total iron binding capacity and SNP rs3811647 in the TF gene (GWAS observed P=7.0×10(-9, corrected P=0.012 was replicated within the VA samples (observed P=0.012. Associations with the C282Y mutation in the HFE gene also were replicated. The joint analysis of the HEIRS and VA samples revealed strong associations between rs2698530 on chr. 2p14 and iron status outcomes. These results confirm a previously-described TF polymorphism and implicate one potential new locus as a target for gene identification.

  4. Genome-wide analytical approaches for reverse metabolic engineering of industrially relevant phenotypes in yeast

    Science.gov (United States)

    Oud, Bart; Maris, Antonius J A; Daran, Jean-Marc; Pronk, Jack T

    2012-01-01

    Successful reverse engineering of mutants that have been obtained by nontargeted strain improvement has long presented a major challenge in yeast biotechnology. This paper reviews the use of genome-wide approaches for analysis of Saccharomyces cerevisiae strains originating from evolutionary engineering or random mutagenesis. On the basis of an evaluation of the strengths and weaknesses of different methods, we conclude that for the initial identification of relevant genetic changes, whole genome sequencing is superior to other analytical techniques, such as transcriptome, metabolome, proteome, or array-based genome analysis. Key advantages of this technique over gene expression analysis include the independency of genome sequences on experimental context and the possibility to directly and precisely reproduce the identified changes in naive strains. The predictive value of genome-wide analysis of strains with industrially relevant characteristics can be further improved by classical genetics or simultaneous analysis of strains derived from parallel, independent strain improvement lineages. PMID:22152095

  5. Genome-wide analytical approaches for reverse metabolic engineering of industrially relevant phenotypes in yeast.

    Science.gov (United States)

    Oud, Bart; van Maris, Antonius J A; Daran, Jean-Marc; Pronk, Jack T

    2012-03-01

    Successful reverse engineering of mutants that have been obtained by nontargeted strain improvement has long presented a major challenge in yeast biotechnology. This paper reviews the use of genome-wide approaches for analysis of Saccharomyces cerevisiae strains originating from evolutionary engineering or random mutagenesis. On the basis of an evaluation of the strengths and weaknesses of different methods, we conclude that for the initial identification of relevant genetic changes, whole genome sequencing is superior to other analytical techniques, such as transcriptome, metabolome, proteome, or array-based genome analysis. Key advantages of this technique over gene expression analysis include the independency of genome sequences on experimental context and the possibility to directly and precisely reproduce the identified changes in naive strains. The predictive value of genome-wide analysis of strains with industrially relevant characteristics can be further improved by classical genetics or simultaneous analysis of strains derived from parallel, independent strain improvement lineages. © 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

  6. Meta-analysis of genome-wide association studies of HDL cholesterol response to statins

    DEFF Research Database (Denmark)

    Postmus, Iris; Warren, Helen R; Trompet, Stella

    2016-01-01

    BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation. METHODS AND RESULTS: We performed...... a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p

  7. Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

    Science.gov (United States)

    Davies, G; Armstrong, N; Bis, J C; Bressler, J; Chouraki, V; Giddaluru, S; Hofer, E; Ibrahim-Verbaas, C A; Kirin, M; Lahti, J; van der Lee, S J; Le Hellard, S; Liu, T; Marioni, R E; Oldmeadow, C; Postmus, I; Smith, A V; Smith, J A; Thalamuthu, A; Thomson, R; Vitart, V; Wang, J; Yu, L; Zgaga, L; Zhao, W; Boxall, R; Harris, S E; Hill, W D; Liewald, D C; Luciano, M; Adams, H; Ames, D; Amin, N; Amouyel, P; Assareh, A A; Au, R; Becker, J T; Beiser, A; Berr, C; Bertram, L; Boerwinkle, E; Buckley, B M; Campbell, H; Corley, J; De Jager, P L; Dufouil, C; Eriksson, J G; Espeseth, T; Faul, J D; Ford, I; Scotland, Generation; Gottesman, R F; Griswold, M E; Gudnason, V; Harris, T B; Heiss, G; Hofman, A; Holliday, E G; Huffman, J; Kardia, S L R; Kochan, N; Knopman, D S; Kwok, J B; Lambert, J-C; Lee, T; Li, G; Li, S-C; Loitfelder, M; Lopez, O L; Lundervold, A J; Lundqvist, A; Mather, K A; Mirza, S S; Nyberg, L; Oostra, B A; Palotie, A; Papenberg, G; Pattie, A; Petrovic, K; Polasek, O; Psaty, B M; Redmond, P; Reppermund, S; Rotter, J I; Schmidt, H; Schuur, M; Schofield, P W; Scott, R J; Steen, V M; Stott, D J; van Swieten, J C; Taylor, K D; Trollor, J; Trompet, S; Uitterlinden, A G; Weinstein, G; Widen, E; Windham, B G; Jukema, J W; Wright, A F; Wright, M J; Yang, Q; Amieva, H; Attia, J R; Bennett, D A; Brodaty, H; de Craen, A J M; Hayward, C; Ikram, M A; Lindenberger, U; Nilsson, L-G; Porteous, D J; Räikkönen, K; Reinvang, I; Rudan, I; Sachdev, P S; Schmidt, R; Schofield, P R; Srikanth, V; Starr, J M; Turner, S T; Weir, D R; Wilson, J F; van Duijn, C; Launer, L; Fitzpatrick, A L; Seshadri, S; Mosley, T H; Deary, I J

    2015-01-01

    General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10−9, MIR2113; rs17522122, P=2.55 × 10−8, AKAP6; rs10119, P=5.67 × 10−9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10−6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10−17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C. PMID:25644384

  8. Genome-wide comparative analysis of four Indian Drosophila species.

    Science.gov (United States)

    Mohanty, Sujata; Khanna, Radhika

    2017-12-01

    Comparative analysis of multiple genomes of closely or distantly related Drosophila species undoubtedly creates excitement among evolutionary biologists in exploring the genomic changes with an ecology and evolutionary perspective. We present herewith the de novo assembled whole genome sequences of four Drosophila species, D. bipectinata, D. takahashii, D. biarmipes and D. nasuta of Indian origin using Next Generation Sequencing technology on an Illumina platform along with their detailed assembly statistics. The comparative genomics analysis, e.g. gene predictions and annotations, functional and orthogroup analysis of coding sequences and genome wide SNP distribution were performed. The whole genome of Zaprionus indianus of Indian origin published earlier by us and the genome sequences of previously sequenced 12 Drosophila species available in the NCBI database were included in the analysis. The present work is a part of our ongoing genomics project of Indian Drosophila species.

  9. Genome-Wide Divergence in the West-African Malaria Vector Anopheles melas

    Directory of Open Access Journals (Sweden)

    Kevin C. Deitz

    2016-09-01

    Full Text Available Anopheles melas is a member of the recently diverged An. gambiae species complex, a model for speciation studies, and is a locally important malaria vector along the West-African coast where it breeds in brackish water. A recent population genetic study of An. melas revealed species-level genetic differentiation between three population clusters. An. melas West extends from The Gambia to the village of Tiko, Cameroon. The other mainland cluster, An. melas South, extends from the southern Cameroonian village of Ipono to Angola. Bioko Island, Equatorial Guinea An. melas populations are genetically isolated from mainland populations. To examine how genetic differentiation between these An. melas forms is distributed across their genomes, we conducted a genome-wide analysis of genetic differentiation and selection using whole genome sequencing data of pooled individuals (Pool-seq from a representative population of each cluster. The An. melas forms exhibit high levels of genetic differentiation throughout their genomes, including the presence of numerous fixed differences between clusters. Although the level of divergence between the clusters is on a par with that of other species within the An. gambiae complex, patterns of genome-wide divergence and diversity do not provide evidence for the presence of pre- and/or postmating isolating mechanisms in the form of speciation islands. These results are consistent with an allopatric divergence process with little or no introgression.

  10. Genome-Wide Detection and Analysis of Multifunctional Genes

    Science.gov (United States)

    Pritykin, Yuri; Ghersi, Dario; Singh, Mona

    2015-01-01

    Many genes can play a role in multiple biological processes or molecular functions. Identifying multifunctional genes at the genome-wide level and studying their properties can shed light upon the complexity of molecular events that underpin cellular functioning, thereby leading to a better understanding of the functional landscape of the cell. However, to date, genome-wide analysis of multifunctional genes (and the proteins they encode) has been limited. Here we introduce a computational approach that uses known functional annotations to extract genes playing a role in at least two distinct biological processes. We leverage functional genomics data sets for three organisms—H. sapiens, D. melanogaster, and S. cerevisiae—and show that, as compared to other annotated genes, genes involved in multiple biological processes possess distinct physicochemical properties, are more broadly expressed, tend to be more central in protein interaction networks, tend to be more evolutionarily conserved, and are more likely to be essential. We also find that multifunctional genes are significantly more likely to be involved in human disorders. These same features also hold when multifunctionality is defined with respect to molecular functions instead of biological processes. Our analysis uncovers key features about multifunctional genes, and is a step towards a better genome-wide understanding of gene multifunctionality. PMID:26436655

  11. Genome wide meta-analysis highlights the role of genetic variation in RARRES2 in the regulation of circulating serum chemerin.

    Directory of Open Access Journals (Sweden)

    Anke Tönjes

    2014-12-01

    Full Text Available Chemerin is an adipokine proposed to link obesity and chronic inflammation of adipose tissue. Genetic factors determining chemerin release from adipose tissue are yet unknown. We conducted a meta-analysis of genome-wide association studies (GWAS for serum chemerin in three independent cohorts from Europe: Sorbs and KORA from Germany and PPP-Botnia from Finland (total N = 2,791. In addition, we measured mRNA expression of genes within the associated loci in peripheral mononuclear cells by micro-arrays, and within adipose tissue by quantitative RT-PCR and performed mRNA expression quantitative trait and expression-chemerin association studies to functionally substantiate our loci. Heritability estimate of circulating chemerin levels was 16.2% in the Sorbs cohort. Thirty single nucleotide polymorphisms (SNPs at chromosome 7 within the retinoic acid receptor responder 2 (RARRES2/Leucine Rich Repeat Containing (LRRC61 locus reached genome-wide significance (p<5.0×10-8 in the meta-analysis (the strongest evidence for association at rs7806429 with p = 7.8×10-14, beta = -0.067, explained variance 2.0%. All other SNPs within the cluster were in linkage disequilibrium with rs7806429 (minimum r2 = 0.43 in the Sorbs cohort. The results of the subgroup analyses of males and females were consistent with the results found in the total cohort. No significant SNP-sex interaction was observed. rs7806429 was associated with mRNA expression of RARRES2 in visceral adipose tissue in women (p<0.05 after adjusting for age and body mass index. In conclusion, the present meta-GWAS combined with mRNA expression studies highlights the role of genetic variation in the RARRES2 locus in the regulation of circulating chemerin concentrations.

  12. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes

    DEFF Research Database (Denmark)

    Barrett, Jeffrey C; Clayton, David G; Concannon, Patrick

    2009-01-01

    Type 1 diabetes (T1D) is a common autoimmune disorder that arises from the action of multiple genetic and environmental risk factors. We report the findings of a genome-wide association study of T1D, combined in a meta-analysis with two previously published studies. The total sample set included 7......,514 cases and 9,045 reference samples. Forty-one distinct genomic locations provided evidence for association with T1D in the meta-analysis (P

  13. Genome-wide Meta-analysis on the Sense of Smell Among US Older Adults

    OpenAIRE

    Dong, Jing; Yang, Jingyun; Tranah, Greg; Franceschini, Nora; Parimi, Neeta; Alkorta-Aranburu, Gorka; Xu, Zongli; Alonso, Alvaro; Cummings, Steven R.; Fornage, Myriam; Huang, Xuemei; Kritchevsky, Stephen; Liu, Yongmei; London, Stephanie; Niu, Liang

    2015-01-01

    Abstract Olfactory dysfunction is common among older adults and affects their safety, nutrition, quality of life, and mortality. More importantly, the decreased sense of smell is an early symptom of neurodegenerative diseases such as Parkinson disease (PD) and Alzheimer disease. However, the genetic determinants for the sense of smell have been poorly investigated. We here performed the first genome-wide meta-analysis on the sense of smell among 6252 US older adults of European descent from t...

  14. Genome-wide DNA methylation patterns and transcription analysis in sheep muscle.

    Directory of Open Access Journals (Sweden)

    Christine Couldrey

    Full Text Available DNA methylation plays a central role in regulating many aspects of growth and development in mammals through regulating gene expression. The development of next generation sequencing technologies have paved the way for genome-wide, high resolution analysis of DNA methylation landscapes using methodology known as reduced representation bisulfite sequencing (RRBS. While RRBS has proven to be effective in understanding DNA methylation landscapes in humans, mice, and rats, to date, few studies have utilised this powerful method for investigating DNA methylation in agricultural animals. Here we describe the utilisation of RRBS to investigate DNA methylation in sheep Longissimus dorsi muscles. RRBS analysis of ∼1% of the genome from Longissimus dorsi muscles provided data of suitably high precision and accuracy for DNA methylation analysis, at all levels of resolution from genome-wide to individual nucleotides. Combining RRBS data with mRNAseq data allowed the sheep Longissimus dorsi muscle methylome to be compared with methylomes from other species. While some species differences were identified, many similarities were observed between DNA methylation patterns in sheep and other more commonly studied species. The RRBS data presented here highlights the complexity of epigenetic regulation of genes. However, the similarities observed across species are promising, in that knowledge gained from epigenetic studies in human and mice may be applied, with caution, to agricultural species. The ability to accurately measure DNA methylation in agricultural animals will contribute an additional layer of information to the genetic analyses currently being used to maximise production gains in these species.

  15. Genome-wide Meta-analysis on the Sense of Smell Among US Older Adults.

    Science.gov (United States)

    Dong, Jing; Yang, Jingyun; Tranah, Greg; Franceschini, Nora; Parimi, Neeta; Alkorta-Aranburu, Gorka; Xu, Zongli; Alonso, Alvaro; Cummings, Steven R; Fornage, Myriam; Huang, Xuemei; Kritchevsky, Stephen; Liu, Yongmei; London, Stephanie; Niu, Liang; Wilson, Robert S; De Jager, Philip L; Yu, Lei; Singleton, Andrew B; Harris, Tamara; Mosley, Thomas H; Pinto, Jayant M; Bennett, David A; Chen, Honglei

    2015-11-01

    Olfactory dysfunction is common among older adults and affects their safety, nutrition, quality of life, and mortality. More importantly, the decreased sense of smell is an early symptom of neurodegenerative diseases such as Parkinson disease (PD) and Alzheimer disease. However, the genetic determinants for the sense of smell have been poorly investigated. We here performed the first genome-wide meta-analysis on the sense of smell among 6252 US older adults of European descent from the Atherosclerosis Risk in Communities (ARIC) study, the Health, Aging, and Body Composition (Health ABC) study, and the Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP). Genome-wide association study analysis was performed first by individual cohorts and then meta-analyzed using fixed-effect models with inverse variance weights. Although no SNPs reached genome-wide statistical significance, we identified 13 loci with suggestive evidence for an association with the sense of smell (Pmeta < 1 × 10). Of these, 2 SNPs at chromosome 17q21.31 (rs199443 in NSF, P = 3.02 × 10; and rs2732614 in KIAA1267-LRRC37A, P = 6.65 × 10) exhibited cis effects on the expression of microtubule-associated protein tau (MAPT, 17q21.31) in 447 frontal-cortex samples obtained postmortem and profiled by RNA-seq (P < 1 × 10). Gene-based and pathway-enrichment analyses further implicated MAPT in regulating the sense of smell in older adults. Similar results were obtained after excluding participants who reported a physician-diagnosed PD or use of PD medications. In conclusion, we provide preliminary evidence that the MAPT locus may play a role in regulating the sense of smell in older adults and therefore offer a potential genetic link between poor sense of smell and major neurodegenerative diseases.

  16. Navigating the Interface Between Landscape Genetics and Landscape Genomics

    Directory of Open Access Journals (Sweden)

    Andrew Storfer

    2018-03-01

    Full Text Available As next-generation sequencing data become increasingly available for non-model organisms, a shift has occurred in the focus of studies of the geographic distribution of genetic variation. Whereas landscape genetics studies primarily focus on testing the effects of landscape variables on gene flow and genetic population structure, landscape genomics studies focus on detecting candidate genes under selection that indicate possible local adaptation. Navigating the transition between landscape genomics and landscape genetics can be challenging. The number of molecular markers analyzed has shifted from what used to be a few dozen loci to thousands of loci and even full genomes. Although genome scale data can be separated into sets of neutral loci for analyses of gene flow and population structure and putative loci under selection for inference of local adaptation, there are inherent differences in the questions that are addressed in the two study frameworks. We discuss these differences and their implications for study design, marker choice and downstream analysis methods. Similar to the rapid proliferation of analysis methods in the early development of landscape genetics, new analytical methods for detection of selection in landscape genomics studies are burgeoning. We focus on genome scan methods for detection of selection, and in particular, outlier differentiation methods and genetic-environment association tests because they are the most widely used. Use of genome scan methods requires an understanding of the potential mismatches between the biology of a species and assumptions inherent in analytical methods used, which can lead to high false positive rates of detected loci under selection. Key to choosing appropriate genome scan methods is an understanding of the underlying demographic structure of study populations, and such data can be obtained using neutral loci from the generated genome-wide data or prior knowledge of a species

  17. Phenotypic and genetic heterogeneity in a genome-wide linkage study of asthma families

    Directory of Open Access Journals (Sweden)

    Schuster Antje

    2005-01-01

    Full Text Available Abstract Background Asthma is a complex genetic disease with more than 20 genome-wide scans conducted so far. Regions on almost every chromosome have been linked to asthma and several genes have been associated. However, most of these associations are weak and are still awaiting replication. Methods In this study, we conducted a second-stage genome-wide scan with 408 microsatellite markers on 201 asthma-affected sib pair families and defined clinical subgroups to identify phenotype-genotype relations. Results The lowest P value for asthma in the total sample was 0.003 on chromosome 11, while several of the clinical subsets reached lower significance levels than in the overall sample. Suggestive evidence for linkage (p = 0.0007 was found for total IgE on chromosomes 1, 7 and again on chromosome 11, as well as for HDM asthma on chromosome 12. Weaker linkage signals could be found on chromosomes 4 and 5 for early onset and HDM, and, newly described, on chromosome 2 for severe asthma and on chromosome 9 for hay fever. Conclusions This phenotypic dissection underlines the importance of detailed clinical characterisations and the extreme genetic heterogeneity of asthma.

  18. Genome-wide association analysis of symbiotic nitrogen fixation in common bean

    Science.gov (United States)

    A genome-wide association study (GWAS) was conducted to explore the genetic basis of variation for symbiotic nitrogen fixation (SNF) and related traits in the Andean diversity panel (ADP) comprised of 259 common bean (Phaseolus vulgaris) genotypes. The ADP was evaluated for SNF and related traits in...

  19. Genetical Genomics for Evolutionary Studies

    NARCIS (Netherlands)

    Prins, J.C.P.; Smant, G.; Jansen, R.C.

    2012-01-01

    Genetical genomics combines acquired high-throughput genomic data with genetic analysis. In this chapter, we discuss the application of genetical genomics for evolutionary studies, where new high-throughput molecular technologies are combined with mapping quantitative trait loci (QTL) on the genome

  20. Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies.

    Science.gov (United States)

    Broce, Iris; Karch, Celeste M; Wen, Natalie; Fan, Chun C; Wang, Yunpeng; Tan, Chin Hong; Kouri, Naomi; Ross, Owen A; Höglinger, Günter U; Muller, Ulrich; Hardy, John; Momeni, Parastoo; Hess, Christopher P; Dillon, William P; Miller, Zachary A; Bonham, Luke W; Rabinovici, Gil D; Rosen, Howard J; Schellenberg, Gerard D; Franke, Andre; Karlsen, Tom H; Veldink, Jan H; Ferrari, Raffaele; Yokoyama, Jennifer S; Miller, Bruce L; Andreassen, Ole A; Dale, Anders M; Desikan, Rahul S; Sugrue, Leo P

    2018-01-01

    Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders-namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)-and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal. We

  1. Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians

    DEFF Research Database (Denmark)

    Cho, Yoon Shin; Chen, Chien-Hsiun; Hu, Cheng

    2012-01-01

    We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis...... (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3...

  2. Population genomic structure and linkage disequilibrium analysis of South African goat breeds using genome-wide SNP data.

    Science.gov (United States)

    Mdladla, K; Dzomba, E F; Huson, H J; Muchadeyi, F C

    2016-08-01

    The sustainability of goat farming in marginal areas of southern Africa depends on local breeds that are adapted to specific agro-ecological conditions. Unimproved non-descript goats are the main genetic resources used for the development of commercial meat-type breeds of South Africa. Little is known about genetic diversity and the genetics of adaptation of these indigenous goat populations. This study investigated the genetic diversity, population structure and breed relations, linkage disequilibrium, effective population size and persistence of gametic phase in goat populations of South Africa. Three locally developed meat-type breeds of the Boer (n = 33), Savanna (n = 31), Kalahari Red (n = 40), a feral breed of Tankwa (n = 25) and unimproved non-descript village ecotypes (n = 110) from four goat-producing provinces of the Eastern Cape, KwaZulu-Natal, Limpopo and North West were assessed using the Illumina Goat 50K SNP Bead Chip assay. The proportion of SNPs with minor allele frequencies >0.05 ranged from 84.22% in the Tankwa to 97.58% in the Xhosa ecotype, with a mean of 0.32 ± 0.13 across populations. Principal components analysis, admixture and pairwise FST identified Tankwa as a genetically distinct population and supported clustering of the populations according to their historical origins. Genome-wide FST identified 101 markers potentially under positive selection in the Tankwa. Average linkage disequilibrium was highest in the Tankwa (r(2)  = 0.25 ± 0.26) and lowest in the village ecotypes (r(2) range = 0.09 ± 0.12 to 0.11 ± 0.14). We observed an effective population size of 100 kb with the exception of those in Savanna and Tswana populations. This study highlights the high level of genetic diversity in South African indigenous goats as well as the utility of the genome-wide SNP marker panels in genetic studies of these populations. © 2016 Stichting International Foundation for Animal Genetics.

  3. Genome-wide association study of clinical dimensions of schizophrenia

    DEFF Research Database (Denmark)

    Fanous, Ayman H; Zhou, Baiyu; Aggen, Steven H

    2012-01-01

    Multiple sources of evidence suggest that genetic factors influence variation in clinical features of schizophrenia. The authors present the first genome-wide association study (GWAS) of dimensional symptom scores among individuals with schizophrenia.......Multiple sources of evidence suggest that genetic factors influence variation in clinical features of schizophrenia. The authors present the first genome-wide association study (GWAS) of dimensional symptom scores among individuals with schizophrenia....

  4. Meta-analysis of Genome-Wide Association Studies for Extraversion

    DEFF Research Database (Denmark)

    van den Berg, Stéphanie M; de Moor, Marleen H M; Verweij, K. J. H.

    2016-01-01

    small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts. Extraversion item data from multiple personality inventories were harmonized across inventories and cohorts. No genome-wide significant associations were found...... at the single nucleotide polymorphism (SNP) level but there was one significant hit at the gene level for a long non-coding RNA site (LOC101928162). Genome-wide complex trait analysis in two large cohorts showed that the additive variance explained by common SNPs was not significantly different from zero...

  5. Estimating Additive and Non-Additive Genetic Variances and Predicting Genetic Merits Using Genome-Wide Dense Single Nucleotide Polymorphism Markers

    DEFF Research Database (Denmark)

    Su, Guosheng; Christensen, Ole Fredslund; Ostersen, Tage

    2012-01-01

    of genomic predictions for daily gain in pigs. In the analysis of daily gain, four linear models were used: 1) a simple additive genetic model (MA), 2) a model including both additive and additive by additive epistatic genetic effects (MAE), 3) a model including both additive and dominance genetic effects...

  6. Genetic loci associated with plasma phospholipid N-3 fatty acids: A Meta-Analysis of Genome-Wide association studies from the charge consortium

    NARCIS (Netherlands)

    R.N. Lemaitre (Rozenn); T. Tanaka (Toshiko); W. Tang (Weihong); A. Manichaikul (Ani); M. Foy (Millennia); E.K. Kabagambe (Edmond); J.A. Nettleton (Jennifer ); I.B. King (Irena); L.-C. Weng; S. Bhattacharya (Sayanti); S. Bandinelli (Stefania); J.C. Bis (Joshua); S.S. Rich (Stephen); D.R. Jacobs (David); A. Cherubini (Antonio); B. McKnight (Barbara); S. Liang (Shuang); X. Gu (Xiangjun); K.M. Rice (Kenneth); C.C. Laurie (Cathy); T. Lumley (Thomas); B.L. Browning (Brian); B.M. Psaty (Bruce); Y.D.I. Chen (Yii-Der Ida); Y. Friedlander (Yechiel); L. Djousse (Luc); J.H.Y. Wu (Jason); D.S. Siscovick (David); A.G. Uitterlinden (André); L. Ferrucci (Luigi); M. Fornage (Myriam); M.Y. Tsai (Michael); D. Mozaffarian (Dariush); L.M. Steffen (Lyn); D.K. Arnett (Donna)

    2011-01-01

    textabstractLong-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide

  7. Genome-wide conserved non-coding microsatellite (CNMS) marker-based integrative genetical genomics for quantitative dissection of seed weight in chickpea.

    Science.gov (United States)

    Bajaj, Deepak; Saxena, Maneesha S; Kujur, Alice; Das, Shouvik; Badoni, Saurabh; Tripathi, Shailesh; Upadhyaya, Hari D; Gowda, C L L; Sharma, Shivali; Singh, Sube; Tyagi, Akhilesh K; Parida, Swarup K

    2015-03-01

    Phylogenetic footprinting identified 666 genome-wide paralogous and orthologous CNMS (conserved non-coding microsatellite) markers from 5'-untranslated and regulatory regions (URRs) of 603 protein-coding chickpea genes. The (CT)n and (GA)n CNMS carrying CTRMCAMV35S and GAGA8BKN3 regulatory elements, respectively, are abundant in the chickpea genome. The mapped genic CNMS markers with robust amplification efficiencies (94.7%) detected higher intraspecific polymorphic potential (37.6%) among genotypes, implying their immense utility in chickpea breeding and genetic analyses. Seventeen differentially expressed CNMS marker-associated genes showing strong preferential and seed tissue/developmental stage-specific expression in contrasting genotypes were selected to narrow down the gene targets underlying seed weight quantitative trait loci (QTLs)/eQTLs (expression QTLs) through integrative genetical genomics. The integration of transcript profiling with seed weight QTL/eQTL mapping, molecular haplotyping, and association analyses identified potential molecular tags (GAGA8BKN3 and RAV1AAT regulatory elements and alleles/haplotypes) in the LOB-domain-containing protein- and KANADI protein-encoding transcription factor genes controlling the cis-regulated expression for seed weight in the chickpea. This emphasizes the potential of CNMS marker-based integrative genetical genomics for the quantitative genetic dissection of complex seed weight in chickpea. © The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  8. Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium.

    Science.gov (United States)

    Power, Robert A; Tansey, Katherine E; Buttenschøn, Henriette Nørmølle; Cohen-Woods, Sarah; Bigdeli, Tim; Hall, Lynsey S; Kutalik, Zoltán; Lee, S Hong; Ripke, Stephan; Steinberg, Stacy; Teumer, Alexander; Viktorin, Alexander; Wray, Naomi R; Arolt, Volker; Baune, Bernard T; Boomsma, Dorret I; Børglum, Anders D; Byrne, Enda M; Castelao, Enrique; Craddock, Nick; Craig, Ian W; Dannlowski, Udo; Deary, Ian J; Degenhardt, Franziska; Forstner, Andreas J; Gordon, Scott D; Grabe, Hans J; Grove, Jakob; Hamilton, Steven P; Hayward, Caroline; Heath, Andrew C; Hocking, Lynne J; Homuth, Georg; Hottenga, Jouke J; Kloiber, Stefan; Krogh, Jesper; Landén, Mikael; Lang, Maren; Levinson, Douglas F; Lichtenstein, Paul; Lucae, Susanne; MacIntyre, Donald J; Madden, Pamela; Magnusson, Patrik K E; Martin, Nicholas G; McIntosh, Andrew M; Middeldorp, Christel M; Milaneschi, Yuri; Montgomery, Grant W; Mors, Ole; Müller-Myhsok, Bertram; Nyholt, Dale R; Oskarsson, Hogni; Owen, Michael J; Padmanabhan, Sandosh; Penninx, Brenda W J H; Pergadia, Michele L; Porteous, David J; Potash, James B; Preisig, Martin; Rivera, Margarita; Shi, Jianxin; Shyn, Stanley I; Sigurdsson, Engilbert; Smit, Johannes H; Smith, Blair H; Stefansson, Hreinn; Stefansson, Kari; Strohmaier, Jana; Sullivan, Patrick F; Thomson, Pippa; Thorgeirsson, Thorgeir E; Van der Auwera, Sandra; Weissman, Myrna M; Breen, Gerome; Lewis, Cathryn M

    2017-02-15

    Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset. Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer's disease, and coronary artery disease. We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11-1.21, p = 5.2 × 10 -11 ). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD. We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  9. Genome-wide generation and use of informative intron-spanning and intron-length polymorphism markers for high-throughput genetic analysis in rice

    Science.gov (United States)

    Badoni, Saurabh; Das, Sweta; Sayal, Yogesh K.; Gopalakrishnan, S.; Singh, Ashok K.; Rao, Atmakuri R.; Agarwal, Pinky; Parida, Swarup K.; Tyagi, Akhilesh K.

    2016-01-01

    We developed genome-wide 84634 ISM (intron-spanning marker) and 16510 InDel-fragment length polymorphism-based ILP (intron-length polymorphism) markers from genes physically mapped on 12 rice chromosomes. These genic markers revealed much higher amplification-efficiency (80%) and polymorphic-potential (66%) among rice accessions even by a cost-effective agarose gel-based assay. A wider level of functional molecular diversity (17–79%) and well-defined precise admixed genetic structure was assayed by 3052 genome-wide markers in a structured population of indica, japonica, aromatic and wild rice. Six major grain weight QTLs (11.9–21.6% phenotypic variation explained) were mapped on five rice chromosomes of a high-density (inter-marker distance: 0.98 cM) genetic linkage map (IR 64 x Sonasal) anchored with 2785 known/candidate gene-derived ISM and ILP markers. The designing of multiple ISM and ILP markers (2 to 4 markers/gene) in an individual gene will broaden the user-preference to select suitable primer combination for efficient assaying of functional allelic variation/diversity and realistic estimation of differential gene expression profiles among rice accessions. The genomic information generated in our study is made publicly accessible through a user-friendly web-resource, “Oryza ISM-ILP marker” database. The known/candidate gene-derived ISM and ILP markers can be enormously deployed to identify functionally relevant trait-associated molecular tags by optimal-resource expenses, leading towards genomics-assisted crop improvement in rice. PMID:27032371

  10. Genome-wide association study to identify common variants associated with brachial circumference: a meta-analysis of 14 cohorts.

    Directory of Open Access Journals (Sweden)

    Vesna Boraska

    Full Text Available Brachial circumference (BC, also known as upper arm or mid arm circumference, can be used as an indicator of muscle mass and fat tissue, which are distributed differently in men and women. Analysis of anthropometric measures of peripheral fat distribution such as BC could help in understanding the complex pathophysiology behind overweight and obesity. The purpose of this study is to identify genetic variants associated with BC through a large-scale genome-wide association scan (GWAS meta-analysis. We used fixed-effects meta-analysis to synthesise summary results across 14 GWAS discovery and 4 replication cohorts comprising overall 22,376 individuals (12,031 women and 10,345 men of European ancestry. Individual analyses were carried out for men, women, and combined across sexes using linear regression and an additive genetic model: adjusted for age and adjusted for age and BMI. We prioritised signals for follow-up in two-stages. We did not detect any signals reaching genome-wide significance. The FTO rs9939609 SNP showed nominal evidence for association (p<0.05 in the age-adjusted strata for men and across both sexes. In this first GWAS meta-analysis for BC to date, we have not identified any genome-wide significant signals and do not observe robust association of previously established obesity loci with BC. Large-scale collaborations will be necessary to achieve higher power to detect loci underlying BC.

  11. Genome-wide association study identifies five new schizophrenia loci

    NARCIS (Netherlands)

    Ripke, S.; Sanders, A. R.; Kendler, K. S.; Levinson, D. F.; Sklar, P.; Holmans, P. A.; Lin, D. Y.; Duan, J.; Ophoff, R. A.; Andreassen, O. A.; Scolnick, E.; Cichon, S.; St Clair, D.; Corvin, A.; Gurling, H.; Werge, T.; Rujescu, D.; Blackwood, D. H.; Pato, C. N.; Malhotra, A. K.; Purcell, S.; Dudbridge, F.; Neale, B. M.; Rossin, L.; Visscher, P. M.; Posthuma, D.; Ruderfer, D. M.; Fanous, A.; Stefansson, H.; Steinberg, S.; Mowry, B. J.; Golimbet, V.; de Hert, M.; Jonsson, E. G.; Bitter, I.; Pietilainen, O. P.; Collier, D. A.; Tosato, S.; Agartz, I.; Albus, M.; Alexander, M.; Amdur, R. L.; Amin, F.; Bass, N.; Bergen, S. E.; Black, D. W.; Borglum, A. D.; Brown, M. A.; Bruggeman, R.; Buccola, N. G.; Byerley, W. F.; Cahn, W.; Cantor, R. M.; Carr, V. J.; Catts, S. V.; Choudhury, K.; Cloninger, C. R.; Cormican, P.; Craddock, N.; Danoy, P. A.; Datta, S.; de Haan, L.; Demontis, D.; Dikeos, D.; Djurovic, S.; Donnely, P.; Donohoe, G.; Duong, L.; Dwyer, S.; Fink-Jensen, A.; Freedman, R.; Freimer, N. B.; Friedl, M.; Georgieva, L.; Giegling, I.; Gill, M.; Glenthoj, B.; Godard, S.; Hamshere, M.; Hansen, M.; Hartmann, A. M.; Henskens, F. A.; Hougaard, D. M.; Hultman, C. M.; Ingason, A.; Jablensky, A. V.; Jakobsen, K. D.; Jay, M.; Jurgens, G.; Kahn, R. S.; Keller, M. C.; Kenis, G.; Kenny, E.; Kim, Y.; Kirov, G. K.; Konnerth, H.; Konte, B.; Krabbendam, L.; Krasucki, R.; Lasseter, V. K.; Laurent, C.; Lawrence, J.; Lencz, T.; Lerer, F. B.; Liang, K. Y.; Lichtenstein, P.; Lieberman, J. A.; Linszen, D. H.; Lonnqvist, J.; Loughland, C. M.; Maclean, A. W.; Maher, B. S.; Maier, W.; Mallet, J.; Malloy, P.; Mattheisen, M.; Mattingsdal, M.; McGhee, K. A.; McGrath, J. J.; McIntosh, A.; McLean, D. E.; McQuillin, A.; Melle, I.; Michie, P. T.; Milanova, V.; Morris, D. W.; Mors, O.; Mortensen, P. B.; Moskvina, V.; Muglia, P.; Myin-Germeys, I.; Nertney, D. A.; Nestadt, G.; Nielsen, J.; Nikolov, I.; Nordentoft, M.; Norton, N.; Nothen, M. M.; O'Dushlaine, C. T.; Olincy, A.; Olsen, L.; O'Neill, F. A.; Orntoft, T. F.; Owen, M. J.; Pantelis, C.; Papadimitriou, G.; Pato, M. T.; Peltonen, L.; Petursson, H.; Pickard, B.; Pimm, J.; Pulver, A. E.; Puri, V.; Quested, D.; Quinn, E. M.; Rasmussen, H. B.; Rethelyi, J. M.; Ribble, R.; Rietschel, M.; Riley, B. P.; Ruggeri, M.; Schall, U.; Schulze, T. G.; Schwab, S. G.; Scott, R. J.; Shi, J.; Sigurdsson, E.; Silvermann, J. M.; Spencer, C. C.; Stefansson, K.; Strange, A.; Strengman, E.; Stroup, T. S.; Suvisaari, J.; Terenius, L.; Thirumalai, S.; Thygesen, J. H.; Timm, S.; Toncheva, D.; van den Oord, E.; van Os, J.; van Winkel, R.; Veldink, J.; Walsh, D.; Wang, A. G.; Wiersma, D.; Wildenauer, D. B.; Williams, H. J.; Williams, N. M.; Wormley, B.; Zammit, S.; Sullivan, P. F.; O'Donovan, M. C.; Daly, M. J.; Gejman, P. V.

    2011-01-01

    We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded

  12. Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Chuong B Do

    2011-06-01

    Full Text Available Although the causes of Parkinson's disease (PD are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and online survey instruments, we conducted the largest case-control genome-wide association study (GWAS of PD based on a single collection of individuals to date (3,426 cases and 29,624 controls. We discovered two novel, genome-wide significant associations with PD-rs6812193 near SCARB2 (p = 7.6 × 10(-10, OR = 0.84 and rs11868035 near SREBF1/RAI1 (p = 5.6 × 10(-8, OR = 0.85-both replicated in an independent cohort. We also replicated 20 previously discovered genetic associations (including LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region, providing support for our novel study design. Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0.27. Finally, using sparse regression techniques, we constructed predictive models that account for 6%-7% of the total variance in liability and that suggest the presence of true associations just beyond genome-wide significance, as confirmed through both internal and external cross-validation. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinson's disease remains to be discovered.

  13. A genome-wide meta-analysis of genetic variants associated with allergic rhinitis and grass sensitization and their interaction with birth order.

    Science.gov (United States)

    Ramasamy, Adaikalavan; Curjuric, Ivan; Coin, Lachlan J; Kumar, Ashish; McArdle, Wendy L; Imboden, Medea; Leynaert, Benedicte; Kogevinas, Manolis; Schmid-Grendelmeier, Peter; Pekkanen, Juha; Wjst, Matthias; Bircher, Andreas J; Sovio, Ulla; Rochat, Thierry; Hartikainen, Anna-Liisa; Balding, David J; Jarvelin, Marjo-Riitta; Probst-Hensch, Nicole; Strachan, David P; Jarvis, Deborah L

    2011-11-01

    Hay fever or seasonal allergic rhinitis (AR) is a chronic disorder associated with IgE sensitization to grass. The underlying genetic variants have not been studied comprehensively. There is overwhelming evidence that those who have older siblings have less AR, although the mechanism for this remains unclear. We sought to identify common genetic variant associations with prevalent AR and grass sensitization using existing genome-wide association study (GWAS) data and to determine whether genetic variants modify the protective effect of older siblings. Approximately 2.2 million genotyped or imputed single nucleotide polymorphisms were investigated in 4 large European adult cohorts for AR (3,933 self-reported cases vs 8,965 control subjects) and grass sensitization (2,315 cases vs 10,032 control subjects). Three loci reached genome-wide significance for either phenotype. The HLA variant rs7775228, which cis-regulates HLA-DRB4, was strongly associated with grass sensitization and weakly with AR (P(grass) = 1.6 × 10(-9); P(AR) = 8.0 × 10(-3)). Variants in a locus near chromosome 11 open reading frame 30 (C11orf30) and leucine-rich repeat containing 32 (LRRC32), which was previously associated with atopic dermatitis and eczema, were also strongly associated with both phenotypes (rs2155219; P(grass) = 9.4 × 10(-9); P(AR) = 3.8 × 10(-8)). The third genome-wide significant variant was rs17513503 (P(grass) = 1.2 × 10(-8); PAR = 7.4 × 10(-7)) which was located near transmembrane protein 232 (TMEM232) and solute carrier family 25, member 46 (SLC25A46). Twelve further loci with suggestive associations were also identified. Using a candidate gene approach, where we considered variants within 164 genes previously thought to be important, we found variants in 3 further genes that may be of interest: thymic stromal lymphopoietin (TSLP), Toll-like receptor 6 (TLR6) and nucleotide-binding oligomerization domain containing 1 (NOD1/CARD4). We found no evidence for variants

  14. Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette's syndrome and OCD.

    Science.gov (United States)

    Yu, Dongmei; Mathews, Carol A; Scharf, Jeremiah M; Neale, Benjamin M; Davis, Lea K; Gamazon, Eric R; Derks, Eske M; Evans, Patrick; Edlund, Christopher K; Crane, Jacquelyn; Fagerness, Jesen A; Osiecki, Lisa; Gallagher, Patience; Gerber, Gloria; Haddad, Stephen; Illmann, Cornelia; McGrath, Lauren M; Mayerfeld, Catherine; Arepalli, Sampath; Barlassina, Cristina; Barr, Cathy L; Bellodi, Laura; Benarroch, Fortu; Berrió, Gabriel Bedoya; Bienvenu, O Joseph; Black, Donald W; Bloch, Michael H; Brentani, Helena; Bruun, Ruth D; Budman, Cathy L; Camarena, Beatriz; Campbell, Desmond D; Cappi, Carolina; Silgado, Julio C Cardona; Cavallini, Maria C; Chavira, Denise A; Chouinard, Sylvain; Cook, Edwin H; Cookson, M R; Coric, Vladimir; Cullen, Bernadette; Cusi, Daniele; Delorme, Richard; Denys, Damiaan; Dion, Yves; Eapen, Valsama; Egberts, Karin; Falkai, Peter; Fernandez, Thomas; Fournier, Eduardo; Garrido, Helena; Geller, Daniel; Gilbert, Donald L; Girard, Simon L; Grabe, Hans J; Grados, Marco A; Greenberg, Benjamin D; Gross-Tsur, Varda; Grünblatt, Edna; Hardy, John; Heiman, Gary A; Hemmings, Sian M J; Herrera, Luis D; Hezel, Dianne M; Hoekstra, Pieter J; Jankovic, Joseph; Kennedy, James L; King, Robert A; Konkashbaev, Anuar I; Kremeyer, Barbara; Kurlan, Roger; Lanzagorta, Nuria; Leboyer, Marion; Leckman, James F; Lennertz, Leonhard; Liu, Chunyu; Lochner, Christine; Lowe, Thomas L; Lupoli, Sara; Macciardi, Fabio; Maier, Wolfgang; Manunta, Paolo; Marconi, Maurizio; McCracken, James T; Mesa Restrepo, Sandra C; Moessner, Rainald; Moorjani, Priya; Morgan, Jubel; Muller, Heike; Murphy, Dennis L; Naarden, Allan L; Nurmi, Erika; Ochoa, William Cornejo; Ophoff, Roel A; Pakstis, Andrew J; Pato, Michele T; Pato, Carlos N; Piacentini, John; Pittenger, Christopher; Pollak, Yehuda; Rauch, Scott L; Renner, Tobias; Reus, Victor I; Richter, Margaret A; Riddle, Mark A; Robertson, Mary M; Romero, Roxana; Rosário, Maria C; Rosenberg, David; Ruhrmann, Stephan; Sabatti, Chiara; Salvi, Erika; Sampaio, Aline S; Samuels, Jack; Sandor, Paul; Service, Susan K; Sheppard, Brooke; Singer, Harvey S; Smit, Jan H; Stein, Dan J; Strengman, Eric; Tischfield, Jay A; Turiel, Maurizio; Valencia Duarte, Ana V; Vallada, Homero; Veenstra-VanderWeele, Jeremy; Walitza, Susanne; Wang, Ying; Weale, Mike; Weiss, Robert; Wendland, Jens R; Westenberg, Herman G M; Shugart, Yin Yao; Hounie, Ana G; Miguel, Euripedes C; Nicolini, Humberto; Wagner, Michael; Ruiz-Linares, Andres; Cath, Danielle C; McMahon, William; Posthuma, Danielle; Oostra, Ben A; Nestadt, Gerald; Rouleau, Guy A; Purcell, Shaun; Jenike, Michael A; Heutink, Peter; Hanna, Gregory L; Conti, David V; Arnold, Paul D; Freimer, Nelson B; Stewart, S Evelyn; Knowles, James A; Cox, Nancy J; Pauls, David L

    2015-01-01

    Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD. The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders. Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01). Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct

  15. Genetic predictors of response to serotonergic and noradrenergic antidepressants in major depressive disorder: a genome-wide analysis of individual-level data and a meta-analysis.

    Science.gov (United States)

    Tansey, Katherine E; Guipponi, Michel; Perroud, Nader; Bondolfi, Guido; Domenici, Enrico; Evans, David; Hall, Stephanie K; Hauser, Joanna; Henigsberg, Neven; Hu, Xiaolan; Jerman, Borut; Maier, Wolfgang; Mors, Ole; O'Donovan, Michael; Peters, Tim J; Placentino, Anna; Rietschel, Marcella; Souery, Daniel; Aitchison, Katherine J; Craig, Ian; Farmer, Anne; Wendland, Jens R; Malafosse, Alain; Holmans, Peter; Lewis, Glyn; Lewis, Cathryn M; Stensbøl, Tine Bryan; Kapur, Shitij; McGuffin, Peter; Uher, Rudolf

    2012-01-01

    It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way. The NEWMEDS consortium, an academia-industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies (three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study). After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants (genome-wide significance panalysis of NEWMEDS and another large sample (STAR*D), with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D. No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study. Please see later in the article for the Editors' Summary.

  16. Meta-analysis of genome-wide linkage scans of attention deficit hyperactivity disorder

    NARCIS (Netherlands)

    Zhou, K.; Dempfle, A.; Arcos-Burgos, M.; Bakker, S.C.; Banaschewski, T.; Biederman, J; Buitelaar, J.K.; Castellanos, F.X.; Doyle, A.; Ebstein, R.; Ekholm, J.; Forabosco, P.; Franke, F.; Freitag, C.; Friedel, S.; Gill, M.; Hebebrand, J.; Hinney, A.; Jacob, C.; Lesch, K.P.; Loo, S.K.; Lopera, F.; McCracken, J.T.; McGough, J.J.; Meyer, J.; Mick, E.; Miranda, A.; Muenkel, M.; Mulas, F.; Nelson, S.F.; Nguyen, T.T.; Oades, R.D.; Ogdie, M.N.; Palacio, J.D.; Pineda, D.; Reif, A.; Renner, T.J.; Roeyers, H.; Romanos, M.; Rothenberger, A.; Schäfer, H.; Sergeant, J.A.; Sinke, R.J.; Smalley, S.L.; Sonuga-Barke, E.; Steinhausen, H.C.; van der Meulen, E.; Walitza, S.; Warnke, A.; Lewis, C.M.; Faraone, S.V.; Asherson, P.

    2008-01-01

    Genetic contribution to the development of attention deficit hyperactivity disorder (ADHD) is well established. Seven independent genome-wide linkage scans have been performed to map loci that increase the risk for ADHD. Although significant linkage signals were identified in some of the studies,

  17. Meta-analysis of genome-wide linkage scans of attention deficit hyperactivity disorder.

    NARCIS (Netherlands)

    Zhou, K.; Dempfle, A.; Arcos-Burgos, M.; Bakker, S.C.; Banaschewski, T.; Biederman, J.; Buitelaar, J.K.; Castellanos, F.X.; Doyle, A.; Ebstein, R.P.; Ekholm, J.; Forabosco, P.; Franke, B.; Freitag, C.; Friedel, S.; Gill, M.; Hebebrand, J.; Hinney, A.; Jacob, C.; Lesch, K.P.; Loo, S.K.; Lopera, F.; McCracken, J.T.; McGough, J.J.; Meyer, J.; Mick, E.; Miranda, A.; Muenke, M.; Mulas, F.; Nelson, S.F.; Nguyen, T.T.; Oades, R.D.; Ogdie, M.N.; Palacio, J.D.; Pineda, D.; Reif, A.; Renner, T.J.; Roeyers, H.; Romanos, M.; Rothenberger, A.; Schafer, H.; Sergeant, J.A.; Sinke, R.J.; Smalley, S.L.; Sonuga-Barke, E.J.S.; Steinhausen, H.C.; Meulen, E. van der; Walitza, S.; Warnke, A.; Lewis, C.M.; Faraone, S.V.; Asherson, P.

    2008-01-01

    Genetic contribution to the development of attention deficit hyperactivity disorder (ADHD) is well established. Seven independent genome-wide linkage scans have been performed to map loci that increase the risk for ADHD. Although significant linkage signals were identified in some of the studies,

  18. A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance

    DEFF Research Database (Denmark)

    Manning, Alisa K; Hivert, Marie-France; Scott, Robert A

    2012-01-01

    pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci...... associated with fasting insulin at P triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci...

  19. A genome-wide association study of cognitive function in Chinese adult twins

    DEFF Research Database (Denmark)

    Xu, Chunsheng; Zhang, Dongfeng; Wu, Yili

    2017-01-01

    Multiple loci or genes have been identified using genome-wide association studies mainly in western countries but with inconsistent results. No similar studies have been conducted in the world's largest and rapidly aging Chinese population. The paper aimed to identify the specific genetic variants....... Gene-based analysis was performed on VEGAS2. The statistically significant genes were then subject to gene set enrichment analysis to further identify the specific biological pathways associated with cognitive function. No SNPs reached genome-wide significance although there were 13 SNPs of suggestive...

  20. Genome-wide association studies and resting heart rate

    DEFF Research Database (Denmark)

    Oskari Kilpeläinen, Tuomas

    2016-01-01

    Genome-wide association studies (GWASs) have revolutionized the search for genetic variants regulating resting heart rate. In the last 10 years, GWASs have led to the identification of at least 21 novel heart rate loci. These discoveries have provided valuable insights into the mechanisms...... and pathways that regulate heart rate and link heart rate to cardiovascular morbidity and mortality. GWASs capture majority of genetic variation in a population sample by utilizing high-throughput genotyping chips measuring genotypes for up to several millions of SNPs across the genome in thousands...... of individuals. This allows the identification of the strongest heart rate associated signals at genome-wide level. While GWASs provide robust statistical evidence of the association of a given genetic locus with heart rate, they are only the starting point for detailed follow-up studies to locate the causal...

  1. Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies

    DEFF Research Database (Denmark)

    Murabito, Joanne M; White, Charles C; Kavousi, Maryam

    2012-01-01

    BACKGROUND: -Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based coh...

  2. Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies

    NARCIS (Netherlands)

    Murabito, Joanne M.; White, Charles C.; Kavousi, Maryam; Sun, Yan V.; Feitosa, Mary F.; Nambi, Vijay; Lamina, Claudia; Schillert, Arne; Coassin, Stefan; Bis, Joshua C.; Broer, Linda; Crawford, Dana C.; Franceschini, Nora; Frikke-Schmidt, Ruth; Haun, Margot; Holewijn, Suzanne; Huffman, Jennifer E.; Hwang, Shih-Jen; Kiechl, Stefan; Kollerits, Barbara; Montasser, May E.; Nolte, Ilja M.; Rudock, Megan E.; Senft, Andrea; Teumer, Alexander; van der Harst, Pim; Vitart, Veronique; Waite, Lindsay L.; Wood, Andrew R.; Wassel, Christina L.; Absher, Devin M.; Allison, Matthew A.; Amin, Najaf; Arnold, Alice; Asselbergs, Folkert W.; Aulchenko, Yurii; Bandinelli, Stefania; Barbalic, Maja; Boban, Mladen; Brown-Gentry, Kristin; Couper, David J.; Criqui, Michael H.; Dehghan, Abbas; den Heijer, Martin; Dieplinger, Benjamin; Ding, Jingzhong; Doerr, Marcus; Espinola-Klein, Christine; Felix, Stephan B.; Ferrucci, Luigi; Folsom, Aaron R.; Fraedrich, Gustav; Gibson, Quince; Goodloe, Robert; Gunjaca, Grgo; Haltmayer, Meinhard; Heiss, Gerardo; Hofman, Albert; Kieback, Arne; Kiemeney, Lambertus A.; Kolcic, Ivana; Kullo, Iftikhar J.; Kritchevsky, Stephen B.; Lackner, Karl J.; Li, Xiaohui; Lieb, Wolfgang; Lohman, Kurt; Meisinger, Christa; Melzer, David; Mohler, Emile R.; Mudnic, Ivana; Mueller, Thomas; Navis, Gerjan; Oberhollenzer, Friedrich; Olin, Jeffrey W.; O'Connell, Jeff; O'Donnell, Christopher J.; Palmas, Walter; Penninx, Brenda W.; Petersmann, Astrid; Polasek, Ozren; Psaty, Bruce M.; Rantner, Barbara; Rice, Ken; Rivadeneira, Fernando; Rotter, Jerome I.; Seldenrijk, Adrie; Stadler, Marietta; Summerer, Monika; Tanaka, Toshiko; Tybjaerg-Hansen, Anne; Uitterlinden, Andre G.; van Gilst, Wiek H.; Vermeulen, Sita H.; Wild, Sarah H.; Wild, Philipp S.; Willeit, Johann; Zeller, Tanja; Zemunik, Tatijana; Zgaga, Lina; Assimes, Themistocles L.; Blankenberg, Stefan; Campbell, Harry; Boerwinkle, Eric; Cooke, John P.; de Graaf, Jacqueline; Herrington, David; Kardia, Sharon L. R.; Mitchell, Braxton D.; Murray, Anna; Muenzel, Thomas; Newman, Anne B.; Oostra, Ben A.; Rudan, Igor; Shuldiner, Alan R.; Snieder, Harold; van Duijn, Cornelia M.; Voelker, Uwe; Wright, Alan F.; Wichmann, H. -Erich; Wilson, James F.; Witteman, Jacqueline C. M.; Liu, Yongmei; Hayward, Caroline; Borecki, Ingrid B.; Ziegler, Andreas; North, Kari E.; Cupples, L. Adrienne; Kronenberg, Florian; Dorr, M.; Munzel, T.; Volker, U.

    Background-Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.

  3. Genome-wide association analysis accounting for environmental factors through propensity-score matching: application to stressful live events in major depressive disorder.

    Science.gov (United States)

    Power, Robert A; Cohen-Woods, Sarah; Ng, Mandy Y; Butler, Amy W; Craddock, Nick; Korszun, Ania; Jones, Lisa; Jones, Ian; Gill, Michael; Rice, John P; Maier, Wolfgang; Zobel, Astrid; Mors, Ole; Placentino, Anna; Rietschel, Marcella; Aitchison, Katherine J; Tozzi, Federica; Muglia, Pierandrea; Breen, Gerome; Farmer, Anne E; McGuffin, Peter; Lewis, Cathryn M; Uher, Rudolf

    2013-09-01

    Stressful life events are an established trigger for depression and may contribute to the heterogeneity within genome-wide association analyses. With depression cases showing an excess of exposure to stressful events compared to controls, there is difficulty in distinguishing between "true" cases and a "normal" response to a stressful environment. This potential contamination of cases, and that from genetically at risk controls that have not yet experienced environmental triggers for onset, may reduce the power of studies to detect causal variants. In the RADIANT sample of 3,690 European individuals, we used propensity score matching to pair cases and controls on exposure to stressful life events. In 805 case-control pairs matched on stressful life event, we tested the influence of 457,670 common genetic variants on the propensity to depression under comparable level of adversity with a sign test. While this analysis produced no significant findings after genome-wide correction for multiple testing, we outline a novel methodology and perspective for providing environmental context in genetic studies. We recommend contextualizing depression by incorporating environmental exposure into genome-wide analyses as a complementary approach to testing gene-environment interactions. Possible explanations for negative findings include a lack of statistical power due to small sample size and conditional effects, resulting from the low rate of adequate matching. Our findings underscore the importance of collecting information on environmental risk factors in studies of depression and other complex phenotypes, so that sufficient sample sizes are available to investigate their effect in genome-wide association analysis. Copyright © 2013 Wiley Periodicals, Inc.

  4. Genome-wide assessment for genetic variants associated with ventricular dysfunction after primary coronary artery bypass graft surgery.

    Directory of Open Access Journals (Sweden)

    Amanda A Fox

    Full Text Available BACKGROUND: Postoperative ventricular dysfunction (VnD occurs in 9-20% of coronary artery bypass graft (CABG surgical patients and is associated with increased postoperative morbidity and mortality. Understanding genetic causes of postoperative VnD should enhance patient risk stratification and improve treatment and prevention strategies. We aimed to determine if genetic variants associate with occurrence of in-hospital VnD after CABG surgery. METHODS: A genome-wide association study identified single nucleotide polymorphisms (SNPs associated with postoperative VnD in male subjects of European ancestry undergoing isolated primary CABG surgery with cardiopulmonary bypass. VnD was defined as the need for ≥2 inotropes or mechanical ventricular support after CABG surgery. Validated SNPs were assessed further in two replication CABG cohorts and meta-analysis was performed. RESULTS: Over 100 SNPs were associated with VnD (P2.1 of developing in-hospital VnD after CABG surgery. However, three genetic loci identified by meta-analysis were more modestly associated with development of postoperative VnD. Studies of larger cohorts to assess these loci as well as to define other genetic mechanisms and related biology that link genetic variants to postoperative ventricular dysfunction are warranted.

  5. Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia

    DEFF Research Database (Denmark)

    Witt, S H; Streit, F; Jungkunz, M

    2017-01-01

    Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report...... describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic...... overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score...

  6. An R package "VariABEL" for genome-wide searching of potentially interacting loci by testing genotypic variance heterogeneity

    Directory of Open Access Journals (Sweden)

    Struchalin Maksim V

    2012-01-01

    Full Text Available Abstract Background Hundreds of new loci have been discovered by genome-wide association studies of human traits. These studies mostly focused on associations between single locus and a trait. Interactions between genes and between genes and environmental factors are of interest as they can improve our understanding of the genetic background underlying complex traits. Genome-wide testing of complex genetic models is a computationally demanding task. Moreover, testing of such models leads to multiple comparison problems that reduce the probability of new findings. Assuming that the genetic model underlying a complex trait can include hundreds of genes and environmental factors, testing of these models in genome-wide association studies represent substantial difficulties. We and Pare with colleagues (2010 developed a method allowing to overcome such difficulties. The method is based on the fact that loci which are involved in interactions can show genotypic variance heterogeneity of a trait. Genome-wide testing of such heterogeneity can be a fast scanning approach which can point to the interacting genetic variants. Results In this work we present a new method, SVLM, allowing for variance heterogeneity analysis of imputed genetic variation. Type I error and power of this test are investigated and contracted with these of the Levene's test. We also present an R package, VariABEL, implementing existing and newly developed tests. Conclusions Variance heterogeneity analysis is a promising method for detection of potentially interacting loci. New method and software package developed in this work will facilitate such analysis in genome-wide context.

  7. A genome-wide analysis of putative functional and exonic variation associated with extremely high intelligence.

    Science.gov (United States)

    Spain, S L; Pedroso, I; Kadeva, N; Miller, M B; Iacono, W G; McGue, M; Stergiakouli, E; Davey Smith, G; Putallaz, M; Lubinski, D; Meaburn, E L; Plomin, R; Simpson, M A

    2016-08-01

    Although individual differences in intelligence (general cognitive ability) are highly heritable, molecular genetic analyses to date have had limited success in identifying specific loci responsible for its heritability. This study is the first to investigate exome variation in individuals of extremely high intelligence. Under the quantitative genetic model, sampling from the high extreme of the distribution should provide increased power to detect associations. We therefore performed a case-control association analysis with 1409 individuals drawn from the top 0.0003 (IQ >170) of the population distribution of intelligence and 3253 unselected population-based controls. Our analysis focused on putative functional exonic variants assayed on the Illumina HumanExome BeadChip. We did not observe any individual protein-altering variants that are reproducibly associated with extremely high intelligence and within the entire distribution of intelligence. Moreover, no significant associations were found for multiple rare alleles within individual genes. However, analyses using genome-wide similarity between unrelated individuals (genome-wide complex trait analysis) indicate that the genotyped functional protein-altering variation yields a heritability estimate of 17.4% (s.e. 1.7%) based on a liability model. In addition, investigation of nominally significant associations revealed fewer rare alleles associated with extremely high intelligence than would be expected under the null hypothesis. This observation is consistent with the hypothesis that rare functional alleles are more frequently detrimental than beneficial to intelligence.

  8. Genome wide SSR high density genetic map construction from an interspecific cross of Gossypium hirsutum × Gossypium tomentosum

    Directory of Open Access Journals (Sweden)

    Muhammad Kashif Riaz eKhan

    2016-04-01

    Full Text Available A high density genetic map was constructed using F2 population derived from an interspecific cross of G. hirsutum x G. tomentosum. The map consisted of 3,093 marker loci distributed across all the 26 chromosomes and covered 4,365.3 cM of cotton genome with an average inter-marker distance of 1.48 cM. The maximum length of chromosome was 218.38 cM and the minimum was 122.09 cM with an average length of 167.90 cM. A sub-genome covers more genetic distance (2,189.01 cM with an average inter loci distance of 1.53 cM than D sub-genome which covers a length of 2,176.29 cM with an average distance of 1.43 cM. There were 716 distorted loci in the map accounting for 23.14% and most distorted loci were distributed on D sub-genome (25.06%, which were more than on A sub-genome (21.23%. In our map 49 segregation hotspots (SDR were distributed across the genome with more on D sub-genome as compared to A genome. Two post-polyploidization reciprocal translocations of A2/A3 and A4/A5 were suggested by 7 pairs of duplicate loci. The map constructed through these studies is one of the three densest genetic maps in cotton however; this is the first dense genome wide SSR interspecific genetic map between G. hirsutum and G. tomentosum.

  9. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.

    Science.gov (United States)

    Wray, Naomi R; Ripke, Stephan; Mattheisen, Manuel; Trzaskowski, Maciej; Byrne, Enda M; Abdellaoui, Abdel; Adams, Mark J; Agerbo, Esben; Air, Tracy M; Andlauer, Till M F; Bacanu, Silviu-Alin; Bækvad-Hansen, Marie; Beekman, Aartjan F T; Bigdeli, Tim B; Binder, Elisabeth B; Blackwood, Douglas R H; Bryois, Julien; Buttenschøn, Henriette N; Bybjerg-Grauholm, Jonas; Cai, Na; Castelao, Enrique; Christensen, Jane Hvarregaard; Clarke, Toni-Kim; Coleman, Jonathan I R; Colodro-Conde, Lucía; Couvy-Duchesne, Baptiste; Craddock, Nick; Crawford, Gregory E; Crowley, Cheynna A; Dashti, Hassan S; Davies, Gail; Deary, Ian J; Degenhardt, Franziska; Derks, Eske M; Direk, Nese; Dolan, Conor V; Dunn, Erin C; Eley, Thalia C; Eriksson, Nicholas; Escott-Price, Valentina; Kiadeh, Farnush Hassan Farhadi; Finucane, Hilary K; Forstner, Andreas J; Frank, Josef; Gaspar, Héléna A; Gill, Michael; Giusti-Rodríguez, Paola; Goes, Fernando S; Gordon, Scott D; Grove, Jakob; Hall, Lynsey S; Hannon, Eilis; Hansen, Christine Søholm; Hansen, Thomas F; Herms, Stefan; Hickie, Ian B; Hoffmann, Per; Homuth, Georg; Horn, Carsten; Hottenga, Jouke-Jan; Hougaard, David M; Hu, Ming; Hyde, Craig L; Ising, Marcus; Jansen, Rick; Jin, Fulai; Jorgenson, Eric; Knowles, James A; Kohane, Isaac S; Kraft, Julia; Kretzschmar, Warren W; Krogh, Jesper; Kutalik, Zoltán; Lane, Jacqueline M; Li, Yihan; Li, Yun; Lind, Penelope A; Liu, Xiaoxiao; Lu, Leina; MacIntyre, Donald J; MacKinnon, Dean F; Maier, Robert M; Maier, Wolfgang; Marchini, Jonathan; Mbarek, Hamdi; McGrath, Patrick; McGuffin, Peter; Medland, Sarah E; Mehta, Divya; Middeldorp, Christel M; Mihailov, Evelin; Milaneschi, Yuri; Milani, Lili; Mill, Jonathan; Mondimore, Francis M; Montgomery, Grant W; Mostafavi, Sara; Mullins, Niamh; Nauck, Matthias; Ng, Bernard; Nivard, Michel G; Nyholt, Dale R; O'Reilly, Paul F; Oskarsson, Hogni; Owen, Michael J; Painter, Jodie N; Pedersen, Carsten Bøcker; Pedersen, Marianne Giørtz; Peterson, Roseann E; Pettersson, Erik; Peyrot, Wouter J; Pistis, Giorgio; Posthuma, Danielle; Purcell, Shaun M; Quiroz, Jorge A; Qvist, Per; Rice, John P; Riley, Brien P; Rivera, Margarita; Saeed Mirza, Saira; Saxena, Richa; Schoevers, Robert; Schulte, Eva C; Shen, Ling; Shi, Jianxin; Shyn, Stanley I; Sigurdsson, Engilbert; Sinnamon, Grant B C; Smit, Johannes H; Smith, Daniel J; Stefansson, Hreinn; Steinberg, Stacy; Stockmeier, Craig A; Streit, Fabian; Strohmaier, Jana; Tansey, Katherine E; Teismann, Henning; Teumer, Alexander; Thompson, Wesley; Thomson, Pippa A; Thorgeirsson, Thorgeir E; Tian, Chao; Traylor, Matthew; Treutlein, Jens; Trubetskoy, Vassily; Uitterlinden, André G; Umbricht, Daniel; Van der Auwera, Sandra; van Hemert, Albert M; Viktorin, Alexander; Visscher, Peter M; Wang, Yunpeng; Webb, Bradley T; Weinsheimer, Shantel Marie; Wellmann, Jürgen; Willemsen, Gonneke; Witt, Stephanie H; Wu, Yang; Xi, Hualin S; Yang, Jian; Zhang, Futao; Arolt, Volker; Baune, Bernhard T; Berger, Klaus; Boomsma, Dorret I; Cichon, Sven; Dannlowski, Udo; de Geus, E C J; DePaulo, J Raymond; Domenici, Enrico; Domschke, Katharina; Esko, Tõnu; Grabe, Hans J; Hamilton, Steven P; Hayward, Caroline; Heath, Andrew C; Hinds, David A; Kendler, Kenneth S; Kloiber, Stefan; Lewis, Glyn; Li, Qingqin S; Lucae, Susanne; Madden, Pamela F A; Magnusson, Patrik K; Martin, Nicholas G; McIntosh, Andrew M; Metspalu, Andres; Mors, Ole; Mortensen, Preben Bo; Müller-Myhsok, Bertram; Nordentoft, Merete; Nöthen, Markus M; O'Donovan, Michael C; Paciga, Sara A; Pedersen, Nancy L; Penninx, Brenda W J H; Perlis, Roy H; Porteous, David J; Potash, James B; Preisig, Martin; Rietschel, Marcella; Schaefer, Catherine; Schulze, Thomas G; Smoller, Jordan W; Stefansson, Kari; Tiemeier, Henning; Uher, Rudolf; Völzke, Henry; Weissman, Myrna M; Werge, Thomas; Winslow, Ashley R; Lewis, Cathryn M; Levinson, Douglas F; Breen, Gerome; Børglum, Anders D; Sullivan, Patrick F

    2018-05-01

    Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

  10. Cross-Disorder Genome-Wide Analyses Suggest a Complex Genetic Relationship Between Tourette Syndrome and Obsessive-Compulsive Disorder

    Science.gov (United States)

    Yu, Dongmei; Mathews, Carol A.; Scharf, Jeremiah M.; Neale, Benjamin M.; Davis, Lea K.; Gamazon, Eric R.; Derks, Eske M.; Evans, Patrick; Edlund, Christopher K.; Crane, Jacquelyn; Fagerness, Jesen A.; Osiecki, Lisa; Gallagher, Patience; Gerber, Gloria; Haddad, Stephen; Illmann, Cornelia; McGrath, Lauren M.; Mayerfeld, Catherine; Arepalli, Sampath; Barlassina, Cristina; Barr, Cathy L.; Bellodi, Laura; Benarroch, Fortu; Berrió, Gabriel Bedoya; Bienvenu, O. Joseph; Black, Donald; Bloch, Michael H.; Brentani, Helena; Bruun, Ruth D.; Budman, Cathy L.; Camarena, Beatriz; Campbell, Desmond D.; Cappi, Carolina; Cardona Silgado, Julio C.; Cavallini, Maria C.; Chavira, Denise A.; Chouinard, Sylvain; Cook, Edwin H.; Cookson, M. R.; Coric, Vladimir; Cullen, Bernadette; Cusi, Daniele; Delorme, Richard; Denys, Damiaan; Dion, Yves; Eapen, Valsama; Egberts, Karin; Falkai, Peter; Fernandez, Thomas; Fournier, Eduardo; Garrido, Helena; Geller, Daniel; Gilbert, Donald; Girard, Simon L.; Grabe, Hans J.; Grados, Marco A.; Greenberg, Benjamin D.; Gross-Tsur, Varda; Grünblatt, Edna; Hardy, John; Heiman, Gary A.; Hemmings, Sian M.J.; Herrera, Luis D.; Hezel, Dianne M.; Hoekstra, Pieter J.; Jankovic, Joseph; Kennedy, James L.; King, Robert A.; Konkashbaev, Anuar I.; Kremeyer, Barbara; Kurlan, Roger; Lanzagorta, Nuria; Leboyer, Marion; Leckman, James F.; Lennertz, Leonhard; Liu, Chunyu; Lochner, Christine; Lowe, Thomas L.; Lupoli, Sara; Macciardi, Fabio; Maier, Wolfgang; Manunta, Paolo; Marconi, Maurizio; McCracken, James T.; Mesa Restrepo, Sandra C.; Moessner, Rainald; Moorjani, Priya; Morgan, Jubel; Muller, Heike; Murphy, Dennis L.; Naarden, Allan L.; Ochoa, William Cornejo; Ophoff, Roel A.; Pakstis, Andrew J.; Pato, Michele T.; Pato, Carlos N.; Piacentini, John; Pittenger, Christopher; Pollak, Yehuda; Rauch, Scott L.; Renner, Tobias; Reus, Victor I.; Richter, Margaret A.; Riddle, Mark A.; Robertson, Mary M.; Romero, Roxana; Rosário, Maria C.; Rosenberg, David; Ruhrmann, Stephan; Sabatti, Chiara; Salvi, Erika; Sampaio, Aline S.; Samuels, Jack; Sandor, Paul; Service, Susan K.; Sheppard, Brooke; Singer, Harvey S.; Smit, Jan H.; Stein, Dan J.; Strengman, Eric; Tischfield, Jay A.; Turiel, Maurizio; Valencia Duarte, Ana V.; Vallada, Homero; Veenstra-VanderWeele, Jeremy; Walitza, Susanne; Walkup, John; Wang, Ying; Weale, Mike; Weiss, Robert; Wendland, Jens R.; Westenberg, Herman G.M.; Yao, Yin; Hounie, Ana G.; Miguel, Euripedes C.; Nicolini, Humberto; Wagner, Michael; Ruiz-Linares, Andres; Cath, Danielle C.; McMahon, William; Posthuma, Danielle; Oostra, Ben A.; Nestadt, Gerald; Rouleau, Guy A.; Purcell, Shaun; Jenike, Michael A.; Heutink, Peter; Hanna, Gregory L.; Conti, David V.; Arnold, Paul D.; Freimer, Nelson; Stewart, S. Evelyn; Knowles, James A.; Cox, Nancy J.; Pauls, David L.

    2014-01-01

    Obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS) are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. Here, we report a combined genome-wide association study (GWAS) of TS and OCD in 2723 cases (1310 with OCD, 834 with TS, 579 with OCD plus TS/chronic tics (CT)), 5667 ancestry-matched controls, and 290 OCD parent-child trios. Although no individual single nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels, i.e. expression quantitative loci (eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10−4), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, TS had a smaller, non-significant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and TS/CT were included in the analysis (p=0.01). Previous work has shown that TS and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of TS and OCD. Furthermore, OCD with co-occurring TS/CT may have different underlying genetic susceptibility compared to OCD alone. PMID:25158072

  11. Genome-wide association study of antisocial personality disorder.

    Science.gov (United States)

    Rautiainen, M-R; Paunio, T; Repo-Tiihonen, E; Virkkunen, M; Ollila, H M; Sulkava, S; Jolanki, O; Palotie, A; Tiihonen, J

    2016-09-06

    The pathophysiology of antisocial personality disorder (ASPD) remains unclear. Although the most consistent biological finding is reduced grey matter volume in the frontal cortex, about 50% of the total liability to developing ASPD has been attributed to genetic factors. The contributing genes remain largely unknown. Therefore, we sought to study the genetic background of ASPD. We conducted a genome-wide association study (GWAS) and a replication analysis of Finnish criminal offenders fulfilling DSM-IV criteria for ASPD (N=370, N=5850 for controls, GWAS; N=173, N=3766 for controls and replication sample). The GWAS resulted in suggestive associations of two clusters of single-nucleotide polymorphisms at 6p21.2 and at 6p21.32 at the human leukocyte antigen (HLA) region. Imputation of HLA alleles revealed an independent association with DRB1*01:01 (odds ratio (OR)=2.19 (1.53-3.14), P=1.9 × 10(-5)). Two polymorphisms at 6p21.2 LINC00951-LRFN2 gene region were replicated in a separate data set, and rs4714329 reached genome-wide significance (OR=1.59 (1.37-1.85), P=1.6 × 10(-9)) in the meta-analysis. The risk allele also associated with antisocial features in the general population conditioned for severe problems in childhood family (β=0.68, P=0.012). Functional analysis in brain tissue in open access GTEx and Braineac databases revealed eQTL associations of rs4714329 with LINC00951 and LRFN2 in cerebellum. In humans, LINC00951 and LRFN2 are both expressed in the brain, especially in the frontal cortex, which is intriguing considering the role of the frontal cortex in behavior and the neuroanatomical findings of reduced gray matter volume in ASPD. To our knowledge, this is the first study showing genome-wide significant and replicable findings on genetic variants associated with any personality disorder.

  12. Genome-wide association study of antisocial personality disorder

    Science.gov (United States)

    Rautiainen, M-R; Paunio, T; Repo-Tiihonen, E; Virkkunen, M; Ollila, H M; Sulkava, S; Jolanki, O; Palotie, A; Tiihonen, J

    2016-01-01

    The pathophysiology of antisocial personality disorder (ASPD) remains unclear. Although the most consistent biological finding is reduced grey matter volume in the frontal cortex, about 50% of the total liability to developing ASPD has been attributed to genetic factors. The contributing genes remain largely unknown. Therefore, we sought to study the genetic background of ASPD. We conducted a genome-wide association study (GWAS) and a replication analysis of Finnish criminal offenders fulfilling DSM-IV criteria for ASPD (N=370, N=5850 for controls, GWAS; N=173, N=3766 for controls and replication sample). The GWAS resulted in suggestive associations of two clusters of single-nucleotide polymorphisms at 6p21.2 and at 6p21.32 at the human leukocyte antigen (HLA) region. Imputation of HLA alleles revealed an independent association with DRB1*01:01 (odds ratio (OR)=2.19 (1.53–3.14), P=1.9 × 10-5). Two polymorphisms at 6p21.2 LINC00951–LRFN2 gene region were replicated in a separate data set, and rs4714329 reached genome-wide significance (OR=1.59 (1.37–1.85), P=1.6 × 10−9) in the meta-analysis. The risk allele also associated with antisocial features in the general population conditioned for severe problems in childhood family (β=0.68, P=0.012). Functional analysis in brain tissue in open access GTEx and Braineac databases revealed eQTL associations of rs4714329 with LINC00951 and LRFN2 in cerebellum. In humans, LINC00951 and LRFN2 are both expressed in the brain, especially in the frontal cortex, which is intriguing considering the role of the frontal cortex in behavior and the neuroanatomical findings of reduced gray matter volume in ASPD. To our knowledge, this is the first study showing genome-wide significant and replicable findings on genetic variants associated with any personality disorder. PMID:27598967

  13. Analysis of genetic diversity in Brown Swiss, Jersey and Holstein populations using genome-wide single nucleotide polymorphism markers

    Directory of Open Access Journals (Sweden)

    Melka Melkaye G

    2012-03-01

    Full Text Available Abstract Background Studies of genetic diversity are essential in understanding the extent of differentiation between breeds, and in designing successful diversity conservation strategies. The objective of this study was to evaluate the level of genetic diversity within and between North American Brown Swiss (BS, n = 900, Jersey (JE, n = 2,922 and Holstein (HO, n = 3,535 cattle, using genotyped bulls. GENEPOP and FSTAT software were used to evaluate the level of genetic diversity within each breed and between each pair of the three breeds based on genome-wide SNP markers (n = 50,972. Results Hardy-Weinberg equilibrium (HWE exact test within breeds showed a significant deviation from equilibrium within each population (P st indicated that the combination of BS and HO in an ideally amalgamated population had higher genetic diversity than the other pairs of breeds. Conclusion Results suggest that the three bull populations have substantially different gene pools. BS and HO show the largest gene differentiation and jointly the highest total expected gene diversity compared to when JE is considered. If the loss of genetic diversity within breeds worsens in the future, the use of crossbreeding might be an option to recover genetic diversity, especially for the breeds with small population size.

  14. Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics

    NARCIS (Netherlands)

    Beaumont, R.N. (Robin N.); N.M. Warrington (Nicole); A. Cavadino (Alana); A.W.R. Tyrrell; M. Nodzenski (Michael); M. Horikoshi (Momoko); F. Geller (Frank); R. Myhre (Ronny); R.C. Richmond (Rebecca C.); Paternoster, L. (Lavinia); J.P. Bradfield (Jonathan); E. Kreiner-Møller (Eskil); V. Huikari (Ville); S. Metrustry (Sarah); K.L. Lunetta (Kathryn); J.N. Painter (Jodie N.); J.J. Hottenga (Jouke Jan); C. Allard (Catherine); S.J. Barton (Sheila J.); Espinosa, A. (Ana); J.A. Marsh (Julie); C. Potter (Catherine); Zhang, G. (Ge); W.Q. Ang (Wei); D. Berry (Diane); L. Bouchard (Luigi); S. Das (Shikta); H. Hakonarson (Hakon); J. Heikkinen (Jani); Helgeland, Ø. (Øyvind); B. Hocher (Berthold); A. Hofman (Albert); H.M. Inskip (Hazel); S.E. Jones (Samuel E.); M. Kogevinas (Manolis); P.A. Lind (Penelope); L. Marullo (Letizia); S.E. Medland (Sarah Elizabeth); Murray, A. (Anna); Murray, J.C. (Jeffrey C.); Njølstad, P.R. (Pa l R.); C. Nohr (Christian); C. Reichetzeder (Christoph); S.M. Ring (Susan); K.S. Ruth (Katherine S.); L. Santa-Marina (Loreto); D.M. Scholtens (Denise M.); Sebert, S. (Sylvain); V. Sengpiel (Verena); Tuke, M.A. (Marcus A.); Vaudel, M. (Marc); M.N. Weedon (Michael); G.A.H.M. Willemsen (Gonneke); Wood, A.R. (Andrew R.); Yaghootkar, H. (Hanieh); Muglia, L.J. (Louis J.); M. Bartels (Meike); C.L. Relton (Caroline); C.E. Pennell (Craig); L. Chatzi (Leda); Estivill, X. (Xavier); Holloway, J.W. (John W.); D.I. Boomsma (Dorret); Montgomery, G.W. (Grant W.); J. Murabito (Joanne); T.D. Spector (Timothy); Power, C. (Christine); Järvelin, M.-R. (Marjo-Ritta); Bisgaard, H. (Hans); Grant, S.F.A. (Struan F.A.); Sørensen, T.I.A. (Thorkild I.A.); Jaddoe, V.W. (Vincent W.); B. Jacobsson (Bo); Melbye, M. (Mads); McCarthy, M.I. (Mark I.); A.T. Hattersley (Andrew); Hayes, M.G. (M. Geoffrey); T.M. Frayling (Timothy); M.-F. Hivert (Marie-France); J.F. Felix (Janine); Hyppönen, E. (Elina); Lowe, W.L. (William L.); Evans, D.M. (David M.); Lawlor, D.A. (Debbie A.); B. Feenstra (Bjarke); R.M. Freathy (Rachel)

    2018-01-01

    textabstractGenome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal

  15. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index

    Science.gov (United States)

    Felix, Janine F.; Bradfield, Jonathan P.; Monnereau, Claire; van der Valk, Ralf J.P.; Stergiakouli, Evie; Chesi, Alessandra; Gaillard, Romy; Feenstra, Bjarke; Thiering, Elisabeth; Kreiner-Møller, Eskil; Mahajan, Anubha; Pitkänen, Niina; Joro, Raimo; Cavadino, Alana; Huikari, Ville; Franks, Steve; Groen-Blokhuis, Maria M.; Cousminer, Diana L.; Marsh, Julie A.; Lehtimäki, Terho; Curtin, John A.; Vioque, Jesus; Ahluwalia, Tarunveer S.; Myhre, Ronny; Price, Thomas S.; Vilor-Tejedor, Natalia; Yengo, Loïc; Grarup, Niels; Ntalla, Ioanna; Ang, Wei; Atalay, Mustafa; Bisgaard, Hans; Blakemore, Alexandra I.; Bonnefond, Amelie; Carstensen, Lisbeth; Eriksson, Johan; Flexeder, Claudia; Franke, Lude; Geller, Frank; Geserick, Mandy; Hartikainen, Anna-Liisa; Haworth, Claire M.A.; Hirschhorn, Joel N.; Hofman, Albert; Holm, Jens-Christian; Horikoshi, Momoko; Hottenga, Jouke Jan; Huang, Jinyan; Kadarmideen, Haja N.; Kähönen, Mika; Kiess, Wieland; Lakka, Hanna-Maaria; Lakka, Timo A.; Lewin, Alexandra M.; Liang, Liming; Lyytikäinen, Leo-Pekka; Ma, Baoshan; Magnus, Per; McCormack, Shana E.; McMahon, George; Mentch, Frank D.; Middeldorp, Christel M.; Murray, Clare S.; Pahkala, Katja; Pers, Tune H.; Pfäffle, Roland; Postma, Dirkje S.; Power, Christine; Simpson, Angela; Sengpiel, Verena; Tiesler, Carla M. T.; Torrent, Maties; Uitterlinden, André G.; van Meurs, Joyce B.; Vinding, Rebecca; Waage, Johannes; Wardle, Jane; Zeggini, Eleftheria; Zemel, Babette S.; Dedoussis, George V.; Pedersen, Oluf; Froguel, Philippe; Sunyer, Jordi; Plomin, Robert; Jacobsson, Bo; Hansen, Torben; Gonzalez, Juan R.; Custovic, Adnan; Raitakari, Olli T.; Pennell, Craig E.; Widén, Elisabeth; Boomsma, Dorret I.; Koppelman, Gerard H.; Sebert, Sylvain; Järvelin, Marjo-Riitta; Hyppönen, Elina; McCarthy, Mark I.; Lindi, Virpi; Harri, Niinikoski; Körner, Antje; Bønnelykke, Klaus; Heinrich, Joachim; Melbye, Mads; Rivadeneira, Fernando; Hakonarson, Hakon; Ring, Susan M.; Smith, George Davey; Sørensen, Thorkild I.A.; Timpson, Nicholas J.; Grant, Struan F.A.; Jaddoe, Vincent W.V.

    2016-01-01

    A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10−8) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10−10) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index. PMID:26604143

  16. Genome-Wide SNP Discovery, Genotyping and Their Preliminary Applications for Population Genetic Inference in Spotted Sea Bass (Lateolabrax maculatus.

    Directory of Open Access Journals (Sweden)

    Juan Wang

    Full Text Available Next-generation sequencing and the collection of genome-wide single-nucleotide polymorphisms (SNPs allow identifying fine-scale population genetic structure and genomic regions under selection. The spotted sea bass (Lateolabrax maculatus is a non-model species of ecological and commercial importance and widely distributed in northwestern Pacific. A total of 22 648 SNPs was discovered across the genome of L. maculatus by paired-end sequencing of restriction-site associated DNA (RAD-PE for 30 individuals from two populations. The nucleotide diversity (π for each population was 0.0028±0.0001 in Dandong and 0.0018±0.0001 in Beihai, respectively. Shallow but significant genetic differentiation was detected between the two populations analyzed by using both the whole data set (FST = 0.0550, P < 0.001 and the putatively neutral SNPs (FST = 0.0347, P < 0.001. However, the two populations were highly differentiated based on the putatively adaptive SNPs (FST = 0.6929, P < 0.001. Moreover, a total of 356 SNPs representing 298 unique loci were detected as outliers putatively under divergent selection by FST-based outlier tests as implemented in BAYESCAN and LOSITAN. Functional annotation of the contigs containing putatively adaptive SNPs yielded hits for 22 of 55 (40% significant BLASTX matches. Candidate genes for local selection constituted a wide array of functions, including binding, catalytic and metabolic activities, etc. The analyses with the SNPs developed in the present study highlighted the importance of genome-wide genetic variation for inference of population structure and local adaptation in L. maculatus.

  17. Genome-wide detection of selection and other evolutionary forces

    DEFF Research Database (Denmark)

    Xu, Zhuofei; Zhou, Rui

    2015-01-01

    As is well known, pathogenic microbes evolve rapidly to escape from the host immune system and antibiotics. Genetic variations among microbial populations occur frequently during the long-term pathogen–host evolutionary arms race, and individual mutation beneficial for the fitness can be fixed...... to scan genome-wide alignments for evidence of positive Darwinian selection, recombination, and other evolutionary forces operating on the coding regions. In this chapter, we describe an integrative analysis pipeline and its application to tracking featured evolutionary trajectories on the genome...

  18. Genome-wide meta-analysis of common variant differences between men and women

    Science.gov (United States)

    Boraska, Vesna; Jerončić, Ana; Colonna, Vincenza; Southam, Lorraine; Nyholt, Dale R.; William Rayner, Nigel; Perry, John R.B.; Toniolo, Daniela; Albrecht, Eva; Ang, Wei; Bandinelli, Stefania; Barbalic, Maja; Barroso, Inês; Beckmann, Jacques S.; Biffar, Reiner; Boomsma, Dorret; Campbell, Harry; Corre, Tanguy; Erdmann, Jeanette; Esko, Tõnu; Fischer, Krista; Franceschini, Nora; Frayling, Timothy M.; Girotto, Giorgia; Gonzalez, Juan R.; Harris, Tamara B.; Heath, Andrew C.; Heid, Iris M.; Hoffmann, Wolfgang; Hofman, Albert; Horikoshi, Momoko; Hua Zhao, Jing; Jackson, Anne U.; Hottenga, Jouke-Jan; Jula, Antti; Kähönen, Mika; Khaw, Kay-Tee; Kiemeney, Lambertus A.; Klopp, Norman; Kutalik, Zoltán; Lagou, Vasiliki; Launer, Lenore J.; Lehtimäki, Terho; Lemire, Mathieu; Lokki, Marja-Liisa; Loley, Christina; Luan, Jian'an; Mangino, Massimo; Mateo Leach, Irene; Medland, Sarah E.; Mihailov, Evelin; Montgomery, Grant W.; Navis, Gerjan; Newnham, John; Nieminen, Markku S.; Palotie, Aarno; Panoutsopoulou, Kalliope; Peters, Annette; Pirastu, Nicola; Polašek, Ozren; Rehnström, Karola; Ripatti, Samuli; Ritchie, Graham R.S.; Rivadeneira, Fernando; Robino, Antonietta; Samani, Nilesh J.; Shin, So-Youn; Sinisalo, Juha; Smit, Johannes H.; Soranzo, Nicole; Stolk, Lisette; Swinkels, Dorine W.; Tanaka, Toshiko; Teumer, Alexander; Tönjes, Anke; Traglia, Michela; Tuomilehto, Jaakko; Valsesia, Armand; van Gilst, Wiek H.; van Meurs, Joyce B.J.; Smith, Albert Vernon; Viikari, Jorma; Vink, Jacqueline M.; Waeber, Gerard; Warrington, Nicole M.; Widen, Elisabeth; Willemsen, Gonneke; Wright, Alan F.; Zanke, Brent W.; Zgaga, Lina; Boehnke, Michael; d'Adamo, Adamo Pio; de Geus, Eco; Demerath, Ellen W.; den Heijer, Martin; Eriksson, Johan G.; Ferrucci, Luigi; Gieger, Christian; Gudnason, Vilmundur; Hayward, Caroline; Hengstenberg, Christian; Hudson, Thomas J.; Järvelin, Marjo-Riitta; Kogevinas, Manolis; Loos, Ruth J.F.; Martin, Nicholas G.; Metspalu, Andres; Pennell, Craig E.; Penninx, Brenda W.; Perola, Markus; Raitakari, Olli; Salomaa, Veikko; Schreiber, Stefan; Schunkert, Heribert; Spector, Tim D.; Stumvoll, Michael; Uitterlinden, André G.; Ulivi, Sheila; van der Harst, Pim; Vollenweider, Peter; Völzke, Henry; Wareham, Nicholas J.; Wichmann, H.-Erich; Wilson, James F.; Rudan, Igor; Xue, Yali; Zeggini, Eleftheria

    2012-01-01

    The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10−8) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ∼115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits. PMID:22843499

  19. Genome-wide analysis of ivermectin response by Onchocerca volvulus reveals that genetic drift and soft selective sweeps contribute to loss of drug sensitivity.

    Directory of Open Access Journals (Sweden)

    Stephen R Doyle

    2017-07-01

    Full Text Available Treatment of onchocerciasis using mass ivermectin administration has reduced morbidity and transmission throughout Africa and Central/South America. Mass drug administration is likely to exert selection pressure on parasites, and phenotypic and genetic changes in several Onchocerca volvulus populations from Cameroon and Ghana-exposed to more than a decade of regular ivermectin treatment-have raised concern that sub-optimal responses to ivermectin's anti-fecundity effect are becoming more frequent and may spread.Pooled next generation sequencing (Pool-seq was used to characterise genetic diversity within and between 108 adult female worms differing in ivermectin treatment history and response. Genome-wide analyses revealed genetic variation that significantly differentiated good responder (GR and sub-optimal responder (SOR parasites. These variants were not randomly distributed but clustered in ~31 quantitative trait loci (QTLs, with little overlap in putative QTL position and gene content between the two countries. Published candidate ivermectin SOR genes were largely absent in these regions; QTLs differentiating GR and SOR worms were enriched for genes in molecular pathways associated with neurotransmission, development, and stress responses. Finally, single worm genotyping demonstrated that geographic isolation and genetic change over time (in the presence of drug exposure had a significantly greater role in shaping genetic diversity than the evolution of SOR.This study is one of the first genome-wide association analyses in a parasitic nematode, and provides insight into the genomics of ivermectin response and population structure of O. volvulus. We argue that ivermectin response is a polygenically-determined quantitative trait (QT whereby identical or related molecular pathways but not necessarily individual genes are likely to determine the extent of ivermectin response in different parasite populations. Furthermore, we propose that genetic

  20. Genome-wide analysis of ivermectin response by Onchocerca volvulus reveals that genetic drift and soft selective sweeps contribute to loss of drug sensitivity

    Science.gov (United States)

    Nana-Djeunga, Hugues C.; Kengne-Ouafo, Jonas A.; Pion, Sébastien D. S.; Bopda, Jean; Kamgno, Joseph; Wanji, Samuel; Che, Hua; Kuesel, Annette C.; Walker, Martin; Basáñez, Maria-Gloria; Boakye, Daniel A.; Osei-Atweneboana, Mike Y.; Boussinesq, Michel; Prichard, Roger K.; Grant, Warwick N.

    2017-01-01

    Background Treatment of onchocerciasis using mass ivermectin administration has reduced morbidity and transmission throughout Africa and Central/South America. Mass drug administration is likely to exert selection pressure on parasites, and phenotypic and genetic changes in several Onchocerca volvulus populations from Cameroon and Ghana—exposed to more than a decade of regular ivermectin treatment—have raised concern that sub-optimal responses to ivermectin's anti-fecundity effect are becoming more frequent and may spread. Methodology/Principal findings Pooled next generation sequencing (Pool-seq) was used to characterise genetic diversity within and between 108 adult female worms differing in ivermectin treatment history and response. Genome-wide analyses revealed genetic variation that significantly differentiated good responder (GR) and sub-optimal responder (SOR) parasites. These variants were not randomly distributed but clustered in ~31 quantitative trait loci (QTLs), with little overlap in putative QTL position and gene content between the two countries. Published candidate ivermectin SOR genes were largely absent in these regions; QTLs differentiating GR and SOR worms were enriched for genes in molecular pathways associated with neurotransmission, development, and stress responses. Finally, single worm genotyping demonstrated that geographic isolation and genetic change over time (in the presence of drug exposure) had a significantly greater role in shaping genetic diversity than the evolution of SOR. Conclusions/Significance This study is one of the first genome-wide association analyses in a parasitic nematode, and provides insight into the genomics of ivermectin response and population structure of O. volvulus. We argue that ivermectin response is a polygenically-determined quantitative trait (QT) whereby identical or related molecular pathways but not necessarily individual genes are likely to determine the extent of ivermectin response in different

  1. Network Biomarkers of Bladder Cancer Based on a Genome-Wide Genetic and Epigenetic Network Derived from Next-Generation Sequencing Data.

    Science.gov (United States)

    Li, Cheng-Wei; Chen, Bor-Sen

    2016-01-01

    Epigenetic and microRNA (miRNA) regulation are associated with carcinogenesis and the development of cancer. By using the available omics data, including those from next-generation sequencing (NGS), genome-wide methylation profiling, candidate integrated genetic and epigenetic network (IGEN) analysis, and drug response genome-wide microarray analysis, we constructed an IGEN system based on three coupling regression models that characterize protein-protein interaction networks (PPINs), gene regulatory networks (GRNs), miRNA regulatory networks (MRNs), and epigenetic regulatory networks (ERNs). By applying system identification method and principal genome-wide network projection (PGNP) to IGEN analysis, we identified the core network biomarkers to investigate bladder carcinogenic mechanisms and design multiple drug combinations for treating bladder cancer with minimal side-effects. The progression of DNA repair and cell proliferation in stage 1 bladder cancer ultimately results not only in the derepression of miR-200a and miR-200b but also in the regulation of the TNF pathway to metastasis-related genes or proteins, cell proliferation, and DNA repair in stage 4 bladder cancer. We designed a multiple drug combination comprising gefitinib, estradiol, yohimbine, and fulvestrant for treating stage 1 bladder cancer with minimal side-effects, and another multiple drug combination comprising gefitinib, estradiol, chlorpromazine, and LY294002 for treating stage 4 bladder cancer with minimal side-effects.

  2. A genome-wide association study of anorexia nervosa suggests a risk locus implicated in dysregulated leptin signaling

    NARCIS (Netherlands)

    Li, Dong; Chang, Xiao; Connolly, John J.; Tian, Lifeng; Liu, Yichuan; Bhoj, Elizabeth J.; Robinson, Nora; Abrams, Debra; Li, Yun R.; Bradfield, Jonathan P.; Kim, Cecilia E.; Li, Jin; Wang, Fengxiang; Snyder, James; Lemma, Maria; Hou, Cuiping; Wei, Zhi; Guo, Yiran; Qiu, Haijun; Mentch, Frank D.; Thomas, Kelly A.; Chiavacci, Rosetta M.; Cone, Roger; Li, Bingshan; Sleiman, Patrick A.; Hakonarson, Hakon; Perica, Vesna Boraska; Franklin, Christopher S.; Floyd, James A.B.; Thornton, Laura M.; Huckins, Laura M.; Southam, Lorraine; Rayner, William N; Tachmazidou, Ioanna; Schmidt, Ulrike; Tozzi, Federica; Kiezebrink, Kirsty; Hebebrand, Johannes; Gorwood, Philip; Adan, Roger A.H.; Kas, Martien J.H.; Favaro, Angela; Santonastaso, Paolo; Fernánde-Aranda, Fernando; Gratacos, Monica; Rybakowski, Filip; Dmitrzak-Weglarz, Monika; Kaprio, Jaakko; Keski-Rahkonen, Anna; Raevuori-Helkamaa, Anu; Furth, Eric F.Van; Slof-Opt Landt, Margarita C.T.; Hudson, James I.; Reichborn-Kjennerud, Ted; Knudsen, Gun Peggy S.; Monteleone, Palmiero; Karwautz, Andreas; Berrettini, Wade H.; Schork, Nicholas J.; Ando, Tetsuya; Inoko, Hidetoshi; Esko, Toñu; Fischer, Krista; Männik, Katrin; Metspalu, Andres; Baker, Jessica H.; DeSocio, Janiece E.; Hilliard, Christopher E.; O'Toole, Julie K.; Pantel, Jacques; Szatkiewicz, Jin P.; Zerwas, Stephanie; Davis, Oliver S P; Helder, Sietske; Bühren, Katharina; Burghardt, Roland; De Zwaan, Martina; Egberts, Karin; Ehrlich, Stefan; Herpertz-Dahlmann, Beate; Herzog, Wolfgang; Imgart, Hartmut; Scherag, André; Zipfel, Stephan; Boni, Claudette; Ramoz, Nicolas; Versini, Audrey; Danner, Unna N.; Hendriks, Judith; Koeleman, Bobby P.C.; Ophoff, Roel A.; Strengman, Eric; van Elburg, Annemarie A.; Bruson, Alice; Clementi, Maurizio; Degortes, Daniela; Forzan, Monica; Tenconi, Elena; Docampo, Elisa; Escaramís, Geòrgia; Jiménez-Murcia, Susana; Lissowska, Jolanta; Rajewski, Andrzej; Szeszenia-Dabrowska, Neonila; Slopien, Agnieszka; Hauser, Joanna; Karhunen, Leila; Meulenbelt, Ingrid; Slagboom, P. Eline; Tortorella, Alfonso; Maj, Mario; Dedoussis, George; DIkeos, DImitris; Gonidakis, Fragiskos; Tziouvas, Konstantinos; Tsitsika, Artemis; Papezova, Hana; Slachtova, Lenka; Martaskova, Debora; Kennedy, James L.; Levitan, Robert D.; Yilmaz, Zeynep; Huemer, Julia; Koubek, Doris; Merl, Elisabeth; Wagner, Gudrun; Lichtenstein, Paul; Breen, Gerome; Cohen-Woods, Sarah; Farmer, Anne; McGuffin, Peter; Cichon, Sven; Giegling, Ina; Herms, Stefan; Rujescu, Dan; Schreiber, Stefan; Wichmann, H-Erich; Dina, Christian; Sladek, Rob; Gambaro, Giovanni; Soranzo, Nicole; Julia, Antonio; Marsal, Sara; Rabionet, Raquel; Gaborieau, Valerie; DIck, Danielle M.; Palotie, Aarno; Ripatti, Samuli; Widén, Elisabeth; Andreassen, Ole A.; Espeseth, Thomas; Lundervold, Astri J; Reinvang, Ivar; Steen, Vidar M.; Le Hellard, Stephanie; Mattingsdal, Morten; Ntalla, Ioanna; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Navratilova, Marie; Gallinger, Steven; Pinto, Dalila; Scherer, Stephen W.; Aschauer, Harald; Carlberg, Laura; Schosser, Alexandra; Alfredsson, Lars; Ding, Bo; Klareskog, Lars; Padyukov, Leonid; Finan, Chris; Kalsi, Gursharan; Roberts, Marion; Barrett, Jeff C.; Estivill, Xavier; Hinney, Anke; Sullivan, Patrick F; Zeggini, Eleftheria; Bulik, Cynthia M.; Brandt, Harry; Crawford, Steve; Crow, Scott; Fichter, Manfred M.; Halmi, Katherine A.; Johnson, Craig; Kaplan, Allan S.; La Via, Maria C.; Mitchell, James R.; Strober, Michael; Rotondo, Alessandro; Treasure, Janet; Woodside, D. Blake; Keel, Pamela K.; Klump, Kelly L.; Lilenfeld, Lisa; Bergen, Andrew W.; Kaye, Walter; Magistretti, Pierre

    2017-01-01

    We conducted a genome-wide association study (GWAS) of anorexia nervosa (AN) using a stringently defined phenotype. Analysis of phenotypic variability led to the identification of a specific genetic risk factor that approached genome-wide significance (rs929626 in EBF1 (Early B-Cell Factor 1); P =

  3. Genome-wide association study identifies five new schizophrenia loci.

    LENUS (Irish Health Repository)

    Ripke, Stephan

    2011-10-01

    We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10(-9)), ANK3 (rs10994359, P = 2.5 × 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10(-9)).

  4. Pathway-Based Kernel Boosting for the Analysis of Genome-Wide Association Studies

    Science.gov (United States)

    Manitz, Juliane; Burger, Patricia; Amos, Christopher I.; Chang-Claude, Jenny; Wichmann, Heinz-Erich; Kneib, Thomas; Bickeböller, Heike

    2017-01-01

    The analysis of genome-wide association studies (GWAS) benefits from the investigation of biologically meaningful gene sets, such as gene-interaction networks (pathways). We propose an extension to a successful kernel-based pathway analysis approach by integrating kernel functions into a powerful algorithmic framework for variable selection, to enable investigation of multiple pathways simultaneously. We employ genetic similarity kernels from the logistic kernel machine test (LKMT) as base-learners in a boosting algorithm. A model to explain case-control status is created iteratively by selecting pathways that improve its prediction ability. We evaluated our method in simulation studies adopting 50 pathways for different sample sizes and genetic effect strengths. Additionally, we included an exemplary application of kernel boosting to a rheumatoid arthritis and a lung cancer dataset. Simulations indicate that kernel boosting outperforms the LKMT in certain genetic scenarios. Applications to GWAS data on rheumatoid arthritis and lung cancer resulted in sparse models which were based on pathways interpretable in a clinical sense. Kernel boosting is highly flexible in terms of considered variables and overcomes the problem of multiple testing. Additionally, it enables the prediction of clinical outcomes. Thus, kernel boosting constitutes a new, powerful tool in the analysis of GWAS data and towards the understanding of biological processes involved in disease susceptibility. PMID:28785300

  5. Pathway-Based Kernel Boosting for the Analysis of Genome-Wide Association Studies.

    Science.gov (United States)

    Friedrichs, Stefanie; Manitz, Juliane; Burger, Patricia; Amos, Christopher I; Risch, Angela; Chang-Claude, Jenny; Wichmann, Heinz-Erich; Kneib, Thomas; Bickeböller, Heike; Hofner, Benjamin

    2017-01-01

    The analysis of genome-wide association studies (GWAS) benefits from the investigation of biologically meaningful gene sets, such as gene-interaction networks (pathways). We propose an extension to a successful kernel-based pathway analysis approach by integrating kernel functions into a powerful algorithmic framework for variable selection, to enable investigation of multiple pathways simultaneously. We employ genetic similarity kernels from the logistic kernel machine test (LKMT) as base-learners in a boosting algorithm. A model to explain case-control status is created iteratively by selecting pathways that improve its prediction ability. We evaluated our method in simulation studies adopting 50 pathways for different sample sizes and genetic effect strengths. Additionally, we included an exemplary application of kernel boosting to a rheumatoid arthritis and a lung cancer dataset. Simulations indicate that kernel boosting outperforms the LKMT in certain genetic scenarios. Applications to GWAS data on rheumatoid arthritis and lung cancer resulted in sparse models which were based on pathways interpretable in a clinical sense. Kernel boosting is highly flexible in terms of considered variables and overcomes the problem of multiple testing. Additionally, it enables the prediction of clinical outcomes. Thus, kernel boosting constitutes a new, powerful tool in the analysis of GWAS data and towards the understanding of biological processes involved in disease susceptibility.

  6. Meta-analysis of Genome-Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology

    OpenAIRE

    Springelkamp, Henriët; Mishra, Aniket; Hysi, Pirro G.; Gharahkhani, Puya; Höhn, René; Khor, Chiea-Chuen; Cooke Bailey, Jessica N.; Luo, Xiaoyan; Ramdas, Wishal D.; Vithana, Eranga; Koh, Victor; Yazar, Seyhan; Xu, Liang; Forward, Hannah; Kearns, Lisa S.

    2015-01-01

    Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asia...

  7. Replication and meta-analysis of common variants identifies a genome-wide significant locus in migraine

    DEFF Research Database (Denmark)

    Esserlind, A-L; Christensen, A F; Le, H

    2013-01-01

    Genetic factors contribute to the aetiology of the prevalent form of migraine without aura (MO) and migraine with typical aura (MTA). Due to the complex inheritance of MO and MTA, the genetic background is still not fully established. In a population-based genome-wide association study by Chasman...

  8. A Genome-wide Combinatorial Strategy Dissects Complex Genetic Architecture of Seed Coat Color in Chickpea.

    Science.gov (United States)

    Bajaj, Deepak; Das, Shouvik; Upadhyaya, Hari D; Ranjan, Rajeev; Badoni, Saurabh; Kumar, Vinod; Tripathi, Shailesh; Gowda, C L Laxmipathi; Sharma, Shivali; Singh, Sube; Tyagi, Akhilesh K; Parida, Swarup K

    2015-01-01

    The study identified 9045 high-quality SNPs employing both genome-wide GBS- and candidate gene-based SNP genotyping assays in 172, including 93 cultivated (desi and kabuli) and 79 wild chickpea accessions. The GWAS in a structured population of 93 sequenced accessions detected 15 major genomic loci exhibiting significant association with seed coat color. Five seed color-associated major genomic loci underlying robust QTLs mapped on a high-density intra-specific genetic linkage map were validated by QTL mapping. The integration of association and QTL mapping with gene haplotype-specific LD mapping and transcript profiling identified novel allelic variants (non-synonymous SNPs) and haplotypes in a MATE secondary transporter gene regulating light/yellow brown and beige seed coat color differentiation in chickpea. The down-regulation and decreased transcript expression of beige seed coat color-associated MATE gene haplotype was correlated with reduced proanthocyanidins accumulation in the mature seed coats of beige than light/yellow brown seed colored desi and kabuli accessions for their coloration/pigmentation. This seed color-regulating MATE gene revealed strong purifying selection pressure primarily in LB/YB seed colored desi and wild Cicer reticulatum accessions compared with the BE seed colored kabuli accessions. The functionally relevant molecular tags identified have potential to decipher the complex transcriptional regulatory gene function of seed coat coloration and for understanding the selective sweep-based seed color trait evolutionary pattern in cultivated and wild accessions during chickpea domestication. The genome-wide integrated approach employed will expedite marker-assisted genetic enhancement for developing cultivars with desirable seed coat color types in chickpea.

  9. Genome-Wide Association Analysis Reveals Genetic Heterogeneity of Sjögren's Syndrome According to Ancestry.

    Science.gov (United States)

    Taylor, Kimberly E; Wong, Quenna; Levine, David M; McHugh, Caitlin; Laurie, Cathy; Doheny, Kimberly; Lam, Mi Y; Baer, Alan N; Challacombe, Stephen; Lanfranchi, Hector; Schiødt, Morten; Srinivasan, M; Umehara, Hisanori; Vivino, Frederick B; Zhao, Yan; Shiboski, Stephen C; Daniels, Troy E; Greenspan, John S; Shiboski, Caroline H; Criswell, Lindsey A

    2017-06-01

    The Sjögren's International Collaborative Clinical Alliance (SICCA) is an international data registry and biorepository derived from a multisite observational study of participants in whom genotyping was performed on the Omni2.5M platform and who had undergone deep phenotyping using common protocol-directed methods. The aim of this study was to examine the genetic etiology of Sjögren's syndrome (SS) across ancestry and disease subsets. We performed genome-wide association study analyses using SICCA subjects and external controls obtained from dbGaP data sets, one using all participants (1,405 cases, 1,622 SICCA controls, and 3,125 external controls), one using European participants (585, 966, and 580, respectively), and one using Asian participants (460, 224, and 901, respectively) with ancestry adjustments via principal components analyses. We also investigated whether subphenotype distributions differ by ethnicity, and whether this contributes to the heterogeneity of genetic associations. We observed significant associations in established regions of the major histocompatibility complex (MHC), IRF5, and STAT4 (P = 3 × 10 -42 , P = 3 × 10 -14 , and P = 9 × 10 -10 , respectively), and several novel suggestive regions (those with 2 or more associations at P ancestry (P = 4 × 10 -15 and P = 4 × 10 -5 , respectively), but that subphenotype differences did not explain most of the ancestry differences in genetic associations. Genetic associations with SS differ markedly according to ancestry; however, this is not explained by differences in subphenotypes. © 2017, The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

  10. Genome-wide association study identifies novel locus for neuroticism and shows polygenic association with Major Depressive Disorder

    Science.gov (United States)

    de Moor, Marleen H.M.; van den Berg, Stéphanie M.; Verweij, Karin J.H.; Krueger, Robert F.; Luciano, Michelle; Vasquez, Alejandro Arias; Matteson, Lindsay K.; Derringer, Jaime; Esko, Tõnu; Amin, Najaf; Gordon, Scott D.; Hansell, Narelle K.; Hart, Amy B.; Seppälä, Ilkka; Huffman, Jennifer E.; Konte, Bettina; Lahti, Jari; Lee, Minyoung; Miller, Mike; Nutile, Teresa; Tanaka, Toshiko; Teumer, Alexander; Viktorin, Alexander; Wedenoja, Juho; Abecasis, Goncalo R.; Adkins, Daniel E.; Agrawal, Arpana; Allik, Jüri; Appel, Katja; Bigdeli, Timothy B.; Busonero, Fabio; Campbell, Harry; Costa, Paul T.; Smith, George Davey; Davies, Gail; de Wit, Harriet; Ding, Jun; Engelhardt, Barbara E.; Eriksson, Johan G.; Fedko, Iryna O.; Ferrucci, Luigi; Franke, Barbara; Giegling, Ina; Grucza, Richard; Hartmann, Annette M.; Heath, Andrew C.; Heinonen, Kati; Henders, Anjali K.; Homuth, Georg; Hottenga, Jouke-Jan; Janzing, Joost; Jokela, Markus; Karlsson, Robert; Kemp, John P.; Kirkpatrick, Matthew G.; Latvala, Antti; Lehtimäki, Terho; Liewald, David C.; Madden, Pamela A.F.; Magri, Chiara; Magnusson, Patrik K.E.; Marten, Jonathan; Maschio, Andrea; Medland, Sarah E.; Mihailov, Evelin; Milaneschi, Yuri; Montgomery, Grant W.; Nauck, Matthias; Ouwens, Klaasjan G.; Palotie, Aarno; Pettersson, Erik; Polasek, Ozren; Qian, Yong; Pulkki-Råback, Laura; Raitakari, Olli T.; Realo, Anu; Rose, Richard J.; Ruggiero, Daniela; Schmidt, Carsten O.; Slutske, Wendy S.; Sorice, Rossella; Starr, John M.; Pourcain, Beate St; Sutin, Angelina R.; Timpson, Nicholas J.; Trochet, Holly; Vermeulen, Sita; Vuoksimaa, Eero; Widen, Elisabeth; Wouda, Jasper; Wright, Margaret J.; Zgaga, Lina; Scotland, Generation; Porteous, David; Minelli, Alessandra; Palmer, Abraham A.; Rujescu, Dan; Ciullo, Marina; Hayward, Caroline; Rudan, Igor; Metspalu, Andres; Kaprio, Jaakko; Deary, Ian J.; Räikkönen, Katri; Wilson, James F.; Keltikangas-Järvinen, Liisa; Bierut, Laura J.; Hettema, John M.; Grabe, Hans J.; van Duijn, Cornelia M.; Evans, David M.; Schlessinger, David; Pedersen, Nancy L.; Terracciano, Antonio; McGue, Matt; Penninx, Brenda W.J.H.; Martin, Nicholas G.; Boomsma, Dorret I.

    2015-01-01

    Importance Neuroticism is a personality trait that is briefly defined by emotional instability. It is a robust genetic risk factor for Major Depressive Disorder (MDD) and other psychiatric disorders. Hence, neuroticism is an important phenotype for psychiatric genetics. The Genetics of Personality Consortium (GPC) has created a resource for genome-wide association analyses of personality traits in over 63,000 participants (including MDD cases). Objective To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association (GWA) results based on 1000Genomes imputation, to evaluate if common genetic variants as assessed by Single Nucleotide Polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability, and to examine whether SNPs that predict neuroticism also predict MDD. Setting 30 cohorts with genome-wide genotype, personality and MDD data from the GPC. Participants The study included 63,661 participants from 29 discovery cohorts and 9,786 participants from a replication cohort. Participants came from Europe, the United States or Australia. Main outcome measure(s) Neuroticism scores harmonized across all cohorts by Item Response Theory (IRT) analysis, and clinically assessed MDD case-control status. Results A genome-wide significant SNP was found in the MAGI1 gene (rs35855737; P=9.26 × 10−9 in the discovery meta-analysis, and P=2.38 × 10−8 in the meta-analysis of all 30 cohorts). Common genetic variants explain 15% of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 of the discovery cohorts significantly predicted neuroticism in 2 independent cohorts. Importantly, polygenic scores also predicted MDD in these cohorts. Conclusions and relevance This study identifies a novel locus for neuroticism. The variant is located in a known gene that has been associated with bipolar disorder and schizophrenia in previous studies. In addition, the study

  11. A novel genome-information content-based statistic for genome-wide association analysis designed for next-generation sequencing data.

    Science.gov (United States)

    Luo, Li; Zhu, Yun; Xiong, Momiao

    2012-06-01

    The genome-wide association studies (GWAS) designed for next-generation sequencing data involve testing association of genomic variants, including common, low frequency, and rare variants. The current strategies for association studies are well developed for identifying association of common variants with the common diseases, but may be ill-suited when large amounts of allelic heterogeneity are present in sequence data. Recently, group tests that analyze their collective frequency differences between cases and controls shift the current variant-by-variant analysis paradigm for GWAS of common variants to the collective test of multiple variants in the association analysis of rare variants. However, group tests ignore differences in genetic effects among SNPs at different genomic locations. As an alternative to group tests, we developed a novel genome-information content-based statistics for testing association of the entire allele frequency spectrum of genomic variation with the diseases. To evaluate the performance of the proposed statistics, we use large-scale simulations based on whole genome low coverage pilot data in the 1000 Genomes Project to calculate the type 1 error rates and power of seven alternative statistics: a genome-information content-based statistic, the generalized T(2), collapsing method, multivariate and collapsing (CMC) method, individual χ(2) test, weighted-sum statistic, and variable threshold statistic. Finally, we apply the seven statistics to published resequencing dataset from ANGPTL3, ANGPTL4, ANGPTL5, and ANGPTL6 genes in the Dallas Heart Study. We report that the genome-information content-based statistic has significantly improved type 1 error rates and higher power than the other six statistics in both simulated and empirical datasets.

  12. Genome-wide analysis of the human Alu Yb-lineage

    Directory of Open Access Journals (Sweden)

    Carter Anthony B

    2004-03-01

    Full Text Available Abstract The Alu Yb-lineage is a 'young' primarily human-specific group of short interspersed element (SINE subfamilies that have integrated throughout the human genome. In this study, we have computationally screened the draft sequence of the human genome for Alu Yb-lineage subfamily members present on autosomal chromosomes. A total of 1,733 Yb Alu subfamily members have integrated into human autosomes. The average ages of Yb-lineage subfamilies, Yb7, Yb8 and Yb9, are estimated as 4.81, 2.39 and 2.32 million years, respectively. In order to determine the contribution of the Alu Yb-lineage to human genomic diversity, 1,202 loci were analysed using polymerase chain reaction (PCR-based assays, which amplify the genomic regions containing individual Yb-lineage subfamily members. Approximately 20 per cent of the Yb-lineage Alu elements are polymorphic for insertion presence/absence in the human genome. Fewer than 0.5 per cent of the Yb loci also demonstrate insertions at orthologous positions in non-human primate genomes. Genomic sequencing of these unusual loci demonstrates that each of the orthologous loci from non-human primate genomes contains older Y, Sg and Sx Alu family members that have been altered, through various mechanisms, into Yb8 sequences. These data suggest that Alu Yb-lineage subfamily members are largely restricted to the human genome. The high copy number, level of insertion polymorphism and estimated age indicate that members of the Alu Yb elements will be useful in a wide range of genetic analyses.

  13. Genome-Wide Association Study and Linkage Analysis of the Healthy Aging Index

    DEFF Research Database (Denmark)

    Minster, Ryan L; Sanders, Jason L; Singh, Jatinder

    2015-01-01

    BACKGROUND: The Healthy Aging Index (HAI) is a tool for measuring the extent of health and disease across multiple systems. METHODS: We conducted a genome-wide association study and a genome-wide linkage analysis to map quantitative trait loci associated with the HAI and a modified HAI weighted...

  14. Genome-wide characterization of genetic variants and putative regions under selection in meat and egg-type chicken lines.

    Science.gov (United States)

    Boschiero, Clarissa; Moreira, Gabriel Costa Monteiro; Gheyas, Almas Ara; Godoy, Thaís Fernanda; Gasparin, Gustavo; Mariani, Pilar Drummond Sampaio Corrêa; Paduan, Marcela; Cesar, Aline Silva Mello; Ledur, Mônica Corrêa; Coutinho, Luiz Lehmann

    2018-01-25

    Meat and egg-type chickens have been selected for several generations for different traits. Artificial and natural selection for different phenotypes can change frequency of genetic variants, leaving particular genomic footprints throghtout the genome. Thus, the aims of this study were to sequence 28 chickens from two Brazilian lines (meat and white egg-type) and use this information to characterize genome-wide genetic variations, identify putative regions under selection using Fst method, and find putative pathways under selection. A total of 13.93 million SNPs and 1.36 million INDELs were identified, with more variants detected from the broiler (meat-type) line. Although most were located in non-coding regions, we identified 7255 intolerant non-synonymous SNPs, 512 stopgain/loss SNPs, 1381 frameshift and 1094 non-frameshift INDELs that may alter protein functions. Genes harboring intolerant non-synonymous SNPs affected metabolic pathways related mainly to reproduction and endocrine systems in the white-egg layer line, and lipid metabolism and metabolic diseases in the broiler line. Fst analysis in sliding windows, using SNPs and INDELs separately, identified over 300 putative regions of selection overlapping with more than 250 genes. For the first time in chicken, INDEL variants were considered for selection signature analysis, showing high level of correlation in results between SNP and INDEL data. The putative regions of selection signatures revealed interesting candidate genes and pathways related to important phenotypic traits in chicken, such as lipid metabolism, growth, reproduction, and cardiac development. In this study, Fst method was applied to identify high confidence putative regions under selection, providing novel insights into selection footprints that can help elucidate the functional mechanisms underlying different phenotypic traits relevant to meat and egg-type chicken lines. In addition, we generated a large catalog of line-specific and common

  15. Genome-wide DNA methylation analysis of pseudohypoparathyroidism patients with GNAS imprinting defects.

    Science.gov (United States)

    Rochtus, Anne; Martin-Trujillo, Alejandro; Izzi, Benedetta; Elli, Francesca; Garin, Intza; Linglart, Agnes; Mantovani, Giovanna; Perez de Nanclares, Guiomar; Thiele, Suzanne; Decallonne, Brigitte; Van Geet, Chris; Monk, David; Freson, Kathleen

    2016-01-01

    Pseudohypoparathyroidism (PHP) is caused by (epi)genetic defects in the imprinted GNAS cluster. Current classification of PHP patients is hampered by clinical and molecular diagnostic overlaps. The European Consortium for the study of PHP designed a genome-wide methylation study to improve molecular diagnosis. The HumanMethylation 450K BeadChip was used to analyze genome-wide methylation in 24 PHP patients with parathyroid hormone resistance and 20 age- and gender-matched controls. Patients were previously diagnosed with GNAS-specific differentially methylated regions (DMRs) and include 6 patients with known STX16 deletion (PHP(Δstx16)) and 18 without deletion (PHP(neg)). The array demonstrated that PHP patients do not show DNA methylation differences at the whole-genome level. Unsupervised clustering of GNAS-specific DMRs divides PHP(Δstx16) versus PHP(neg) patients. Interestingly, in contrast to the notion that all PHP patients share methylation defects in the A/B DMR while only PHP(Δstx16) patients have normal NESP, GNAS-AS1 and XL methylation, we found a novel DMR (named GNAS-AS2) in the GNAS-AS1 region that is significantly different in both PHP(Δstx16) and PHP(neg), as validated by Sequenom EpiTYPER in a larger PHP cohort. The analysis of 58 DMRs revealed that 8/18 PHP(neg) and 1/6 PHP(Δstx16) patients have multi-locus methylation defects. Validation was performed for FANCC and SVOPL DMRs. This is the first genome-wide methylation study for PHP patients that confirmed that GNAS is the most significant DMR, and the presence of STX16 deletion divides PHP patients in two groups. Moreover, a novel GNAS-AS2 DMR affects all PHP patients, and PHP patients seem sensitive to multi-locus methylation defects.

  16. A genome-wide association meta-analysis identifies new childhood obesity loci

    Science.gov (United States)

    Bradfield, Jonathan P.; Taal, H. Rob; Timpson, Nicholas J.; Scherag, André; Lecoeur, Cecile; Warrington, Nicole M.; Hypponen, Elina; Holst, Claus; Valcarcel, Beatriz; Thiering, Elisabeth; Salem, Rany M.; Schumacher, Fredrick R.; Cousminer, Diana L.; Sleiman, Patrick M.A.; Zhao, Jianhua; Berkowitz, Robert I.; Vimaleswaran, Karani S.; Jarick, Ivonne; Pennell, Craig E.; Evans, David M.; St. Pourcain, Beate; Berry, Diane J.; Mook-Kanamori, Dennis O; Hofman, Albert; Rivadeinera, Fernando; Uitterlinden, André G.; van Duijn, Cornelia M.; van der Valk, Ralf J.P.; de Jongste, Johan C.; Postma, Dirkje S.; Boomsma, Dorret I.; Gauderman, William J.; Hassanein, Mohamed T.; Lindgren, Cecilia M.; Mägi, Reedik; Boreham, Colin A.G.; Neville, Charlotte E.; Moreno, Luis A.; Elliott, Paul; Pouta, Anneli; Hartikainen, Anna-Liisa; Li, Mingyao; Raitakari, Olli; Lehtimäki, Terho; Eriksson, Johan G.; Palotie, Aarno; Dallongeville, Jean; Das, Shikta; Deloukas, Panos; McMahon, George; Ring, Susan M.; Kemp, John P.; Buxton, Jessica L.; Blakemore, Alexandra I.F.; Bustamante, Mariona; Guxens, Mònica; Hirschhorn, Joel N.; Gillman, Matthew W.; Kreiner-Møller, Eskil; Bisgaard, Hans; Gilliland, Frank D.; Heinrich, Joachim; Wheeler, Eleanor; Barroso, Inês; O'Rahilly, Stephen; Meirhaeghe, Aline; Sørensen, Thorkild I.A.; Power, Chris; Palmer, Lyle J.; Hinney, Anke; Widen, Elisabeth; Farooqi, I. Sadaf; McCarthy, Mark I.; Froguel, Philippe; Meyre, David; Hebebrand, Johannes; Jarvelin, Marjo-Riitta; Jaddoe, Vincent W.V.; Smith, George Davey; Hakonarson, Hakon; Grant, Struan F.A.

    2012-01-01

    Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made to establish genetic influences on common early-onset obesity. We performed a North American-Australian-European collaborative meta-analysis of fourteen studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight novel signals yielding association with P < 5×10−6 in to nine independent datasets (n = 2,818 cases and 4,083 controls) we observed two loci that yielded a genome wide significant combined P-value, namely near OLFM4 on 13q14 (rs9568856; P=1.82×10−9; OR=1.22) and within HOXB5 on 17q21 (rs9299; P=3.54×10−9; OR=1.14). Both loci continued to show association when including two extreme childhood obesity cohorts (n = 2,214 cases and 2,674 controls). Finally, these two loci yielded directionally consistent associations in the GIANT meta-analysis of adult BMI1. PMID:22484627

  17. Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies.

    Directory of Open Access Journals (Sweden)

    Iris Broce

    2018-01-01

    Full Text Available Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD. Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed.Using large genome-wide association studies (GWASs (total n = 192,886 cases and controls and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs jointly associated with FTD-related disorders-namely, FTD, corticobasal degeneration (CBD, progressive supranuclear palsy (PSP, and amyotrophic lateral sclerosis (ALS-and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC, rheumatoid arthritis (RA, type 1 diabetes (T1D, celiac disease (CeD, and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold. For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA region on Chromosome (Chr 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2, TBKBP1 (TBK1 binding protein 1, and PGBD5 (piggyBac transposable element

  18. Genome-Wide Meta-Analysis of Sciatica in Finnish Population.

    Science.gov (United States)

    Lemmelä, Susanna; Solovieva, Svetlana; Shiri, Rahman; Benner, Christian; Heliövaara, Markku; Kettunen, Johannes; Anttila, Verneri; Ripatti, Samuli; Perola, Markus; Seppälä, Ilkka; Juonala, Markus; Kähönen, Mika; Salomaa, Veikko; Viikari, Jorma; Raitakari, Olli T; Lehtimäki, Terho; Palotie, Aarno; Viikari-Juntura, Eira; Husgafvel-Pursiainen, Kirsti

    2016-01-01

    Sciatica or the sciatic syndrome is a common and often disabling low back disorder in the working-age population. It has a relatively high heritability but poorly understood molecular mechanisms. The Finnish population is a genetic isolate where small founder population and bottleneck events have led to enrichment of certain rare and low frequency variants. We performed here the first genome-wide association (GWAS) and meta-analysis of sciatica. The meta-analysis was conducted across two GWAS covering 291 Finnish sciatica cases and 3671 controls genotyped and imputed at 7.7 million autosomal variants. The most promising loci (psciatica patients and 18,489 controls. We identified five intragenic variants, with relatively low frequencies, at two novel loci associated with sciatica at genome-wide significance. These included chr9:14344410:I (rs71321981) at 9p22.3 (NFIB gene; p = 1.30x10-8, MAF = 0.08) and four variants at 15q21.2: rs145901849, rs80035109, rs190200374 and rs117458827 (MYO5A; p = 1.34x10-8, MAF = 0.06; p = 2.32x10-8, MAF = 0.07; p = 3.85x10-8, MAF = 0.06; p = 4.78x10-8, MAF = 0.07, respectively). The most significant association in the meta-analysis, a single base insertion rs71321981 within the regulatory region of the transcription factor NFIB, replicated in an independent Finnish population sample (p = 0.04). Despite identifying 15q21.2 as a promising locus, we were not able to replicate it. It was differentiated; the lead variants within 15q21.2 were more frequent in Finland (6-7%) than in other European populations (1-2%). Imputation accuracies of the three significantly associated variants (chr9:14344410:I, rs190200374, and rs80035109) were validated by genotyping. In summary, our results suggest a novel locus, 9p22.3 (NFIB), which may be involved in susceptibility to sciatica. In addition, another locus, 15q21.2, emerged as a promising one, but failed to replicate.

  19. Effects of in ovo electroporation on endogenous gene expression: genome-wide analysis

    Directory of Open Access Journals (Sweden)

    Chambers David

    2011-04-01

    Full Text Available Abstract Background In ovo electroporation is a widely used technique to study gene function in developmental biology. Despite the widespread acceptance of this technique, no genome-wide analysis of the effects of in ovo electroporation, principally the current applied across the tissue and exogenous vector DNA introduced, on endogenous gene expression has been undertaken. Here, the effects of electric current and expression of a GFP-containing construct, via electroporation into the midbrain of Hamburger-Hamilton stage 10 chicken embryos, are analysed by microarray. Results Both current alone and in combination with exogenous DNA expression have a small but reproducible effect on endogenous gene expression, changing the expression of the genes represented on the array by less than 0.1% (current and less than 0.5% (current + DNA, respectively. The subset of genes regulated by electric current and exogenous DNA span a disparate set of cellular functions. However, no genes involved in the regional identity were affected. In sharp contrast to this, electroporation of a known transcription factor, Dmrt5, caused a much greater change in gene expression. Conclusions These findings represent the first systematic genome-wide analysis of the effects of in ovo electroporation on gene expression during embryonic development. The analysis reveals that this process has minimal impact on the genetic basis of cell fate specification. Thus, the study demonstrates the validity of the in ovo electroporation technique to study gene function and expression during development. Furthermore, the data presented here can be used as a resource to refine the set of transcriptional responders in future in ovo electroporation studies of specific gene function.

  20. Genome-wide expressions in autologous eutopic and ectopic endometrium of fertile women with endometriosis

    OpenAIRE

    Khan, Meraj A; Sengupta, Jayasree; Mittal, Suneeta; Ghosh, Debabrata

    2012-01-01

    Abstract Background In order to obtain a lead of the pathophysiology of endometriosis, genome-wide expressional analyses of eutopic and ectopic endometrium have earlier been reported, however, the effects of stages of severity and phases of menstrual cycle on expressional profiles have not been examined. The effect of genetic heterogeneity and fertility history on transcriptional activity was also not considered. In the present study, a genome-wide expression analysis of autologous, paired eu...

  1. Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci

    DEFF Research Database (Denmark)

    Børglum, A D; Demontis, D; Grove, J

    2014-01-01

    Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals...... born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases...... was found for rs7902091 (P(SNP × CMV)=7.3 × 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies....

  2. A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease

    DEFF Research Database (Denmark)

    Amin Al Olama, Ali; Kote-Jarai, Zsofia; Schumacher, Fredrick R

    2013-01-01

    Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS inc...

  3. Arabidopsis transcription factors: genome-wide comparative analysis among eukaryotes.

    Science.gov (United States)

    Riechmann, J L; Heard, J; Martin, G; Reuber, L; Jiang, C; Keddie, J; Adam, L; Pineda, O; Ratcliffe, O J; Samaha, R R; Creelman, R; Pilgrim, M; Broun, P; Zhang, J Z; Ghandehari, D; Sherman, B K; Yu, G

    2000-12-15

    The completion of the Arabidopsis thaliana genome sequence allows a comparative analysis of transcriptional regulators across the three eukaryotic kingdoms. Arabidopsis dedicates over 5% of its genome to code for more than 1500 transcription factors, about 45% of which are from families specific to plants. Arabidopsis transcription factors that belong to families common to all eukaryotes do not share significant similarity with those of the other kingdoms beyond the conserved DNA binding domains, many of which have been arranged in combinations specific to each lineage. The genome-wide comparison reveals the evolutionary generation of diversity in the regulation of transcription.

  4. A Genome-Wide mQTL Analysis in Human Adipose Tissue Identifies Genetic Variants Associated with DNA Methylation, Gene Expression and Metabolic Traits.

    Directory of Open Access Journals (Sweden)

    Petr Volkov

    Full Text Available Little is known about the extent to which interactions between genetics and epigenetics may affect the risk of complex metabolic diseases and/or their intermediary phenotypes. We performed a genome-wide DNA methylation quantitative trait locus (mQTL analysis in human adipose tissue of 119 men, where 592,794 single nucleotide polymorphisms (SNPs were related to DNA methylation of 477,891 CpG sites, covering 99% of RefSeq genes. SNPs in significant mQTLs were further related to gene expression in adipose tissue and obesity related traits. We found 101,911 SNP-CpG pairs (mQTLs in cis and 5,342 SNP-CpG pairs in trans showing significant associations between genotype and DNA methylation in adipose tissue after correction for multiple testing, where cis is defined as distance less than 500 kb between a SNP and CpG site. These mQTLs include reported obesity, lipid and type 2 diabetes loci, e.g. ADCY3/POMC, APOA5, CETP, FADS2, GCKR, SORT1 and LEPR. Significant mQTLs were overrepresented in intergenic regions meanwhile underrepresented in promoter regions and CpG islands. We further identified 635 SNPs in significant cis-mQTLs associated with expression of 86 genes in adipose tissue including CHRNA5, G6PC2, GPX7, RPL27A, THNSL2 and ZFP57. SNPs in significant mQTLs were also associated with body mass index (BMI, lipid traits and glucose and insulin levels in our study cohort and public available consortia data. Importantly, the Causal Inference Test (CIT demonstrates how genetic variants mediate their effects on metabolic traits (e.g. BMI, cholesterol, high-density lipoprotein (HDL, hemoglobin A1c (HbA1c and homeostatic model assessment of insulin resistance (HOMA-IR via altered DNA methylation in human adipose tissue. This study identifies genome-wide interactions between genetic and epigenetic variation in both cis and trans positions influencing gene expression in adipose tissue and in vivo (dysmetabolic traits associated with the development of

  5. Genome-wide significant locus for Research Diagnostic Criteria Schizoaffective Disorder Bipolar type.

    Science.gov (United States)

    Green, Elaine K; Di Florio, Arianna; Forty, Liz; Gordon-Smith, Katherine; Grozeva, Detelina; Fraser, Christine; Richards, Alexander L; Moran, Jennifer L; Purcell, Shaun; Sklar, Pamela; Kirov, George; Owen, Michael J; O'Donovan, Michael C; Craddock, Nick; Jones, Lisa; Jones, Ian R

    2017-12-01

    Studies have suggested that Research Diagnostic Criteria for Schizoaffective Disorder Bipolar type (RDC-SABP) might identify a more genetically homogenous subgroup of bipolar disorder. Aiming to identify loci associated with RDC-SABP, we have performed a replication study using independent RDC-SABP cases (n = 144) and controls (n = 6,559), focusing on the 10 loci that reached a p-value bipolar disorder sample. Combining the WTCCC and replication datasets by meta-analysis (combined RDC-SABP, n = 423, controls, n = 9,494), we observed genome-wide significant association at one SNP, rs2352974, located within the intron of the gene TRAIP on chromosome 3p21.31 (p-value, 4.37 × 10 -8 ). This locus did not reach genome-wide significance in bipolar disorder or schizophrenia large Psychiatric Genomic Consortium datasets, suggesting that it may represent a relatively specific genetic risk for the bipolar subtype of schizoaffective disorder. © 2017 Wiley Periodicals, Inc.

  6. Genome-wide association studies dissect the genetic networks underlying agronomical traits in soybean.

    Science.gov (United States)

    Fang, Chao; Ma, Yanming; Wu, Shiwen; Liu, Zhi; Wang, Zheng; Yang, Rui; Hu, Guanghui; Zhou, Zhengkui; Yu, Hong; Zhang, Min; Pan, Yi; Zhou, Guoan; Ren, Haixiang; Du, Weiguang; Yan, Hongrui; Wang, Yanping; Han, Dezhi; Shen, Yanting; Liu, Shulin; Liu, Tengfei; Zhang, Jixiang; Qin, Hao; Yuan, Jia; Yuan, Xiaohui; Kong, Fanjiang; Liu, Baohui; Li, Jiayang; Zhang, Zhiwu; Wang, Guodong; Zhu, Baoge; Tian, Zhixi

    2017-08-24

    Soybean (Glycine max [L.] Merr.) is one of the most important oil and protein crops. Ever-increasing soybean consumption necessitates the improvement of varieties for more efficient production. However, both correlations among different traits and genetic interactions among genes that affect a single trait pose a challenge to soybean breeding. To understand the genetic networks underlying phenotypic correlations, we collected 809 soybean accessions worldwide and phenotyped them for two years at three locations for 84 agronomic traits. Genome-wide association studies identified 245 significant genetic loci, among which 95 genetically interacted with other loci. We determined that 14 oil synthesis-related genes are responsible for fatty acid accumulation in soybean and function in line with an additive model. Network analyses demonstrated that 51 traits could be linked through the linkage disequilibrium of 115 associated loci and these links reflect phenotypic correlations. We revealed that 23 loci, including the known Dt1, E2, E1, Ln, Dt2, Fan, and Fap loci, as well as 16 undefined associated loci, have pleiotropic effects on different traits. This study provides insights into the genetic correlation among complex traits and will facilitate future soybean functional studies and breeding through molecular design.

  7. Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study.

    Science.gov (United States)

    Li, Zheng; Xia, Yi; Feng, Li-Na; Chen, Jie-Rong; Li, Hong-Min; Cui, Jing; Cai, Qing-Qing; Sim, Kar Seng; Nairismägi, Maarja-Liisa; Laurensia, Yurike; Meah, Wee Yang; Liu, Wen-Sheng; Guo, Yun-Miao; Chen, Li-Zhen; Feng, Qi-Sheng; Pang, Chi Pui; Chen, Li Jia; Chew, Soo Hong; Ebstein, Richard P; Foo, Jia Nee; Liu, Jianjun; Ha, Jeslin; Khoo, Lay Poh; Chin, Suk Teng; Zeng, Yi-Xin; Aung, Tin; Chowbay, Balram; Diong, Colin Phipps; Zhang, Fen; Liu, Yan-Hui; Tang, Tiffany; Tao, Miriam; Quek, Richard; Mohamad, Farid; Tan, Soo Yong; Teh, Bin Tean; Ng, Siok Bian; Chng, Wee Joo; Ong, Choon Kiat; Okada, Yukinori; Raychaudhuri, Soumya; Lim, Soon Thye; Tan, Wen; Peng, Rou-Jun; Khor, Chiea Chuen; Bei, Jin-Xin

    2016-09-01

    Extranodal natural killer T-cell lymphoma (NKTCL), nasal type, is a rare and aggressive malignancy that occurs predominantly in Asian and Latin American populations. Although Epstein-Barr virus infection is a known risk factor, other risk factors and the pathogenesis of NKTCL are not well understood. We aimed to identify common genetic variants affecting individual risk of NKTCL. We did a genome-wide association study of 189 patients with extranodal NKTCL, nasal type (WHO classification criteria; cases) and 957 controls from Guangdong province, southern China. We validated our findings in four independent case-control series, including 75 cases from Guangdong province and 296 controls from Hong Kong, 65 cases and 983 controls from Guangdong province, 125 cases and 1110 controls from Beijing (northern China), and 60 cases and 2476 controls from Singapore. We used imputation and conditional logistic regression analyses to fine-map the associations. We also did a meta-analysis of the replication series and of the entire dataset. Associations exceeding the genome-wide significance threshold (p<5 × 10(-8)) were seen at 51 single-nucleotide polymorphisms (SNPs) mapping to the class II MHC region on chromosome 6, with rs9277378 (located in HLA-DPB1) having the strongest association with NKTCL susceptibility (p=4·21 × 10(-19), odds ratio [OR] 1·84 [95% CI 1·61-2·11] in meta-analysis of entire dataset). Imputation-based fine-mapping across the class II MHC region suggests that four aminoacid residues (Gly84-Gly85-Pro86-Met87) in near-complete linkage disequilibrium at the edge of the peptide-binding groove of HLA-DPB1 could account for most of the association between the rs9277378*A risk allele and NKTCL susceptibility (OR 2·38, p value for haplotype 2·32 × 10(-14)). This association is distinct from MHC associations with Epstein-Barr virus infection. To our knowledge, this is the first time that a genetic variant conferring an NKTCL risk is noted at

  8. Genome-wide Association Analysis of Kernel Weight in Hard Winter Wheat

    Science.gov (United States)

    Wheat kernel weight is an important and heritable component of wheat grain yield and a key predictor of flour extraction. Genome-wide association analysis was conducted to identify genomic regions associated with kernel weight and kernel weight environmental response in 8 trials of 299 hard winter ...

  9. Sex-stratified Genome-wide Association Studies Including 270000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

    NARCIS (Netherlands)

    Randall, J.C.; Winkler, T.W.; Kutalik, Z.; Berndt, S.I.; Jackson, A.U.; Monda, K.L.; Kilpeläinen, T.O.; Esko, T.; Mägi, R.; Li, S.; Workalemahu, T.; Feitosa, M.F.; Croteau-Chonka, D.C.; Day, F.R.; Fall, T.; Ferreira, T.; Gustafsson, S.; Locke, A.E.; Mathieson, I.; Scherag, A.; Vedantam, S.; Wood, A.R.; Liang, L.; Steinthorsdottir, V.; Thorleifsson, G.; Dermitzakis, E.T.; Dimas, A.S.; Karpe, F.; Min, J.L.; Nicholson, G.; Clegg, D.J.; Person, T.; Krohn, J.P.; Bauer, S.; Buechler, C.; Eisinger, K.; Bonnefond, A.; Froguel, P.; Hottenga, J.J.; Prokopenko, I.; Waite, L.L.; Harris, T.B.; Smith, A.V.; Shuldiner, A.R.; McArdle, W.L.; Caulfield, M.J.; Munroe, P.B.; Grönberg, H.; Chen, Y.D.; Li, G.; Beckmann, J.S.; Johnson, T.; Thorsteinsdottir, U.; Teder-Laving, M.; Khaw, K.T.; Wareham, N.J.; Zhao, J.H.; Amin, N.; Oostra, B.A.; Kraja, A.T.; Province, M.A.; Cupples, L.A.; Heard-Costa, N.L.; Kaprio, J.; Ripatti, S.; Surakka, I.; Collins, F.S.; Saramies, J.; Tuomilehto, J.; Jula, A.; Salomaa, V.; Erdmann, J.; Hengstenberg, C.; Loley, C.; Schunkert, H.; Lamina, C.; Wichmann, H.E.; Albrecht, E.; Gieger, C.; Hicks, A.A.; Johansson, A.; Pramstaller, P.P.; Kathiresan, S.; Speliotes, E.K.; Penninx, B.W.J.H.; Hartikainen, A.L.; Järvelin, M.R.; Gyllensten, U.; Boomsma, D.I.; Campbell, H.; Wilson, J.F.; Chanock, S.J.; Farrall, M.; Goel, A.; Medina-Gomez, C.; Rivadeneira, F.; Estrada, K.; Uitterlinden, A.G.; Hofman, A.; Zillikens, M.C.; den Heijer, M.; Kiemeney, L.A.; Maschio, A.; Hall, P.; Tyrer, J.; Teumer, A.; Völzke, H.; Kovacs, P.; Tönjes, A.; Mangino, M.; Spector, T.D.; Hayward, C.; Rudan, I.; Hall, A.S.; Samani, N.J.; Attwood, A.P.; Sambrook, J.G.; Hung, J.; Palmer, L.J.; Lokki, M.L.; Sinisalo, J.; Boucher, G.; Huikuri, H.V.; Lorentzon, M.; Ohlsson, C.; Eklund, N.; Eriksson, J.G.; Barlassina, C.; Rivolta, C.; Nolte, I.M.; Snieder, H.; van der Klauw, M.M.; van Vliet-Ostaptchouk, J.V.; Gejman, P.V.; Shi, J.; Jacobs, K.B.; Wang, Z.; Bakker, S.J.; Mateo Leach, I.; Navis, G.; van der Harst, P.; Martin, N.G.; Medland, S.E.; Montgomery, G.W.; Yang, J.; Chasman, D.I.; Ridker, P.M.; Rose, L.M.; Lehtimäki, T.; Raitakari, O.; Absher, D.; Iribarren, C.; Basart, H.; Hovingh, K.G.; Hyppönen, E.; Power, C.; Anderson, D.; Beilby, J.P.; Hui, J.; Jolley, J.; Sager, H.; Bornstein, S.R.; Schwarz, P.E.; Kristiansson, K.; Perola, M.; Lindström, J.; Swift, A.J.; Uusitupa, M.; Atalay, M.; Lakka, T.A.; Rauramaa, R.; Bolton, J.L.; Fowkes, G.; Fraser, R.M.; Price, J.F.; Fischer, K.; Krjuta Kov, K.; Metspalu, A.; Mihailov, E.; Langenberg, C.; Luan, J.; Ong, K.K.; Chines, P.S.; Keinanen-Kiukaanniemie, S.; Saaristo, T.E.; Edkins, S.; Franks, P.W.; Hallmans, G.; Shungin, D.; Morris, A.D.; Palmer, C.N.A.; Erbel, R.; Moebus, S.; Nöthen, M.M.; Pechlivanis, S.; Hveem, K.; Narisu, N.; Hamsten, A.; Humphries, S.E.; Strawbridge, R.J.; Tremoli, E.; Grallert, H.; Thorand, B.; Illig, T.; Koenig, W.; Müller-Nurasyid, M.; Peters, A.; Boehm, B.O.; Kleber, M.E.; März, W.; Winkelmann, B.R.; Kuusisto, J.; Laakso, M.; Arveiler, D.; Cesana, G.; Kuulasmaa, K.; Virtamo, J.; Yarnell, J.W.; Kuh, D; Wong, A.; Lind, L.; de Faire, U.; Gigante, B.; Magnusson, P.K.E.; Pedersen, N.L.; Dedoussis, G.; Dimitriou, M.; Kolovou, G.; Kanoni, S.; Stirrups, K.; Bonnycastle, L.L.; Njolstad, I.; Wilsgaard, T.; Ganna, A.; Rehnberg, E.; Hingorani, A.D.; Kivimaki, M.; Kumari, M.; Assimes, T.L.; Barroso, I.; Boehnke, M.; Borecki, I.B.; Deloukas, P.; Fox, C.S.; Frayling, T.M.; Groop, L.C.; Haritunians, T.; Hunter, D.; Ingelsson, E.; Kaplan, R.; Mohlke, K.L.; O'Connell, J.R.; Schlessinger, D.; Strachan, D.P.; Stefansson, K.; van Duijn, C.M.; Abecasis, G.R.; McCarthy, M.I.; Hirschhorn, J.N.; Qi, L.; Loos, R.J.; Lindgren, C.M.; North, K.E.; Heid, I.M.

    2013-01-01

    Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723

  10. Admixture patterns and genetic differentiation in negrito groups from West Malaysia estimated from genome-wide SNP data.

    Science.gov (United States)

    Jinam, Timothy A; Phipps, Maude E; Saitou, Naruya

    2013-01-01

    Southeast Asia houses various culturally and linguistically diverse ethnic groups. In Malaysia, where the Malay, Chinese, and Indian ethnic groups form the majority, there exist minority groups such as the "negritos" who are believed to be descendants of the earliest settlers of Southeast Asia. Here we report patterns of genetic substructure and admixture in two Malaysian negrito populations (Jehai and Kensiu), using ~50,000 genome-wide single-nucleotide polymorphism (SNP) data. We found traces of recent admixture in both the negrito populations, particularly in the Jehai, with the Malay through principal component analysis and STRUCTURE analysis software, which suggested that the admixture was as recent as one generation ago. We also identified significantly differentiated nonsynonymous SNPs and haplotype blocks related to intracellular transport, metabolic processes, and detection of stimulus. These results highlight the different levels of admixture experienced by the two Malaysian negritos. Delineating admixture and differentiated genomic regions should be of importance in designing and interpretation of molecular anthropology and disease association studies. Copyright © 2013 Wayne State University Press, Detroit, Michigan 48201-1309.

  11. Genome-Wide Association Meta-Analyses to Identify Common Genetic Variants Associated with Hallux Valgus in Caucasian and African Americans

    Science.gov (United States)

    Hsu, Yi-Hsiang; Liu, Youfang; Hannan, Marian T.; Maixner, William; Smith, Shad B.; Diatchenko, Luda; Golightly, Yvonne M.; Menz, Hylton B.; Kraus, Virginia B.; Doherty, Michael; Wilson, A.G.; Jordan, Joanne M.

    2016-01-01

    Objective Hallux valgus (HV) affects ~36% of Caucasian adults. Although considered highly heritable, the underlying genetic determinants are unclear. We conducted the first genome-wide association study (GWAS) aimed to identify genetic variants associated with HV. Methods HV was assessed in 3 Caucasian cohorts (n=2,263, n=915, and n=1,231 participants, respectively). In each cohort, a GWAS was conducted using 2.5M imputed single nucleotide polymorphisms (SNPs). Mixed-effect regression with the additive genetic model adjusted for age, sex, weight and within-family correlations was used for both sex-specific and combined analyses. To combine GWAS results across cohorts, fixed-effect inverse-variance meta-analyses were used. Following meta-analyses, top-associated findings were also examined in an African American cohort (n=327). Results The proportion of HV variance explained by genome-wide genotyped SNPs was 50% in men and 48% in women. A higher proportion of genetic determinants of HV was sex-specific. The most significantly associated SNP in men was rs9675316 located on chr17q23-a24 near the AXIN2 gene (p=5.46×10−7); the most significantly associated SNP in women was rs7996797 located on chr13q14.1-q14.2 near the ESD gene (p=7.21×10−7). Genome-wide significant SNP-by-sex interaction was found for SNP rs1563374 located on chr11p15.1 near the MRGPRX3 gene (interaction p-value =4.1×10−9). The association signals diminished when combining men and women. Conclusion Findings suggest that the potential pathophysiological mechanisms of HV are complex and strongly underlined by sex-specific interactions. The identified genetic variants imply contribution of biological pathways observed in osteoarthritis as well as new pathways, influencing skeletal development and inflammation. PMID:26337638

  12. Genome-wide association study of Tourette Syndrome

    Science.gov (United States)

    Scharf, Jeremiah M.; Yu, Dongmei; Mathews, Carol A.; Neale, Benjamin M.; Stewart, S. Evelyn; Fagerness, Jesen A; Evans, Patrick; Gamazon, Eric; Edlund, Christopher K.; Service, Susan; Tikhomirov, Anna; Osiecki, Lisa; Illmann, Cornelia; Pluzhnikov, Anna; Konkashbaev, Anuar; Davis, Lea K; Han, Buhm; Crane, Jacquelyn; Moorjani, Priya; Crenshaw, Andrew T.; Parkin, Melissa A.; Reus, Victor I.; Lowe, Thomas L.; Rangel-Lugo, Martha; Chouinard, Sylvain; Dion, Yves; Girard, Simon; Cath, Danielle C; Smit, Jan H; King, Robert A.; Fernandez, Thomas; Leckman, James F.; Kidd, Kenneth K.; Kidd, Judith R.; Pakstis, Andrew J.; State, Matthew; Herrera, Luis Diego; Romero, Roxana; Fournier, Eduardo; Sandor, Paul; Barr, Cathy L; Phan, Nam; Gross-Tsur, Varda; Benarroch, Fortu; Pollak, Yehuda; Budman, Cathy L.; Bruun, Ruth D.; Erenberg, Gerald; Naarden, Allan L; Lee, Paul C; Weiss, Nicholas; Kremeyer, Barbara; Berrío, Gabriel Bedoya; Campbell, Desmond; Silgado, Julio C. Cardona; Ochoa, William Cornejo; Restrepo, Sandra C. Mesa; Muller, Heike; Duarte, Ana V. Valencia; Lyon, Gholson J; Leppert, Mark; Morgan, Jubel; Weiss, Robert; Grados, Marco A.; Anderson, Kelley; Davarya, Sarah; Singer, Harvey; Walkup, John; Jankovic, Joseph; Tischfield, Jay A.; Heiman, Gary A.; Gilbert, Donald L.; Hoekstra, Pieter J.; Robertson, Mary M.; Kurlan, Roger; Liu, Chunyu; Gibbs, J. Raphael; Singleton, Andrew; Hardy, John; Strengman, Eric; Ophoff, Roel; Wagner, Michael; Moessner, Rainald; Mirel, Daniel B.; Posthuma, Danielle; Sabatti, Chiara; Eskin, Eleazar; Conti, David V.; Knowles, James A.; Ruiz-Linares, Andres; Rouleau, Guy A.; Purcell, Shaun; Heutink, Peter; Oostra, Ben A.; McMahon, William; Freimer, Nelson; Cox, Nancy J.; Pauls, David L.

    2012-01-01

    Tourette Syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel, and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (p<5 × 10−8); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (p=1.85 × 10−6). A secondary analysis including an additional 211 cases and 285 controls from two closely-related Latin-American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (p=3.6 × 10−7 for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder. PMID:22889924

  13. SQC: secure quality control for meta-analysis of genome-wide association studies.

    Science.gov (United States)

    Huang, Zhicong; Lin, Huang; Fellay, Jacques; Kutalik, Zoltán; Hubaux, Jean-Pierre

    2017-08-01

    Due to the limited power of small-scale genome-wide association studies (GWAS), researchers tend to collaborate and establish a larger consortium in order to perform large-scale GWAS. Genome-wide association meta-analysis (GWAMA) is a statistical tool that aims to synthesize results from multiple independent studies to increase the statistical power and reduce false-positive findings of GWAS. However, it has been demonstrated that the aggregate data of individual studies are subject to inference attacks, hence privacy concerns arise when researchers share study data in GWAMA. In this article, we propose a secure quality control (SQC) protocol, which enables checking the quality of data in a privacy-preserving way without revealing sensitive information to a potential adversary. SQC employs state-of-the-art cryptographic and statistical techniques for privacy protection. We implement the solution in a meta-analysis pipeline with real data to demonstrate the efficiency and scalability on commodity machines. The distributed execution of SQC on a cluster of 128 cores for one million genetic variants takes less than one hour, which is a modest cost considering the 10-month time span usually observed for the completion of the QC procedure that includes timing of logistics. SQC is implemented in Java and is publicly available at https://github.com/acs6610987/secureqc. jean-pierre.hubaux@epfl.ch. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  14. Adaptive divergence despite strong genetic drift: genomic analysis of the evolutionary mechanisms causing genetic differentiation in the island fox (Urocyon littoralis)

    Science.gov (United States)

    FUNK, W. CHRIS; LOVICH, ROBERT E.; HOHENLOHE, PAUL A.; HOFMAN, COURTNEY A.; MORRISON, SCOTT A.; SILLETT, T. SCOTT; GHALAMBOR, CAMERON K.; MALDONADO, JESUS E.; RICK, TORBEN C.; DAY, MITCH D.; POLATO, NICHOLAS R.; FITZPATRICK, SARAH W.; COONAN, TIMOTHY J.; CROOKS, KEVIN R.; DILLON, ADAM; GARCELON, DAVID K.; KING, JULIE L.; BOSER, CHRISTINA L.; GOULD, NICHOLAS; ANDELT, WILLIAM F.

    2016-01-01

    The evolutionary mechanisms generating the tremendous biodiversity of islands have long fascinated evolutionary biologists. Genetic drift and divergent selection are predicted to be strong on islands and both could drive population divergence and speciation. Alternatively, strong genetic drift may preclude adaptation. We conducted a genomic analysis to test the roles of genetic drift and divergent selection in causing genetic differentiation among populations of the island fox (Urocyon littoralis). This species consists of 6 subspecies, each of which occupies a different California Channel Island. Analysis of 5293 SNP loci generated using Restriction-site Associated DNA (RAD) sequencing found support for genetic drift as the dominant evolutionary mechanism driving population divergence among island fox populations. In particular, populations had exceptionally low genetic variation, small Ne (range = 2.1–89.7; median = 19.4), and significant genetic signatures of bottlenecks. Moreover, islands with the lowest genetic variation (and, by inference, the strongest historical genetic drift) were most genetically differentiated from mainland gray foxes, and vice versa, indicating genetic drift drives genome-wide divergence. Nonetheless, outlier tests identified 3.6–6.6% of loci as high FST outliers, suggesting that despite strong genetic drift, divergent selection contributes to population divergence. Patterns of similarity among populations based on high FST outliers mirrored patterns based on morphology, providing additional evidence that outliers reflect adaptive divergence. Extremely low genetic variation and small Ne in some island fox populations, particularly on San Nicolas Island, suggest that they may be vulnerable to fixation of deleterious alleles, decreased fitness, and reduced adaptive potential. PMID:26992010

  15. Adaptive divergence despite strong genetic drift: genomic analysis of the evolutionary mechanisms causing genetic differentiation in the island fox (Urocyon littoralis).

    Science.gov (United States)

    Funk, W Chris; Lovich, Robert E; Hohenlohe, Paul A; Hofman, Courtney A; Morrison, Scott A; Sillett, T Scott; Ghalambor, Cameron K; Maldonado, Jesus E; Rick, Torben C; Day, Mitch D; Polato, Nicholas R; Fitzpatrick, Sarah W; Coonan, Timothy J; Crooks, Kevin R; Dillon, Adam; Garcelon, David K; King, Julie L; Boser, Christina L; Gould, Nicholas; Andelt, William F

    2016-05-01

    The evolutionary mechanisms generating the tremendous biodiversity of islands have long fascinated evolutionary biologists. Genetic drift and divergent selection are predicted to be strong on islands and both could drive population divergence and speciation. Alternatively, strong genetic drift may preclude adaptation. We conducted a genomic analysis to test the roles of genetic drift and divergent selection in causing genetic differentiation among populations of the island fox (Urocyon littoralis). This species consists of six subspecies, each of which occupies a different California Channel Island. Analysis of 5293 SNP loci generated using Restriction-site Associated DNA (RAD) sequencing found support for genetic drift as the dominant evolutionary mechanism driving population divergence among island fox populations. In particular, populations had exceptionally low genetic variation, small Ne (range = 2.1-89.7; median = 19.4), and significant genetic signatures of bottlenecks. Moreover, islands with the lowest genetic variation (and, by inference, the strongest historical genetic drift) were most genetically differentiated from mainland grey foxes, and vice versa, indicating genetic drift drives genome-wide divergence. Nonetheless, outlier tests identified 3.6-6.6% of loci as high FST outliers, suggesting that despite strong genetic drift, divergent selection contributes to population divergence. Patterns of similarity among populations based on high FST outliers mirrored patterns based on morphology, providing additional evidence that outliers reflect adaptive divergence. Extremely low genetic variation and small Ne in some island fox populations, particularly on San Nicolas Island, suggest that they may be vulnerable to fixation of deleterious alleles, decreased fitness and reduced adaptive potential. © 2016 John Wiley & Sons Ltd.

  16. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

    Directory of Open Access Journals (Sweden)

    Thomas W Winkler

    2015-10-01

    Full Text Available Genome-wide association studies (GWAS have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI, a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE, sex-specific effects (G x SEX or age-specific effects that differed between men and women (G x AGE x SEX. For BMI, we identified 15 loci (11 previously established for main effects, four novel that showed significant (FDR<5% age-specific effects, of which 11 had larger effects in younger (<50y than in older adults (≥50y. No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

  17. Whole-genome sequencing and genetic variant analysis of a Quarter Horse mare.

    KAUST Repository

    Doan, Ryan; Cohen, Noah D; Sawyer, Jason; Ghaffari, Noushin; Johnson, Charlie D; Dindot, Scott V

    2012-01-01

    BACKGROUND: The catalog of genetic variants in the horse genome originates from a few select animals, the majority originating from the Thoroughbred mare used for the equine genome sequencing project. The purpose of this study was to identify genetic variants, including single nucleotide polymorphisms (SNPs), insertion/deletion polymorphisms (INDELs), and copy number variants (CNVs) in the genome of an individual Quarter Horse mare sequenced by next-generation sequencing. RESULTS: Using massively parallel paired-end sequencing, we generated 59.6 Gb of DNA sequence from a Quarter Horse mare resulting in an average of 24.7X sequence coverage. Reads were mapped to approximately 97% of the reference Thoroughbred genome. Unmapped reads were de novo assembled resulting in 19.1 Mb of new genomic sequence in the horse. Using a stringent filtering method, we identified 3.1 million SNPs, 193 thousand INDELs, and 282 CNVs. Genetic variants were annotated to determine their impact on gene structure and function. Additionally, we genotyped this Quarter Horse for mutations of known diseases and for variants associated with particular traits. Functional clustering analysis of genetic variants revealed that most of the genetic variation in the horse's genome was enriched in sensory perception, signal transduction, and immunity and defense pathways. CONCLUSIONS: This is the first sequencing of a horse genome by next-generation sequencing and the first genomic sequence of an individual Quarter Horse mare. We have increased the catalog of genetic variants for use in equine genomics by the addition of novel SNPs, INDELs, and CNVs. The genetic variants described here will be a useful resource for future studies of genetic variation regulating performance traits and diseases in equids.

  18. Whole-genome sequencing and genetic variant analysis of a Quarter Horse mare.

    KAUST Repository

    Doan, Ryan

    2012-02-17

    BACKGROUND: The catalog of genetic variants in the horse genome originates from a few select animals, the majority originating from the Thoroughbred mare used for the equine genome sequencing project. The purpose of this study was to identify genetic variants, including single nucleotide polymorphisms (SNPs), insertion/deletion polymorphisms (INDELs), and copy number variants (CNVs) in the genome of an individual Quarter Horse mare sequenced by next-generation sequencing. RESULTS: Using massively parallel paired-end sequencing, we generated 59.6 Gb of DNA sequence from a Quarter Horse mare resulting in an average of 24.7X sequence coverage. Reads were mapped to approximately 97% of the reference Thoroughbred genome. Unmapped reads were de novo assembled resulting in 19.1 Mb of new genomic sequence in the horse. Using a stringent filtering method, we identified 3.1 million SNPs, 193 thousand INDELs, and 282 CNVs. Genetic variants were annotated to determine their impact on gene structure and function. Additionally, we genotyped this Quarter Horse for mutations of known diseases and for variants associated with particular traits. Functional clustering analysis of genetic variants revealed that most of the genetic variation in the horse\\'s genome was enriched in sensory perception, signal transduction, and immunity and defense pathways. CONCLUSIONS: This is the first sequencing of a horse genome by next-generation sequencing and the first genomic sequence of an individual Quarter Horse mare. We have increased the catalog of genetic variants for use in equine genomics by the addition of novel SNPs, INDELs, and CNVs. The genetic variants described here will be a useful resource for future studies of genetic variation regulating performance traits and diseases in equids.

  19. SNP-based pathway enrichment analysis for genome-wide association studies

    Directory of Open Access Journals (Sweden)

    Potkin Steven G

    2011-04-01

    Full Text Available Abstract Background Recently we have witnessed a surge of interest in using genome-wide association studies (GWAS to discover the genetic basis of complex diseases. Many genetic variations, mostly in the form of single nucleotide polymorphisms (SNPs, have been identified in a wide spectrum of diseases, including diabetes, cancer, and psychiatric diseases. A common theme arising from these studies is that the genetic variations discovered by GWAS can only explain a small fraction of the genetic risks associated with the complex diseases. New strategies and statistical approaches are needed to address this lack of explanation. One such approach is the pathway analysis, which considers the genetic variations underlying a biological pathway, rather than separately as in the traditional GWAS studies. A critical challenge in the pathway analysis is how to combine evidences of association over multiple SNPs within a gene and multiple genes within a pathway. Most current methods choose the most significant SNP from each gene as a representative, ignoring the joint action of multiple SNPs within a gene. This approach leads to preferential identification of genes with a greater number of SNPs. Results We describe a SNP-based pathway enrichment method for GWAS studies. The method consists of the following two main steps: 1 for a given pathway, using an adaptive truncated product statistic to identify all representative (potentially more than one SNPs of each gene, calculating the average number of representative SNPs for the genes, then re-selecting the representative SNPs of genes in the pathway based on this number; and 2 ranking all selected SNPs by the significance of their statistical association with a trait of interest, and testing if the set of SNPs from a particular pathway is significantly enriched with high ranks using a weighted Kolmogorov-Smirnov test. We applied our method to two large genetically distinct GWAS data sets of schizophrenia, one

  20. a potential source of spurious associations in genome-wide ...

    Indian Academy of Sciences (India)

    2010-04-01

    Apr 1, 2010 ... Genome-wide association studies (GWAS) examine the entire human genome with the goal of identifying genetic variants. (usually single nucleotide polymorphisms (SNPs)) that are associated with phenotypic traits such as disease status and drug response. The discordance of significantly associated ...

  1. A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women

    Directory of Open Access Journals (Sweden)

    Kira C. Taylor

    2016-12-01

    Full Text Available Background: Osteoporosis is a major public health problem associated with excess disability and mortality. It is estimated that 50–70% of the variation in osteoporotic fracture risk is attributable to genetic factors. The purpose of this hypothesis-generating study was to identify possible genetic determinants of fracture among African American (AA women in a GWAS meta-analysis. Methods: Data on clinical fractures (all fractures except fingers, toes, face, skull or sternum were analyzed among AA female participants in the Women's Health Initiative (WHI (N = 8155, Cardiovascular Health Study (CHS (N = 504, BioVU (N = 704, Health ABC (N = 651, and the Johnston County Osteoarthritis Project (JoCoOA (N = 291. Affymetrix (WHI and Illumina (Health ABC, JoCoOA, BioVU, CHS GWAS panels were used for genotyping, and a 1:1 ratio of YRI:CEU HapMap haplotypes was used as an imputation reference panel. We used Cox proportional hazard models or logistic regression to evaluate the association of ~2.5 million SNPs with fracture risk, adjusting for ancestry, age, and geographic region where applicable. We conducted a fixed-effects, inverse variance-weighted meta-analysis. Genome-wide significance was set at P < 5 × 10−8. Results: One SNP, rs12775980 in an intron of SVIL on chromosome 10p11.2, reached genome-wide significance (P = 4.0 × 10−8. Although this SNP has a low minor allele frequency (0.03, there was no evidence for heterogeneity of effects across the studies (I2 = 0. This locus was not reported in any previous osteoporosis-related GWA studies. We also interrogated previously reported GWA-significant loci associated with fracture or bone mineral density in our data. One locus (SMOC1 generalized, but overall there was not substantial evidence of generalization. Possible reasons for the lack of generalization are discussed. Conclusion: This GWAS meta-analysis of fractures in African American women identified a potentially novel

  2. A comparison of multivariate genome-wide association methods

    DEFF Research Database (Denmark)

    Galesloot, Tessel E; Van Steen, Kristel; Kiemeney, Lambertus A L M

    2014-01-01

    Joint association analysis of multiple traits in a genome-wide association study (GWAS), i.e. a multivariate GWAS, offers several advantages over analyzing each trait in a separate GWAS. In this study we directly compared a number of multivariate GWAS methods using simulated data. We focused on six...... methods that are implemented in the software packages PLINK, SNPTEST, MultiPhen, BIMBAM, PCHAT and TATES, and also compared them to standard univariate GWAS, analysis of the first principal component of the traits, and meta-analysis of univariate results. We simulated data (N = 1000) for three...... for scenarios with an opposite sign of genetic and residual correlation. All multivariate analyses resulted in a higher power than univariate analyses, even when only one of the traits was associated with the QTL. Hence, use of multivariate GWAS methods can be recommended, even when genetic correlations between...

  3. Genome-wide analysis in Brazilian Xavante Indians reveals low degree of admixture.

    Science.gov (United States)

    Kuhn, Patricia C; Horimoto, Andréa R V Russo; Sanches, José Maurício; Vieira Filho, João Paulo B; Franco, Luciana; Fabbro, Amaury Dal; Franco, Laercio Joel; Pereira, Alexandre C; Moises, Regina S

    2012-01-01

    Characterization of population genetic variation and structure can be used as tools for research in human genetics and population isolates are of great interest. The aim of the present study was to characterize the genetic structure of Xavante Indians and compare it with other populations. The Xavante, an indigenous population living in Brazilian Central Plateau, is one of the largest native groups in Brazil. A subset of 53 unrelated subjects was selected from the initial sample of 300 Xavante Indians. Using 86,197 markers, Xavante were compared with all populations of HapMap Phase III and HGDP-CEPH projects and with a Southeast Brazilian population sample to establish its population structure. Principal Components Analysis showed that the Xavante Indians are concentrated in the Amerindian axis near other populations of known Amerindian ancestry such as Karitiana, Pima, Surui and Maya and a low degree of genetic admixture was observed. This is consistent with the historical records of bottlenecks experience and cultural isolation. By calculating pair-wise F(st) statistics we characterized the genetic differentiation between Xavante Indians and representative populations of the HapMap and from HGDP-CEPH project. We found that the genetic differentiation between Xavante Indians and populations of Ameridian, Asian, European, and African ancestry increased progressively. Our results indicate that the Xavante is a population that remained genetically isolated over the past decades and can offer advantages for genome-wide mapping studies of inherited disorders.

  4. Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases.

    Directory of Open Access Journals (Sweden)

    Vincent Plagnol

    2011-08-01

    Full Text Available The genetic basis of autoantibody production is largely unknown outside of associations located in the major histocompatibility complex (MHC human leukocyte antigen (HLA region. The aim of this study is the discovery of new genetic associations with autoantibody positivity using genome-wide association scan single nucleotide polymorphism (SNP data in type 1 diabetes (T1D patients with autoantibody measurements. We measured two anti-islet autoantibodies, glutamate decarboxylase (GADA, n = 2,506, insulinoma-associated antigen 2 (IA-2A, n = 2,498, antibodies to the autoimmune thyroid (Graves' disease (AITD autoantigen thyroid peroxidase (TPOA, n = 8,300, and antibodies against gastric parietal cells (PCA, n = 4,328 that are associated with autoimmune gastritis. Two loci passed a stringent genome-wide significance level (p<10(-10: 1q23/FCRL3 with IA-2A and 9q34/ABO with PCA. Eleven of 52 non-MHC T1D loci showed evidence of association with at least one autoantibody at a false discovery rate of 16%: 16p11/IL27-IA-2A, 2q24/IFIH1-IA-2A and PCA, 2q32/STAT4-TPOA, 10p15/IL2RA-GADA, 6q15/BACH2-TPOA, 21q22/UBASH3A-TPOA, 1p13/PTPN22-TPOA, 2q33/CTLA4-TPOA, 4q27/IL2/TPOA, 15q14/RASGRP1/TPOA, and 12q24/SH2B3-GADA and TPOA. Analysis of the TPOA-associated loci in 2,477 cases with Graves' disease identified two new AITD loci (BACH2 and UBASH3A.

  5. Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

    Science.gov (United States)

    Jackson, Anne U.; Monda, Keri L.; Kilpeläinen, Tuomas O.; Esko, Tõnu; Mägi, Reedik; Li, Shengxu; Workalemahu, Tsegaselassie; Feitosa, Mary F.; Croteau-Chonka, Damien C.; Day, Felix R.; Fall, Tove; Ferreira, Teresa; Gustafsson, Stefan; Locke, Adam E.; Mathieson, Iain; Scherag, Andre; Vedantam, Sailaja; Wood, Andrew R.; Liang, Liming; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Dermitzakis, Emmanouil T.; Dimas, Antigone S.; Karpe, Fredrik; Min, Josine L.; Nicholson, George; Clegg, Deborah J.; Person, Thomas; Krohn, Jon P.; Bauer, Sabrina; Buechler, Christa; Eisinger, Kristina; Bonnefond, Amélie; Froguel, Philippe; Hottenga, Jouke-Jan; Prokopenko, Inga; Waite, Lindsay L.; Harris, Tamara B.; Smith, Albert Vernon; Shuldiner, Alan R.; McArdle, Wendy L.; Caulfield, Mark J.; Munroe, Patricia B.; Grönberg, Henrik; Chen, Yii-Der Ida; Li, Guo; Beckmann, Jacques S.; Johnson, Toby; Thorsteinsdottir, Unnur; Teder-Laving, Maris; Khaw, Kay-Tee; Wareham, Nicholas J.; Zhao, Jing Hua; Amin, Najaf; Oostra, Ben A.; Kraja, Aldi T.; Province, Michael A.; Cupples, L. Adrienne; Heard-Costa, Nancy L.; Kaprio, Jaakko; Ripatti, Samuli; Surakka, Ida; Collins, Francis S.; Saramies, Jouko; Tuomilehto, Jaakko; Jula, Antti; Salomaa, Veikko; Erdmann, Jeanette; Hengstenberg, Christian; Loley, Christina; Schunkert, Heribert; Lamina, Claudia; Wichmann, H. Erich; Albrecht, Eva; Gieger, Christian; Hicks, Andrew A.; Johansson, Åsa; Pramstaller, Peter P.; Kathiresan, Sekar; Speliotes, Elizabeth K.; Penninx, Brenda; Hartikainen, Anna-Liisa; Jarvelin, Marjo-Riitta; Gyllensten, Ulf; Boomsma, Dorret I.; Campbell, Harry; Wilson, James F.; Chanock, Stephen J.; Farrall, Martin; Goel, Anuj; Medina-Gomez, Carolina; Rivadeneira, Fernando; Estrada, Karol; Uitterlinden, André G.; Hofman, Albert; Zillikens, M. Carola; den Heijer, Martin; Kiemeney, Lambertus A.; Maschio, Andrea; Hall, Per; Tyrer, Jonathan; Teumer, Alexander; Völzke, Henry; Kovacs, Peter; Tönjes, Anke; Mangino, Massimo; Spector, Tim D.; Hayward, Caroline; Rudan, Igor; Hall, Alistair S.; Samani, Nilesh J.; Attwood, Antony Paul; Sambrook, Jennifer G.; Hung, Joseph; Palmer, Lyle J.; Lokki, Marja-Liisa; Sinisalo, Juha; Boucher, Gabrielle; Huikuri, Heikki; Lorentzon, Mattias; Ohlsson, Claes; Eklund, Niina; Eriksson, Johan G.; Barlassina, Cristina; Rivolta, Carlo; Nolte, Ilja M.; Snieder, Harold; Van der Klauw, Melanie M.; Van Vliet-Ostaptchouk, Jana V.; Gejman, Pablo V.; Shi, Jianxin; Jacobs, Kevin B.; Wang, Zhaoming; Bakker, Stephan J. L.; Mateo Leach, Irene; Navis, Gerjan; van der Harst, Pim; Martin, Nicholas G.; Medland, Sarah E.; Montgomery, Grant W.; Yang, Jian; Chasman, Daniel I.; Ridker, Paul M.; Rose, Lynda M.; Lehtimäki, Terho; Raitakari, Olli; Absher, Devin; Iribarren, Carlos; Basart, Hanneke; Hovingh, Kees G.; Hyppönen, Elina; Power, Chris; Anderson, Denise; Beilby, John P.; Hui, Jennie; Jolley, Jennifer; Sager, Hendrik; Bornstein, Stefan R.; Schwarz, Peter E. H.; Kristiansson, Kati; Perola, Markus; Lindström, Jaana; Swift, Amy J.; Uusitupa, Matti; Atalay, Mustafa; Lakka, Timo A.; Rauramaa, Rainer; Bolton, Jennifer L.; Fowkes, Gerry; Fraser, Ross M.; Price, Jackie F.; Fischer, Krista; KrjutÅ¡kov, Kaarel; Metspalu, Andres; Mihailov, Evelin; Langenberg, Claudia; Luan, Jian'an; Ong, Ken K.; Chines, Peter S.; Keinanen-Kiukaanniemi, Sirkka M.; Saaristo, Timo E.; Edkins, Sarah; Franks, Paul W.; Hallmans, Göran; Shungin, Dmitry; Morris, Andrew David; Palmer, Colin N. A.; Erbel, Raimund; Moebus, Susanne; Nöthen, Markus M.; Pechlivanis, Sonali; Hveem, Kristian; Narisu, Narisu; Hamsten, Anders; Humphries, Steve E.; Strawbridge, Rona J.; Tremoli, Elena; Grallert, Harald; Thorand, Barbara; Illig, Thomas; Koenig, Wolfgang; Müller-Nurasyid, Martina; Peters, Annette; Boehm, Bernhard O.; Kleber, Marcus E.; März, Winfried; Winkelmann, Bernhard R.; Kuusisto, Johanna; Laakso, Markku; Arveiler, Dominique; Cesana, Giancarlo; Kuulasmaa, Kari; Virtamo, Jarmo; Yarnell, John W. G.; Kuh, Diana; Wong, Andrew; Lind, Lars; de Faire, Ulf; Gigante, Bruna; Magnusson, Patrik K. E.; Pedersen, Nancy L.; Dedoussis, George; Dimitriou, Maria; Kolovou, Genovefa; Kanoni, Stavroula; Stirrups, Kathleen; Bonnycastle, Lori L.; Njølstad, Inger; Wilsgaard, Tom; Ganna, Andrea; Rehnberg, Emil; Hingorani, Aroon; Kivimaki, Mika; Kumari, Meena; Assimes, Themistocles L.; Barroso, Inês; Boehnke, Michael; Borecki, Ingrid B.; Deloukas, Panos; Fox, Caroline S.; Frayling, Timothy; Groop, Leif C.; Haritunians, Talin; Hunter, David; Ingelsson, Erik; Kaplan, Robert; Mohlke, Karen L.; O'Connell, Jeffrey R.; Schlessinger, David; Strachan, David P.; Stefansson, Kari; van Duijn, Cornelia M.; Abecasis, Gonçalo R.; McCarthy, Mark I.; Hirschhorn, Joel N.; Qi, Lu; Loos, Ruth J. F.; Lindgren, Cecilia M.; North, Kari E.; Heid, Iris M.

    2013-01-01

    Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10−8), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits. PMID:23754948

  6. Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.

    Directory of Open Access Journals (Sweden)

    Joshua C Randall

    2013-06-01

    Full Text Available Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals and took forward 348 SNPs into follow-up (additional 137,052 individuals in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%, including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9 and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG, all of which were genome-wide significant in women (P<5×10(-8, but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

  7. Adiponectin Concentrations: A Genome-wide Association Study

    Science.gov (United States)

    Jee, Sun Ha; Sull, Jae Woong; Lee, Jong-Eun; Shin, Chol; Park, Jongkeun; Kimm, Heejin; Cho, Eun-Young; Shin, Eun-Soon; Yun, Ji Eun; Park, Ji Wan; Kim, Sang Yeun; Lee, Sun Ju; Jee, Eun Jung; Baik, Inkyung; Kao, Linda; Yoon, Sungjoo Kim; Jang, Yangsoo; Beaty, Terri H.

    2010-01-01

    Adiponectin is associated with obesity and insulin resistance. To date, there has been no genome-wide association study (GWAS) of adiponectin levels in Asians. Here we present a GWAS of a cohort of Korean volunteers. A total of 4,001 subjects were genotyped by using a genome-wide marker panel in a two-stage design (979 subjects initially and 3,022 in a second stage). Another 2,304 subjects were used for follow-up replication studies with selected markers. In the discovery phase, the top SNP associated with mean log adiponectin was rs3865188 in CDH13 on chromosome 16 (p = 1.69 × 10−15 in the initial sample, p = 6.58 × 10−39 in the second genome-wide sample, and p = 2.12 × 10−32 in the replication sample). The meta-analysis p value for rs3865188 in all 6,305 individuals was 2.82 × 10−83. The association of rs3865188 with high-molecular-weight adiponectin (p = 7.36 × 10−58) was even stronger in the third sample. A reporter assay that evaluated the effects of a CDH13 promoter SNP in complete linkage disequilibrium with rs3865188 revealed that the major allele increased expression 2.2-fold. This study clearly shows that genetic variants in CDH13 influence adiponectin levels in Korean adults. PMID:20887962

  8. Gene Set Analyses of Genome-Wide Association Studies on 49 Quantitative Traits Measured in a Single Genetic Epidemiology Dataset

    Directory of Open Access Journals (Sweden)

    Jihye Kim

    2013-09-01

    Full Text Available Gene set analysis is a powerful tool for interpreting a genome-wide association study result and is gaining popularity these days. Comparison of the gene sets obtained for a variety of traits measured from a single genetic epidemiology dataset may give insights into the biological mechanisms underlying these traits. Based on the previously published single nucleotide polymorphism (SNP genotype data on 8,842 individuals enrolled in the Korea Association Resource project, we performed a series of systematic genome-wide association analyses for 49 quantitative traits of basic epidemiological, anthropometric, or blood chemistry parameters. Each analysis result was subjected to subsequent gene set analyses based on Gene Ontology (GO terms using gene set analysis software, GSA-SNP, identifying a set of GO terms significantly associated to each trait (pcorr < 0.05. Pairwise comparison of the traits in terms of the semantic similarity in their GO sets revealed surprising cases where phenotypically uncorrelated traits showed high similarity in terms of biological pathways. For example, the pH level was related to 7 other traits that showed low phenotypic correlations with it. A literature survey implies that these traits may be regulated partly by common pathways that involve neuronal or nerve systems.

  9. Development and Integration of Genome-Wide Polymorphic Microsatellite Markers onto a Reference Linkage Map for Constructing a High-Density Genetic Map of Chickpea.

    Directory of Open Access Journals (Sweden)

    Yash Paul Khajuria

    Full Text Available The identification of informative in silico polymorphic genomic and genic microsatellite markers by comparing the genome and transcriptome sequences of crop genotypes is a rapid, cost-effective and non-laborious approach for large-scale marker validation and genotyping applications, including construction of high-density genetic maps. We designed 1494 markers, including 1016 genomic and 478 transcript-derived microsatellite markers showing in-silico fragment length polymorphism between two parental genotypes (Cicer arietinum ICC4958 and C. reticulatum PI489777 of an inter-specific reference mapping population. High amplification efficiency (87%, experimental validation success rate (81% and polymorphic potential (55% of these microsatellite markers suggest their effective use in various applications of chickpea genetics and breeding. Intra-specific polymorphic potential (48% detected by microsatellite markers in 22 desi and kabuli chickpea genotypes was lower than inter-specific polymorphic potential (59%. An advanced, high-density, integrated and inter-specific chickpea genetic map (ICC4958 x PI489777 having 1697 map positions spanning 1061.16 cM with an average inter-marker distance of 0.625 cM was constructed by assigning 634 novel informative transcript-derived and genomic microsatellite markers on eight linkage groups (LGs of our prior documented, 1063 marker-based genetic map. The constructed genome map identified 88, including four major (7-23 cM longest high-resolution genomic regions on LGs 3, 5 and 8, where the maximum number of novel genomic and genic microsatellite markers were specifically clustered within 1 cM genetic distance. It was for the first time in chickpea that in silico FLP analysis at genome-wide level was carried out and such a large number of microsatellite markers were identified, experimentally validated and further used in genetic mapping. To best of our knowledge, in the presently constructed genetic map, we mapped

  10. Meta-analysis of genome-wide association studies for personality

    NARCIS (Netherlands)

    M.H.M. de Moor; P.T. Costa Jr; A. Terracciano; R.F. Krueger; E.J.C. de Geus (Eco); T. Toshiko; B.W.J.H. Penninx (Brenda); T. Esko; P.A.F. Madden (Pamela); J. Derringer; N. Amin (Najaf); G.A.H.M. Willemsen (Gonneke); J.J. Hottenga (Jouke Jan); M.A. Distel (Marijn); M. Uda (Manuela); S. Sanna (Serena); P. Spinhoven; C.A. Hartman; P.F. Sullivan (Patrick); A. Realo; J. Allik; A.C. Heath; M.L. Pergadia; P. Lin; R. Grucza; T. Nutile; M. Ciullo; D. Rujescu (Dan); I. Giegling (Ina); B. Konte; E. Widen (Elisabeth); D.L. Cousminer (Diana); J.G. Eriksson; A. Palotie; L. Peltonen; M. Luciano (Michelle); A. Tenesa (Albert); G. Davies; L.M. Lopez; N.K. Hansell (Narelle); S.E. Medland (Sarah Elizabeth); L. Ferrucci; D. Schlessinger; G.W. Montgomery; M.J. Wright (Margaret); Y.S. Aulchenko (Yurii); A.C.J.W. Janssens (Cécile); B.A. Oostra (Ben); A. Metspalu (Andres); I.J. Deary; K. Räikkönen (Katri); L.J. Bierut (Laura); N.G. Martin; C.M. van Duijn (Cornelia); D.I. Boomsma (Dorret); G.R. Abecasis (Gonçalo); A. Agrawal (Arpana)

    2012-01-01

    textabstractPersonality can be thought of as a set of characteristics that influence people's thoughts, feelings and behavior across a variety of settings. Variation in personality is predictive of many outcomes in life, including mental health. Here we report on a meta-analysis of genome-wide

  11. Investigation of Maternal Genotype Effects in Autism by Genome-Wide Association

    Science.gov (United States)

    Yuan, Han; Dougherty, Joseph D.

    2014-01-01

    probands as cases and either fathers of probands or normal females as controls. Autism Genetic Resource Exchange (AGRE) and Illumina Genotype Control Database (iCon) were used as our discovery cohort (n=1616). The same analysis was then replicated on Simon Simplex Collection (SSC) and Study of Addiction: Genetics and Environment (SAGE) datasets (n=2732). We did not identify any SNP that reached genome-wide significance (p<10−8) and thus a common variant of large effect is unlikely. However, there was evidence for the possibility of a large number of alleles of effective size marginally below our power to detect. PMID:24574247

  12. Efficient genome-wide genotyping strategies and data integration in crop plants.

    Science.gov (United States)

    Torkamaneh, Davoud; Boyle, Brian; Belzile, François

    2018-03-01

    Next-generation sequencing (NGS) has revolutionized plant and animal research by providing powerful genotyping methods. This review describes and discusses the advantages, challenges and, most importantly, solutions to facilitate data processing, the handling of missing data, and cross-platform data integration. Next-generation sequencing technologies provide powerful and flexible genotyping methods to plant breeders and researchers. These methods offer a wide range of applications from genome-wide analysis to routine screening with a high level of accuracy and reproducibility. Furthermore, they provide a straightforward workflow to identify, validate, and screen genetic variants in a short time with a low cost. NGS-based genotyping methods include whole-genome re-sequencing, SNP arrays, and reduced representation sequencing, which are widely applied in crops. The main challenges facing breeders and geneticists today is how to choose an appropriate genotyping method and how to integrate genotyping data sets obtained from various sources. Here, we review and discuss the advantages and challenges of several NGS methods for genome-wide genetic marker development and genotyping in crop plants. We also discuss how imputation methods can be used to both fill in missing data in genotypic data sets and to integrate data sets obtained using different genotyping tools. It is our hope that this synthetic view of genotyping methods will help geneticists and breeders to integrate these NGS-based methods in crop plant breeding and research.

  13. Genome-wide screening identifies a KCNIP1 copy number variant as a genetic predictor for atrial fibrillation

    Science.gov (United States)

    Tsai, Chia-Ti; Hsieh, Chia-Shan; Chang, Sheng-Nan; Chuang, Eric Y.; Ueng, Kwo-Chang; Tsai, Chin-Feng; Lin, Tsung-Hsien; Wu, Cho-Kai; Lee, Jen-Kuang; Lin, Lian-Yu; Wang, Yi-Chih; Yu, Chih-Chieh; Lai, Ling-Ping; Tseng, Chuen-Den; Hwang, Juey-Jen; Chiang, Fu-Tien; Lin, Jiunn-Lee

    2016-01-01

    Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Previous genome-wide association studies had identified single-nucleotide polymorphisms in several genomic regions to be associated with AF. In human genome, copy number variations (CNVs) are known to contribute to disease susceptibility. Using a genome-wide multistage approach to identify AF susceptibility CNVs, we here show a common 4,470-bp diallelic CNV in the first intron of potassium interacting channel 1 gene (KCNIP1) is strongly associated with AF in Taiwanese populations (odds ratio=2.27 for insertion allele; P=6.23 × 10−24). KCNIP1 insertion is associated with higher KCNIP1 mRNA expression. KCNIP1-encoded protein potassium interacting channel 1 (KCHIP1) is physically associated with potassium Kv channels and modulates atrial transient outward current in cardiac myocytes. Overexpression of KCNIP1 results in inducible AF in zebrafish. In conclusions, a common CNV in KCNIP1 gene is a genetic predictor of AF risk possibly pointing to a functional pathway. PMID:26831368

  14. Genome-wide distribution of genetic diversity and linkage disequilibrium in a mass-selected population of maritime pine

    Science.gov (United States)

    2014-01-01

    Background The accessibility of high-throughput genotyping technologies has contributed greatly to the development of genomic resources in non-model organisms. High-density genotyping arrays have only recently been developed for some economically important species such as conifers. The potential for using genomic technologies in association mapping and breeding depends largely on the genome wide patterns of diversity and linkage disequilibrium in current breeding populations. This study aims to deepen our knowledge regarding these issues in maritime pine, the first species used for reforestation in south western Europe. Results Using a new map merging algorithm, we first established a 1,712 cM composite linkage map (comprising 1,838 SNP markers in 12 linkage groups) by bringing together three already available genetic maps. Using rigorous statistical testing based on kernel density estimation and resampling we identified cold and hot spots of recombination. In parallel, 186 unrelated trees of a mass-selected population were genotyped using a 12k-SNP array. A total of 2,600 informative SNPs allowed to describe historical recombination, genetic diversity and genetic structure of this recently domesticated breeding pool that forms the basis of much of the current and future breeding of this species. We observe very low levels of population genetic structure and find no evidence that artificial selection has caused a reduction in genetic diversity. By combining these two pieces of information, we provided the map position of 1,671 SNPs corresponding to 1,192 different loci. This made it possible to analyze the spatial pattern of genetic diversity (H e ) and long distance linkage disequilibrium (LD) along the chromosomes. We found no particular pattern in the empirical variogram of H e across the 12 linkage groups and, as expected for an outcrossing species with large effective population size, we observed an almost complete lack of long distance LD. Conclusions These

  15. Genome-wide identification of the regulatory targets of a transcription factor using biochemical characterization and computational genomic analysis

    Directory of Open Access Journals (Sweden)

    Jolly Emmitt R

    2005-11-01

    Full Text Available Abstract Background A major challenge in computational genomics is the development of methodologies that allow accurate genome-wide prediction of the regulatory targets of a transcription factor. We present a method for target identification that combines experimental characterization of binding requirements with computational genomic analysis. Results Our method identified potential target genes of the transcription factor Ndt80, a key transcriptional regulator involved in yeast sporulation, using the combined information of binding affinity, positional distribution, and conservation of the binding sites across multiple species. We have also developed a mathematical approach to compute the false positive rate and the total number of targets in the genome based on the multiple selection criteria. Conclusion We have shown that combining biochemical characterization and computational genomic analysis leads to accurate identification of the genome-wide targets of a transcription factor. The method can be extended to other transcription factors and can complement other genomic approaches to transcriptional regulation.

  16. Wrapper-based selection of genetic features in genome-wide association studies through fast matrix operations

    Science.gov (United States)

    2012-01-01

    Background Through the wealth of information contained within them, genome-wide association studies (GWAS) have the potential to provide researchers with a systematic means of associating genetic variants with a wide variety of disease phenotypes. Due to the limitations of approaches that have analyzed single variants one at a time, it has been proposed that the genetic basis of these disorders could be determined through detailed analysis of the genetic variants themselves and in conjunction with one another. The construction of models that account for these subsets of variants requires methodologies that generate predictions based on the total risk of a particular group of polymorphisms. However, due to the excessive number of variants, constructing these types of models has so far been computationally infeasible. Results We have implemented an algorithm, known as greedy RLS, that we use to perform the first known wrapper-based feature selection on the genome-wide level. The running time of greedy RLS grows linearly in the number of training examples, the number of features in the original data set, and the number of selected features. This speed is achieved through computational short-cuts based on matrix calculus. Since the memory consumption in present-day computers can form an even tighter bottleneck than running time, we also developed a space efficient variation of greedy RLS which trades running time for memory. These approaches are then compared to traditional wrapper-based feature selection implementations based on support vector machines (SVM) to reveal the relative speed-up and to assess the feasibility of the new algorithm. As a proof of concept, we apply greedy RLS to the Hypertension – UK National Blood Service WTCCC dataset and select the most predictive variants using 3-fold external cross-validation in less than 26 minutes on a high-end desktop. On this dataset, we also show that greedy RLS has a better classification performance on independent

  17. An innovative procedure of genome-wide association analysis fits studies on germplasm population and plant breeding.

    Science.gov (United States)

    He, Jianbo; Meng, Shan; Zhao, Tuanjie; Xing, Guangnan; Yang, Shouping; Li, Yan; Guan, Rongzhan; Lu, Jiangjie; Wang, Yufeng; Xia, Qiuju; Yang, Bing; Gai, Junyi

    2017-11-01

    The innovative RTM-GWAS procedure provides a relatively thorough detection of QTL and their multiple alleles for germplasm population characterization, gene network identification, and genomic selection strategy innovation in plant breeding. The previous genome-wide association studies (GWAS) have been concentrated on finding a handful of major quantitative trait loci (QTL), but plant breeders are interested in revealing the whole-genome QTL-allele constitution in breeding materials/germplasm (in which tremendous historical allelic variation has been accumulated) for genome-wide improvement. To match this requirement, two innovations were suggested for GWAS: first grouping tightly linked sequential SNPs into linkage disequilibrium blocks (SNPLDBs) to form markers with multi-allelic haplotypes, and second utilizing two-stage association analysis for QTL identification, where the markers were preselected by single-locus model followed by multi-locus multi-allele model stepwise regression. Our proposed GWAS procedure is characterized as a novel restricted two-stage multi-locus multi-allele GWAS (RTM-GWAS, https://github.com/njau-sri/rtm-gwas ). The Chinese soybean germplasm population (CSGP) composed of 1024 accessions with 36,952 SNPLDBs (generated from 145,558 SNPs, with reduced linkage disequilibrium decay distance) was used to demonstrate the power and efficiency of RTM-GWAS. Using the CSGP marker information, simulation studies demonstrated that RTM-GWAS achieved the highest QTL detection power and efficiency compared with the previous procedures, especially under large sample size and high trait heritability conditions. A relatively thorough detection of QTL with their multiple alleles was achieved by RTM-GWAS compared with the linear mixed model method on 100-seed weight in CSGP. A QTL-allele matrix (402 alleles of 139 QTL × 1024 accessions) was established as a compact form of the population genetic constitution. The 100-seed weight QTL-allele matrix was

  18. Genome-Wide Meta-Analysis of Sciatica in Finnish Population.

    Directory of Open Access Journals (Sweden)

    Susanna Lemmelä

    Full Text Available Sciatica or the sciatic syndrome is a common and often disabling low back disorder in the working-age population. It has a relatively high heritability but poorly understood molecular mechanisms. The Finnish population is a genetic isolate where small founder population and bottleneck events have led to enrichment of certain rare and low frequency variants. We performed here the first genome-wide association (GWAS and meta-analysis of sciatica. The meta-analysis was conducted across two GWAS covering 291 Finnish sciatica cases and 3671 controls genotyped and imputed at 7.7 million autosomal variants. The most promising loci (p<1x10-6 were replicated in 776 Finnish sciatica patients and 18,489 controls. We identified five intragenic variants, with relatively low frequencies, at two novel loci associated with sciatica at genome-wide significance. These included chr9:14344410:I (rs71321981 at 9p22.3 (NFIB gene; p = 1.30x10-8, MAF = 0.08 and four variants at 15q21.2: rs145901849, rs80035109, rs190200374 and rs117458827 (MYO5A; p = 1.34x10-8, MAF = 0.06; p = 2.32x10-8, MAF = 0.07; p = 3.85x10-8, MAF = 0.06; p = 4.78x10-8, MAF = 0.07, respectively. The most significant association in the meta-analysis, a single base insertion rs71321981 within the regulatory region of the transcription factor NFIB, replicated in an independent Finnish population sample (p = 0.04. Despite identifying 15q21.2 as a promising locus, we were not able to replicate it. It was differentiated; the lead variants within 15q21.2 were more frequent in Finland (6-7% than in other European populations (1-2%. Imputation accuracies of the three significantly associated variants (chr9:14344410:I, rs190200374, and rs80035109 were validated by genotyping. In summary, our results suggest a novel locus, 9p22.3 (NFIB, which may be involved in susceptibility to sciatica. In addition, another locus, 15q21.2, emerged as a promising one, but failed to replicate.

  19. Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

    DEFF Research Database (Denmark)

    Randall, Joshua C; Winkler, Thomas W; Kutalik, Zoltán

    2013-01-01

    Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133...

  20. Identification of shared genetic susceptibility locus for coronary artery disease, type 2 diabetes and obesity: a meta-analysis of genome-wide studies

    Directory of Open Access Journals (Sweden)

    Wu Chaoneng

    2012-06-01

    Full Text Available Abstract Type 2 diabetes (2DM, obesity, and coronary artery disease (CAD are frequently coexisted being as key components of metabolic syndrome. Whether there is shared genetic background underlying these diseases remained unclear. We performed a meta-analysis of 35 genome screens for 2DM, 36 for obesity or body mass index (BMI-defined obesity, and 21 for CAD using genome search meta-analysis (GSMA, which combines linkage results to identify regions with only weak evidence and provide genetic interactions among different diseases. For each study, 120 genomic bins of approximately 30 cM were defined and ranked according to the best linkage evidence within each bin. For each disease, bin 6.2 achieved genomic significanct evidence, and bin 9.3, 10.5, 16.3 reached suggestive level for 2DM. Bin 11.2 and 16.3, and bin 10.5 and 9.3, reached suggestive evidence for obesity and CAD respectively. In pooled all three diseases, bin 9.3 and 6.5 reached genomic significant and suggestive evidence respectively, being relatively much weaker for 2DM/CAD or 2DM/obesity or CAD/obesity. Further, genomewide significant evidence was observed of bin 16.3 and 4.5 for 2DM/obesity, which is decreased when CAD was added. These findings indicated that bin 9.3 and 6.5 are most likely to be shared by 2DM, obesity and CAD. And bin 16.3 and 4.5 are potentially common regions to 2DM and obesity only. The observed shared susceptibility regions imply a partly overlapping genetic aspects of disease development. Fine scanning of these regions will definitely identify more susceptibility genes and causal variants.

  1. Genome wide selection in Citrus breeding.

    Science.gov (United States)

    Gois, I B; Borém, A; Cristofani-Yaly, M; de Resende, M D V; Azevedo, C F; Bastianel, M; Novelli, V M; Machado, M A

    2016-10-17

    Genome wide selection (GWS) is essential for the genetic improvement of perennial species such as Citrus because of its ability to increase gain per unit time and to enable the efficient selection of characteristics with low heritability. This study assessed GWS efficiency in a population of Citrus and compared it with selection based on phenotypic data. A total of 180 individual trees from a cross between Pera sweet orange (Citrus sinensis Osbeck) and Murcott tangor (Citrus sinensis Osbeck x Citrus reticulata Blanco) were evaluated for 10 characteristics related to fruit quality. The hybrids were genotyped using 5287 DArT_seq TM (diversity arrays technology) molecular markers and their effects on phenotypes were predicted using the random regression - best linear unbiased predictor (rr-BLUP) method. The predictive ability, prediction bias, and accuracy of GWS were estimated to verify its effectiveness for phenotype prediction. The proportion of genetic variance explained by the markers was also computed. The heritability of the traits, as determined by markers, was 16-28%. The predictive ability of these markers ranged from 0.53 to 0.64, and the regression coefficients between predicted and observed phenotypes were close to unity. Over 35% of the genetic variance was accounted for by the markers. Accuracy estimates with GWS were lower than those obtained by phenotypic analysis; however, GWS was superior in terms of genetic gain per unit time. Thus, GWS may be useful for Citrus breeding as it can predict phenotypes early and accurately, and reduce the length of the selection cycle. This study demonstrates the feasibility of genomic selection in Citrus.

  2. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1.

    Science.gov (United States)

    de Boer, Ynto S; van Gerven, Nicole M F; Zwiers, Antonie; Verwer, Bart J; van Hoek, Bart; van Erpecum, Karel J; Beuers, Ulrich; van Buuren, Henk R; Drenth, Joost P H; den Ouden, Jannie W; Verdonk, Robert C; Koek, Ger H; Brouwer, Johannes T; Guichelaar, Maureen M J; Vrolijk, Jan M; Kraal, Georg; Mulder, Chris J J; van Nieuwkerk, Carin M J; Fischer, Janett; Berg, Thomas; Stickel, Felix; Sarrazin, Christoph; Schramm, Christoph; Lohse, Ansgar W; Weiler-Normann, Christina; Lerch, Markus M; Nauck, Matthias; Völzke, Henry; Homuth, Georg; Bloemena, Elisabeth; Verspaget, Hein W; Kumar, Vinod; Zhernakova, Alexandra; Wijmenga, Cisca; Franke, Lude; Bouma, Gerd

    2014-08-01

    Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. We used a genome-wide approach to identify genetic variants that predispose individuals to AIH. We performed a genome-wide association study of 649 adults in The Netherlands with AIH type 1 and 13,436 controls. Initial associations were further analyzed in an independent replication panel comprising 451 patients with AIH type 1 in Germany and 4103 controls. We also performed an association analysis in the discovery cohort using imputed genotypes of the major histocompatibility complex region. We associated AIH with a variant in the major histocompatibility complex region at rs2187668 (P = 1.5 × 10(-78)). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3 × 10(-49)) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8 × 10(-18)) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P = 7.7 × 10(-8)) and CARD10 (rs6000782, 22q13.1; P = 3.0 × 10(-6)). In addition, strong inflation of association signal was found with single-nucleotide polymorphisms associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with single-nucleotide polymorphisms associated with other genetic traits. In a genome-wide association study, we associated AIH type 1 with variants in the major histocompatibility complex region, and identified variants of SH2B3and CARD10 as likely risk factors. These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

  3. Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults

    NARCIS (Netherlands)

    Graff, Mariaelisa; Scott, Robert A; Justice, Anne E; Young, Kristin L; Feitosa, Mary F; Barata, Llilda; Winkler, Thomas W; Chu, Audrey Y; Mahajan, Anubha; Hadley, David; Xue, Luting; Workalemahu, Tsegaselassie; Heard-Costa, Nancy L; den Hoed, Marcel; Ahluwalia, Tarunveer S; Qi, Qibin; Ngwa, Julius S; Renström, Frida; Quaye, Lydia; Eicher, John D; Hayes, James E; Cornelis, Marilyn; Kutalik, Zoltan; Lim, Elise; Luan, Jian'an; Huffman, Jennifer E; Zhang, Weihua; Zhao, Wei; Griffin, Paula J; Haller, Toomas; Ahmad, Shafqat; Marques-Vidal, Pedro M; Bien, Stephanie; Yengo, Loic; Teumer, Alexander; Smith, Albert Vernon; Kumari, Meena; Harder, Marie Neergaard; Justesen, Johanne Marie; Kleber, Marcus E; Hollensted, Mette; Lohman, Kurt; Rivera, Natalia V; Whitfield, John B; Zhao, Jing Hua; Stringham, Heather M; Lyytikäinen, Leo-Pekka; Huppertz, Charlotte; Willemsen, Gonneke; Peyrot, Wouter J; Wu, Ying; Kristiansson, Kati; Demirkan, Ayse; Fornage, Myriam; Hassinen, Maija; Bielak, Lawrence F; Cadby, Gemma; Tanaka, Toshiko; Mägi, Reedik; van der Most, Peter J; Jackson, Anne U; Bragg-Gresham, Jennifer L; Vitart, Veronique; Marten, Jonathan; Navarro, Pau; Bellis, Claire; Pasko, Dorota; Johansson, Åsa; Snitker, Søren; Cheng, Ching-Yu; Eriksson, Joel; Lim, Unhee; Aadahl, Mette; Adair, Linda S; Amin, Najaf; Balkau, Beverley; Auvinen, Juha; Beilby, John; Bergman, Richard N; Bergmann, Sven; Bertoni, Alain G; Blangero, John; Bonnefond, Amélie; Bonnycastle, Lori L; Borja, Judith B; Brage, Søren; Busonero, Fabio; Buyske, Steve; Campbell, Harry; Chines, Peter S; Collins, Francis S; Corre, Tanguy; Smith, George Davey; Delgado, Graciela E; Dueker, Nicole; Dörr, Marcus; Ebeling, Tapani; Eiriksdottir, Gudny; Esko, Tõnu; Faul, Jessica D; Fu, Mao; Færch, Kristine; Gieger, Christian; Gläser, Sven; Gong, Jian; Gordon-Larsen, Penny; Grallert, Harald; Grammer, Tanja B; Grarup, Niels; van Grootheest, Gerard; Harald, Kennet; Hastie, Nicholas D; Havulinna, Aki S; Hernandez, Dena G; Hindorff, Lucia; Hocking, Lynne J; Holmens, Oddgeir L; Holzapfel, Christina; Hottenga, Jouke Jan; Huang, Jie; Huang, Tao; Hui, Jennie; Huth, Cornelia; Hutri-Kähönen, Nina; James, Alan L; Jansson, John-Olov; Jhun, Min A; Juonala, Markus; Kinnunen, Leena; Koistinen, Heikki A; Kolcic, Ivana; Komulainen, Pirjo; Kuusisto, Johanna; Kvaløy, Kirsti; Kähönen, Mika; Lakka, Timo A; Launer, Lenore J; Lehne, Benjamin; Lindgren, Cecilia M; Lorentzon, Mattias; Luben, Robert; Marre, Michel; Milaneschi, Yuri; Monda, Keri L; Montgomery, Grant W; De Moor, Marleen H M; Mulas, Antonella; Müller-Nurasyid, Martina; Musk, A.W.; Männikkö, Reija; Männistö, Satu; Narisu, Narisu; Nauck, Matthias; Nettleton, Jennifer A; Nolte, Ilja M; Oldehinkel, Albertine J; Olden, Matthias; Ong, Ken K; Padmanabhan, Sandosh; Paternoster, Lavinia; Perez, Jeremiah; Perola, Markus; Peters, Annette; Peters, Ulrike; Peyser, Patricia A; Prokopenko, Inga; Puolijoki, Hannu; Raitakari, Olli T; Rankinen, Tuomo; Rasmussen-Torvik, Laura J; Rawal, Rajesh; Ridker, Paul M; Rose, Lynda M; Rudan, Igor; Sarti, Cinzia; Sarzynski, Mark A; Savonen, Kai; Scott, William R; Sanna, Serena; Shuldiner, Alan R; Sidney, Steve; Silbernagel, Günther; Smith, Blair H; Smith, Jennifer A; Snieder, Harold; Stančáková, Alena; Sternfeld, Barbara; Swift, Amy J; Tammelin, Tuija; Tan, Sian-Tsung; Thorand, Barbara; Thuillier, Dorothée; Vandenput, Liesbeth; Vestergaard, Henrik; van Vliet-Ostaptchouk, Jana V; Vohl, Marie-Claude; Völker, Uwe; Waeber, Gérard; Walker, Mark; Wild, Sarah; Wong, Andrew; Wright, Alan F; Zillikens, M Carola; Zubair, Niha; Haiman, Christopher A; Lemarchand, Loic; Gyllensten, Ulf; Ohlsson, Claes; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, André G; Pérusse, Louis; Wilson, James F; Hayward, Caroline; Polasek, Ozren; Cucca, Francesco; Hveem, Kristian; Hartman, Catharina A; Tönjes, Anke; Bandinelli, Stefania; Palmer, Lyle J; Kardia, Sharon L R; Rauramaa, Rainer; Sørensen, Thorkild I A; Tuomilehto, Jaakko; Salomaa, Veikko; Penninx, Brenda W J H; de Geus, Eco J C; Boomsma, Dorret I; Lehtimäki, Terho; Mangino, Massimo; Laakso, Markku; Bouchard, Claude; Martin, Nicholas G; Kuh, Diana; Liu, YongMei; Linneberg, Allan; März, Winfried; Strauch, Konstantin; Kivimäki, Mika; Harris, Tamara B; Gudnason, Vilmundur; Völzke, Henry; Qi, Lu; Järvelin, Marjo-Riitta; Chambers, John C; Kooner, Jaspal S; Froguel, Philippe; Kooperberg, Charles; Vollenweider, Peter; Hallmans, Göran; Hansen, Torben; Pedersen, Oluf; Metspalu, Andres; Wareham, Nicholas J; Langenberg, Claudia; Weir, David R; Porteous, David J; Boerwinkle, Eric; Chasman, Daniel I; Abecasis, Gonçalo R; Barroso, Inês; McCarthy, Mark I; Frayling, Timothy M; O'Connell, Jeffrey R; van Duijn, Cornelia M; Boehnke, Michael; Heid, Iris M; Mohlke, Karen L; Strachan, David P; Fox, Caroline S; Liu, Ching-Ti; Hirschhorn, Joel N; Klein, Robert J; Johnson, Andrew D; Borecki, Ingrid B; Franks, Paul W; North, Kari E; Cupples, L Adrienne; Loos, Ruth J F; Kilpeläinen, Tuomas O

    Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults

  4. A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Paediatric Cohorts

    OpenAIRE

    Middeldorp, Christel M.; Hammerschlag, Anke R.; Ouwens, Klaasjan G.; Groen-Blokhuis, Maria M.; St. Pourcain, Beate; Greven, Corina U.; Pappa, Irene; Tiesler, Carla M.T.; Ang, Wei; Nolte, Ilja M.; Vilor-Tejedor, Natalia; Bacelis, Jonas; Ebejer, Jane L.; Zhao, Huiying; Davies, Gareth E.

    2016-01-01

    ObjectiveTo elucidate the influence of common genetic variants on childhood attention-deficit/hyperactivity disorder (ADHD) symptoms, to identify genetic variants that explain its high heritability, and to investigate the genetic overlap of ADHD symptom scores with ADHD diagnosis.MethodWithin the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, genome-wide single nucleotide polymorphisms (SNPs) and ADHD symptom scores were available for 17,666 children (< 13 years) from nine ...

  5. Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study.

    Science.gov (United States)

    Dehghan, Abbas; Köttgen, Anna; Yang, Qiong; Hwang, Shih-Jen; Kao, Wh Linda; Rivadeneira, Fernando; Boerwinkle, Eric; Levy, Daniel; Hofman, Albert; Astor, Brad C; Benjamin, Emelia J; van Duijn, Cornelia M; Witteman, Jacqueline C; Coresh, Josef; Fox, Caroline S

    2008-12-06

    Hyperuricaemia, a highly heritable trait, is a key risk factor for gout. We aimed to identify novel genes associated with serum uric acid concentration and gout. Genome-wide association studies were done for serum uric acid in 7699 participants in the Framingham cohort and in 4148 participants in the Rotterdam cohort. Genome-wide significant single nucleotide polymorphisms (SNPs) were replicated in white (n=11 024) and black (n=3843) individuals who took part in the study of Atherosclerosis Risk in Communities (ARIC). The SNPs that reached genome-wide significant association with uric acid in either the Framingham cohort (pgout. The results obtained in white participants were combined using meta-analysis. Three loci in the Framingham cohort and two in the Rotterdam cohort showed genome-wide association with uric acid. Top SNPs in each locus were: missense rs16890979 in SLC2A9 (p=7.0 x 10(-168) and 2.9 x 10(-18) for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2.5 x 10(-60) and 9.8 x 10(-4)), and rs1165205 in SLC17A3 (p=3.3 x 10(-26) and 0.33). All SNPs were direction-consistent with gout in white participants: rs16890979 (OR 0.59 per T allele, 95% CI 0.52-0.68, p=7.0 x 10(-14)), rs2231142 (1.74, 1.51-1.99, p=3.3 x 10(-15)), and rs1165205 (0.85, 0.77-0.94, p=0.002). In black participants of the ARIC study, rs2231142 was direction-consistent with gout (1.71, 1.06-2.77, p=0.028). An additive genetic risk score of high-risk alleles at the three loci showed graded associations with uric acid (272-351 mumol/L in the Framingham cohort, 269-386 mumol/L in the Rotterdam cohort, and 303-426 mumol/L in white participants of the ARIC study) and gout (frequency 2-13% in the Framingham cohort, 2-8% in the Rotterdam cohort, and 1-18% in white participants in the ARIC study). We identified three genetic loci associated with uric acid concentration and gout. A score based on genes with a putative role in renal urate handling showed a substantial risk

  6. Genetic parameters and genome-wide association study of hyperpigmentation of the visceral peritoneum in chickens.

    Science.gov (United States)

    Luo, Chenglong; Qu, Hao; Wang, Jie; Wang, Yan; Ma, Jie; Li, Chunyu; Yang, Chunfen; Hu, Xiaoxiang; Li, Ning; Shu, Dingming

    2013-05-16

    Hyperpigmentation of the visceral peritoneum (HVP) has recently garnered much attention in the poultry industry because of the possible risk to the health of affected animals and the damage it causes to the appearance of commercial chicken carcasses. However, the heritable characters of HVP remain unclear. The objective of this study was to investigate the genetic parameters of HVP by genome-wide association study (GWAS) in chickens. HVP was found to be influenced by genetic factors, with a heritability score of 0.33. HVP had positive genetic correlations with growth and carcass traits, such as leg muscle weight (rg = 0.34), but had negative genetic correlations with immune traits, such as the antibody response to Newcastle disease virus (rg = -0.42). The GWAS for HVP using 39,833 single nucleotide polymorphisms indicated the genetic factors associated with HVP displayed an additive effect rather than a dominance effect. In addition, we determined that three genomic regions, involving the 50.5-54.0 Mb region of chicken (Gallus gallus) chromosome 1 (GGA1), the 58.5-60.5 Mb region of GGA1, and the 10.5-12.0 Mb region of GGA20, were strongly associated (P HVP in chickens. Variants in these regions explained >50% of additive genetic variance for HVP. This study also confirmed that expression of BMP7, which codes for a bone morphogenetic protein and is located in one of the candidate regions, was significantly higher in the visceral peritoneum of Huiyang Beard chickens with HVP than in that of chickens without pigmentation (P HVP is a quantitative trait with moderate heritability. Genomic variants resulting in HVP were identified on GGA1 and GGA20, and expression of the BMP7 gene appears to be upregulated in HVP-affected chickens. Findings from this study should be used as a basis for further functional validation of candidate genes involved in HVP.

  7. Meta-analysis of genome-wide linkage studies in BMI and obesity.

    Science.gov (United States)

    Saunders, Catherine L; Chiodini, Benedetta D; Sham, Pak; Lewis, Cathryn M; Abkevich, Victor; Adeyemo, Adebowale A; de Andrade, Mariza; Arya, Rector; Berenson, Gerald S; Blangero, John; Boehnke, Michael; Borecki, Ingrid B; Chagnon, Yvon C; Chen, Wei; Comuzzie, Anthony G; Deng, Hong-Wen; Duggirala, Ravindranath; Feitosa, Mary F; Froguel, Philippe; Hanson, Robert L; Hebebrand, Johannes; Huezo-Dias, Patricia; Kissebah, Ahmed H; Li, Weidong; Luke, Amy; Martin, Lisa J; Nash, Matthew; Ohman, Miina; Palmer, Lyle J; Peltonen, Leena; Perola, Markus; Price, R Arlen; Redline, Susan; Srinivasan, Sathanur R; Stern, Michael P; Stone, Steven; Stringham, Heather; Turner, Stephen; Wijmenga, Cisca; Collier, David A

    2007-09-01

    The objective was to provide an overall assessment of genetic linkage data of BMI and BMI-defined obesity using a nonparametric genome scan meta-analysis. We identified 37 published studies containing data on over 31,000 individuals from more than >10,000 families and obtained genome-wide logarithm of the odds (LOD) scores, non-parametric linkage (NPL) scores, or maximum likelihood scores (MLS). BMI was analyzed in a pooled set of all studies, as a subgroup of 10 studies that used BMI-defined obesity, and for subgroups ascertained through type 2 diabetes, hypertension, or subjects of European ancestry. Bins at chromosome 13q13.2- q33.1, 12q23-q24.3 achieved suggestive evidence of linkage to BMI in the pooled analysis and samples ascertained for hypertension. Nominal evidence of linkage to these regions and suggestive evidence for 11q13.3-22.3 were also observed for BMI-defined obesity. The FTO obesity gene locus at 16q12.2 also showed nominal evidence for linkage. However, overall distribution of summed rank p values <0.05 is not different from that expected by chance. The strongest evidence was obtained in the families ascertained for hypertension at 9q31.1-qter and 12p11.21-q23 (p < 0.01). Despite having substantial statistical power, we did not unequivocally implicate specific loci for BMI or obesity. This may be because genes influencing adiposity are of very small effect, with substantial genetic heterogeneity and variable dependence on environmental factors. However, the observation that the FTO gene maps to one of the highest ranking bins for obesity is interesting and, while not a validation of this approach, indicates that other potential loci identified in this study should be investigated further.

  8. Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits

    NARCIS (Netherlands)

    Randall, Joshua C.; Winkler, Thomas W.; Kutalik, Zoltán; Berndt, Sonja I.; Jackson, Anne U.; Monda, Keri L.; Kilpeläinen, Tuomas O.; Esko, Tõnu; Mägi, Reedik; Li, Shengxu; Workalemahu, Tsegaselassie; Feitosa, Mary F.; Croteau-Chonka, Damien C.; Day, Felix R.; Fall, Tove; Ferreira, Teresa; Gustafsson, Stefan; Locke, Adam E.; Mathieson, Iain; Scherag, Andre; Vedantam, Sailaja; Wood, Andrew R.; Liang, Liming; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Dermitzakis, Emmanouil T.; Dimas, Antigone S.; Karpe, Fredrik; Min, Josine L.; Nicholson, George; Clegg, Deborah J.; Person, Thomas; Krohn, Jon P.; Bauer, Sabrina; Buechler, Christa; Eisinger, Kristina; Bonnefond, Amélie; Froguel, Philippe; Hottenga, Jouke-Jan; Prokopenko, Inga; Waite, Lindsay L.; Harris, Tamara B.; Smith, Albert Vernon; Shuldiner, Alan R.; McArdle, Wendy L.; Caulfield, Mark J.; Munroe, Patricia B.; Grönberg, Henrik; Chen, Yii-Der Ida; Li, Guo; Beckmann, Jacques S.; Johnson, Toby; Thorsteinsdottir, Unnur; Teder-Laving, Maris; Khaw, Kay-Tee; Wareham, Nicholas J.; Zhao, Jing Hua; Amin, Najaf; Oostra, Ben A.; Kraja, Aldi T.; Province, Michael A.; Cupples, L. Adrienne; Heard-Costa, Nancy L.; Kaprio, Jaakko; Ripatti, Samuli; Surakka, Ida; Collins, Francis S.; Saramies, Jouko; Tuomilehto, Jaakko; Jula, Antti; Salomaa, Veikko; Erdmann, Jeanette; Hengstenberg, Christian; Loley, Christina; Schunkert, Heribert; Lamina, Claudia; Wichmann, H. Erich; Albrecht, Eva; Gieger, Christian; Hicks, Andrew A.; Johansson, Asa; Pramstaller, Peter P.; Kathiresan, Sekar; Speliotes, Elizabeth K.; Penninx, Brenda; Hartikainen, Anna-Liisa; Jarvelin, Marjo-Riitta; Gyllensten, Ulf; Boomsma, Dorret I.; Campbell, Harry; Wilson, James F.; Chanock, Stephen J.; Farrall, Martin; Goel, Anuj; Medina-Gomez, Carolina; Rivadeneira, Fernando; Estrada, Karol; Uitterlinden, André G.; Hofman, Albert; Zillikens, M. Carola; den Heijer, Martin; Kiemeney, Lambertus A.; Maschio, Andrea; Hall, Per; Tyrer, Jonathan; Teumer, Alexander; Völzke, Henry; Kovacs, Peter; Tönjes, Anke; Mangino, Massimo; Spector, Tim D.; Hayward, Caroline; Rudan, Igor; Hall, Alistair S.; Samani, Nilesh J.; Attwood, Antony Paul; Sambrook, Jennifer G.; Hung, Joseph; Palmer, Lyle J.; Lokki, Marja-Liisa; Sinisalo, Juha; Boucher, Gabrielle; Huikuri, Heikki; Lorentzon, Mattias; Ohlsson, Claes; Eklund, Niina; Eriksson, Johan G.; Barlassina, Cristina; Rivolta, Carlo; Nolte, Ilja M.; Snieder, Harold; van der Klauw, Melanie M.; van Vliet-Ostaptchouk, Jana V.; Gejman, Pablo V.; Shi, Jianxin; Jacobs, Kevin B.; Wang, Zhaoming; Bakker, Stephan J. L.; Mateo Leach, Irene; Navis, Gerjan; van der Harst, Pim; Martin, Nicholas G.; Medland, Sarah E.; Montgomery, Grant W.; Yang, Jian; Chasman, Daniel I.; Ridker, Paul M.; Rose, Lynda M.; Lehtimäki, Terho; Raitakari, Olli; Absher, Devin; Iribarren, Carlos; Basart, Hanneke; Hovingh, Kees G.; Hyppönen, Elina; Power, Chris; Anderson, Denise; Beilby, John P.; Hui, Jennie; Jolley, Jennifer; Sager, Hendrik; Bornstein, Stefan R.; Schwarz, Peter E. H.; Kristiansson, Kati; Perola, Markus; Lindström, Jaana; Swift, Amy J.; Uusitupa, Matti; Atalay, Mustafa; Lakka, Timo A.; Rauramaa, Rainer; Bolton, Jennifer L.; Fowkes, Gerry; Fraser, Ross M.; Price, Jackie F.; Fischer, Krista; Krjutå Kov, Kaarel; Metspalu, Andres; Mihailov, Evelin; Langenberg, Claudia; Luan, Jian'an; Ong, Ken K.; Chines, Peter S.; Keinanen-Kiukaanniemi, Sirkka M.; Saaristo, Timo E.; Edkins, Sarah; Franks, Paul W.; Hallmans, Göran; Shungin, Dmitry; Morris, Andrew David; Palmer, Colin N. A.; Erbel, Raimund; Moebus, Susanne; Nöthen, Markus M.; Pechlivanis, Sonali; Hveem, Kristian; Narisu, Narisu; Hamsten, Anders; Humphries, Steve E.; Strawbridge, Rona J.; Tremoli, Elena; Grallert, Harald; Thorand, Barbara; Illig, Thomas; Koenig, Wolfgang; Müller-Nurasyid, Martina; Peters, Annette; Boehm, Bernhard O.; Kleber, Marcus E.; März, Winfried; Winkelmann, Bernhard R.; Kuusisto, Johanna; Laakso, Markku; Arveiler, Dominique; Cesana, Giancarlo; Kuulasmaa, Kari; Virtamo, Jarmo; Yarnell, John W. G.; Kuh, Diana; Wong, Andrew; Lind, Lars; de Faire, Ulf; Gigante, Bruna; Magnusson, Patrik K. E.; Pedersen, Nancy L.; Dedoussis, George; Dimitriou, Maria; Kolovou, Genovefa; Kanoni, Stavroula; Stirrups, Kathleen; Bonnycastle, Lori L.; Njølstad, Inger; Wilsgaard, Tom; Ganna, Andrea; Rehnberg, Emil; Hingorani, Aroon; Kivimaki, Mika; Kumari, Meena; Assimes, Themistocles L.; Barroso, Inês; Boehnke, Michael; Borecki, Ingrid B.; Deloukas, Panos; Fox, Caroline S.; Frayling, Timothy; Groop, Leif C.; Haritunians, Talin; Hunter, David; Ingelsson, Erik; Kaplan, Robert; Mohlke, Karen L.; O'Connell, Jeffrey R.; Schlessinger, David; Strachan, David P.; Stefansson, Kari; van Duijn, Cornelia M.; Abecasis, Gonçalo R.; McCarthy, Mark I.; Hirschhorn, Joel N.; Qi, Lu; Loos, Ruth J. F.; Lindgren, Cecilia M.; North, Kari E.; Heid, Iris M.

    2013-01-01

    Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723

  9. A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance

    NARCIS (Netherlands)

    Manning, Alisa K.; Hivert, Marie-France; Scott, Robert A.; Grimsby, Jonna L.; Bouatia-Naji, Nabila; Chen, Han; Rybin, Denis; Liu, Ching-Ti; Bielak, Lawrence F.; Prokopenko, Inga; Amin, Najaf; Barnes, Daniel; Cadby, Gemma; Hottenga, Jouke-Jan; Ingelsson, Erik; Jackson, Anne U.; Johnson, Toby; Kanoni, Stavroula; Ladenvall, Claes; Lagou, Vasiliki; Lahti, Jari; Lecoeur, Cecile; Liu, Yongmei; Martinez-Larrad, Maria Teresa; Montasser, May E.; Navarro, Pau; Perry, John R. B.; Rasmussen-Torvik, Laura J.; Salo, Perttu; Sattar, Naveed; Shungin, Dmitry; Strawbridge, Rona J.; Tanaka, Toshiko; van Duijn, Cornelia M.; An, Ping; de Andrade, Mariza; Andrews, Jeanette S.; Aspelund, Thor; Atalay, Mustafa; Aulchenko, Yurii; Balkau, Beverley; Bandinelli, Stefania; Beckmann, Jacques S.; Beilby, John P.; Bellis, Claire; Bergman, Richard N.; Blangero, John; Boban, Mladen; Kumari, Meena; Penninx, Brenda

    Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance

  10. Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

    NARCIS (Netherlands)

    Randall, J.C.; Winkler, T.W.; Kutalik, Z.; Berndt, S.I.; Jackson, A.U.; Monda, K.L.; Kilpelainen, T.O.; Esko, T.; Magi, R.; Li, S.; Workalemahu, T.; Feitosa, M.F.; Croteau-Chonka, D.C.; Day, F.R.; Fall, T.; Ferreira, T.; Gustafsson, S.; Locke, A.E.; Mathieson, I.; Scherag, A.; Vedantam, S.; Wood, A.R.; Liang, L.; Steinthorsdottir, V.; Thorleifsson, G.; Dermitzakis, E.T.; Dimas, A.S.; Karpe, F.; Min, J.L.; Nicholson, G.; Clegg, D.J.; Person, T.; Krohn, J.P.; Bauer, S.; Buechler, C.; Eisinger, K.; Bonnefond, A.; Froguel, P.; Hottenga, J.J.; Prokopenko, I.; Waite, L.L.; Harris, T.B.; Smith, A.V.; Shuldiner, A.R.; McArdle, W.L.; Caulfield, M.J.; Munroe, P.B.; Gronberg, H.; Chen, Y.D.; Li, G.; Beckmann, J.S.; Johnson, T.; Thorsteinsdottir, U.; Teder-Laving, M.; Khaw, K.T.; Wareham, N.J.; Zhao, J.H.; Amin, N.; Oostra, B.A.; Kraja, A.T.; Province, M.A.; Cupples, L.A.; Heard-Costa, N.L.; Kaprio, J.; Ripatti, S.; Surakka, I.; Collins, F.S.; Saramies, J.; Tuomilehto, J.; Jula, A.; Salomaa, V.; Erdmann, J.; Hengstenberg, C.; Loley, C.; Schunkert, H.; Lamina, C.; Wichmann, H.E.; Albrecht, E.; Gieger, C.; Hicks, A.A.; Johansson, A; Pramstaller, P.P.; Kathiresan, S.; Speliotes, E.K.; Penninx, B.; Hartikainen, A.L.; Jarvelin, M.R.; Gyllensten, U.; Boomsma, D.I.; Campbell, H.; Wilson, J.F.; Chanock, S.J.; Farrall, M.; Goel, A.; Medina-Gomez, C.; Rivadeneira, F.; Estrada, K.; Uitterlinden, A.G.; Heijer, M. den; Kiemeney, L.A.L.M.; et al.,

    2013-01-01

    Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723

  11. Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits

    NARCIS (Netherlands)

    Randall, Joshua C; Winkler, Thomas W; Kutalik, Zoltán; Berndt, Sonja I; Jackson, Anne U; Monda, Keri L; Kilpeläinen, Tuomas O; Esko, Tõnu; Mägi, Reedik; Li, Shengxu; Workalemahu, Tsegaselassie; Feitosa, Mary F; Croteau-Chonka, Damien C; Day, Felix R; Fall, Tove; Ferreira, Teresa; Gustafsson, Stefan; Locke, Adam E; Mathieson, Iain; Scherag, Andre; Vedantam, Sailaja; Wood, Andrew R; Liang, Liming; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Dermitzakis, Emmanouil T; Dimas, Antigone S; Karpe, Fredrik; Min, Josine L; Nicholson, George; Clegg, Deborah J; Person, Thomas; Krohn, Jon P; Bauer, Sabrina; Buechler, Christa; Eisinger, Kristina; Bonnefond, Amélie; Froguel, Philippe; Smith, Albert Vernon; Zhao, Jing Hua; Penninx, Brenda; Nolte, Ilja M; Snieder, Harold; Van der Klauw, Melanie M; Van Vliet-Ostaptchouk, Jana V; Bakker, Stephan J L; Mateo Leach, Irene; Navis, Gerjan; van der Harst, Pim; Kumari, Meena

    Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723

  12. Meta-analysis of genome-wide linkage studies in BMI and obesity

    NARCIS (Netherlands)

    Saunders, Catherine L.; Chiodini, Benedetta D.; Sham, Pak; Lewis, Cathryn M.; Abkevich, Victor; Adeyemo, Adebowale A.; de Andrade, Mariza; Arya, Rector; Berenson, Gerald S.; Blangero, John; Boehnke, Michael; Borecki, Ingrid B.; Chagnon, Yvon C.; Chen, Wei; Comuzzie, Anthony G.; Deng, Hong-Wen; Duggirala, Ravindranath; Feitosa, Mary F.; Froguel, Philippe; Hanson, Robert L.; Hebebrand, Johannes; Huezo-Dias, Patricia; Kissebah, Ahmed H.; Li, Weidong; Luke, Amy; Martin, Lisa J.; Nash, Matthew; Ohman, Muena; Palmer, Lyle J.; Peltonen, Leena; Perola, Markus; Price, R. Arlen; Redline, Susan; Srinivasan, Sathanur R.; Stern, Michael P.; Stone, Steven; Stringham, Heather; Turner, Stephen; Wijmenga, Cisca; Collier, David A.

    Objective: The objective was to provide an overall assessment of genetic linkage data of BMI and BMI-defined obesity using a nonparametric genome scan meta-analysis. Research Methods and Procedures: We identified 37 published studies containing data on over 31,000 individuals from more than >10,000

  13. Genome-wide association studies in an isolated founder population from the Pacific Island of Kosrae.

    Directory of Open Access Journals (Sweden)

    Jennifer K Lowe

    2009-02-01

    Full Text Available It has been argued that the limited genetic diversity and reduced allelic heterogeneity observed in isolated founder populations facilitates discovery of loci contributing to both Mendelian and complex disease. A strong founder effect, severe isolation, and substantial inbreeding have dramatically reduced genetic diversity in natives from the island of Kosrae, Federated States of Micronesia, who exhibit a high prevalence of obesity and other metabolic disorders. We hypothesized that genetic drift and possibly natural selection on Kosrae might have increased the frequency of previously rare genetic variants with relatively large effects, making these alleles readily detectable in genome-wide association analysis. However, mapping in large, inbred cohorts introduces analytic challenges, as extensive relatedness between subjects violates the assumptions of independence upon which traditional association test statistics are based. We performed genome-wide association analysis for 15 quantitative traits in 2,906 members of the Kosrae population, using novel approaches to manage the extreme relatedness in the sample. As positive controls, we observe association to known loci for plasma cholesterol, triglycerides, and C-reactive protein and to a compelling candidate loci for thyroid stimulating hormone and fasting plasma glucose. We show that our study is well powered to detect common alleles explaining >/=5% phenotypic variance. However, no such large effects were observed with genome-wide significance, arguing that even in such a severely inbred population, common alleles typically have modest effects. Finally, we show that a majority of common variants discovered in Caucasians have indistinguishable effect sizes on Kosrae, despite the major differences in population genetics and environment.

  14. Genetic influences on political ideologies: twin analyses of 19 measures of political ideologies from five democracies and genome-wide findings from three populations.

    Science.gov (United States)

    Hatemi, Peter K; Medland, Sarah E; Klemmensen, Robert; Oskarsson, Sven; Littvay, Levente; Dawes, Christopher T; Verhulst, Brad; McDermott, Rose; Nørgaard, Asbjørn Sonne; Klofstad, Casey A; Christensen, Kaare; Johannesson, Magnus; Magnusson, Patrik K E; Eaves, Lindon J; Martin, Nicholas G

    2014-05-01

    Almost 40 years ago, evidence from large studies of adult twins and their relatives suggested that between 30 and 60% of the variance in social and political attitudes could be explained by genetic influences. However, these findings have not been widely accepted or incorporated into the dominant paradigms that explain the etiology of political ideology. This has been attributed in part to measurement and sample limitations, as well the relative absence of molecular genetic studies. Here we present results from original analyses of a combined sample of over 12,000 twins pairs, ascertained from nine different studies conducted in five democracies, sampled over the course of four decades. We provide evidence that genetic factors play a role in the formation of political ideology, regardless of how ideology is measured, the era, or the population sampled. The only exception is a question that explicitly uses the phrase "Left-Right". We then present results from one of the first genome-wide association studies on political ideology using data from three samples: a 1990 Australian sample involving 6,894 individuals from 3,516 families; a 2008 Australian sample of 1,160 related individuals from 635 families and a 2010 Swedish sample involving 3,334 individuals from 2,607 families. No polymorphisms reached genome-wide significance in the meta-analysis. The combined evidence suggests that political ideology constitutes a fundamental aspect of one's genetically informed psychological disposition, but as Fisher proposed long ago, genetic influences on complex traits will be composed of thousands of markers of very small effects and it will require extremely large samples to have enough power in order to identify specific polymorphisms related to complex social traits.

  15. Genome-wide haplotype analysis of cis expression quantitative trait loci in monocytes.

    Directory of Open Access Journals (Sweden)

    Sophie Garnier

    Full Text Available In order to assess whether gene expression variability could be influenced by several SNPs acting in cis, either through additive or more complex haplotype effects, a systematic genome-wide search for cis haplotype expression quantitative trait loci (eQTL was conducted in a sample of 758 individuals, part of the Cardiogenics Transcriptomic Study, for which genome-wide monocyte expression and GWAS data were available. 19,805 RNA probes were assessed for cis haplotypic regulation through investigation of ~2,1 × 10(9 haplotypic combinations. 2,650 probes demonstrated haplotypic p-values >10(4-fold smaller than the best single SNP p-value. Replication of significant haplotype effects were tested for 412 probes for which SNPs (or proxies that defined the detected haplotypes were available in the Gutenberg Health Study composed of 1,374 individuals. At the Bonferroni correction level of 1.2 × 10(-4 (~0.05/412, 193 haplotypic signals replicated. 1000 G imputation was then conducted, and 105 haplotypic signals still remained more informative than imputed SNPs. In-depth analysis of these 105 cis eQTL revealed that at 76 loci genetic associations were compatible with additive effects of several SNPs, while for the 29 remaining regions data could be compatible with a more complex haplotypic pattern. As 24 of the 105 cis eQTL have previously been reported to be disease-associated loci, this work highlights the need for conducting haplotype-based and 1000 G imputed cis eQTL analysis before commencing functional studies at disease-associated loci.

  16. Gene set analysis for interpreting genetic studies

    DEFF Research Database (Denmark)

    Pers, Tune H

    2016-01-01

    Interpretation of genome-wide association study (GWAS) results is lacking behind the discovery of new genetic associations. Consequently, there is an urgent need for data-driven methods for interpreting genetic association studies. Gene set analysis (GSA) can identify aetiologic pathways...

  17. Controversy and debate on clinical genomics sequencing-paper 2: clinical genome-wide sequencing: don't throw out the baby with the bathwater!

    Science.gov (United States)

    Adam, Shelin; Friedman, Jan M

    2017-12-01

    Genome-wide (exome or whole genome) sequencing with appropriate genetic counseling should be considered for any patient with a suspected Mendelian disease that has not been identified by conventional testing. Clinical genome-wide sequencing provides a powerful and effective means of identifying specific genetic causes of serious disease and improving clinical care. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Sarah L. Kerns

    2016-08-01

    Full Text Available Nearly 50% of cancer patients undergo radiotherapy. Late radiotherapy toxicity affects quality-of-life in long-term cancer survivors and risk of side-effects in a minority limits doses prescribed to the majority of patients. Development of a test predicting risk of toxicity could benefit many cancer patients. We aimed to meta-analyze individual level data from four genome-wide association studies from prostate cancer radiotherapy cohorts including 1564 men to identify genetic markers of toxicity. Prospectively assessed two-year toxicity endpoints (urinary frequency, decreased urine stream, rectal bleeding, overall toxicity and single nucleotide polymorphism (SNP associations were tested using multivariable regression, adjusting for clinical and patient-related risk factors. A fixed-effects meta-analysis identified two SNPs: rs17599026 on 5q31.2 with urinary frequency (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.08–4.69, p-value 4.16 × 10−8 and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90–3.86, p-value = 3.21 × 10−8. These SNPs lie within genes that are expressed in tissues adversely affected by pelvic radiotherapy including bladder, kidney, rectum and small intestine. The results show that heterogeneous radiotherapy cohorts can be combined to identify new moderate-penetrance genetic variants associated with radiotherapy toxicity. The work provides a basis for larger collaborative efforts to identify enough variants for a future test involving polygenic risk profiling.

  19. Regulatory network construction in Arabidopsis by using genome-wide gene expression quantitative trait loci

    NARCIS (Netherlands)

    Keurentjes, Joost J.B.; Fu, Jingyuan; Terpstra, Inez R.; Garcia, Juan M.; Ackerveken, Guido van den; Snoek, L. Basten; Peeters, Anton J.M.; Vreugdenhil, Dick; Koornneef, Maarten; Jansen, Ritsert C.

    2007-01-01

    Accessions of a plant species can show considerable genetic differences that are analyzed effectively by using recombinant inbred line (RIL) populations. Here we describe the results of genome-wide expression variation analysis in an RIL population of Arabidopsis thaliana. For many genes, variation

  20. Genome-Wide Association Study of Intelligence: Additive Effects of Novel Brain Expressed Genes

    Science.gov (United States)

    Loo, Sandra K.; Shtir, Corina; Doyle, Alysa E.; Mick, Eric; McGough, James J.; McCracken, James; Biederman, Joseph; Smalley, Susan L.; Cantor, Rita M.; Faraone, Stephen V.; Nelson, Stanley F.

    2012-01-01

    Objective: The purpose of the present study was to identify common genetic variants that are associated with human intelligence or general cognitive ability. Method: We performed a genome-wide association analysis with a dense set of 1 million single-nucleotide polymorphisms (SNPs) and quantitative intelligence scores within an ancestrally…

  1. Genome-wide analysis of LTR-retrotransposons in oil palm.

    Science.gov (United States)

    Beulé, Thierry; Agbessi, Mawussé Dt; Dussert, Stephane; Jaligot, Estelle; Guyot, Romain

    2015-10-15

    The oil palm (Elaeis guineensis Jacq.) is a major cultivated crop and the world's largest source of edible vegetable oil. The genus Elaeis comprises two species E. guineensis, the commercial African oil palm and E. oleifera, which is used in oil palm genetic breeding. The recent publication of both the African oil palm genome assembly and the first draft sequence of its Latin American relative now allows us to tackle the challenge of understanding the genome composition, structure and evolution of these palm genomes through the annotation of their repeated sequences. In this study, we identified, annotated and compared Transposable Elements (TE) from the African and Latin American oil palms. In a first step, Transposable Element databases were built through de novo detection in both genome sequences then the TE content of both genomes was estimated. Then putative full-length retrotransposons with Long Terminal Repeats (LTRs) were further identified in the E. guineensis genome for characterization of their structural diversity, copy number and chromosomal distribution. Finally, their relative expression in several tissues was determined through in silico analysis of publicly available transcriptome data. Our results reveal a congruence in the transpositional history of LTR retrotransposons between E. oleifera and E. guineensis, especially the Sto-4 family. Also, we have identified and described 583 full-length LTR-retrotransposons in the Elaeis guineensis genome. Our work shows that these elements are most likely no longer mobile and that no recent insertion event has occurred. Moreover, the analysis of chromosomal distribution suggests a preferential insertion of Copia elements in gene-rich regions, whereas Gypsy elements appear to be evenly distributed throughout the genome. Considering the high proportion of LTR retrotransposon in the oil palm genome, our work will contribute to a greater understanding of their impact on genome organization and evolution

  2. A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance

    Science.gov (United States)

    Manning, Alisa K.; Hivert, Marie-France; Scott, Robert A.; Grimsby, Jonna L.; Bouatia-Naji, Nabila; Chen, Han; Rybin, Denis; Liu, Ching-Ti; Bielak, Lawrence F.; Prokopenko, Inga; Amin, Najaf; Barnes, Daniel; Cadby, Gemma; Hottenga, Jouke-Jan; Ingelsson, Erik; Jackson, Anne U.; Johnson, Toby; Kanoni, Stavroula; Ladenvall, Claes; Lagou, Vasiliki; Lahti, Jari; Lecoeur, Cecile; Liu, Yongmei; Martinez-Larrad, Maria Teresa; Montasser, May E.; Navarro, Pau; Perry, John R. B.; Rasmussen-Torvik, Laura J.; Salo, Perttu; Sattar, Naveed; Shungin, Dmitry; Strawbridge, Rona J.; Tanaka, Toshiko; van Duijn, Cornelia M.; An, Ping; de Andrade, Mariza; Andrews, Jeanette S.; Aspelund, Thor; Atalay, Mustafa; Aulchenko, Yurii; Balkau, Beverley; Bandinelli, Stefania; Beckmann, Jacques S.; Beilby, John P.; Bellis, Claire; Bergman, Richard N.; Blangero, John; Boban, Mladen; Boehnke, Michael; Boerwinkle, Eric; Bonnycastle, Lori L.; Boomsma, Dorret I.; Borecki, Ingrid B.; Böttcher, Yvonne; Bouchard, Claude; Brunner, Eric; Budimir, Danijela; Campbell, Harry; Carlson, Olga; Chines, Peter S.; Clarke, Robert; Collins, Francis S.; Corbatón-Anchuelo, Arturo; Couper, David; de Faire, Ulf; Dedoussis, George V; Deloukas, Panos; Dimitriou, Maria; Egan, Josephine M; Eiriksdottir, Gudny; Erdos, Michael R.; Eriksson, Johan G.; Eury, Elodie; Ferrucci, Luigi; Ford, Ian; Forouhi, Nita G.; Fox, Caroline S; Franzosi, Maria Grazia; Franks, Paul W; Frayling, Timothy M; Froguel, Philippe; Galan, Pilar; de Geus, Eco; Gigante, Bruna; Glazer, Nicole L.; Goel, Anuj; Groop, Leif; Gudnason, Vilmundur; Hallmans, Göran; Hamsten, Anders; Hansson, Ola; Harris, Tamara B.; Hayward, Caroline; Heath, Simon; Hercberg, Serge; Hicks, Andrew A.; Hingorani, Aroon; Hofman, Albert; Hui, Jennie; Hung, Joseph; Jarvelin, Marjo Riitta; Jhun, Min A.; Johnson, Paul C.D.; Jukema, J Wouter; Jula, Antti; Kao, W.H.; Kaprio, Jaakko; Kardia, Sharon L. R.; Keinanen-Kiukaanniemi, Sirkka; Kivimaki, Mika; Kolcic, Ivana; Kovacs, Peter; Kumari, Meena; Kuusisto, Johanna; Kyvik, Kirsten Ohm; Laakso, Markku; Lakka, Timo; Lannfelt, Lars; Lathrop, G Mark; Launer, Lenore J.; Leander, Karin; Li, Guo; Lind, Lars; Lindstrom, Jaana; Lobbens, Stéphane; Loos, Ruth J. F.; Luan, Jian’an; Lyssenko, Valeriya; Mägi, Reedik; Magnusson, Patrik K. E.; Marmot, Michael; Meneton, Pierre; Mohlke, Karen L.; Mooser, Vincent; Morken, Mario A.; Miljkovic, Iva; Narisu, Narisu; O’Connell, Jeff; Ong, Ken K.; Oostra, Ben A.; Palmer, Lyle J.; Palotie, Aarno; Pankow, James S.; Peden, John F.; Pedersen, Nancy L.; Pehlic, Marina; Peltonen, Leena; Penninx, Brenda; Pericic, Marijana; Perola, Markus; Perusse, Louis; Peyser, Patricia A; Polasek, Ozren; Pramstaller, Peter P.; Province, Michael A.; Räikkönen, Katri; Rauramaa, Rainer; Rehnberg, Emil; Rice, Ken; Rotter, Jerome I.; Rudan, Igor; Ruokonen, Aimo; Saaristo, Timo; Sabater-Lleal, Maria; Salomaa, Veikko; Savage, David B.; Saxena, Richa; Schwarz, Peter; Seedorf, Udo; Sennblad, Bengt; Serrano-Rios, Manuel; Shuldiner, Alan R.; Sijbrands, Eric J.G.; Siscovick, David S.; Smit, Johannes H.; Small, Kerrin S.; Smith, Nicholas L.; Smith, Albert Vernon; Stančáková, Alena; Stirrups, Kathleen; Stumvoll, Michael; Sun, Yan V.; Swift, Amy J.; Tönjes, Anke; Tuomilehto, Jaakko; Trompet, Stella; Uitterlinden, Andre G.; Uusitupa, Matti; Vikström, Max; Vitart, Veronique; Vohl, Marie-Claude; Voight, Benjamin F.; Vollenweider, Peter; Waeber, Gerard; Waterworth, Dawn M; Watkins, Hugh; Wheeler, Eleanor; Widen, Elisabeth; Wild, Sarah H.; Willems, Sara M.; Willemsen, Gonneke; Wilson, James F.; Witteman, Jacqueline C.M.; Wright, Alan F.; Yaghootkar, Hanieh; Zelenika, Diana; Zemunik, Tatijana; Zgaga, Lina; Wareham, Nicholas J.; McCarthy, Mark I.; Barroso, Ines; Watanabe, Richard M.; Florez, Jose C.; Dupuis, Josée; Meigs, James B.; Langenberg, Claudia

    2013-01-01

    Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction, but contributed little to our understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways may be uncovered by accounting for differences in body mass index (BMI) and potential interaction between BMI and genetic variants. We applied a novel joint meta-analytical approach to test associations with fasting insulin (FI) and glucose (FG) on a genome-wide scale. We present six previously unknown FI loci at P<5×10−8 in combined discovery and follow-up analyses of 52 studies comprising up to 96,496non-diabetic individuals. Risk variants were associated with higher triglyceride and lower HDL cholesterol levels, suggestive of a role for these FI loci in insulin resistance pathways. The localization of these additional loci will aid further characterization of the role of insulin resistance in T2D pathophysiology. PMID:22581228

  3. A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11

    NARCIS (Netherlands)

    Siddiq, Afshan; Couch, Fergus J.; Chen, Gary K.; Lindström, Sara; Eccles, Diana; Millikan, Robert C.; Michailidou, Kyriaki; Stram, Daniel O.; Beckmann, Lars; Rhie, Suhn Kyong; Ambrosone, Christine B.; Aittomäki, Kristiina; Amiano, Pilar; Apicella, Carmel; Baglietto, Laura; Bandera, Elisa V.; Beckmann, Matthias W.; Berg, Christine D.; Bernstein, Leslie; Blomqvist, Carl; Brauch, Hiltrud; Brinton, Louise; Bui, Quang M.; Buring, Julie E.; Buys, Saundra S.; Campa, Daniele; Carpenter, Jane E.; Chasman, Daniel I.; Chang-Claude, Jenny; Chen, Constance; Clavel-Chapelon, Françoise; Cox, Angela; Cross, Simon S.; Czene, Kamila; Deming, Sandra L.; Diasio, Robert B.; Diver, W. Ryan; Dunning, Alison M.; Durcan, Lorraine; Ekici, Arif B.; Fasching, Peter A.; Feigelson, Heather Spencer; Fejerman, Laura; Figueroa, Jonine D.; Fletcher, Olivia; Flesch-Janys, Dieter; Gaudet, Mia M.; Gerty, Susan M.; Rodriguez-Gil, Jorge L.; Giles, Graham G.; van Gils, Carla H.; Godwin, Andrew K.; Graham, Nikki; Greco, Dario; Hall, Per; Hankinson, Susan E.; Hartmann, Arndt; Hein, Rebecca; Heinz, Judith; Hoover, Robert N.; Hopper, John L.; Hu, Jennifer J.; Huntsman, Scott; Ingles, Sue A.; Irwanto, Astrid; Isaacs, Claudine; Jacobs, Kevin B.; John, Esther M.; Justenhoven, Christina; Kaaks, Rudolf; Kolonel, Laurence N.; Coetzee, Gerhard A.; Lathrop, Mark; Le Marchand, Loic; Lee, Adam M.; Lee, I.-Min; Lesnick, Timothy; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Martin, Nicholas G.; McLean, Catriona A.; Meijers-Heijboer, Hanne; Meindl, Alfons; Miron, Penelope; Monroe, Kristine R.; Montgomery, Grant W.; Müller-Myhsok, Bertram; Nickels, Stefan; Nyante, Sarah J.; Olswold, Curtis; Overvad, Kim; Palli, Domenico; Park, Daniel J.; Palmer, Julie R.; Pathak, Harsh; Peto, Julian; Pharoah, Paul; Rahman, Nazneen; Rivadeneira, Fernando; Schmidt, Daniel F.; Schmutzler, Rita K.; Slager, Susan; Southey, Melissa C.; Stevens, Kristen N.; Sinn, Hans-Peter; Press, Michael F.; Ross, Eric; Riboli, Elio; Ridker, Paul M.; Schumacher, Fredrick R.; Severi, Gianluca; dos Santos Silva, Isabel; Stone, Jennifer; Sund, Malin; Tapper, William J.; Thun, Michael J.; Travis, Ruth C.; Turnbull, Clare; Uitterlinden, Andre G.; Waisfisz, Quinten; Wang, Xianshu; Wang, Zhaoming; Weaver, Joellen; Schulz-Wendtland, Rüdiger; Wilkens, Lynne R.; van den Berg, David; Zheng, Wei; Ziegler, Regina G.; Ziv, Elad; Nevanlinna, Heli; Easton, Douglas F.; Hunter, David J.; Henderson, Brian E.; Chanock, Stephen J.; Garcia-Closas, Montserrat; Kraft, Peter; Haiman, Christopher A.; Vachon, Celine M.

    2012-01-01

    Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of

  4. Research Guidelines in the Era of Large-scale Collaborations: An Analysis of Genome-wide Association Study Consortia

    Science.gov (United States)

    Austin, Melissa A.; Hair, Marilyn S.; Fullerton, Stephanie M.

    2012-01-01

    Scientific research has shifted from studies conducted by single investigators to the creation of large consortia. Genetic epidemiologists, for example, now collaborate extensively for genome-wide association studies (GWAS). The effect has been a stream of confirmed disease-gene associations. However, effects on human subjects oversight, data-sharing, publication and authorship practices, research organization and productivity, and intellectual property remain to be examined. The aim of this analysis was to identify all research consortia that had published the results of a GWAS analysis since 2005, characterize them, determine which have publicly accessible guidelines for research practices, and summarize the policies in these guidelines. A review of the National Human Genome Research Institute’s Catalog of Published Genome-Wide Association Studies identified 55 GWAS consortia as of April 1, 2011. These consortia were comprised of individual investigators, research centers, studies, or other consortia and studied 48 different diseases or traits. Only 14 (25%) were found to have publicly accessible research guidelines on consortia websites. The available guidelines provide information on organization, governance, and research protocols; half address institutional review board approval. Details of publication, authorship, data-sharing, and intellectual property vary considerably. Wider access to consortia guidelines is needed to establish appropriate research standards with broad applicability to emerging forms of large-scale collaboration. PMID:22491085

  5. Genome-wide analysis of Dongxiang wild rice (Oryza rufipogon Griff.) to investigate lost/acquired genes during rice domestication.

    Science.gov (United States)

    Zhang, Fantao; Xu, Tao; Mao, Linyong; Yan, Shuangyong; Chen, Xiwen; Wu, Zhenfeng; Chen, Rui; Luo, Xiangdong; Xie, Jiankun; Gao, Shan

    2016-04-26

    It is widely accepted that cultivated rice (Oryza sativa L.) was domesticated from common wild rice (Oryza rufipogon Griff.). Compared to other studies which concentrate on rice origin, this study is to genetically elucidate the substantially phenotypic and physiological changes from wild rice to cultivated rice at the whole genome level. Instead of comparing two assembled genomes, this study directly compared the Dongxiang wild rice (DXWR) Illumina sequencing reads with the Nipponbare (O. sativa) complete genome without assembly of the DXWR genome. Based on the results from the comparative genomics analysis, structural variations (SVs) between DXWR and Nipponbare were determined to locate deleted genes which could have been acquired by Nipponbare during rice domestication. To overcome the limit of the SV detection, the DXWR transcriptome was also sequenced and compared with the Nipponbare transcriptome to discover the genes which could have been lost in DXWR during domestication. Both 1591 Nipponbare-acquired genes and 206 DXWR-lost transcripts were further analyzed using annotations from multiple sources. The NGS data are available in the NCBI SRA database with ID SRP070627. These results help better understanding the domestication from wild rice to cultivated rice at the whole genome level and provide a genomic data resource for rice genetic research or breeding. One finding confirmed transposable elements contribute greatly to the genome evolution from wild rice to cultivated rice. Another finding suggested the photophosphorylation and oxidative phosphorylation system in cultivated rice could have adapted to environmental changes simultaneously during domestication.

  6. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

    Science.gov (United States)

    Berndt, Sonja I.; Gustafsson, Stefan; Mägi, Reedik; Ganna, Andrea; Wheeler, Eleanor; Feitosa, Mary F.; Justice, Anne E.; Monda, Keri L.; Croteau-Chonka, Damien C.; Day, Felix R.; Esko, Tõnu; Fall, Tove; Ferreira, Teresa; Gentilini, Davide; Jackson, Anne U.; Luan, Jian’an; Randall, Joshua C.; Vedantam, Sailaja; Willer, Cristen J.; Winkler, Thomas W.; Wood, Andrew R.; Workalemahu, Tsegaselassie; Hu, Yi-Juan; Lee, Sang Hong; Liang, Liming; Lin, Dan-Yu; Min, Josine L.; Neale, Benjamin M.; Thorleifsson, Gudmar; Yang, Jian; Albrecht, Eva; Amin, Najaf; Bragg-Gresham, Jennifer L.; Cadby, Gemma; den Heijer, Martin; Eklund, Niina; Fischer, Krista; Goel, Anuj; Hottenga, Jouke-Jan; Huffman, Jennifer E.; Jarick, Ivonne; Johansson, Åsa; Johnson, Toby; Kanoni, Stavroula; Kleber, Marcus E.; König, Inke R.; Kristiansson, Kati; Kutalik, Zoltán; Lamina, Claudia; Lecoeur, Cecile; Li, Guo; Mangino, Massimo; McArdle, Wendy L.; Medina-Gomez, Carolina; Müller-Nurasyid, Martina; Ngwa, Julius S.; Nolte, Ilja M.; Paternoster, Lavinia; Pechlivanis, Sonali; Perola, Markus; Peters, Marjolein J.; Preuss, Michael; Rose, Lynda M.; Shi, Jianxin; Shungin, Dmitry; Smith, Albert Vernon; Strawbridge, Rona J.; Surakka, Ida; Teumer, Alexander; Trip, Mieke D.; Tyrer, Jonathan; Van Vliet-Ostaptchouk, Jana V.; Vandenput, Liesbeth; Waite, Lindsay L.; Zhao, Jing Hua; Absher, Devin; Asselbergs, Folkert W.; Atalay, Mustafa; Attwood, Antony P.; Balmforth, Anthony J.; Basart, Hanneke; Beilby, John; Bonnycastle, Lori L.; Brambilla, Paolo; Bruinenberg, Marcel; Campbell, Harry; Chasman, Daniel I.; Chines, Peter S.; Collins, Francis S.; Connell, John M.; Cookson, William; de Faire, Ulf; de Vegt, Femmie; Dei, Mariano; Dimitriou, Maria; Edkins, Sarah; Estrada, Karol; Evans, David M.; Farrall, Martin; Ferrario, Marco M.; Ferrières, Jean; Franke, Lude; Frau, Francesca; Gejman, Pablo V.; Grallert, Harald; Grönberg, Henrik; Gudnason, Vilmundur; Hall, Alistair S.; Hall, Per; Hartikainen, Anna-Liisa; Hayward, Caroline; Heard-Costa, Nancy L.; Heath, Andrew C.; Hebebrand, Johannes; Homuth, Georg; Hu, Frank B.; Hunt, Sarah E.; Hyppönen, Elina; Iribarren, Carlos; Jacobs, Kevin B.; Jansson, John-Olov; Jula, Antti; Kähönen, Mika; Kathiresan, Sekar; Kee, Frank; Khaw, Kay-Tee; Kivimaki, Mika; Koenig, Wolfgang; Kraja, Aldi T.; Kumari, Meena; Kuulasmaa, Kari; Kuusisto, Johanna; Laitinen, Jaana H.; Lakka, Timo A.; Langenberg, Claudia; Launer, Lenore J.; Lind, Lars; Lindström, Jaana; Liu, Jianjun; Liuzzi, Antonio; Lokki, Marja-Liisa; Lorentzon, Mattias; Madden, Pamela A.; Magnusson, Patrik K.; Manunta, Paolo; Marek, Diana; März, Winfried; Mateo Leach, Irene; McKnight, Barbara; Medland, Sarah E.; Mihailov, Evelin; Milani, Lili; Montgomery, Grant W.; Mooser, Vincent; Mühleisen, Thomas W.; Munroe, Patricia B.; Musk, Arthur W.; Narisu, Narisu; Navis, Gerjan; Nicholson, George; Nohr, Ellen A.; Ong, Ken K.; Oostra, Ben A.; Palmer, Colin N.A.; Palotie, Aarno; Peden, John F.; Pedersen, Nancy; Peters, Annette; Polasek, Ozren; Pouta, Anneli; Pramstaller, Peter P.; Prokopenko, Inga; Pütter, Carolin; Radhakrishnan, Aparna; Raitakari, Olli; Rendon, Augusto; Rivadeneira, Fernando; Rudan, Igor; Saaristo, Timo E.; Sambrook, Jennifer G.; Sanders, Alan R.; Sanna, Serena; Saramies, Jouko; Schipf, Sabine; Schreiber, Stefan; Schunkert, Heribert; Shin, So-Youn; Signorini, Stefano; Sinisalo, Juha; Skrobek, Boris; Soranzo, Nicole; Stančáková, Alena; Stark, Klaus; Stephens, Jonathan C.; Stirrups, Kathleen; Stolk, Ronald P.; Stumvoll, Michael; Swift, Amy J.; Theodoraki, Eirini V.; Thorand, Barbara; Tregouet, David-Alexandre; Tremoli, Elena; Van der Klauw, Melanie M.; van Meurs, Joyce B.J.; Vermeulen, Sita H.; Viikari, Jorma; Virtamo, Jarmo; Vitart, Veronique; Waeber, Gérard; Wang, Zhaoming; Widén, Elisabeth; Wild, Sarah H.; Willemsen, Gonneke; Winkelmann, Bernhard R.; Witteman, Jacqueline C.M.; Wolffenbuttel, Bruce H.R.; Wong, Andrew; Wright, Alan F.; Zillikens, M. Carola; Amouyel, Philippe; Boehm, Bernhard O.; Boerwinkle, Eric; Boomsma, Dorret I.; Caulfield, Mark J.; Chanock, Stephen J.; Cupples, L. Adrienne; Cusi, Daniele; Dedoussis, George V.; Erdmann, Jeanette; Eriksson, Johan G.; Franks, Paul W.; Froguel, Philippe; Gieger, Christian; Gyllensten, Ulf; Hamsten, Anders; Harris, Tamara B.; Hengstenberg, Christian; Hicks, Andrew A.; Hingorani, Aroon; Hinney, Anke; Hofman, Albert; Hovingh, Kees G.; Hveem, Kristian; Illig, Thomas; Jarvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Keinanen-Kiukaanniemi, Sirkka M.; Kiemeney, Lambertus A.; Kuh, Diana; Laakso, Markku; Lehtimäki, Terho; Levinson, Douglas F.; Martin, Nicholas G.; Metspalu, Andres; Morris, Andrew D.; Nieminen, Markku S.; Njølstad, Inger; Ohlsson, Claes; Oldehinkel, Albertine J.; Ouwehand, Willem H.; Palmer, Lyle J.; Penninx, Brenda; Power, Chris; Province, Michael A.; Psaty, Bruce M.; Qi, Lu; Rauramaa, Rainer; Ridker, Paul M.; Ripatti, Samuli; Salomaa, Veikko; Samani, Nilesh J.; Snieder, Harold; Sørensen, Thorkild I.A.; Spector, Timothy D.; Stefansson, Kari; Tönjes, Anke; Tuomilehto, Jaakko; Uitterlinden, André G.; Uusitupa, Matti; van der Harst, Pim; Vollenweider, Peter; Wallaschofski, Henri; Wareham, Nicholas J.; Watkins, Hugh; Wichmann, H.-Erich; Wilson, James F.; Abecasis, Goncalo R.; Assimes, Themistocles L.; Barroso, Inês; Boehnke, Michael; Borecki, Ingrid B.; Deloukas, Panos; Fox, Caroline S.; Frayling, Timothy; Groop, Leif C.; Haritunian, Talin; Heid, Iris M.; Hunter, David; Kaplan, Robert C.; Karpe, Fredrik; Moffatt, Miriam; Mohlke, Karen L.; O’Connell, Jeffrey R.; Pawitan, Yudi; Schadt, Eric E.; Schlessinger, David; Steinthorsdottir, Valgerdur; Strachan, David P.; Thorsteinsdottir, Unnur; van Duijn, Cornelia M.; Visscher, Peter M.; Di Blasio, Anna Maria; Hirschhorn, Joel N.; Lindgren, Cecilia M.; Morris, Andrew P.; Meyre, David; Scherag, André; McCarthy, Mark I.; Speliotes, Elizabeth K.; North, Kari E.; Loos, Ruth J.F.; Ingelsson, Erik

    2014-01-01

    Approaches exploiting extremes of the trait distribution may reveal novel loci for common traits, but it is unknown whether such loci are generalizable to the general population. In a genome-wide search for loci associated with upper vs. lower 5th percentiles of body mass index, height and waist-hip ratio, as well as clinical classes of obesity including up to 263,407 European individuals, we identified four new loci (IGFBP4, H6PD, RSRC1, PPP2R2A) influencing height detected in the tails and seven new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3, ZZZ3) for clinical classes of obesity. Further, we show that there is large overlap in terms of genetic structure and distribution of variants between traits based on extremes and the general population and little etiologic heterogeneity between obesity subgroups. PMID:23563607

  7. Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies

    NARCIS (Netherlands)

    Nalls, M.A.; Plagnol, V.; Hernandez, D.G.; Sharma, M.; Sheerin, U.M.; Saad, M.; Simon-Sanchez, J.; Schulte, C.; Lesage, S.; Sveinbjornsdottir, S.; Stefansson, K.; Martinez, M.; Hardy, J.; Heutink, P.; Brice, A.; Gasser, T.; Singleton, A.B.; Wood, N.W.; Bloem, B.R.; Post, B.; Scheffer, H.; Warrenburg, B.P.C. van de; et al.,

    2011-01-01

    BACKGROUND: Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. METHODS: We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA

  8. A genome-wide search for genes involved in type 2 diabetes in a recently genetically isolated population from the Netherlands

    NARCIS (Netherlands)

    Y.S. Aulchenko (Yurii); N. Vaessen (Norbert); P. Heutink (Peter); J. Pullen (Jan); P.J.L.M. Snijders (Pieter); A. Hofman (Albert); L.A. Sandkuijl (Lodewijk); J.J. Houwing-Duistermaat (Jeanine); S. Bennett (Simon); B.A. Oostra (Ben); C.M. van Duijn (Cornelia); M. Edwards (Mark)

    2003-01-01

    textabstractMultiple genes, interacting with the environment, contribute to the susceptibility to type 2 diabetes. We performed a genome-wide search to localize type 2 diabetes susceptibility genes in a recently genetically isolated population in the Netherlands. We identified 79 nuclear families

  9. Genome-wide comparative analysis of NBS-encoding genes between Brassica species and Arabidopsis thaliana.

    Science.gov (United States)

    Yu, Jingyin; Tehrim, Sadia; Zhang, Fengqi; Tong, Chaobo; Huang, Junyan; Cheng, Xiaohui; Dong, Caihua; Zhou, Yanqiu; Qin, Rui; Hua, Wei; Liu, Shengyi

    2014-01-03

    Plant disease resistance (R) genes with the nucleotide binding site (NBS) play an important role in offering resistance to pathogens. The availability of complete genome sequences of Brassica oleracea and Brassica rapa provides an important opportunity for researchers to identify and characterize NBS-encoding R genes in Brassica species and to compare with analogues in Arabidopsis thaliana based on a comparative genomics approach. However, little is known about the evolutionary fate of NBS-encoding genes in the Brassica lineage after split from A. thaliana. Here we present genome-wide analysis of NBS-encoding genes in B. oleracea, B. rapa and A. thaliana. Through the employment of HMM search and manual curation, we identified 157, 206 and 167 NBS-encoding genes in B. oleracea, B. rapa and A. thaliana genomes, respectively. Phylogenetic analysis among 3 species classified NBS-encoding genes into 6 subgroups. Tandem duplication and whole genome triplication (WGT) analyses revealed that after WGT of the Brassica ancestor, NBS-encoding homologous gene pairs on triplicated regions in Brassica ancestor were deleted or lost quickly, but NBS-encoding genes in Brassica species experienced species-specific gene amplification by tandem duplication after divergence of B. rapa and B. oleracea. Expression profiling of NBS-encoding orthologous gene pairs indicated the differential expression pattern of retained orthologous gene copies in B. oleracea and B. rapa. Furthermore, evolutionary analysis of CNL type NBS-encoding orthologous gene pairs among 3 species suggested that orthologous genes in B. rapa species have undergone stronger negative selection than those in B .oleracea species. But for TNL type, there are no significant differences in the orthologous gene pairs between the two species. This study is first identification and characterization of NBS-encoding genes in B. rapa and B. oleracea based on whole genome sequences. Through tandem duplication and whole genome

  10. Genetic variation of temperature-regulated curd induction in cauliflower: elucidation of floral transition by genome-wide association mapping and gene expression analysis

    Science.gov (United States)

    Matschegewski, Claudia; Zetzsche, Holger; Hasan, Yaser; Leibeguth, Lena; Briggs, William; Ordon, Frank; Uptmoor, Ralf

    2015-01-01

    Cauliflower (Brassica oleracea var. botrytis) is a vernalization-responsive crop. High ambient temperatures delay harvest time. The elucidation of the genetic regulation of floral transition is highly interesting for a precise harvest scheduling and to ensure stable market supply. This study aims at genetic dissection of temperature-dependent curd induction in cauliflower by genome-wide association studies and gene expression analysis. To assess temperature-dependent curd induction, two greenhouse trials under distinct temperature regimes were conducted on a diversity panel consisting of 111 cauliflower commercial parent lines, genotyped with 14,385 SNPs. Broad phenotypic variation and high heritability (0.93) were observed for temperature-related curd induction within the cauliflower population. GWA mapping identified a total of 18 QTL localized on chromosomes O1, O2, O3, O4, O6, O8, and O9 for curding time under two distinct temperature regimes. Among those, several QTL are localized within regions of promising candidate flowering genes. Inferring population structure and genetic relatedness among the diversity set assigned three main genetic clusters. Linkage disequilibrium (LD) patterns estimated global LD extent of r2 = 0.06 and a maximum physical distance of 400 kb for genetic linkage. Transcriptional profiling of flowering genes FLOWERING LOCUS C (BoFLC) and VERNALIZATION 2 (BoVRN2) was performed, showing increased expression levels of BoVRN2 in genotypes with faster curding. However, functional relevance of BoVRN2 and BoFLC2 could not consistently be supported, which probably suggests to act facultative and/or might evidence for BoVRN2/BoFLC-independent mechanisms in temperature-regulated floral transition in cauliflower. Genetic insights in temperature-regulated curd induction can underpin genetically informed phenology models and benefit molecular breeding strategies toward the development of thermo-tolerant cultivars. PMID:26442034

  11. A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

    Science.gov (United States)

    Lane, Jérôme; McLaren, Paul J.; Dorrell, Lucy; Shianna, Kevin V.; Stemke, Amanda; Pelak, Kimberly; Moore, Stephen; Oldenburg, Johannes; Alvarez-Roman, Maria Teresa; Angelillo-Scherrer, Anne; Boehlen, Francoise; Bolton-Maggs, Paula H.B.; Brand, Brigit; Brown, Deborah; Chiang, Elaine; Cid-Haro, Ana Rosa; Clotet, Bonaventura; Collins, Peter; Colombo, Sara; Dalmau, Judith; Fogarty, Patrick; Giangrande, Paul; Gringeri, Alessandro; Iyer, Rathi; Katsarou, Olga; Kempton, Christine; Kuriakose, Philip; Lin, Judith; Makris, Mike; Manco-Johnson, Marilyn; Tsakiris, Dimitrios A.; Martinez-Picado, Javier; Mauser-Bunschoten, Evelien; Neff, Anne; Oka, Shinichi; Oyesiku, Lara; Parra, Rafael; Peter-Salonen, Kristiina; Powell, Jerry; Recht, Michael; Shapiro, Amy; Stine, Kimo; Talks, Katherine; Telenti, Amalio; Wilde, Jonathan; Yee, Thynn Thynn; Wolinsky, Steven M.; Martinson, Jeremy; Hussain, Shehnaz K.; Bream, Jay H.; Jacobson, Lisa P.; Carrington, Mary; Goedert, James J.; Haynes, Barton F.; McMichael, Andrew J.; Goldstein, David B.; Fellay, Jacques

    2013-01-01

    Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979–1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population. PMID:23372042

  12. Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes.

    Directory of Open Access Journals (Sweden)

    Elijah R Behr

    Full Text Available Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants. Cases of drug-induced Torsades de Pointes (diTdP, treatment tolerant controls, and general population controls were ascertained across multiple sites using common definitions, and genotyped on the Illumina 610k or 1M-Duo BeadChips. Principal Components Analysis was used to select 216 Northwestern European diTdP cases and 771 ancestry-matched controls, including treatment-tolerant and general population subjects. With these sample sizes, there is 80% power to detect a variant at genome-wide significance with minor allele frequency of 10% and conferring an odds ratio of ≥2.7. Tests of association were carried out for each single nucleotide polymorphism (SNP by logistic regression adjusting for gender and population structure. No SNP reached genome wide-significance; the variant with the lowest P value was rs2276314, a non-synonymous coding variant in C18orf21 (p  =  3×10(-7, odds ratio = 2, 95% confidence intervals: 1.5-2.6. The haplotype formed by rs2276314 and a second SNP, rs767531, was significantly more frequent in controls than cases (p  =  3×10(-9. Expanding the number of controls and a gene-based analysis did not yield significant associations. This study argues that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs.

  13. Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.

    Directory of Open Access Journals (Sweden)

    Gary W Beecham

    2014-09-01

    Full Text Available Alzheimer's disease (AD and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs, and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA, Lewy body disease (LBD, hippocampal sclerosis of the elderly (HS, and vascular brain injury (VBI. Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE. GalNAc transferase 7 (GALNT7, ATP-Binding Cassette, Sub-Family G (WHITE, Member 1 (ABCG1, and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2 was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related

  14. Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis.

    Directory of Open Access Journals (Sweden)

    Elizabeth G Holliday

    Full Text Available Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD. While genome-wide association studies (GWAS for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH (peak P = 1.5×10(-31 and age-related maculopathy susceptibility 2 (ARMS2 (P = 4.3×10(-24 loci, and suggested Apolipoprotein E (ApoE polymorphisms (rs2075650; P = 1.1×10(-6 associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10(-6 and upstream of GLI2 (rs6721654; P = 6.5×10(-6, encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR gene (rs621313; P = 3.5×10(-6, involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.

  15. Adaptation of maize to temperate climates: mid-density genome-wide association genetics and diversity patterns reveal key genomic regions, with a major contribution of the Vgt2 (ZCN8 locus.

    Directory of Open Access Journals (Sweden)

    Sophie Bouchet

    Full Text Available The migration of maize from tropical to temperate climates was accompanied by a dramatic evolution in flowering time. To gain insight into the genetic architecture of this adaptive trait, we conducted a 50K SNP-based genome-wide association and diversity investigation on a panel of tropical and temperate American and European representatives. Eighteen genomic regions were associated with flowering time. The number of early alleles cumulated along these regions was highly correlated with flowering time. Polymorphism in the vicinity of the ZCN8 gene, which is the closest maize homologue to Arabidopsis major flowering time (FT gene, had the strongest effect. This polymorphism is in the vicinity of the causal factor of Vgt2 QTL. Diversity was lower, whereas differentiation and LD were higher for associated loci compared to the rest of the genome, which is consistent with selection acting on flowering time during maize migration. Selection tests also revealed supplementary loci that were highly differentiated among groups and not associated with flowering time in our panel, whereas they were in other linkage-based studies. This suggests that allele fixation led to a lack of statistical power when structure and relatedness were taken into account in a linear mixed model. Complementary designs and analysis methods are necessary to unravel the architecture of complex traits. Based on linkage disequilibrium (LD estimates corrected for population structure, we concluded that the number of SNPs genotyped should be at least doubled to capture all QTLs contributing to the genetic architecture of polygenic traits in this panel. These results show that maize flowering time is controlled by numerous QTLs of small additive effect and that strong polygenic selection occurred under cool climatic conditions. They should contribute to more efficient genomic predictions of flowering time and facilitate the dissemination of diverse maize genetic resources under a wide

  16. Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies

    NARCIS (Netherlands)

    Nalls, Michael A.; Plagnol, Vincent; Hernandez, Dena G.; Sharma, Manu; Sheerin, Una-Marie; Saad, Mohamad; Simon-Sanchez, Javier; Schulte, Claudia; Lesage, Suzanne; Sveinbjornsdottir, Sigurlaug; Arepalli, Sampath; Barker, Roger; Ben-Shlomo, Yoav; Berendse, Henk W.; Berg, Daniela; Bhatia, Kailash; de Bie, Rob M. A.; Biffi, Alessandro; Bloem, Bas; Bochdanovits, Zoltan; Bonin, Michael; Bras, Jose M.; Brockmann, Kathrin; Brooks, Janet; Burn, David J.; Charlesworth, Gavin; Chen, Honglei; Chinnery, Patrick F.; Chong, Sean; Clarke, Carl E.; Cookson, Mark R.; Cooper, J. Mark; Corvol, Jean Christophe; Counsell, Carl; Damier, Philippe; Dartigues, Jean-Francois; Deloukas, Panos; Deuschl, Guenther; Dexter, David T.; van Dijk, Karin D.; Dillman, Allissa; Durif, Frank; Duerr, Alexandra; Edkins, Sarah; Evans, Jonathan R.; Foltynie, Thomas; Gao, Jianjun; Gardner, Michelle; Gibbs, J. Raphael; Goate, Alison; Gray, Emma; Guerreiro, Rita; Gustafsson, Omar; Harris, Clare; van Hilten, Jacobus J.; Hofman, Albert; Hollenbeck, Albert; Holton, Janice; Hu, Michele; Huang, Xuemei; Huber, Heiko; Hudson, Gavin; Hunt, Sarah E.; Huttenlocher, Johanna; Illig, Thomas; Jonsson, Palmi V.; Lambert, Jean-Charles; Langford, Cordelia; Lees, Andrew; Lichtner, Peter; Limousin, Patricia; Lopez, Grisel; Lorenz, Delia; McNeill, Alisdair; Moorby, Catriona; Moore, Matthew; Morris, Huw R.; Morrison, Karen E.; Mudanohwo, Ese; O'Sullivan, Sean S.; Pearson, Justin; Perlmutter, Joel S.; Petursson, Hjoervar; Pollak, Pierre; Post, Bart; Potter, Simon; Ravina, Bernard; Revesz, Tamas; Riess, Olaf; Rivadeneira, Fernando; Rizzu, Patrizia; Ryten, Mina; Sawcer, Stephen; Schapira, Anthony; Scheffer, Hans; Shaw, Karen; Shoulson, Ira; Sidransky, Ellen; Smith, Colin; Spencer, Chris C. A.; Stefansson, Hreinn; Stockton, Joanna D.; Strange, Amy; Talbot, Kevin; Tanner, Carlie M.; Tashakkori-Ghanbaria, Avazeh; Tison, Francois; Trabzuni, Daniah; Traynor, Bryan J.; Uitterlinden, Andre G.; Velseboer, Daan; Vidailhet, Marie; Walker, Robert; van de Warrenburg, Bart; Wickremaratchi, Mirdhu; Williams, Nigel; Williams-Gray, Caroline H.; Winder-Rhodes, Sophie; Stefansson, Kari; Martinez, Maria; Hardy, John; Heutink, Peter; Brice, Alexis; Gasser, Thomas; Singleton, Andrew B.; Wood, Nicholas W.

    2011-01-01

    Background Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. Methods We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA and

  17. A bias-reducing pathway enrichment analysis of genome-wide association data confirmed association of the MHC region with schizophrenia.

    LENUS (Irish Health Repository)

    Jia, Peilin

    2012-02-01

    After the recent successes of genome-wide association studies (GWAS), one key challenge is to identify genetic variants that might have a significant joint effect on complex diseases but have failed to be identified individually due to weak to moderate marginal effect. One popular and effective approach is gene set based analysis, which investigates the joint effect of multiple functionally related genes (eg, pathways). However, a typical gene set analysis method is biased towards long genes, a problem that is especially severe in psychiatric diseases.

  18. Genetic Influences on Political Ideologies: Twin Analyses of 19 Measures of Political Ideologies from Five Democracies and Genome-Wide Findings from Three Populations

    Science.gov (United States)

    Hatemi, Peter K.; Medland, Sarah E.; Klemmensen, Robert; Oskarrson, Sven; Littvay, Levente; Dawes, Chris; Verhulst, Brad; McDermott, Rose; Nørgaard, Asbjørn Sonne; Klofstad, Casey; Christensen, Kaare; Johannesson, Magnus; Magnusson, Patrik K.E.; Eaves, Lindon J.; Martin, Nicholas G.

    2014-01-01

    Almost forty years ago, evidence from large studies of adult twins and their relatives suggested that between 30-60% of the variance in social and political attitudes could be explained by genetic influences. However, these findings have not been widely accepted or incorporated into the dominant paradigms that explain the etiology of political ideology. This has been attributed in part to measurement and sample limitations, as well the relative absence of molecular genetic studies. Here we present results from original analyses of a combined sample of over 12,000 twins pairs, ascertained from nine different studies conducted in five democracies, sampled over the course of four decades. We provide evidence that genetic factors play a role in the formation of political ideology, regardless of how ideology is measured, the era, or the population sampled. The only exception is a question that explicitly uses the phrase “Left-Right”. We then present results from one of the first genome-wide association studies on political ideology using data from three samples: a 1990 Australian sample involving 6,894 individuals from 3,516 families; a 2008 Australian sample of 1,160 related individuals from 635 families and a 2010 Swedish sample involving 3,334 individuals from 2,607 families. No polymorphisms reached genome-wide significance in the meta-analysis. The combined evidence suggests that political ideology constitutes a fundamental aspect of one’s genetically informed psychological disposition, but as Fisher proposed long ago, genetic influences on complex traits will be composed of thousands of markers of very small effects and it will require extremely large samples to have enough power in order to identify specific polymorphisms related to complex social traits. PMID:24569950

  19. Genome-wide association analysis of oxidative stress resistance in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Allison L Weber

    Full Text Available Aerobic organisms are susceptible to damage by reactive oxygen species. Oxidative stress resistance is a quantitative trait with population variation attributable to the interplay between genetic and environmental factors. Drosophila melanogaster provides an ideal system to study the genetics of variation for resistance to oxidative stress.We used 167 wild-derived inbred lines of the Drosophila Genetic Reference Panel for a genome-wide association study of acute oxidative stress resistance to two oxidizing agents, paraquat and menadione sodium bisulfite. We found significant genetic variation for both stressors. Single nucleotide polymorphisms (SNPs associated with variation in oxidative stress resistance were often sex-specific and agent-dependent, with a small subset common for both sexes or treatments. Associated SNPs had moderately large effects, with an inverse relationship between effect size and allele frequency. Linear models with up to 12 SNPs explained 67-79% and 56-66% of the phenotypic variance for resistance to paraquat and menadione sodium bisulfite, respectively. Many genes implicated were novel with no known role in oxidative stress resistance. Bioinformatics analyses revealed a cellular network comprising DNA metabolism and neuronal development, consistent with targets of oxidative stress-inducing agents. We confirmed associations of seven candidate genes associated with natural variation in oxidative stress resistance through mutational analysis.We identified novel candidate genes associated with variation in resistance to oxidative stress that have context-dependent effects. These results form the basis for future translational studies to identify oxidative stress susceptibility/resistance genes that are evolutionary conserved and might play a role in human disease.

  20. Genome-wide meta-analysis identifies new susceptibility loci for migraine

    NARCIS (Netherlands)

    Anttila, Verneri; Winsvold, Bendik S.; Gormley, Padhraig; Kurth, Tobias; Bettella, Francesco; McMahon, George; Kallela, Mikko; Malik, Rainer; de Vries, Boukje; Terwindt, Gisela; Medland, Sarah E.; Todt, Unda; McArdle, Wendy L.; Quaye, Lydia; Koiranen, Markku; Ikram, M. Arfan; Lehtimaki, Terho; Stam, Anine H.; Ligthart, Lannie; Wedenoja, Juho; Dunham, Ian; Neale, Benjamin M.; Palta, Priit; Hamalainen, Eija; Schuerks, Markus; Rose, Lynda M.; Buring, Julie E.; Ridker, Paul M.; Steinberg, Stacy; Stefansson, Hreinn; Jakobsson, Finnbogi; Lawlor, Debbie A.; Evans, David M.; Ring, Susan M.; Farkkila, Markus; Artto, Ville; Kaunisto, Mari A.; Freilinger, Tobias; Schoenen, Jean; Frants, Rune R.; Pelzer, Nadine; Weller, Claudia M.; Zielman, Ronald; Heath, Andrew C.; Madden, Pamela A. F.; Montgomery, Grant W.; Martin, Nicholas G.; Borck, Guntram; Goebel, Hartmut; Heinze, Axel

    Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and

  1. Genome-wide meta-analysis identifies new susceptibility loci for migraine

    NARCIS (Netherlands)

    Anttila, V.; Winsvold, B.S.; Gormley, P.; Kurth, T.; Bettella, F.; McMahon, G.; Kallela, M.; Malik, R.; de Vries, B.; Terwindt, G.; Medland, S.E.; Todt, U.; McArdle, W.L.; Quaye, L.; Koiranen, M.; Ikram, M.A.; Lehtimäki, T.; Stam, A.H.; Ligthart, R.S.L.; Wedenoja, J.; Dunham, I.; Neale, B. M.; Palta, P.; Hamalainen, E.; Schürks, M.; Rose, L.M.; Buring, J.E.; Ridker, P.M.; Steinberg, S.; Stefansson, H.; Jakobsson, F.; Lawlor, D.A.; Evans, D.M.; Ring, S.M.; Färkkilä, M.; Artto, V.; Kaunisto, M.A.; Freilinger, T.; Schoenen, J.; Frants, R.R.; Pelzer, N.; Weller, C.M.; Zielman, R.; Heath, A.C.; Madden, P.A.F.; Montgomery, G.W.; Martin, N.G.; Borck, G.; Göbel, H.; Heinze, A.; Heinze-Kuhn, K.; Williams, F.M.; Hartikainen, A.-L.; Pouta, A.; van den Ende, J..; Uitterlinden, A.G.; Hofman, A.; Amin, N.; Hottenga, J.J.; Vink, J.M.; Heikkilä, K.; Alexander, M.; Muller-Myhsok, B.; Schreiber, S; Meitinger, T.; Wichmann, H. E.; Aromaa, A.; Eriksson, J.G.; Traynor, B.J.; Trabzuni, D.; Rossin, E.; Lage, K.; Jacobs, S.B.; Gibbs, J.R.; Birney, E.; Kaprio, J.; Penninx, B.W.J.H.; Boomsma, D.I.; van Duijn, C.M.; Raitakari, O.; Jarvelin, M.-R.; Zwart, J.A.; Cherkas, L.; Strachan, D.P.; Kubisch, C.; Ferrari, M.D.; van den Maagdenberg, A.M.J.M.; Dichgans, M.; Wessman, M.; Smith, G.D.; Stefansson, K.; Daly, M.J.; Nyholt, DR; Chasman, D.I.; Palotie, A.

    2013-01-01

    Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and

  2. Genome-wide meta-analysis identifies new susceptibility loci for migraine

    DEFF Research Database (Denmark)

    Anttila, Verneri; Winsvold, Bendik S; Gormley, Padhraig

    2013-01-01

    Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) an...

  3. On the analysis of genome-wide association studies in family-based designs: a universal, robust analysis approach and an application to four genome-wide association studies.

    Directory of Open Access Journals (Sweden)

    Sungho Won

    2009-11-01

    Full Text Available For genome-wide association studies in family-based designs, we propose a new, universally applicable approach. The new test statistic exploits all available information about the association, while, by virtue of its design, it maintains the same robustness against population admixture as traditional family-based approaches that are based exclusively on the within-family information. The approach is suitable for the analysis of almost any trait type, e.g. binary, continuous, time-to-onset, multivariate, etc., and combinations of those. We use simulation studies to verify all theoretically derived properties of the approach, estimate its power, and compare it with other standard approaches. We illustrate the practical implications of the new analysis method by an application to a lung-function phenotype, forced expiratory volume in one second (FEV1 in 4 genome-wide association studies.

  4. Genetic Characterization and Comparative Genome Analysis of Brucella melitensis Isolates from India

    Directory of Open Access Journals (Sweden)

    Sarwar Azam

    2016-01-01

    Full Text Available Brucellosis is the most frequent zoonotic disease worldwide, with over 500,000 new human infections every year. Brucella melitensis, the most virulent species in humans, primarily affects goats and the zoonotic transmission occurs by ingestion of unpasteurized milk products or through direct contact with fetal tissues. Brucellosis is endemic in India but no information is available on population structure and genetic diversity of Brucella spp. in India. We performed multilocus sequence typing of four B. melitensis strains isolated from naturally infected goats from India. For more detailed genetic characterization, we carried out whole genome sequencing and comparative genome analysis of one of the B. melitensis isolates, Bm IND1. Genome analysis identified 141 unique SNPs, 78 VNTRs, 51 Indels, and 2 putative prophage integrations in the Bm IND1 genome. Our data may help to develop improved epidemiological typing tools and efficient preventive strategies to control brucellosis.

  5. Genome-wide analysis of the diversity and ancestry of Korean dogs.

    Science.gov (United States)

    Choi, Bong Hwan; Wijayananda, Hasini I; Lee, Soo Hyun; Lee, Doo Ho; Kim, Jong Seok; Oh, Seok Il; Park, Eung Woo; Lee, Cheul Koo; Lee, Seung Hwan

    2017-01-01

    There are various hypotheses on dog domestication based on archeological and genetic studies. Although many studies have been conducted on the origin of dogs, the existing literature about the ancestry, diversity, and population structure of Korean dogs is sparse. Therefore, this study is focused on the origin, diversity and population structure of Korean dogs. The study sample comprised four major categories, including non-dogs (coyotes and wolves), ancient, modern and Korean dogs. Selected samples were genotyped using an Illumina CanineHD array containing 173,662 single nucleotide polymorphisms. The genome-wide data were filtered using quality control parameters in PLINK 1.9. Only autosomal chromosomes were used for further analysis. The negative off-diagonal variance of the genetic relationship matrix analysis depicted, the variability of samples in each population. FIS (inbreeding rate within a population) values indicated, a low level of inbreeding within populations, and the patterns were in concordance with the results of Nei's genetic distance analysis. The lowest FST (inbreeding rate between populations) values among Korean and Chinese breeds, using a phylogenetic tree, multi-dimensional scaling, and a TreeMix likelihood tree showed Korean breeds are highly related to Chinese breeds. The Korean breeds possessed a unique and large diversity of admixtures compared with other breeds. The highest and lowest effective population sizes were observed in Korean Jindo Black (485) and Korean Donggyeong White (109), respectively. The historical effective population size of all Korean dogs showed declining trend from the past to present. It is important to take immediate action to protect the Korean dog population while conserving their diversity. Furthermore, this study suggests that Korean dogs have unique diversity and are one of the basal lineages of East Asian dogs, originating from China.

  6. Genome-wide analysis of the diversity and ancestry of Korean dogs.

    Directory of Open Access Journals (Sweden)

    Bong Hwan Choi

    Full Text Available There are various hypotheses on dog domestication based on archeological and genetic studies. Although many studies have been conducted on the origin of dogs, the existing literature about the ancestry, diversity, and population structure of Korean dogs is sparse. Therefore, this study is focused on the origin, diversity and population structure of Korean dogs. The study sample comprised four major categories, including non-dogs (coyotes and wolves, ancient, modern and Korean dogs. Selected samples were genotyped using an Illumina CanineHD array containing 173,662 single nucleotide polymorphisms. The genome-wide data were filtered using quality control parameters in PLINK 1.9. Only autosomal chromosomes were used for further analysis. The negative off-diagonal variance of the genetic relationship matrix analysis depicted, the variability of samples in each population. FIS (inbreeding rate within a population values indicated, a low level of inbreeding within populations, and the patterns were in concordance with the results of Nei's genetic distance analysis. The lowest FST (inbreeding rate between populations values among Korean and Chinese breeds, using a phylogenetic tree, multi-dimensional scaling, and a TreeMix likelihood tree showed Korean breeds are highly related to Chinese breeds. The Korean breeds possessed a unique and large diversity of admixtures compared with other breeds. The highest and lowest effective population sizes were observed in Korean Jindo Black (485 and Korean Donggyeong White (109, respectively. The historical effective population size of all Korean dogs showed declining trend from the past to present. It is important to take immediate action to protect the Korean dog population while conserving their diversity. Furthermore, this study suggests that Korean dogs have unique diversity and are one of the basal lineages of East Asian dogs, originating from China.

  7. Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations : A transethnic genome-wide meta-analysis

    NARCIS (Netherlands)

    Wheeler, Eleanor; Leong, Aaron; Liu, Ching-Ti; Hivert, Marie-France; Strawbridge, Rona J; Podmore, Clara; Li, Man; Yao, Jie; Sim, Xueling; Hong, Jaeyoung; Chu, Audrey Y; Zhang, Weihua; Wang, Xu; Chen, Peng; Maruthur, Nisa M; Porneala, Bianca C; Sharp, Stephen J; Jia, Yucheng; Kabagambe, Edmond K; Chang, Li-Ching; Chen, Wei-Min; Elks, Cathy E; Evans, Daniel S; Fan, Qiao; Giulianini, Franco; Go, Min Jin; Hottenga, Jouke-Jan; Hu, Yao; Jackson, Anne U; Kanoni, Stavroula; Kim, Young Jin; Kleber, Marcus E; Ladenvall, Claes; Lecoeur, Cecile; Lim, Sing-Hui; Lu, Yingchang; Mahajan, Anubha; Marzi, Carola; Nalls, Mike A; Navarro, Pau; Nolte, Ilja M; Sanna, Serena; van der Most, Peter J; Van Vliet-Ostaptchouk, Jana V.; Alizadeh, Behrooz Z; Hartman, Catharina A; Swertz, Morris; Oldehinkel, Albertine J; Snieder, Harold; Wolffenbuttel, Bruce H R

    2017-01-01

    Background Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely

  8. Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations : A transethnic genome-wide meta-analysis

    NARCIS (Netherlands)

    Wheeler, Eleanor; Leong, Aaron; Liu, Ching-Ti; Hivert, Marie-France; Strawbridge, Rona J; Podmore, Clara; Li, Man; Yao, Jie; Sim, Xueling; Hong, Jaeyoung; Chu, Audrey Y; Zhang, Weihua; Wang, Xu; Chen, Peng; Maruthur, Nisa M; Porneala, Bianca C; Sharp, Stephen J; Jia, Yucheng; Kabagambe, Edmond K; Chang, Li-Ching; Chen, Wei-Min; Elks, Cathy E; Evans, Daniel S; Fan, Qiao; Giulianini, Franco; Go, Min Jin; Hottenga, Jouke-Jan; Hu, Yao; Jackson, Anne U; Kanoni, Stavroula; Kim, Young Jin; Kleber, Marcus E; Ladenvall, Claes; Lecoeur, Cecile; Lim, Sing-Hui; Lu, Yingchang; Mahajan, Anubha; Marzi, Carola; Nalls, Mike A; Navarro, Pau; Nolte, Ilja M; Rose, Lynda M; Rybin, Denis V; Sanna, Serena; Shi, Yuan; Stram, Daniel O; Takeuchi, Fumihiko; Tan, Shu Pei; van der Most, Peter J; van Vliet-Ostaptchouk, Jana V; Wong, Andrew; Yengo, Loic; Zhao, Wanting; Goel, Anuj; Martinez Larrad, Maria Teresa; Radke, Dörte; Salo, Perttu; Tanaka, Toshiko; van Iperen, Erik P A; Abecasis, Goncalo; Afaq, Saima; Alizadeh, Behrooz Z; Bertoni, Alain G; Bonnefond, Amelie; Böttcher, Yvonne; Bottinger, Erwin P; Campbell, Harry; Carlson, Olga D; Chen, Chien-Hsiun; Cho, Yoon Shin; Garvey, W Timothy; Gieger, Christian; Goodarzi, Mark O; Grallert, Harald; Hamsten, Anders; Hartman, Catharina A; Herder, Christian; Hsiung, Chao Agnes; Huang, Jie; Igase, Michiya; Isono, Masato; Katsuya, Tomohiro; Khor, Chiea-Chuen; Kiess, Wieland; Kohara, Katsuhiko; Kovacs, Peter; Lee, Juyoung; Lee, Wen-Jane; Lehne, Benjamin; Li, Huaixing; Liu, Jianjun; Lobbens, Stephane; Luan, Jian'an; Lyssenko, Valeriya; Meitinger, Thomas; Miki, Tetsuro; Miljkovic, Iva; Moon, Sanghoon; Mulas, Antonella; Müller, Gabriele; Müller-Nurasyid, Martina; Nagaraja, Ramaiah; Nauck, Matthias; Pankow, James S; Polasek, Ozren; Prokopenko, Inga; Ramos, Paula S; Rasmussen-Torvik, Laura J; Rathmann, Wolfgang; Rich, Stephen S; Robertson, Neil R; Roden, Michael; Roussel, Ronan; Rudan, Igor; Scott, Robert A; Scott, William R; Sennblad, Bengt; Siscovick, David S; Strauch, Konstantin; Sun, Shan-Liang; Swertz, Morris a.; Tajuddin, Salman M; Taylor, Kent D; Teo, Yik-Ying; Tham, Yih Chung; Tönjes, Anke; Wareham, Nicholas J; Willemsen, Gonneke; Wilsgaard, Tom; Hingorani, Aroon D; Egan, Josephine; Ferrucci, Luigi; Hovingh, G. Kees; Jula, Antti; Kivimaki, Mika; Kumari, Meena; Njølstad, Inger; Palmer, Colin N A; Serrano Ríos, Manuel; Stumvoll, Michael; Watkins, Hugh; Aung, Tin; Blüher, Matthias; Boehnke, Michael; Boomsma, Dorret I; Bornstein, Stefan R; Chambers, John C; Chasman, Daniel I; Chen, Yii-Der Ida; Chen, Yduan-Tsong; Cheng, Ching-Yu; Cucca, Francesco; de Geus, Eco J C; Deloukas, Panos; Evans, Michele K; Fornage, Myriam; Friedlander, Yechiel; Froguel, Philippe; Groop, Leif; Gross, Myron D; Harris, Tamara B; Hayward, Caroline; Heng, Chew-Kiat; Ingelsson, Erik; Kato, Norihiro; Kim, Bong-Jo; Koh, Woon-Puay; Kooner, Jaspal S; Körner, Antje; Kuh, Diana; Kuusisto, Johanna; Laakso, Markku; Lin, Xu; Liu, YongMei; Loos, Ruth J F; Magnusson, Patrik K E; März, Winfried; McCarthy, Mark I; Oldehinkel, Albertine J; Ong, Ken K; Pedersen, Nancy L; Pereira, Mark A; Peters, Annette; Ridker, Paul M; Sabanayagam, Charumathi; Sale, Michele; Saleheen, Danish; Saltevo, Juha; Schwarz, Peter Eh; Sheu, Wayne H H; Snieder, Harold; Spector, Timothy D; Tabara, Yasuharu; Tuomilehto, Jaakko; van Dam, Rob M; Wilson, James G; Wilson, James F; Wolffenbuttel, Bruce H R; Wong, Tien Yin; Wu, Jer-Yuarn; Yuan, Jian-Min; Zonderman, Alan B; Soranzo, Nicole; Guo, Xiuqing; Roberts, David J; Florez, Jose C; Sladek, Robert; Dupuis, Josée; Morris, Andrew P; Tai, E Shyong; Selvin, Elizabeth; Rotter, Jerome I; Langenberg, Claudia; Barroso, Inês; Meigs, James B

    BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely

  9. Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations : A transethnic genome-wide meta-analysis

    NARCIS (Netherlands)

    Wheeler, Eleanor; Leong, Aaron; Liu, Ching Ti; Hivert, Marie France; Strawbridge, Rona J.; Podmore, Clara; Li, Man; Yao, Jie; Sim, Xueling; Hong, Jaeyoung; Chu, Audrey Y.; Zhang, Weihua; Wang, Xu; Chen, Peng; Maruthur, Nisa M.; Porneala, Bianca C.; Sharp, Stephen J.; Jia, Yucheng; Kabagambe, Edmond K.; Chang, Li Ching; Chen, Wei Min; Elks, Cathy E.; Evans, Daniel S.; Fan, Qiao; Giulianini, Franco; Go, Min Jin; Hottenga, Jouke Jan; Hu, Yao; Jackson, Anne U.; Kanoni, Stavroula; Kim, Young Jin; Kleber, Marcus E.; Ladenvall, Claes; Lecoeur, Cecile; Lim, Sing Hui; Lu, Yingchang; Mahajan, Anubha; Marzi, Carola; Nalls, Mike A.; Navarro, Pau; Nolte, Ilja M.; Rose, Lynda M.; Rybin, Denis V.; Sanna, Serena; Shi, Yuan; Stram, Daniel O.; Takeuchi, Fumihiko; Tan, Shu Pei; van der Most, Peter J.; Van Vliet-Ostaptchouk, Jana V.; Wong, Andrew; Yengo, Loic; Zhao, Wanting; Goel, Anuj; Martinez Larrad, Maria Teresa; Radke, Dörte; Salo, Perttu; Tanaka, Toshiko; van Iperen, Erik P.A.; Abecasis, Goncalo; Afaq, Saima; Alizadeh, Behrooz Z.; Bertoni, Alain G.; Bonnefond, Amelie; Böttcher, Yvonne; Bottinger, Erwin P.; Campbell, Harry; Carlson, Olga D.; Chen, Chien Hsiun; Cho, Yoon Shin; Garvey, W. Timothy; Gieger, Christian; Goodarzi, Mark O.; Grallert, Harald; Hamsten, Anders; Hartman, Catharina A.; Herder, Christian; Hsiung, Chao Agnes; Huang, Jie; Igase, Michiya; Isono, Masato; Katsuya, Tomohiro; Khor, Chiea Chuen; Kiess, Wieland; Kohara, Katsuhiko; Kovacs, Peter; Lee, Juyoung; Lee, Wen Jane; Lehne, Benjamin; Li, Huaixing; Liu, Jianjun; Lobbens, Stephane; Luan, Jian'an; Lyssenko, Valeriya; Meitinger, Thomas; Miki, Tetsuro; Miljkovic, Iva; Moon, Sanghoon; Mulas, Antonella; Müller, Gabriele; Müller-Nurasyid, Martina; Nagaraja, Ramaiah; Nauck, Matthias; Pankow, James S.; Polasek, Ozren; Prokopenko, Inga; Ramos, Paula S.; Rasmussen-Torvik, Laura; Rathmann, Wolfgang; Rich, Stephen S.; Robertson, Neil R.; Roden, Michael; Roussel, Ronan; Rudan, Igor; Scott, Robert A.; Scott, William R.; Sennblad, Bengt; Siscovick, David S.; Strauch, Konstantin; Sun, Liang; Swertz, Morris; Tajuddin, Salman M.; Taylor, Kent D.; Teo, Yik Ying; Tham, Yih Chung; Tönjes, Anke; Wareham, Nicholas J.; Willemsen, Gonneke; Wilsgaard, Tom; Hingorani, Aroon D.; Egan, Josephine; Ferrucci, Luigi; Hovingh, G. Kees; Jula, Antti; Kivimaki, Mika; Kumari, Meena; Njølstad, Inger; Palmer, Colin N.A.; Serrano Ríos, Manuel; Stumvoll, Michael; Watkins, Hugh; Aung, Tin; Blüher, Matthias; Boehnke, Michael; Boomsma, Dorret I.; Bornstein, Stefan R.; Chambers, John C.; Chasman, Daniel I.; Chen, Yii Der Ida; Chen, Yduan Tsong; Cheng, Ching Yu; Cucca, Francesco; de Geus, Eco J.C.; Deloukas, Panos; Evans, Michele K.; Fornage, Myriam; Friedlander, Yechiel; Froguel, Philippe; Groop, Leif; Gross, Myron D.; Harris, Tamara B.; Hayward, Caroline; Heng, Chew Kiat; Ingelsson, Erik; Kato, Norihiro; Kim, Bong Jo; Koh, Woon Puay; Kooner, Jaspal S.; Körner, Antje; Kuh, Diana; Kuusisto, Johanna; Laakso, Markku; Lin, Xu; Liu, Yongmei; Loos, Ruth J.F.; Magnusson, Patrik K.E.; März, Winfried; McCarthy, Mark I.; Oldehinkel, Albertine J.; Ong, Ken K.; Pedersen, Nancy L.; Pereira, Mark A.; Peters, Annette; Ridker, Paul M.; Sabanayagam, Charumathi; Sale, Michele; Saleheen, Danish; Saltevo, Juha; Schwarz, Peter E.H.; Sheu, Wayne H.H.; Snieder, Harold; Spector, Timothy D.; Tabara, Yasuharu; Tuomilehto, Jaakko; van Dam, Rob M.; Wilson, James G.; Wilson, James F.; Wolffenbuttel, Bruce H.R.; Wong, Tien Yin; Wu, Jer Yuarn; Yuan, Jian Min; Zonderman, Alan B.; Soranzo, Nicole; Guo, Xiuqing; Roberts, David J.; Florez, Jose C.; Sladek, Robert; Dupuis, Josée; Morris, Andrew P.; Tai, E. Shyong; Selvin, Elizabeth; Rotter, Jerome I.; Langenberg, Claudia; Barroso, Inês; Meigs, James B.

    2017-01-01

    Background: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely

  10. Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis

    NARCIS (Netherlands)

    Wheeler, Eleanor; Leong, Aaron; Liu, Ching-Ti; Hivert, Marie-France; Strawbridge, Rona J.; Podmore, Clara; Li, Man; Yao, Jie; Sim, Xueling; Hong, Jaeyoung; Chu, Audrey Y.; Zhang, Weihua; Wang, Xu; Chen, Peng; Maruthur, Nisa M.; Porneala, Bianca C.; Sharp, Stephen J.; Jia, Yucheng; Kabagambe, Edmond K.; Chang, Li-Ching; Chen, Wei-Min; Elks, Cathy E.; Evans, Daniel S.; Fan, Qiao; Giulianini, Franco; Go, Min Jin; Hottenga, Jouke-Jan; Hu, Yao; Jackson, Anne U.; Kanoni, Stavroula; Kim, Young Jin; Kleber, Marcus E.; Ladenvall, Claes; Lecoeur, Cecile; Lim, Sing-Hui; Lu, Yingchang; Mahajan, Anubha; Marzi, Carola; Nalls, Mike A.; Navarro, Pau; Nolte, Ilja M.; Rose, Lynda M.; Rybin, Denis V.; Sanna, Serena; Shi, Yuan; Stram, Daniel O.; Takeuchi, Fumihiko; Tan, Shu Pei; van der Most, Peter J.; van Vliet-Ostaptchouk, Jana V.; Wong, Andrew; Yengo, Loic; Zhao, Wanting; Goel, Anuj; Martinez Larrad, Maria Teresa; Radke, Dorte; Salo, Perttu; Tanaka, Toshiko; van Iperen, Erik P. A.; Abecasis, Goncalo; Afaq, Saima; Alizadeh, Behrooz Z.; Bertoni, Alain G.; Bonnefond, Amelie; Bottcher, Yvonne; Bottinger, Erwin P.; Campbell, Harry; Carlson, Olga D.; Chen, Chien-Hsiun; Cho, Yoon Shin; Garvey, W. Timothy; Gieger, Christian; Goodarzi, Mark O.; Grallert, Harald; Hamsten, Anders; Hartman, Catharina A.; Herder, Christian; Hsiung, Chao Agnes; Huang, Jie; Igase, Michiya; Isono, Masato; Katsuya, Tomohiro; Khor, Chiea-Chuen; Kiess, Wieland; Kohara, Katsuhiko; Kovacs, Peter; Lee, Juyoung; Lee, Wen-Jane; Lehne, Benjamin; Li, Huaixing; Liu, Jianjun; Lobbens, Stephane; Luan, Jian'an; Lyssenko, Valeriya; Meitinger, Thomas; Miki, Tetsuro; Miljkovic, Iva; Moon, Sanghoon; Mulas, Antonella; Muller, Gabriele; Muller-Nurasyid, Martina; Nagaraja, Ramaiah; Nauck, Matthias; Pankow, James S.; Polasek, Ozren; Prokopenko, Inga; Ramos, Paula S.; Rasmussen-Torvik, Laura; Rathmann, Wolfgang; Rich, Stephen S.; Robertson, Neil R.; Roden, Michael; Roussel, Ronan; Rudan, Igor; Scott, Robert A.; Scott, William R.; Sennblad, Bengt; Siscovick, David S.; Strauch, Konstantin; Sun, Liang; Swertz, Morris; Tajuddin, Salman M.; Taylor, Kent D.; teo, Yik-Ying; Tham, Yih Chung; Tonjes, Anke; Wareham, Nicholas J.; Willemsen, Gonneke; Wilsgaard, Tom; Hingorani, Aroon D.; Egan, Josephine; Ferrucci, Luigi; Hovingh, G. Kees; Jula, Antti; Kivimaki, Mika; Kumari, Meena; Njolstad, Inger; Palmer, Colin N. A.; Serrano Rios, Manuel; Stumvoll, Michael; Watkins, Hugh; Aung, Tin; Bluher, Matthias; Boehnke, Michael; Boomsma, Dorret I.; Bornstein, Stefan R.; Chambers, John C.; Chasman, Daniel I.; Chen, Yii-Der Ida; Chen, Yduan-Tsong; Cheng, Ching-Yu; Cucca, Francesco; de Geus, Eco J. C.; Deloukas, Panos; Evans, Michele K.; Fornage, Myriam; Friedlander, Yechiel; Froguel, Philippe; Groop, Leif; Gross, Myron D.; Harris, Tamara B.; Hayward, Caroline; Heng, Chew-Kiat; Ingelsson, Erik; Kato, Norihiro; Kim, Bong-Jo; Koh, Woon-Puay; Kooner, Jaspal S.; Korner, Antje; Kuh, Diana; Kuusisto, Johanna; Laakso, Markku; Lin, Xu; Liu, Yongmei; Loos, Ruth J. F.; Magnusson, Patrik K. E.; Marz, Winfried; McCarthy, Mark I.; Oldehinkel, Albertine J.; Ong, Ken K.; Pedersen, Nancy L.; Pereira, Mark A.; Peters, Annette; Ridker, Paul M.; Sabanayagam, Charumathi; Sale, Michele; Saleheen, Danish; Saltevo, Juha; Schwarz, Peter Eh; Sheu, Wayne H. H.; Snieder, Harold; Spector, Timothy D.; Tabara, Yasuharu; Tuomilehto, Jaakko; van Dam, Rob M.; Wilson, James G.; Wilson, James F.; Wolffenbuttel, Bruce H. R.; Wong, Tien Yin; Wu, Jer-Yuarn; Yuan, Jian-Min; Zonderman, Alan B.; Soranzo, Nicole; Guo, Xiuqing; Roberts, David J.; Florez, Jose C.; Sladek, Robert; Dupuis, Josee; Morris, Andrew P.; Tai, E.-Shyong; Selvin, Elizabeth; Rotter, Jerome I.; Langenberg, Claudia; Barroso, Ines; Meigs, James B.

    2017-01-01

    Background Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely

  11. Genome-wide physical activity interactions in adiposity ― A meta-analysis of 200,452 adults

    DEFF Research Database (Denmark)

    Graff, Mariaelisa; Scott, Robert A.; Justice, Anne E.

    2017-01-01

    Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adu...

  12. Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease

    NARCIS (Netherlands)

    Khor, Chiea Chuen; Davila, Sonia; Breunis, Willemijn B.; Lee, Yi-Ching; Shimizu, Chisato; Wright, Victoria J.; Yeung, Rae S. M.; Tan, Dennis E. K.; Sim, Kar Seng; Wang, Jie Jin; Wong, Tien Yin; Pang, Junxiong; Mitchell, Paul; Cimaz, Rolando; Dahdah, Nagib; Cheung, Yiu-Fai; Huang, Guo-Ying; Yang, Wanling; Park, In-Sook; Lee, Jong-Keuk; Wu, Jer-Yuarn; Levin, Michael; Burns, Jane C.; Burgner, David; Kuijpers, Taco W.; Hibberd, Martin L.; Lau, Yu-Lung; Zhang, Jing; Ma, Xiao-Jing; Liu, Fang; Wu, Lin; Yoo, Jeong-Jin; Hong, Soo-Jong; Kim, Kwi-Joo; Kim, Jae-Jung; Park, Young-Mi; Mi Hong, Young; Sohn, Sejung; Young Jang, Gi; Ha, Kee-Soo; Nam, Hyo-Kyoung; Byeon, Jung-Hye; Weon Yun, Sin; Ki Han, Myung; Lee, Kyung-Yil; Hwang, Ja-Young; Kuipers, Irene M.; Ottenkamp, Jaap J.; Biezeveld, Maarten; Tacke, Carline

    2011-01-01

    Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide association study and replication analysis in 2,173 individuals with Kawasaki disease and 9,383 controls from

  13. The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position Statement of the Canadian College of Medical Geneticists

    Science.gov (United States)

    Boycott, Kym; Hartley, Taila; Adam, Shelin; Bernier, Francois; Chong, Karen; Fernandez, Bridget A; Friedman, Jan M; Geraghty, Michael T; Hume, Stacey; Knoppers, Bartha M; Laberge, Anne-Marie; Majewski, Jacek; Mendoza-Londono, Roberto; Meyn, M Stephen; Michaud, Jacques L; Nelson, Tanya N; Richer, Julie; Sadikovic, Bekim; Skidmore, David L; Stockley, Tracy; Taylor, Sherry; van Karnebeek, Clara; Zawati, Ma'n H; Lauzon, Julie; Armour, Christine M

    2015-01-01

    Purpose and scope The aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it does not address the clinical application of this technology in other fields such as molecular investigation of cancer or for population screening of healthy individuals. Methods of statement development Two multidisciplinary groups consisting of medical geneticists, clinical laboratory geneticists, genetic counsellors, ethicists, lawyers and genetic researchers were assembled to review existing literature and guidelines on genome-wide sequencing for clinical genetic diagnosis in the context of monogenic diseases, and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. Results and conclusions Recommendations include (1) clinical genome-wide sequencing is an appropriate approach in the diagnostic assessment of a patient for whom there is suspicion of a significant monogenic disease that is associated with a high degree of genetic heterogeneity, or where specific genetic tests have failed to provide a diagnosis; (2) until the benefits of reporting incidental findings are established, we do not endorse the intentional clinical analysis of disease-associated genes

  14. The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position Statement of the Canadian College of Medical Geneticists.

    Science.gov (United States)

    Boycott, Kym; Hartley, Taila; Adam, Shelin; Bernier, Francois; Chong, Karen; Fernandez, Bridget A; Friedman, Jan M; Geraghty, Michael T; Hume, Stacey; Knoppers, Bartha M; Laberge, Anne-Marie; Majewski, Jacek; Mendoza-Londono, Roberto; Meyn, M Stephen; Michaud, Jacques L; Nelson, Tanya N; Richer, Julie; Sadikovic, Bekim; Skidmore, David L; Stockley, Tracy; Taylor, Sherry; van Karnebeek, Clara; Zawati, Ma'n H; Lauzon, Julie; Armour, Christine M

    2015-07-01

    The aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it does not address the clinical application of this technology in other fields such as molecular investigation of cancer or for population screening of healthy individuals. Two multidisciplinary groups consisting of medical geneticists, clinical laboratory geneticists, genetic counsellors, ethicists, lawyers and genetic researchers were assembled to review existing literature and guidelines on genome-wide sequencing for clinical genetic diagnosis in the context of monogenic diseases, and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. Recommendations include (1) clinical genome-wide sequencing is an appropriate approach in the diagnostic assessment of a patient for whom there is suspicion of a significant monogenic disease that is associated with a high degree of genetic heterogeneity, or where specific genetic tests have failed to provide a diagnosis; (2) until the benefits of reporting incidental findings are established, we do not endorse the intentional clinical analysis of disease-associated genes other than those linked to the primary indication; and (3) clinicians should

  15. A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure

    DEFF Research Database (Denmark)

    Sung, Yun J; Winkler, Thomas W; de Las Fuentes, Lisa

    2018-01-01

    Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genom...

  16. Metabolome-genome-wide association study dissects genetic architecture for generating natural variation in rice secondary metabolism

    Science.gov (United States)

    Matsuda, Fumio; Nakabayashi, Ryo; Yang, Zhigang; Okazaki, Yozo; Yonemaru, Jun-ichi; Ebana, Kaworu; Yano, Masahiro; Saito, Kazuki

    2015-01-01

    Plants produce structurally diverse secondary (specialized) metabolites to increase their fitness for survival under adverse environments. Several bioactive compounds for new drugs have been identified through screening of plant extracts. In this study, genome-wide association studies (GWAS) were conducted to investigate the genetic architecture behind the natural variation of rice secondary metabolites. GWAS using the metabolome data of 175 rice accessions successfully identified 323 associations among 143 single nucleotide polymorphisms (SNPs) and 89 metabolites. The data analysis highlighted that levels of many metabolites are tightly associated with a small number of strong quantitative trait loci (QTLs). The tight association may be a mechanism generating strains with distinct metabolic composition through the crossing of two different strains. The results indicate that one plant species produces more diverse phytochemicals than previously expected, and plants still contain many useful compounds for human applications. PMID:25267402

  17. Genetic determinants of cardiovascular events among women with migraine: a genome-wide association study.

    Directory of Open Access Journals (Sweden)

    Markus Schürks

    Full Text Available Migraine is associated with an increased risk for cardiovascular disease (CVD. Both migraine and CVD are highly heritable. However, the genetic liability for CVD among migraineurs is unclear.We performed a genome-wide association study for incident CVD events during 12 years of follow-up among 5,122 migraineurs participating in the population-based Women's Genome Health Study. Migraine was self-reported and CVD events were confirmed after medical records review. We calculated odds ratios (OR and 95% confidence intervals (CI and considered a genome-wide p-value <5×10(-8 as significant.Among the 5,122 women with migraine 164 incident CVD events occurred during follow-up. No SNP was associated with major CVD, ischemic stroke, myocardial infarction, or CVD death at the genome-wide level; however, five SNPs showed association with p<5×10(-6. Among migraineurs with aura rs7698623 in MEPE (OR = 6.37; 95% CI 3.15-12.90; p = 2.7×10(-7 and rs4975709 in IRX4 (OR = 5.06; 95% CI 2.66-9.62; p = 7.7×10(-7 appeared to be associated with ischemic stroke, rs2143678 located close to MDF1 with major CVD (OR = 3.05; 95% CI 1.98-4.69; p = 4.3×10(-7, and the intergenic rs1406961 with CVD death (OR = 12.33; 95% CI 4.62-32.87; p = 5.2×10(-7. Further, rs1047964 in BACE1 appeared to be associated with CVD death among women with any migraine (OR = 4.67; 95% CI 2.53-8.62; p = 8.0×10(-7.Our results provide some suggestion for an association of five SNPs with CVD events among women with migraine; none of the results was genome-wide significant. Four associations appeared among migraineurs with aura, two of those with ischemic stroke. Although our population is among the largest with migraine and incident CVD information, these results must be treated with caution, given the limited number of CVD events among women with migraine and the low minor allele frequencies for three of the SNPs. Our results await independent replication

  18. Mouse Genome Informatics (MGI) Resource: Genetic, Genomic, and Biological Knowledgebase for the Laboratory Mouse.

    Science.gov (United States)

    Eppig, Janan T

    2017-07-01

    The Mouse Genome Informatics (MGI) Resource supports basic, translational, and computational research by providing high-quality, integrated data on the genetics, genomics, and biology of the laboratory mouse. MGI serves a strategic role for the scientific community in facilitating biomedical, experimental, and computational studies investigating the genetics and processes of diseases and enabling the development and testing of new disease models and therapeutic interventions. This review describes the nexus of the body of growing genetic and biological data and the advances in computer technology in the late 1980s, including the World Wide Web, that together launched the beginnings of MGI. MGI develops and maintains a gold-standard resource that reflects the current state of knowledge, provides semantic and contextual data integration that fosters hypothesis testing, continually develops new and improved tools for searching and analysis, and partners with the scientific community to assure research data needs are met. Here we describe one slice of MGI relating to the development of community-wide large-scale mutagenesis and phenotyping projects and introduce ways to access and use these MGI data. References and links to additional MGI aspects are provided. © The Author 2017. Published by Oxford University Press.

  19. Genome-wide association study of a nicotine metabolism biomarker in African American smokers: impact of chromosome 19 genetic influences.

    Science.gov (United States)

    Chenoweth, Meghan J; Ware, Jennifer J; Zhu, Andy Z X; Cole, Christopher B; Cox, Lisa Sanderson; Nollen, Nikki; Ahluwalia, Jasjit S; Benowitz, Neal L; Schnoll, Robert A; Hawk, Larry W; Cinciripini, Paul M; George, Tony P; Lerman, Caryn; Knight, Joanne; Tyndale, Rachel F

    2018-03-01

    The activity of CYP2A6, the major nicotine-inactivating enzyme, is measurable in smokers using the nicotine metabolite ratio (NMR; 3'hydroxycotinine/cotinine). Due to its role in nicotine clearance, the NMR is associated with smoking behaviours and response to pharmacotherapies. The NMR is highly heritable (~80%), and on average lower in African Americans (AA) versus whites. We previously identified several reduce and loss-of-function CYP2A6 variants common in individuals of African descent. Our current aim was to identify novel genetic influences on the NMR in AA smokers using genome-wide approaches. Genome-wide association study (GWAS). Multiple sites within Canada and the United States. AA smokers from two clinical trials: Pharmacogenetics of Nicotine Addiction Treatment (PNAT)-2 (NCT01314001; n = 504) and Kick-it-at-Swope (KIS)-3 (NCT00666978; n = 450). Genome-wide SNP genotyping, the NMR (phenotype) and population substructure and NMR covariates. Meta-analysis revealed three independent chromosome 19 signals (rs12459249, rs111645190 and rs185430475) associated with the NMR. The top overall hit, rs12459249 (P = 1.47e-39; beta = 0.59 per C (versus T) allele, SE = 0.045), located ~9.5 kb 3' of CYP2A6, remained genome-wide significant after controlling for the common (~10% in AA) non-functional CYP2A6*17 allele. In contrast, rs111645190 and rs185430475 were not genome-wide significant when controlling for CYP2A6*17. In total, 96 signals associated with the NMR were identified; many were not found in prior NMR GWASs in individuals of European descent. The top hits were also associated with the NMR in a third cohort of AA (KIS2; n = 480). None of the hits were in UGT or OCT2 genes. Three independent chromosome 19 signals account for ~20% of the variability in the nicotine metabolite ratio in African American smokers. The hits identified may contribute to inter-ethnic variability in nicotine metabolism, smoking behaviours and tobacco-related disease risk

  20. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma

    NARCIS (Netherlands)

    Cerhan, James R.; Berndt, Sonja I.; Vijai, Joseph; Ghesquières, Hervé; McKay, James; Wang, Sophia S.; Wang, Zhaoming; Yeager, Meredith; Conde, Lucia; De Bakker, Paul I W; Nieters, Alexandra; Cox, David; Burdett, Laurie; Monnereau, Alain; Flowers, Christopher R.; De Roos, Anneclaire J.; Brooks-Wilson, Angela R.; Lan, Qing; Severi, Gianluca; Melbye, Mads; Gu, Jian; Jackson, Rebecca D.; Kane, Eleanor; Teras, Lauren R.; Purdue, Mark P.; Vajdic, Claire M.; Spinelli, John J.; Giles, Graham G.; Albanes, Demetrius; Kelly, Rachel S.; Zucca, Mariagrazia; Bertrand, Kimberly A.; Zeleniuch-Jacquotte, Anne; Lawrence, Charles; Hutchinson, Amy; Zhi, Degui; Habermann, Thomas M.; Link, Brian K.; Novak, Anne J.; Dogan, Ahmet; Asmann, Yan W.; Liebow, Mark; Thompson, Carrie A.; Ansell, Stephen M.; Witzig, Thomas E.; Weiner, George J.; Veron, Amelie S.; Zelenika, Diana; Tilly, Hervé; Haioun, Corinne; Molina, Thierry Jo; Hjalgrim, Henrik; Glimelius, Bengt; Adami, Hans Olov; Bracci, Paige M.; Riby, Jacques; Smith, Martyn T.; Holly, Elizabeth A.; Cozen, Wendy; Hartge, Patricia; Morton, Lindsay M.; Severson, Richard K.; Tinker, Lesley F.; North, Kari E.; Becker, Nikolaus; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; Staines, Anthony; Lightfoot, Tracy; Crouch, Simon; Smith, Alex; Roman, Eve; Diver, W. Ryan; Offit, Kenneth; Zelenetz, Andrew; Klein, Robert J.; Villano, Danylo J.; Zheng, Tongzhang; Zhang, Yawei; Holford, Theodore R.; Kricker, Anne; Turner, Jenny; Southey, Melissa C.; Clavel, Jacqueline; Virtamo, Jarmo; Weinstein, Stephanie; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolph; Trichopoulos, Dimitrios; Vermeulen, Roel C H; Boeing, Heiner; Tjonneland, Anne; Angelucci, Emanuele; Di Lollo, Simonetta; Rais, Marco; Birmann, Brenda M.; Laden, Francine; Giovannucci, Edward; Kraft, Peter; Huang, Jinyan; Ma, Baoshan; Ye, Yuanqing; Chiu, Brian C H; Sampson, Joshua; Liang, Liming; Park, Ju Hyun; Chung, Charles C.; Weisenburger, Dennis D.; Chatterjee, Nilanjan; Fraumeni, Joseph F.; Slager, Susan L.; Wu, Xifeng; De Sanjose, Silvia; Smedby, Karin E.; Salles, Gilles; Skibola, Christine F.; Rothman, Nathaniel; Chanock, Stephen J.

    2014-01-01

    Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of

  1. Identification of neural outgrowth genes using genome-wide RNAi.

    Directory of Open Access Journals (Sweden)

    Katharine J Sepp

    2008-07-01

    Full Text Available While genetic screens have identified many genes essential for neurite outgrowth, they have been limited in their ability to identify neural genes that also have earlier critical roles in the gastrula, or neural genes for which maternally contributed RNA compensates for gene mutations in the zygote. To address this, we developed methods to screen the Drosophila genome using RNA-interference (RNAi on primary neural cells and present the results of the first full-genome RNAi screen in neurons. We used live-cell imaging and quantitative image analysis to characterize the morphological phenotypes of fluorescently labelled primary neurons and glia in response to RNAi-mediated gene knockdown. From the full genome screen, we focused our analysis on 104 evolutionarily conserved genes that when downregulated by RNAi, have morphological defects such as reduced axon extension, excessive branching, loss of fasciculation, and blebbing. To assist in the phenotypic analysis of the large data sets, we generated image analysis algorithms that could assess the statistical significance of the mutant phenotypes. The algorithms were essential for the analysis of the thousands of images generated by the screening process and will become a valuable tool for future genome-wide screens in primary neurons. Our analysis revealed unexpected, essential roles in neurite outgrowth for genes representing a wide range of functional categories including signalling molecules, enzymes, channels, receptors, and cytoskeletal proteins. We also found that genes known to be involved in protein and vesicle trafficking showed similar RNAi phenotypes. We confirmed phenotypes of the protein trafficking genes Sec61alpha and Ran GTPase using Drosophila embryo and mouse embryonic cerebral cortical neurons, respectively. Collectively, our results showed that RNAi phenotypes in primary neural culture can parallel in vivo phenotypes, and the screening technique can be used to identify many new

  2. A meta-analysis of genome-wide association studies of follicular lymphoma

    Directory of Open Access Journals (Sweden)

    Skibola Christine F

    2012-10-01

    Full Text Available Abstract Background B-cell non-Hodgkin lymphoma represents a diverse group of hematological malignancies, of which follicular lymphoma (FL is one of the most common subtypes. Family and epidemiological studies suggest an important genetic role in the etiology of FL. In recent genome-wide association studies (GWAS of FL, several genetic susceptibility loci have been identified on chromosome 6p21.33 (rs6457327 and 6p21.32 (rs10484561, rs2647012 in the human leukocyte antigen class I and class II regions. To identify new genetic variants and further elucidate the genetic basis of FL, a meta-analysis was performed of the top 1000 SNPs associated with FL risk from two GWAS in the US, Denmark and Sweden (592 cases, 1541 controls, with independent validation in 107 cases and 681 controls. Results rs9275517 and rs3117222 in the HLA class II region were validated and inversely associated with FL risk (rs9275517: OR = 0.63, 95% CI = 0.55-0.73, p = 4.03 × 10-11; rs3117222: OR = 0.66, 95% CI = 0.57-0.77, p = 1.45 × 10-7. rs9275517, which is in high linkage disequilibrium with rs2647012 (r2 = 0.9, was no longer associated with FL after conditioning on rs2647012. The rs3117222 association was independent of established FL SNPs, but not of the HLA-DPB1*0301 allele. Using publicly available gene expression profiles with matching genotype information, we found that rs3117222 also was significantly correlated with increased HLA-DPB1 expression. Conclusions By performing a meta-analysis of two GWAS of FL, we further validated the relevance of HLA-DPB1*0301 as a protective allele in the pathogenesis of FL. Moreover, the protective rs3117222 A allele correlated with increased levels of HLA-DPB1, suggesting a possible disease mechanism involving HLA-DPB1 expression regulation. Our results add further support to the major role of HLA genetic variation in the pathogenesis of FL.

  3. Detection of genetic variants affecting cattle behaviour and their impact on milk production: a genome-wide association study.

    Science.gov (United States)

    Friedrich, Juliane; Brand, Bodo; Ponsuksili, Siriluck; Graunke, Katharina L; Langbein, Jan; Knaust, Jacqueline; Kühn, Christa; Schwerin, Manfred

    2016-02-01

    Behaviour traits of cattle have been reported to affect important production traits, such as meat quality and milk performance as well as reproduction and health. Genetic predisposition is, together with environmental stimuli, undoubtedly involved in the development of behaviour phenotypes. Underlying molecular mechanisms affecting behaviour in general and behaviour and productions traits in particular still have to be studied in detail. Therefore, we performed a genome-wide association study in an F2 Charolais × German Holstein cross-breed population to identify genetic variants that affect behaviour-related traits assessed in an open-field and novel-object test and analysed their putative impact on milk performance. Of 37,201 tested single nucleotide polymorphism (SNPs), four showed a genome-wide and 37 a chromosome-wide significant association with behaviour traits assessed in both tests. Nine of the SNPs that were associated with behaviour traits likewise showed a nominal significant association with milk performance traits. On chromosomes 14 and 29, six SNPs were identified to be associated with exploratory behaviour and inactivity during the novel-object test as well as with milk yield traits. Least squares means for behaviour and milk performance traits for these SNPs revealed that genotypes associated with higher inactivity and less exploratory behaviour promote higher milk yields. Whether these results are due to molecular mechanisms simultaneously affecting behaviour and milk performance or due to a behaviour predisposition, which causes indirect effects on milk performance by influencing individual reactivity, needs further investigation. © 2015 Stichting International Foundation for Animal Genetics.

  4. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    van Rheenen, Wouter; Shatunov, Aleksey; Dekker, Annelot M; McLaughlin, Russell L; Diekstra, Frank P; Pulit, Sara L; van der Spek, Rick A A; Võsa, Urmo; de Jong, Simone; Robinson, Matthew R; Yang, Jian; Fogh, Isabella; van Doormaal, Perry Tc; Tazelaar, Gijs H P; Koppers, Max; Blokhuis, Anna M; Sproviero, William; Jones, Ashley R; Kenna, Kevin P; van Eijk, Kristel R; Harschnitz, Oliver; Schellevis, Raymond D; Brands, William J; Medic, Jelena; Menelaou, Androniki; Vajda, Alice; Ticozzi, Nicola; Lin, Kuang; Rogelj, Boris; Vrabec, Katarina; Ravnik-Glavač, Metka; Koritnik, Blaž; Zidar, Janez; Leonardis, Lea; Grošelj, Leja Dolenc; Millecamps, Stéphanie; Salachas, François; Meininger, Vincent; de Carvalho, Mamede; Pinto, Susana; Mora, Jesus S; Rojas-García, Ricardo; Polak, Meraida; Chandran, Siddharthan; Colville, Shuna; Swingler, Robert; Morrison, Karen E; Shaw, Pamela J; Hardy, John; Orrell, Richard W; Pittman, Alan; Sidle, Katie; Fratta, Pietro; Malaspina, Andrea; Topp, Simon; Petri, Susanne; Abdulla, Susanne; Drepper, Carsten; Sendtner, Michael; Meyer, Thomas; Ophoff, Roel A.; Staats, Kim A; Wiedau-Pazos, Martina; Lomen-Hoerth, Catherine; Van Deerlin, Vivianna M; Trojanowski, John Q; Elman, Lauren; McCluskey, Leo; Basak, A Nazli; Tunca, Ceren; Hamzeiy, Hamid; Parman, Yesim; Meitinger, Thomas; Lichtner, Peter; Radivojkov-Blagojevic, Milena; Andres, Christian R; Maurel, Cindy; Bensimon, Gilbert; Landwehrmeyer, Bernhard; Brice, Alexis; Payan, Christine A M; Saker-Delye, Safaa; Dürr, Alexandra; Wood, Nicholas W; Tittmann, Lukas; Lieb, Wolfgang; Franke, Andre; Rietschel, Marcella; Cichon, Sven; Nöthen, Markus M; Amouyel, Philippe; Tzourio, Christophe; Dartigues, Jean-François; Uitterlinden, Andre G; Rivadeneira, Fernando; Estrada, Karol; Hofman, Albert; Curtis, Charles; Blauw, Hylke M; van der Kooi, Anneke J; de Visser, Marianne; Goris, An; Weber, Markus; Shaw, Christopher E; Smith, Bradley N; Pansarasa, Orietta; Cereda, Cristina; Del Bo, Roberto; Comi, Giacomo P; D'Alfonso, Sandra; Bertolin, Cinzia; Sorarù, Gianni; Mazzini, Letizia; Pensato, Viviana; Gellera, Cinzia; Tiloca, Cinzia; Ratti, Antonia; Calvo, Andrea; Moglia, Cristina; Brunetti, Maura; Arcuti, Simona; Capozzo, Rosa; Zecca, Chiara; Lunetta, Christian; Penco, Silvana; Riva, Nilo; Padovani, Alessandro; Filosto, Massimiliano; Muller, Bernard; Stuit, Robbert Jan; Blair, Ian; Zhang, Katharine; McCann, Emily P; Fifita, Jennifer A; Nicholson, Garth A; Rowe, Dominic B; Pamphlett, Roger; Kiernan, Matthew C; Grosskreutz, Julian; Witte, Otto W; Ringer, Thomas; Prell, Tino; Stubendorff, Beatrice; Kurth, Ingo; Hübner, Christian A; Leigh, P Nigel; Casale, Federico; Chio, Adriano; Beghi, Ettore; Pupillo, Elisabetta; Tortelli, Rosanna; Logroscino, Giancarlo; Powell, John; Ludolph, Albert C; Weishaupt, Jochen H; Robberecht, Wim; Van Damme, Philip; Franke, Lude; Pers, Tune H; Brown, Robert H; Glass, Jonathan D; Landers, John E; Hardiman, Orla; Andersen, Peter M; Corcia, Philippe; Vourc'h, Patrick; Silani, Vincenzo; Wray, Naomi R; Visscher, Peter M; de Bakker, Paul I W; van Es, Michael A; Pasterkamp, R Jeroen; Lewis, Cathryn M; Breen, Gerome; Al-Chalabi, Ammar; van den Berg, Leonard H; Veldink, Jan H

    To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577

  5. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    van Rheenen, Wouter; Shatunov, Aleksey; Dekker, Annelot M.; McLaughlin, Russell L.; Diekstra, Frank P.; Pulit, Sara L.; van der Spek, Rick A. A.; Võsa, Urmo; de Jong, Simone; Robinson, Matthew R.; Yang, Jian; Fogh, Isabella; van Doormaal, Perry Tc; Tazelaar, Gijs H. P.; Koppers, Max; Blokhuis, Anna M.; Sproviero, William; Jones, Ashley R.; Kenna, Kevin P.; van Eijk, Kristel R.; Harschnitz, Oliver; Schellevis, Raymond D.; Brands, William J.; Medic, Jelena; Menelaou, Androniki; Vajda, Alice; Ticozzi, Nicola; Lin, Kuang; Rogelj, Boris; Vrabec, Katarina; Ravnik-Glavač, Metka; Koritnik, Blaž; Zidar, Janez; Leonardis, Lea; Grošelj, Leja Dolenc; Millecamps, Stéphanie; Salachas, François; Meininger, Vincent; de Carvalho, Mamede; Pinto, Susana; Mora, Jesus S.; Rojas-García, Ricardo; Polak, Meraida; Chandran, Siddharthan; Colville, Shuna; Swingler, Robert; Morrison, Karen E.; Shaw, Pamela J.; Hardy, John; Orrell, Richard W.; Pittman, Alan; Sidle, Katie; Fratta, Pietro; Malaspina, Andrea; Topp, Simon; Petri, Susanne; Abdulla, Susanne; Drepper, Carsten; Sendtner, Michael; Meyer, Thomas; Ophoff, Roel A.; Staats, Kim A.; Wiedau-Pazos, Martina; Lomen-Hoerth, Catherine; van Deerlin, Vivianna M.; Trojanowski, John Q.; Elman, Lauren; McCluskey, Leo; Basak, A. Nazli; Tunca, Ceren; Hamzeiy, Hamid; Parman, Yesim; Meitinger, Thomas; Lichtner, Peter; Radivojkov-Blagojevic, Milena; Andres, Christian R.; Maurel, Cindy; Bensimon, Gilbert; Landwehrmeyer, Bernhard; Brice, Alexis; Payan, Christine A. M.; Saker-Delye, Safaa; Dürr, Alexandra; Wood, Nicholas W.; Tittmann, Lukas; Lieb, Wolfgang; Franke, Andre; Rietschel, Marcella; Cichon, Sven; Nöthen, Markus M.; Amouyel, Philippe; Tzourio, Christophe; Dartigues, Jean-François; Uitterlinden, Andre G.; Rivadeneira, Fernando; Estrada, Karol; Hofman, Albert; Curtis, Charles; Blauw, Hylke M.; van der Kooi, Anneke J.; de Visser, Marianne; Goris, An; Weber, Markus; Shaw, Christopher E.; Smith, Bradley N.; Pansarasa, Orietta; Cereda, Cristina; del Bo, Roberto; Comi, Giacomo P.; D'alfonso, Sandra; Bertolin, Cinzia; Sorarù, Gianni; Mazzini, Letizia; Pensato, Viviana; Gellera, Cinzia; Tiloca, Cinzia; Ratti, Antonia; Calvo, Andrea; Moglia, Cristina; Brunetti, Maura; Arcuti, Simona; Capozzo, Rosa; Zecca, Chiara; Lunetta, Christian; Penco, Silvana; Riva, Nilo; Padovani, Alessandro; Filosto, Massimiliano; Muller, Bernard; Stuit, Robbert Jan; Blair, Ian; Zhang, Katharine; McCann, Emily P.; Fifita, Jennifer A.; Nicholson, Garth A.; Rowe, Dominic B.; Pamphlett, Roger; Kiernan, Matthew C.; Grosskreutz, Julian; Witte, Otto W.; Ringer, Thomas; Prell, Tino; Stubendorff, Beatrice; Kurth, Ingo; Hübner, Christian A.; Leigh, P. Nigel; Casale, Federico; Chio, Adriano; Beghi, Ettore; Pupillo, Elisabetta; Tortelli, Rosanna; Logroscino, Giancarlo; Powell, John; Ludolph, Albert C.; Weishaupt, Jochen H.; Robberecht, Wim; van Damme, Philip; Franke, Lude; Pers, Tune H.; Brown, Robert H.; Glass, Jonathan D.; Landers, John E.; Hardiman, Orla; Andersen, Peter M.; Corcia, Philippe; Vourc'h, Patrick; Silani, Vincenzo; Wray, Naomi R.; Visscher, Peter M.; de Bakker, Paul I. W.; van Es, Michael A.; Pasterkamp, R. Jeroen; Lewis, Cathryn M.; Breen, Gerome; Al-Chalabi, Ammar; van den Berg, Leonard H.; Veldink, Jan H.

    2016-01-01

    To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577

  6. Genome-wide association scan for variants associated with early-onset prostate cancer.

    Directory of Open Access Journals (Sweden)

    Ethan M Lange

    Full Text Available Prostate cancer is the most common non-skin cancer and the second leading cause of cancer related mortality for men in the United States. There is strong empirical and epidemiological evidence supporting a stronger role of genetics in early-onset prostate cancer. We performed a genome-wide association scan for early-onset prostate cancer. Novel aspects of this study include the focus on early-onset disease (defined as men with prostate cancer diagnosed before age 56 years and use of publically available control genotype data from previous genome-wide association studies. We found genome-wide significant (p<5×10(-8 evidence for variants at 8q24 and 11p15 and strong supportive evidence for a number of previously reported loci. We found little evidence for individual or systematic inflated association findings resulting from using public controls, demonstrating the utility of using public control data in large-scale genetic association studies of common variants. Taken together, these results demonstrate the importance of established common genetic variants for early-onset prostate cancer and the power of including early-onset prostate cancer cases in genetic association studies.

  7. Genome-wide meta-analysis of cerebral white matter hyperintensities in patients with stroke

    NARCIS (Netherlands)

    Traylor, M.; Zhang, C.R.; Adib-Samii, P.; Devan, W.J.; Parsons, O.E.; Lanfranconi, S.; Gregory, S.; Cloonan, L.; Falcone, G.J.; Radmanesh, F.; Fitzpatrick, K.; Kanakis, A.; Barrick, T.R.; Moynihan, B.; Lewis, C.M.; Boncoraglio, G.B.; Lemmens, R.; Thijs, V.; Sudlow, C.; Wardlaw, J.; Rothwell, P.M.; Meschia, J.F.; Worrall, B.B.; Levi, C.; Bevan, S.; Furie, K.L.; Dichgans, M.; Rosand, J.; Markus, H.S.; Rost, N.; Klijn, C.J.M.; et al.,

    2016-01-01

    OBJECTIVE: For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms.

  8. Using the Pareto principle in genome-wide breeding value estimation.

    Science.gov (United States)

    Yu, Xijiang; Meuwissen, Theo H E

    2011-11-01

    Genome-wide breeding value (GWEBV) estimation methods can be classified based on the prior distribution assumptions of marker effects. Genome-wide BLUP methods assume a normal prior distribution for all markers with a constant variance, and are computationally fast. In Bayesian methods, more flexible prior distributions of SNP effects are applied that allow for very large SNP effects although most are small or even zero, but these prior distributions are often also computationally demanding as they rely on Monte Carlo Markov chain sampling. In this study, we adopted the Pareto principle to weight available marker loci, i.e., we consider that x% of the loci explain (100 - x)% of the total genetic variance. Assuming this principle, it is also possible to define the variances of the prior distribution of the 'big' and 'small' SNP. The relatively few large SNP explain a large proportion of the genetic variance and the majority of the SNP show small effects and explain a minor proportion of the genetic variance. We name this method MixP, where the prior distribution is a mixture of two normal distributions, i.e. one with a big variance and one with a small variance. Simulation results, using a real Norwegian Red cattle pedigree, show that MixP is at least as accurate as the other methods in all studied cases. This method also reduces the hyper-parameters of the prior distribution from 2 (proportion and variance of SNP with big effects) to 1 (proportion of SNP with big effects), assuming the overall genetic variance is known. The mixture of normal distribution prior made it possible to solve the equations iteratively, which greatly reduced computation loads by two orders of magnitude. In the era of marker density reaching million(s) and whole-genome sequence data, MixP provides a computationally feasible Bayesian method of analysis.

  9. Genome-wide quantitative trait loci mapping of the human cerebrospinal fluid proteome.

    Science.gov (United States)

    Sasayama, Daimei; Hattori, Kotaro; Ogawa, Shintaro; Yokota, Yuuki; Matsumura, Ryo; Teraishi, Toshiya; Hori, Hiroaki; Ota, Miho; Yoshida, Sumiko; Kunugi, Hiroshi

    2017-01-01

    Cerebrospinal fluid (CSF) is virtually the only one accessible source of proteins derived from the central nervous system (CNS) of living humans and possibly reflects the pathophysiology of a variety of neuropsychiatric diseases. However, little is known regarding the genetic basis of variation in protein levels of human CSF. We examined CSF levels of 1,126 proteins in 133 subjects and performed a genome-wide association analysis of 514,227 single nucleotide polymorphisms (SNPs) to detect protein quantitative trait loci (pQTLs). To be conservative, Spearman's correlation was used to identify an association between genotypes of SNPs and protein levels. A total of 421 cis and 25 trans SNP-protein pairs were significantly correlated at a false discovery rate (FDR) of less than 0.01 (nominal P genome-wide association studies. The present findings suggest that genetic variations play an important role in the regulation of protein expression in the CNS. The obtained database may serve as a valuable resource to understand the genetic bases for CNS protein expression pattern in humans. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  10. A genome-wide gene expression signature of environmental geography in leukocytes of Moroccan Amazighs.

    Directory of Open Access Journals (Sweden)

    Youssef Idaghdour

    2008-04-01

    Full Text Available The different environments that humans experience are likely to impact physiology and disease susceptibility. In order to estimate the magnitude of the impact of environment on transcript abundance, we examined gene expression in peripheral blood leukocyte samples from 46 desert nomadic, mountain agrarian and coastal urban Moroccan Amazigh individuals. Despite great expression heterogeneity in humans, as much as one third of the leukocyte transcriptome was found to be associated with differences among regions. Genome-wide polymorphism analysis indicates that genetic differentiation in the total sample is limited and is unlikely to explain the expression divergence. Methylation profiling of 1,505 CpG sites suggests limited contribution of methylation to the observed differences in gene expression. Genetic network analysis further implies that specific aspects of immune function are strongly affected by regional factors and may influence susceptibility to respiratory and inflammatory disease. Our results show a strong genome-wide gene expression signature of regional population differences that presumably include lifestyle, geography, and biotic factors, implying that these can play at least as great a role as genetic divergence in modulating gene expression variation in humans.

  11. Genome-wide association study of response to cognitive–behavioural therapy in children with anxiety disorders

    Science.gov (United States)

    Coleman, Jonathan R. I.; Lester, Kathryn J.; Keers, Robert; Roberts, Susanna; Curtis, Charles; Arendt, Kristian; Bögels, Susan; Cooper, Peter; Creswell, Cathy; Dalgleish, Tim; Hartman, Catharina A.; Heiervang, Einar R.; Hötzel, Katrin; Hudson, Jennifer L.; In-Albon, Tina; Lavallee, Kristen; Lyneham, Heidi J.; Marin, Carla E.; Meiser-Stedman, Richard; Morris, Talia; Nauta, Maaike H.; Rapee, Ronald M.; Schneider, Silvia; Schneider, Sophie C.; Silverman, Wendy K.; Thastum, Mikael; Thirlwall, Kerstin; Waite, Polly; Wergeland, Gro Janne; Breen, Gerome; Eley, Thalia C.

    2016-01-01

    Background Anxiety disorders are common, and cognitive–behavioural therapy (CBT) is a first-line treatment. Candidate gene studies have suggested a genetic basis to treatment response, but findings have been inconsistent. Aims To perform the first genome-wide association study (GWAS) of psychological treatment response in children with anxiety disorders (n = 980). Method Presence and severity of anxiety was assessed using semi-structured interview at baseline, on completion of treatment (post-treatment), and 3 to 12 months after treatment completion (follow-up). DNA was genotyped using the Illumina Human Core Exome-12v1.0 array. Linear mixed models were used to test associations between genetic variants and response (change in symptom severity) immediately post-treatment and at 6-month follow-up. Results No variants passed a genome-wide significance threshold (P = 5 × 10−8) in either analysis. Four variants met criteria for suggestive significance (P<5 × 10−6) in association with response post-treatment, and three variants in the 6-month follow-up analysis. Conclusions This is the first genome-wide therapygenetic study. It suggests no common variants of very high effect underlie response to CBT. Future investigations should maximise power to detect single-variant and polygenic effects by using larger, more homogeneous cohorts. PMID:26989097

  12. Sparse redundancy analysis of high-dimensional genetic and genomic data

    NARCIS (Netherlands)

    Csala, Attila; Voorbraak, Frans P. J. M.; Zwinderman, Aeilko H.; Hof, Michel H.

    2017-01-01

    Motivation: Recent technological developments have enabled the possibility of genetic and genomic integrated data analysis approaches, where multiple omics datasets from various biological levels are combined and used to describe (disease) phenotypic variations. The main goal is to explain and

  13. Parent-of-origin effects in autism identified through genome-wide linkage analysis of 16,000 SNPs.

    Directory of Open Access Journals (Sweden)

    Delphine Fradin

    2010-09-01

    Full Text Available Autism is a common heritable neurodevelopmental disorder with complex etiology. Several genome-wide linkage and association scans have been carried out to identify regions harboring genes related to autism or autism spectrum disorders, with mixed results. Given the overlap in autism features with genetic abnormalities known to be associated with imprinting, one possible reason for lack of consistency would be the influence of parent-of-origin effects that may mask the ability to detect linkage and association.We have performed a genome-wide linkage scan that accounts for potential parent-of-origin effects using 16,311 SNPs among families from the Autism Genetic Resource Exchange (AGRE and the National Institute of Mental Health (NIMH autism repository. We report parametric (GH, Genehunter and allele-sharing linkage (Aspex results using a broad spectrum disorder case definition. Paternal-origin genome-wide statistically significant linkage was observed on chromosomes 4 (LOD(GH = 3.79, empirical p<0.005 and LOD(Aspex = 2.96, p = 0.008, 15 (LOD(GH = 3.09, empirical p<0.005 and LOD(Aspex = 3.62, empirical p = 0.003 and 20 (LOD(GH = 3.36, empirical p<0.005 and LOD(Aspex = 3.38, empirical p = 0.006.These regions may harbor imprinted sites associated with the development of autism and offer fruitful domains for molecular investigation into the role of epigenetic mechanisms in autism.

  14. Genome-wide and gene-based association studies of anxiety disorders in European and African American samples.

    Directory of Open Access Journals (Sweden)

    Takeshi Otowa

    Full Text Available Anxiety disorders (ADs are common mental disorders caused by a combination of genetic and environmental factors. Since ADs are highly comorbid with each other, partially due to shared genetic basis, studying AD phenotypes in a coordinated manner may be a powerful strategy for identifying potential genetic loci for ADs. To detect these loci, we performed genome-wide association studies (GWAS of ADs. In addition, as a complementary approach to single-locus analysis, we also conducted gene- and pathway-based analyses. GWAS data were derived from the control sample of the Molecular Genetics of Schizophrenia (MGS project (2,540 European American and 849 African American subjects genotyped on the Affymetrix GeneChip 6.0 array. We applied two phenotypic approaches: (1 categorical case-control comparisons (CC based upon psychiatric diagnoses, and (2 quantitative phenotypic factor scores (FS derived from a multivariate analysis combining information across the clinical phenotypes. Linear and logistic models were used to analyse the association with ADs using FS and CC traits, respectively. At the single locus level, no genome-wide significant association was found. A trans-population gene-based meta-analysis across both ethnic subsamples using FS identified three genes (MFAP3L on 4q32.3, NDUFAB1 and PALB2 on 16p12 with genome-wide significance (false discovery rate (FDR] <5%. At the pathway level, several terms such as transcription regulation, cytokine binding, and developmental process were significantly enriched in ADs (FDR <5%. Our approaches studying ADs as quantitative traits and utilizing the full GWAS data may be useful in identifying susceptibility genes and pathways for ADs.

  15. The challenges of genome-wide interaction studies: lessons to learn from the analysis of HDL blood levels.

    Directory of Open Access Journals (Sweden)

    Elisabeth M van Leeuwen

    Full Text Available Genome-wide association studies (GWAS have revealed 74 single nucleotide polymorphisms (SNPs associated with high-density lipoprotein cholesterol (HDL blood levels. This study is, to our knowledge, the first genome-wide interaction study (GWIS to identify SNP×SNP interactions associated with HDL levels. We performed a GWIS in the Rotterdam Study (RS cohort I (RS-I using the GLIDE tool which leverages the massively parallel computing power of Graphics Processing Units (GPUs to perform linear regression on all genome-wide pairs of SNPs. By performing a meta-analysis together with Rotterdam Study cohorts II and III (RS-II and RS-III, we were able to filter 181 interaction terms with a p-value<1 · 10-8 that replicated in the two independent cohorts. We were not able to replicate any of these interaction term in the AGES, ARIC, CHS, ERF, FHS and NFBC-66 cohorts (Ntotal = 30,011 when adjusting for multiple testing. Our GWIS resulted in the consistent finding of a possible interaction between rs774801 in ARMC8 (ENSG00000114098 and rs12442098 in SPATA8 (ENSG00000185594 being associated with HDL levels. However, p-values do not reach the preset Bonferroni correction of the p-values. Our study suggest that even for highly genetically determined traits such as HDL the sample sizes needed to detect SNP×SNP interactions are large and the 2-step filtering approaches do not yield a solution. Here we present our analysis plan and our reservations concerning GWIS.

  16. Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity

    Science.gov (United States)

    Jahanshad, Neda; Rajagopalan, Priya; Hua, Xue; Hibar, Derrek P.; Nir, Talia M.; Toga, Arthur W.; Jack, Clifford R.; Saykin, Andrew J.; Green, Robert C.; Weiner, Michael W.; Medland, Sarah E.; Montgomery, Grant W.; Hansell, Narelle K.; McMahon, Katie L.; de Zubicaray, Greig I.; Martin, Nicholas G.; Wright, Margaret J.; Thompson, Paul M.; Weiner, Michael; Aisen, Paul; Weiner, Michael; Aisen, Paul; Petersen, Ronald; Jack, Clifford R.; Jagust, William; Trojanowski, John Q.; Toga, Arthur W.; Beckett, Laurel; Green, Robert C.; Saykin, Andrew J.; Morris, John; Liu, Enchi; Green, Robert C.; Montine, Tom; Petersen, Ronald; Aisen, Paul; Gamst, Anthony; Thomas, Ronald G.; Donohue, Michael; Walter, Sarah; Gessert, Devon; Sather, Tamie; Beckett, Laurel; Harvey, Danielle; Gamst, Anthony; Donohue, Michael; Kornak, John; Jack, Clifford R.; Dale, Anders; Bernstein, Matthew; Felmlee, Joel; Fox, Nick; Thompson, Paul; Schuff, Norbert; Alexander, Gene; DeCarli, Charles; Jagust, William; Bandy, Dan; Koeppe, Robert A.; Foster, Norm; Reiman, Eric M.; Chen, Kewei; Mathis, Chet; Morris, John; Cairns, Nigel J.; Taylor-Reinwald, Lisa; Trojanowki, J.Q.; Shaw, Les; Lee, Virginia M.Y.; Korecka, Magdalena; Toga, Arthur W.; Crawford, Karen; Neu, Scott; Saykin, Andrew J.; Foroud, Tatiana M.; Potkin, Steven; Shen, Li; Khachaturian, Zaven; Frank, Richard; Snyder, Peter J.; Molchan, Susan; Kaye, Jeffrey; Quinn, Joseph; Lind, Betty; Dolen, Sara; Schneider, Lon S.; Pawluczyk, Sonia; Spann, Bryan M.; Brewer, James; Vanderswag, Helen; Heidebrink, Judith L.; Lord, Joanne L.; Petersen, Ronald; Johnson, Kris; Doody, Rachelle S.; Villanueva-Meyer, Javier; Chowdhury, Munir; Stern, Yaakov; Honig, Lawrence S.; Bell, Karen L.; Morris, John C.; Ances, Beau; Carroll, Maria; Leon, Sue; Mintun, Mark A.; Schneider, Stacy; Marson, Daniel; Griffith, Randall; Clark, David; Grossman, Hillel; Mitsis, Effie; Romirowsky, Aliza; deToledo-Morrell, Leyla; Shah, Raj C.; Duara, Ranjan; Varon, Daniel; Roberts, Peggy; Albert, Marilyn; Onyike, Chiadi; Kielb, Stephanie; Rusinek, Henry; de Leon, Mony J.; Glodzik, Lidia; De Santi, Susan; Doraiswamy, P. Murali; Petrella, Jeffrey R.; Coleman, R. Edward; Arnold, Steven E.; Karlawish, Jason H.; Wolk, David; Smith, Charles D.; Jicha, Greg; Hardy, Peter; Lopez, Oscar L.; Oakley, MaryAnn; Simpson, Donna M.; Porsteinsson, Anton P.; Goldstein, Bonnie S.; Martin, Kim; Makino, Kelly M.; Ismail, M. Saleem; Brand, Connie; Mulnard, Ruth A.; Thai, Gaby; Mc-Adams-Ortiz, Catherine; Womack, Kyle; Mathews, Dana; Quiceno, Mary; Diaz-Arrastia, Ramon; King, Richard; Weiner, Myron; Martin-Cook, Kristen; DeVous, Michael; Levey, Allan I.; Lah, James J.; Cellar, Janet S.; Burns, Jeffrey M.; Anderson, Heather S.; Swerdlow, Russell H.; Apostolova, Liana; Lu, Po H.; Bartzokis, George; Silverman, Daniel H.S.; Graff-Radford, Neill R.; Parfitt, Francine; Johnson, Heather; Farlow, Martin R.; Hake, Ann Marie; Matthews, Brandy R.; Herring, Scott; van Dyck, Christopher H.; Carson, Richard E.; MacAvoy, Martha G.; Chertkow, Howard; Bergman, Howard; Hosein, Chris; Black, Sandra; Stefanovic, Bojana; Caldwell, Curtis; Hsiung, Ging-Yuek Robin; Feldman, Howard; Mudge, Benita; Assaly, Michele; Kertesz, Andrew; Rogers, John; Trost, Dick; Bernick, Charles; Munic, Donna; Kerwin, Diana; Mesulam, Marek-Marsel; Lipowski, Kristina; Wu, Chuang-Kuo; Johnson, Nancy; Sadowsky, Carl; Martinez, Walter; Villena, Teresa; Turner, Raymond Scott; Johnson, Kathleen; Reynolds, Brigid; Sperling, Reisa A.; Johnson, Keith A.; Marshall, Gad; Frey, Meghan; Yesavage, Jerome; Taylor, Joy L.; Lane, Barton; Rosen, Allyson; Tinklenberg, Jared; Sabbagh, Marwan; Belden, Christine; Jacobson, Sandra; Kowall, Neil; Killiany, Ronald; Budson, Andrew E.; Norbash, Alexander; Johnson, Patricia Lynn; Obisesan, Thomas O.; Wolday, Saba; Bwayo, Salome K.; Lerner, Alan; Hudson, Leon; Ogrocki, Paula; Fletcher, Evan; Carmichael, Owen; Olichney, John; DeCarli, Charles; Kittur, Smita; Borrie, Michael; Lee, T.-Y.; Bartha, Rob; Johnson, Sterling; Asthana, Sanjay; Carlsson, Cynthia M.; Potkin, Steven G.; Preda, Adrian; Nguyen, Dana; Tariot, Pierre; Fleisher, Adam; Reeder, Stephanie; Bates, Vernice; Capote, Horacio; Rainka, Michelle; Scharre, Douglas W.; Kataki, Maria; Zimmerman, Earl A.; Celmins, Dzintra; Brown, Alice D.; Pearlson, Godfrey D.; Blank, Karen; Anderson, Karen; Saykin, Andrew J.; Santulli, Robert B.; Schwartz, Eben S.; Sink, Kaycee M.; Williamson, Jeff D.; Garg, Pradeep; Watkins, Franklin; Ott, Brian R.; Querfurth, Henry; Tremont, Geoffrey; Salloway, Stephen; Malloy, Paul; Correia, Stephen; Rosen, Howard J.; Miller, Bruce L.; Mintzer, Jacobo; Longmire, Crystal Flynn; Spicer, Kenneth; Finger, Elizabeth; Rachinsky, Irina; Rogers, John; Kertesz, Andrew; Drost, Dick

    2013-01-01

    Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain’s connectivity pattern, allowing us to discover genetic variants that affect the human brain’s wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer’s disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism (MACROD2), development (NEDD4), and mental retardation (UBE2A) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases. PMID:23471985

  17. Genome-wide single nucleotide polymorphisms (SNPs) for a model invasive ascidian Botryllus schlosseri.

    Science.gov (United States)

    Gao, Yangchun; Li, Shiguo; Zhan, Aibin

    2018-04-01

    Invasive species cause huge damages to ecology, environment and economy globally. The comprehensive understanding of invasion mechanisms, particularly genetic bases of micro-evolutionary processes responsible for invasion success, is essential for reducing potential damages caused by invasive species. The golden star tunicate, Botryllus schlosseri, has become a model species in invasion biology, mainly owing to its high invasiveness nature and small well-sequenced genome. However, the genome-wide genetic markers have not been well developed in this highly invasive species, thus limiting the comprehensive understanding of genetic mechanisms of invasion success. Using restriction site-associated DNA (RAD) tag sequencing, here we developed a high-quality resource of 14,119 out of 158,821 SNPs for B. schlosseri. These SNPs were relatively evenly distributed at each chromosome. SNP annotations showed that the majority of SNPs (63.20%) were located at intergenic regions, and 21.51% and 14.58% were located at introns and exons, respectively. In addition, the potential use of the developed SNPs for population genomics studies was primarily assessed, such as the estimate of observed heterozygosity (H O ), expected heterozygosity (H E ), nucleotide diversity (π), Wright's inbreeding coefficient (F IS ) and effective population size (Ne). Our developed SNP resource would provide future studies the genome-wide genetic markers for genetic and genomic investigations, such as genetic bases of micro-evolutionary processes responsible for invasion success.

  18. From human monocytes to genome-wide binding sites--a protocol for small amounts of blood: monocyte isolation/ChIP-protocol/library amplification/genome wide computational data analysis.

    Directory of Open Access Journals (Sweden)

    Sebastian Weiterer

    Full Text Available Chromatin immunoprecipitation in combination with a genome-wide analysis via high-throughput sequencing is the state of the art method to gain genome-wide representation of histone modification or transcription factor binding profiles. However, chromatin immunoprecipitation analysis in the context of human experimental samples is limited, especially in the case of blood cells. The typically extremely low yields of precipitated DNA are usually not compatible with library amplification for next generation sequencing. We developed a highly reproducible protocol to present a guideline from the first step of isolating monocytes from a blood sample to analyse the distribution of histone modifications in a genome-wide manner.The protocol describes the whole work flow from isolating monocytes from human blood samples followed by a high-sensitivity and small-scale chromatin immunoprecipitation assay with guidance for generating libraries compatible with next generation sequencing from small amounts of immunoprecipitated DNA.

  19. Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci.

    Science.gov (United States)

    Børglum, A D; Demontis, D; Grove, J; Pallesen, J; Hollegaard, M V; Pedersen, C B; Hedemand, A; Mattheisen, M; Uitterlinden, A; Nyegaard, M; Ørntoft, T; Wiuf, C; Didriksen, M; Nordentoft, M; Nöthen, M M; Rietschel, M; Ophoff, R A; Cichon, S; Yolken, R H; Hougaard, D M; Mortensen, P B; Mors, O

    2014-03-01

    Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 × 10(-6)) and rs8057927 in CDH13 (P=1.39 × 10(-5)). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10(-7)). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 × 10(-2)). Significant interaction with maternal CMV infection was found for rs7902091 (P(SNP × CMV)=7.3 × 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies.

  20. Genome-wide association studies on HIV susceptibility, pathogenesis and pharmacogenomics

    Directory of Open Access Journals (Sweden)

    van Manen Daniëlle

    2012-08-01

    Full Text Available Abstract Susceptibility to HIV-1 and the clinical course after infection show a substantial heterogeneity between individuals. Part of this variability can be attributed to host genetic variation. Initial candidate gene studies have revealed interesting host factors that influence HIV infection, replication and pathogenesis. Recently, genome-wide association studies (GWAS were utilized for unbiased searches at a genome-wide level to discover novel genetic factors and pathways involved in HIV-1 infection. This review gives an overview of findings from the GWAS performed on HIV infection, within different cohorts, with variable patient and phenotype selection. Furthermore, novel techniques and strategies in research that might contribute to the complete understanding of virus-host interactions and its role on the pathogenesis of HIV infection are discussed.

  1. Genome-wide approaches towards identification of susceptibility genes in complex diseases

    NARCIS (Netherlands)

    Franke, L.H.

    2008-01-01

    Throughout the human genome millions of places exist where humans differ gentically. The aim of this PhD thesis was to systematically assess this genetic variation and its biological consequences in a genome-wide way, through the utilization of DNA oligonucleotide arrays that assess hundres of

  2. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia.

    NARCIS (Netherlands)

    Lan, Q.; Hsiung, C.A.; Matsuo, K.; Hong, Y.C.; Seow, A.; Wang, Z.; Hosgood, H.D.; Chen, K.; Wang, J.C.; Chatterjee, N.; Hu, W.; Wong, M.P.; Zheng, W.; Caporaso, N.; Park, J.Y.; Chen, C.J.; Kim, Y.H.; Kim, Y.T.; Landi, M.T.; Shen, H.; Lawrence, C.; Burdett, L.; Yeager, M.; Yuenger, J.; Jacobs, K.B.; Chang, I.S.; Mitsudomi, T.; Kim, H.N.; Chang, G.C.; Bassig, B.A.; Tucker, M.; Wei, F.; Yin, Y.; Wu, C.; An, S.J.; Qian, B.; Lee, V.H.; Lu, D.; Liu, J.; Jeon, H.S.; Hsiao, C.F.; Sung, J.S.; Kim, J.H.; Gao, Y.T.; Tsai, Y.H.; Jung, Y.J.; Guo, H.; Hu, Z.; Hutchinson, A.; Wang, W.C.; Klein, R.; Chung, C.C.; Oh, I.J.; Chen, K.Y.; Berndt, S.I.; He, X.; Wu, W.; Chang, J.; Zhang, X.C.; Huang, M.S.; Zheng, H.; Wang, J.; Zhao, X.|info:eu-repo/dai/nl/413577805; Li, Y.; Choi, J.E.; Su, W.C.; Park, K.H.; Sung, S.W.; Shu, X.O.; Chen, Y.M.; Liu, L.; Kang, C.H.; Hu, L.; Chen, C.H.; Pao, W.; Kim, Y.C.; Yang, T.Y.; Xu, J.; Guan, P.; Tan, W.; Su, J.; Wang, C.L.; Li, H.; Sihoe, A.D.; Zhao, Z.|info:eu-repo/dai/nl/304120995; Chen, Y.; Choi, Y.Y.; Hung, J.Y.; Kim, J.S.; Yoon, H.I.; Cai, Q.; Lin, C.C.; Park, I.K.; Xu, P.; Dong, J.; Kim, C.; He, Q; Perng, R.P.; Kohno, T.; Kweon, S.S.; Chen, C.Y.; Vermeulen, R.|info:eu-repo/dai/nl/216532620; Wu, J.; Lim, W.Y.; Chen, K.C.; Chow, W.H.; Ji, B.T.; Chan, J.K.; Chu, M.; Li, Y.J.; Yokota, J.; Li, J.; Chen, H.; Xiang, Y.B.; Yu, C.J.; Kunitoh, H.; Wu, G.; Jin, L.; Lo, Y.L.; Shiraishi, K.; Chen, Y.H.; Lin, H.C.; Wu, T.; WU, Y.; Yang, P.C.; Zhou, B.; Shin, M.H.; Fraumeni, J.F.; Lin, D.; Chanock, S.J.; Rothman, N.

    2012-01-01

    To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland

  3. Genome-wide analysis reveals signatures of selection for important traits in domestic sheep from different ecoregions.

    Science.gov (United States)

    Liu, Zhaohua; Ji, Zhibin; Wang, Guizhi; Chao, Tianle; Hou, Lei; Wang, Jianmin

    2016-11-03

    Throughout a long period of adaptation and selection, sheep have thrived in a diverse range of ecological environments. Mongolian sheep is the common ancestor of the Chinese short fat-tailed sheep. Migration to different ecoregions leads to changes in selection pressures and results in microevolution. Mongolian sheep and its subspecies differ in a number of important traits, especially reproductive traits. Genome-wide intraspecific variation is required to dissect the genetic basis of these traits. This research resequenced 3 short fat-tailed sheep breeds with a 43.2-fold coverage of the sheep genome. We report more than 17 million single nucleotide polymorphisms and 2.9 million indels and identify 143 genomic regions with reduced pooled heterozygosity or increased genetic distance to each other breed that represent likely targets for selection during the migration. These regions harbor genes related to developmental processes, cellular processes, multicellular organismal processes, biological regulation, metabolic processes, reproduction, localization, growth and various components of the stress responses. Furthermore, we examined the haplotype diversity of 3 genomic regions involved in reproduction and found significant differences in TSHR and PRL gene regions among 8 sheep breeds. Our results provide useful genomic information for identifying genes or causal mutations associated with important economic traits in sheep and for understanding the genetic basis of adaptation to different ecological environments.

  4. Genome wide linkage disequilibrium in Chinese asparagus bean (Vigna. unguiculata ssp. sesquipedialis) germplasm: implications for domestication history and genome wide association studies.

    Science.gov (United States)

    Xu, P; Wu, X; Wang, B; Luo, J; Liu, Y; Ehlers, J D; Close, T J; Roberts, P A; Lu, Z; Wang, S; Li, G

    2012-07-01

    Association mapping of important traits of crop plants relies on first understanding the extent and patterns of linkage disequilibrium (LD) in the particular germplasm being investigated. We characterize here the genetic diversity, population structure and genome wide LD patterns in a set of asparagus bean (Vigna. unguiculata ssp. sesquipedialis) germplasm from China. A diverse collection of 99 asparagus bean and normal cowpea accessions were genotyped with 1127 expressed sequence tag-derived single nucleotide polymorphism markers (SNPs). The proportion of polymorphic SNPs across the collection was relatively low (39%), with an average number of SNPs per locus of 1.33. Bayesian population structure analysis indicated two subdivisions within the collection sampled that generally represented the 'standard vegetable' type (subgroup SV) and the 'non-standard vegetable' type (subgroup NSV), respectively. Level of LD (r(2)) was higher and extent of LD persisted longer in subgroup SV than in subgroup NSV, whereas LD decayed rapidly (0-2 cM) in both subgroups. LD decay distance varied among chromosomes, with the longest (≈ 5 cM) five times longer than the shortest (≈ 1 cM). Partitioning of LD variance into within- and between-subgroup components coupled with comparative LD decay analysis suggested that linkage group 5, 7 and 10 may have undergone the most intensive epistatic selection toward traits favorable for vegetable use. This work provides a first population genetic insight into domestication history of asparagus bean and demonstrates the feasibility of mapping complex traits by genome wide association study in asparagus bean using a currently available cowpea SNPs marker platform.

  5. Challenges and Opportunities in Genome-Wide Environmental Interaction (GWEI) studies

    Science.gov (United States)

    Aschard, Hugues; Lutz, Sharon; Maus, Bärbel; Duell, Eric J.; Fingerlin, Tasha; Chatterjee, Nilanjan; Kraft, Peter; Van Steen, Kristel

    2012-01-01

    The interest in performing gene-environment interaction studies has seen a significant increase with the increase of advanced molecular genetics techniques. Practically, it became possible to investigate the role of environmental factors in disease risk and hence to investigate their role as genetic effect modifiers. The understanding that genetics is important in the uptake and metabolism of toxic substances is an example of how genetic profiles can modify important environmental risk factors to disease. Several rationales exist to set up gene-environment interaction studies and the technical challenges related to these studies – when the number of environmental or genetic risk factors is relatively small – has been described before. In the post-genomic era, it is now possible to study thousands of genes and their interaction with the environment. This brings along a whole range of new challenges and opportunities. Despite a continuing effort in developing efficient methods and optimal bioinformatics infrastructures to deal with the available wealth of data, the challenge remains how to best present and analyze Genome-Wide Environmental Interaction (GWEI) studies involving multiple genetic and environmental factors. Since GWEIs are performed at the intersection of statistical genetics, bioinformatics and epidemiology, usually similar problems need to be dealt with as for Genome-Wide Association gene-gene Interaction (GWAI) studies. However, additional complexities need to be considered which are typical for large-scale epidemiological studies, but are also related to “joining” two heterogeneous types of data in explaining complex disease trait variation or for prediction purposes. PMID:22760307

  6. Genome-wide association study (GWAS) for molar-incisor hypomineralization (MIH).

    Science.gov (United States)

    Kühnisch, Jan; Thiering, Elisabeth; Heitmüller, Daniela; Tiesler, Carla M T; Grallert, Harald; Heinrich-Weltzien, Roswitha; Hickel, Reinhard; Heinrich, Joachim

    2014-01-01

    This genome-wide association study (GWAS) investigated the relationship between molar-incisor hypomineralization (MIH) and possible genetic loci. Clinical and genetic data from the 10-year follow-up of 668 children from the Munich GINI-plus and LISA-plus birth cohort studies were analyzed. The dental examinations included the diagnosis of MIH according to the criteria of the European Academy of Paediatric Dentistry (EAPD). Children with MIH were categorized as those with a minimum of one hypomineralized first permanent molar. A GWAS was implemented following a quality-control step and an additive genetic effect was assumed. A total of 2,013,491 single-nucleotide polymorphisms (SNPs) were available for analysis. Rs13058467, which is located near the SCUBE1 gene on chromosome 22 (p MIH when using a threshold of p value MIH.

  7. Cross-cancer genome-wide analysis of lung, ovary, breast, prostate, and colorectal cancer reveals novel pleiotropic associations

    NARCIS (Netherlands)

    Fehringer, G. (Gordon); P. Kraft (Peter); P.D.P. Pharoah (Paul); R. Eeles (Rosalind); Chatterjee, N. (Nilanjan); F.R. Schumacher (Fredrick R); J.M. Schildkraut (Joellen); S. Lindstrom (Stephen); P. Brennan (Paul); H. Bickeböller (Heike); R. Houlston (Richard); M.T. Landi (Maria Teresa); N.E. Caporaso (Neil); Risch, A. (Angela); A.A. Al Olama (Ali Amin); S.I. Berndt (Sonja); Giovannucci, E.L. (Edward L.); H. Grönberg (Henrik); Z. Kote-Jarai; Ma, J. (Jing); K.R. Muir (K.); M.J. Stampfer (Meir J.); Stevens, V.L. (Victoria L.); F. Wiklund (Fredrik); W.C. Willett (Walter C.); E.L. Goode (Ellen); Permuth, J.B. (Jennifer B.); H. Risch (Harvey); Reid, B.M. (Brett M.); Bezieau, S. (Stephane); H. Brenner (Hermann); Chan, A.T. (Andrew T.); J. Chang-Claude (Jenny); T.J. Hudson (Thomas); Kocarnik, J.K. (Jonathan K.); P. Newcomb (Polly); Schoen, R.E. (Robert E.); Slattery, M.L. (Martha L.); White, E. (Emily); M.A. Adank (Muriel); H. Ahsan (Habibul); K. Aittomäki (Kristiina); Baglietto, L. (Laura); Blomquist, C. (Carl); F. Canzian (Federico); K. Czene (Kamila); I. dos Santos Silva (Isabel); Eliassen, A.H. (A. Heather); J.D. Figueroa (Jonine); D. Flesch-Janys (Dieter); O. Fletcher (Olivia); M. García-Closas (Montserrat); M.M. Gaudet (Mia); Johnson, N. (Nichola); P. Hall (Per); A. Hazra (Aditi); R. Hein (Rebecca); Hofman, A. (Albert); J.L. Hopper (John); A. Irwanto (Astrid); M. Johansson (Mattias); R. Kaaks (Rudolf); M.G. Kibriya (Muhammad); P. Lichtner (Peter); J. Liu (Jianjun); E. Lund (Eiliv); Makalic, E. (Enes); A. Meindl (Alfons); B. Müller-Myhsok (B.); Muranen, T.A. (Taru A.); H. Nevanlinna (Heli); P.H.M. Peeters; J. Peto (Julian); R. Prentice (Ross); N. Rahman (Nazneen); M.-J. Sanchez (Maria-Jose); D.F. Schmidt (Daniel); R.K. Schmutzler (Rita); M.C. Southey (Melissa); Tamimi, R. (Rulla); S.P.L. Travis (Simon); C. Turnbull (Clare); Uitterlinden, A.G. (Andre G.); Z. Wang (Zhaoming); A.S. Whittemore (Alice); X.R. Yang (Xiaohong); W. Zheng (Wei); D. Buchanan (Daniel); G. Casey (Graham); G. Conti (Giario); C.K. Edlund (Christopher); S. Gallinger (Steve); R. Haile (Robert); M. Jenkins (Mark); Marchand, L. (Loïcle); Li, L. (Li); N.M. Lindor (Noralane); Schmit, S.L. (Stephanie L.); S.N. Thibodeau (Stephen); M.O. Woods (Michael); T. Rafnar (Thorunn); J. Gudmundsson (Julius); S.N. Stacey (Simon); Stefansson, K. (Kari); P. Sulem (Patrick); Chen, Y.A. (Y. Ann); J.P. Tyrer (Jonathan); Christiani, D.C. (David C.); Wei, Y. (Yongyue); H. Shen (Hongbing); Z. Hu (Zhibin); X.-O. Shu (Xiao-Ou); Shiraishi, K. (Kouya); A. Takahashi (Atsushi); Y. Bossé (Yohan); M. Obeidat (Ma'en); D.C. Nickle (David); W. Timens (Wim); M. Freedman (Matthew); Li, Q. (Qiyuan); D. Seminara (Daniela); S.J. Chanock (Stephen); Gong, J. (Jian); U. Peters (Ulrike); S.B. Gruber (Stephen); Amos, C.I. (Christopher I.); T.A. Sellers (Thomas A.); D.F. Easton (Douglas F.); D. Hunter (David); C.A. Haiman (Christopher A.); B.E. Henderson (Brian); R.J. Hung (Rayjean)

    2016-01-01

    textabstractIdentifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851

  8. Combining high-throughput phenotyping and genome-wide association studies to reveal natural genetic variation in rice

    Science.gov (United States)

    Yang, Wanneng; Guo, Zilong; Huang, Chenglong; Duan, Lingfeng; Chen, Guoxing; Jiang, Ni; Fang, Wei; Feng, Hui; Xie, Weibo; Lian, Xingming; Wang, Gongwei; Luo, Qingming; Zhang, Qifa; Liu, Qian; Xiong, Lizhong

    2014-01-01

    Even as the study of plant genomics rapidly develops through the use of high-throughput sequencing techniques, traditional plant phenotyping lags far behind. Here we develop a high-throughput rice phenotyping facility (HRPF) to monitor 13 traditional agronomic traits and 2 newly defined traits during the rice growth period. Using genome-wide association studies (GWAS) of the 15 traits, we identify 141 associated loci, 25 of which contain known genes such as the Green Revolution semi-dwarf gene, SD1. Based on a performance evaluation of the HRPF and GWAS results, we demonstrate that high-throughput phenotyping has the potential to replace traditional phenotyping techniques and can provide valuable gene identification information. The combination of the multifunctional phenotyping tools HRPF and GWAS provides deep insights into the genetic architecture of important traits. PMID:25295980

  9. Genome-wide expression analysis of salt-stressed diploid and autotetraploid Paulownia tomentosa.

    Directory of Open Access Journals (Sweden)

    Zhenli Zhao

    Full Text Available Paulownia tomentosa is a fast-growing tree species with multiple uses. It is grown worldwide, but is native to China, where it is widely cultivated in saline regions. We previously confirmed that autotetraploid P. tomentosa plants are more stress-tolerant than the diploid plants. However, the molecular mechanism underlying P. tomentosa salinity tolerance has not been fully characterized. Using the complete Paulownia fortunei genome as a reference, we applied next-generation RNA-sequencing technology to analyze the effects of salt stress on diploid and autotetraploid P. tomentosa plants. We generated 175 million clean reads and identified 15,873 differentially expressed genes (DEGs from four P. tomentosa libraries (two diploid and two autotetraploid. Functional annotations of the differentially expressed genes using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases revealed that plant hormone signal transduction and photosynthetic activities are vital for plant responses to high-salt conditions. We also identified several transcription factors, including members of the AP2/EREBP, bHLH, MYB, and NAC families. Quantitative real-time PCR analysis validated the expression patterns of eight differentially expressed genes. Our findings and the generated transcriptome data may help to accelerate the genetic improvement of cultivated P. tomentosa and other plant species for enhanced growth in saline soils.

  10. Population genetic inference from personal genome data: impact of ancestry and admixture on human genomic variation.

    Science.gov (United States)

    Kidd, Jeffrey M; Gravel, Simon; Byrnes, Jake; Moreno-Estrada, Andres; Musharoff, Shaila; Bryc, Katarzyna; Degenhardt, Jeremiah D; Brisbin, Abra; Sheth, Vrunda; Chen, Rong; McLaughlin, Stephen F; Peckham, Heather E; Omberg, Larsson; Bormann Chung, Christina A; Stanley, Sarah; Pearlstein, Kevin; Levandowsky, Elizabeth; Acevedo-Acevedo, Suehelay; Auton, Adam; Keinan, Alon; Acuña-Alonzo, Victor; Barquera-Lozano, Rodrigo; Canizales-Quinteros, Samuel; Eng, Celeste; Burchard, Esteban G; Russell, Archie; Reynolds, Andy; Clark, Andrew G; Reese, Martin G; Lincoln, Stephen E; Butte, Atul J; De La Vega, Francisco M; Bustamante, Carlos D

    2012-10-05

    Full sequencing of individual human genomes has greatly expanded our understanding of human genetic variation and population history. Here, we present a systematic analysis of 50 human genomes from 11 diverse global populations sequenced at high coverage. Our sample includes 12 individuals who have admixed ancestry and who have varying degrees of recent (within the last 500 years) African, Native American, and European ancestry. We found over 21 million single-nucleotide variants that contribute to a 1.75-fold range in nucleotide heterozygosity across diverse human genomes. This heterozygosity ranged from a high of one heterozygous site per kilobase in west African genomes to a low of 0.57 heterozygous sites per kilobase in segments inferred to have diploid Native American ancestry from the genomes of Mexican and Puerto Rican individuals. We show evidence of all three continental ancestries in the genomes of Mexican, Puerto Rican, and African American populations, and the genome-wide statistics are highly consistent across individuals from a population once ancestry proportions have been accounted for. Using a generalized linear model, we identified subtle variations across populations in the proportion of neutral versus deleterious variation and found that genome-wide statistics vary in admixed populations even once ancestry proportions have been factored in. We further infer that multiple periods of gene flow shaped the diversity of admixed populations in the Americas-70% of the European ancestry in today's African Americans dates back to European gene flow happening only 7-8 generations ago. Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  11. Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function.

    Directory of Open Access Journals (Sweden)

    Dana B Hancock

    Full Text Available Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1, and its ratio to forced vital capacity (FEV(1/FVC. Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA of single nucleotide polymorphism (SNP and SNP-by-smoking (ever-smoking or pack-years associations on FEV(1 and FEV(1/FVC across 19 studies (total N = 50,047. We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = 5.00×10(-11, HLA-DQB1 and HLA-DQA2 (smallest P(JMA = 4.35×10(-9, and KCNJ2 and SOX9 (smallest P(JMA = 1.28×10(-8 were associated with FEV(1/FVC or FEV(1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

  12. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

    NARCIS (Netherlands)

    N. Kato (Norihiro); M. Loh (Marie); F. Takeuchi (Fumihiko); N. Verweij (Niek); X. Wang (Xu); W. Zhang (Weihua); T. NKelly (Tanika); D. Saleheen; B. Lehne (Benjamin); I.M. Leach (Irene Mateo); A. Drong (Alexander); J. Abbott (James); S. Wahl (Simone); S.-T. Tan (Sian-Tsung); W.R. Scott (William R.); G. Campanella (Gianluca); M. Chadeau-Hyam (Marc); U. Afzal (Uzma); T.S. Ahluwalia (Tarunveer Singh); M.J. Bonder (Marc); P. Chen (Ping); A. Dehghan (Abbas); T.L. Edwards (Todd L.); T. Esko (Tõnu); M.J. Go (Min Jin); S.E. Harris (Sarah); J. Hartiala (Jaana); S. Kasela (Silva); A. Kasturiratne (Anuradhani); C.C. Khor; M.E. Kleber (Marcus); H. Li (Huaixing); Z.Y. Mok (Zuan Yu); M. Nakatochi (Masahiro); N.S. Sapari (Nur Sabrina); R. Saxena (Richa); A.F. Stewart (Alexandre F.); L. Stolk (Lisette); Y. Tabara (Yasuharu); A.L. Teh (Ai Ling); Y. Wu (Ying); J.-Y. Wu (Jer-Yuarn); Y. Zhang (Yi); I. Aits (Imke); A. Da Silva Couto Alves (Alexessander); S. Das (Shikta); R. Dorajoo (Rajkumar); J. CHopewell (Jemma); Y.K. Kim (Yun Kyoung); R. WKoivula (Robert); J. Luan (Jian'An); L.-P. Lyytikäinen (Leo-Pekka); Q. NNguyen (Quang); M.A. Pereira (Mark A); D. Postmus (Douwe); O. TRaitakari (Olli); M. Scannell Bryan (Molly); R.A. Scott (Robert); R. Sorice; V. Tragante (Vinicius); M. Traglia (Michela); J. White (Jon); K. Yamamoto (Ken); Y. Zhang (Yonghong); L.S. Adair (Linda); A. Ahmed (Alauddin); K. Akiyama (Koichi); R. Asif (Rasheed); T. Aung (Tin); I.E. Barroso (Inês); A. Bjonnes (Andrew); T.R. Braun (Timothy R.); H. Cai (Hui); L.-C. Chang (Li-Ching); C.-H. Chen; C-Y. Cheng (Ching-Yu); Y.-S. Chong (Yap-Seng); F.S. Collins (Francis); R. Courtney (Regina); G. Davies (Gail); G. Delgado; L.D. Do (Loi D.); P.A. Doevendans (Pieter); R.T. Gansevoort (Ron); Y. Gao; T.B. Grammer (Tanja B); N. Grarup (Niels); J. Grewal (Jagvir); D. Gu (D.); G. SWander (Gurpreet); A.L. Hartikainen; S.L. Hazen (Stanley); J. He (Jing); C.K. Heng (Chew-Kiat); E.J.A. Hixso (E. James Ames); A. Hofman (Albert); C. Hsu (Chris); W. Huang (Wei); L.L.N. Husemoen (Lise Lotte); J.-Y. Hwang (Joo-Yeon); S. Ichihara (Sahoko); M. Igase (Michiya); M. Isono (Masato); J.M. Justesen (Johanne M.); T. Katsuya (Tomohiro); M. GKibriya (Muhammad); Y.J. Kim; M. Kishimoto (Miyako); W.-P. Koh (Woon-Puay); K. Kohara (Katsuhiko); M. Kumari (Meena); K. Kwek (Kenneth); N.R. Lee (Nanette); J. Lee (Jeannette); J. Liao (Jie); W. Lieb (Wolfgang); D.C. Liewald (David C.); T. Matsubara (Tatsuaki); Y. Matsushita (Yumi); T. Meitinger (Thomas); E. Mihailov (Evelin); L. Milani (Lili); R. Mills (Rebecca); K. Mononen (Kari); M. Müller-Nurasyid (Martina); T. Nabika (Toru); E. Nakashima (Eitaro); H.K. Ng (Hong Kiat); K. Nikus (Kjell); T. Nutile; T. Ohkubo (Takayoshi); K. Ohnaka (Keizo); S. Parish (Sarah); L. Paternoster (Lavinia); H. Peng (Hao); A. Peters (Annette); S. TPham (Son); M.J. Pinidiyapathirage (Mohitha J.); M. Rahman (Mahfuzar); H. Rakugi (Hiromi); O. Rolandsson (Olov); M.A. Rozario (Michelle Ann); D. Ruggiero; C. Sala (Cinzia); R. Sarju (Ralhan); K. Shimokawa (Kazuro); H. Snieder (Harold); T. Sparsø (Thomas); W. Spiering (Wilko); J.M. Starr (John); D.J. Stott (David J.); D. OStram (Daniel); T. Sugiyama (Takao); S. Szymczak (Silke); W.H.W. Tang (W.H. Wilson); L. Tong (Lin); S. Trompet (Stella); V. Turjanmaa (Väinö); H. Ueshima (Hirotsugu); A.G. Uitterlinden (André); S. Umemura (Satoshi); M. Vaarasmaki (Marja); R.M. Dam (Rob Mvan); W.H. van Gilst (Wiek); D.J. van Veldhuisen (Dirk); J. Viikari (Jorma); M. Waldenberger (Melanie); Y. Wang (Yiqin); A. Wang (Aili); R. Wilson (Rory); T.Y. Wong (Tien Yin); Y.-B. Xiang (Yong-Bing); S. Yamaguchi (Shuhei); X. Ye (Xingwang); R. Young (Robin); T.L. Young (Terri); J.-M. Yuan (Jian-Min); X. Zhou (Xueya); F.W. Asselbergs (Folkert); M. Ciullo; R. Clarke (Robert); P. Deloukas (Panagiotis); A. Franke (Andre); W.F. Paul (W. Frank); S. Franks (Steve); Y. Friedlander (Yechiel); M.D. Gross (Myron D.); Z. Guo (Zhirong); T. Hansen (T.); M.-R. Jarvelin (Marjo-Riitta); T. Jørgensen (Torben); J.W. Jukema (Jan Wouter); M. Kähönen (Mika); H. Kajio (Hiroshi); M. Kivimaki (Mika); J.-Y. Lee (Jong-Young); T. Lehtimäki (Terho); A. Linneberg (Allan); T. Miki (Tetsuro); O. Pedersen (Oluf); N.J. Samani (Nilesh); T.I.A. Sørensen (Thorkild); R. Takayanagi (Ryoichi); D. Toniolo (Daniela); H. Ahsan (Habibul); H. Allayee (Hooman); Y.-T. Chen (Yuan-Tsong); J. Danesh (John); I.J. Deary (Ian J.); O.H. Franco (Oscar); L. Franke (Lude); B. THeijman (Bastiaan); J.D. Holbrook (Joanna D.); A.J. Isaacs (Aaron); B.-J. Kim (Bong-Jo); X. Lin (Xu); J. Liu (Jianjun); W. März (Winfried); A. Metspalu (Andres); K.L. Mohlke (Karen); K. Sangher; D. Harambir (Dharambir); X.-O. Shu (Xiao-Ou); J.B.J. van Meurs (Joyce); E.N. Vithana (Eranga); A.R. Wickremasinghe (Ananda); C. Wijmenga (Cisca); B.H.W. Wolffenbuttel (Bruce H.W.); M. Yokota (Mitsuhiro); W. Zheng (Wei); D. Zhu (Dingliang); P. Vineis (Paolo); S.A. Kyrtopoulos (Soterios A.); J.C.S. Kleinjans (Jos C.S.); M.I. McCarthy (Mark); R. Soong (Richie); C. Gieger (Christian); J. Scott (James); Y.Y. Teo (Yik Ying); J. He (Jiang); P. Elliott (Paul); E.S. Tai (Shyong); P. van der Harst (Pim); J.S. Kooner (Jaspal S.); J.C. Chambers (John)

    2015-01-01

    textabstractWe carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10 -11 to

  13. Genome-wide comparison of paired fresh frozen and formalin-fixed paraffin-embedded gliomas by custom BAC and oligonucleotide array comparative genomic hybridization: facilitating analysis of archival gliomas

    Science.gov (United States)

    Mohapatra, Gayatry; Engler, David A.; Starbuck, Kristen D.; Kim, James C.; Bernay, Derek C.; Scangas, George A.; Rousseau, Audrey; Batchelor, Tracy T.; Betensky, Rebecca A.; Louis, David N.

    2010-01-01

    Molecular genetic analysis of cancer is rapidly evolving as a result of improvement in genomic technologies and the growing applicability of such analyses to clinical oncology. Array based comparative genomic hybridization (aCGH) is a powerful tool for detecting DNA copy number alterations (CNA), particularly in solid tumors, and has been applied to the study of malignant gliomas. In the clinical setting, however, gliomas are often sampled by small biopsies and thus formalin-fixed paraffin-embedded (FFPE) blocks are often the only tissue available for genetic analysis, especially for rare types of gliomas. Moreover, the biological basis for the marked intratumoral heterogeneity in gliomas is most readily addressed in FFPE material. Therefore, for gliomas, the ability to use DNA from FFPE tissue is essential for both clinical and research applications. In this study, we have constructed a custom bacterial artificial chromosome (BAC) array and show excellent sensitivity and specificity for detecting CNAs in a panel of paired frozen and FFPE glioma samples. Our study demonstrates a high concordance rate between CNAs detected in FFPE compared to frozen DNA. We have also developed a method of labeling DNA from FFPE tissue that allows efficient hybridization to oligonucleotide arrays. This labeling technique was applied to a panel of biphasic anaplastic oligoastrocytomas (AOA) to identify genetic changes unique to each component. Together, results from these studies suggest that BAC and oligonucleotide aCGH are sensitive tools for detecting CNAs in FFPE DNA, and can enable genome-wide analysis of rare, small and/or histologically heterogeneous gliomas. PMID:21080181

  14. Genome wide association studies on yield components using a lentil genetic diversity panel

    Science.gov (United States)

    The cool season food legume research community are now at the threshold of deploying the cutting-edge molecular genetics and genomics tools that have led to significant and rapid expansion of gene discovery, knowledge of gene function (including tolerance to biotic and abiotic stresses) and genetic ...

  15. BioMet Toolbox: genome-wide analysis of metabolism

    DEFF Research Database (Denmark)

    Cvijovic, M.; Olivares Hernandez, Roberto; Agren, R.

    2010-01-01

    The rapid progress of molecular biology tools for directed genetic modifications, accurate quantitative experimental approaches, high-throughput measurements, together with development of genome sequencing has made the foundation for a new area of metabolic engineering that is driven by metabolic...

  16. Identification of the genetic and clinical characteristics of neuroblastomas using genome-wide analysis.

    Science.gov (United States)

    Uryu, Kumiko; Nishimura, Riki; Kataoka, Keisuke; Sato, Yusuke; Nakazawa, Atsuko; Suzuki, Hiromichi; Yoshida, Kenichi; Seki, Masafumi; Hiwatari, Mitsuteru; Isobe, Tomoya; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Koh, Katsuyoshi; Hanada, Ryoji; Oka, Akira; Hayashi, Yasuhide; Ohira, Miki; Kamijo, Takehiko; Nagase, Hiroki; Takimoto, Tetsuya; Tajiri, Tatsuro; Nakagawara, Akira; Ogawa, Seishi; Takita, Junko

    2017-12-08

    To provide better insight into the genetic signatures of neuroblastomas, we analyzed 500 neuroblastomas (included specimens from JNBSG) using targeted-deep sequencing for 10 neuroblastoma-related genes and SNP arrays analysis. ALK expression was evaluated using immunohistochemical analysis in 259 samples. Based on genetic alterations, the following 6 subgroups were identified: groups A ( ALK abnormalities), B (other gene mutations), C ( MYCN amplification), D (11q loss of heterozygosity [LOH]), E (at least 1 copy number variants), and F (no genetic changes). Groups A to D showed advanced disease and poor prognosis, whereas groups E and F showed excellent prognosis. Intriguingly, in group A, MYCN amplification was not a significant prognostic marker, while high ALK expression was a relevant indicator for prognosis ( P = 0.033). Notably, the co-existence of MYCN amplification and 1p LOH, and the co-deletion of 3p and 11q were significant predictors of relapse ( P = 0.043 and P = 0.040). Additionally, 6q/8p LOH and 17q gain were promising indicators of survival in patients older than 5 years, and 1p, 4p, and 11q LOH potentially contributed to outcome prediction in the intermediate-risk group. Our genetic overview clarifies the clinical impact of genetic signatures and aids in the better understanding of genetic basis of neuroblastoma.

  17. Genome-Wide Analysis of Genetic Risk Factors for Rheumatic Heart Disease in Aboriginal Australians Provides Support for Pathogenic Molecular Mimicry.

    Science.gov (United States)

    Gray, Lesley-Ann; D'Antoine, Heather A; Tong, Steven Y C; McKinnon, Melita; Bessarab, Dawn; Brown, Ngiare; Reményi, Bo; Steer, Andrew; Syn, Genevieve; Blackwell, Jenefer M; Inouye, Michael; Carapetis, Jonathan R

    2017-12-12

    Rheumatic heart disease (RHD) after group A streptococcus (GAS) infections is heritable and prevalent in Indigenous populations. Molecular mimicry between human and GAS proteins triggers proinflammatory cardiac valve-reactive T cells. Genome-wide genetic analysis was undertaken in 1263 Aboriginal Australians (398 RHD cases; 865 controls). Single-nucleotide polymorphisms were genotyped using Illumina HumanCoreExome BeadChips. Direct typing and imputation was used to fine-map the human leukocyte antigen (HLA) region. Epitope binding affinities were mapped for human cross-reactive GAS proteins, including M5 and M6. The strongest genetic association was intronic to HLA-DQA1 (rs9272622; P = 1.86 × 10-7). Conditional analyses showed rs9272622 and/or DQA1*AA16 account for the HLA signal. HLA-DQA1*0101_DQB1*0503 (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.09-1.90; P = 9.56 × 10-3) and HLA-DQA1*0103_DQB1*0601 (OR, 1.27; 95% CI, 1.07-1.52; P = 7.15 × 10-3) were risk haplotypes; HLA_DQA1*0301-DQB1*0402 (OR 0.30, 95%CI 0.14-0.65, P = 2.36 × 10-3) was protective. Human myosin cross-reactive N-terminal and B repeat epitopes of GAS M5/M6 bind with higher affinity to DQA1/DQB1 alpha/beta dimers for the 2-risk haplotypes than the protective haplotype. Variation at HLA_DQA1-DQB1 is the major genetic risk factor for RHD in Aboriginal Australians studied here. Cross-reactive epitopes bind with higher affinity to alpha/beta dimers formed by risk haplotypes, supporting molecular mimicry as the key mechanism of RHD pathogenesis. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  18. Statistical power and utility of meta-analysis methods for cross-phenotype genome-wide association studies.

    Science.gov (United States)

    Zhu, Zhaozhong; Anttila, Verneri; Smoller, Jordan W; Lee, Phil H

    2018-01-01

    Advances in recent genome wide association studies (GWAS) suggest that pleiotropic effects on human complex traits are widespread. A number of classic and recent meta-analysis methods have been used to identify genetic loci with pleiotropic effects, but the overall performance of these methods is not well understood. In this work, we use extensive simulations and case studies of GWAS datasets to investigate the power and type-I error rates of ten meta-analysis methods. We specifically focus on three conditions commonly encountered in the studies of multiple traits: (1) extensive heterogeneity of genetic effects; (2) characterization of trait-specific association; and (3) inflated correlation of GWAS due to overlapping samples. Although the statistical power is highly variable under distinct study conditions, we found the superior power of several methods under diverse heterogeneity. In particular, classic fixed-effects model showed surprisingly good performance when a variant is associated with more than a half of study traits. As the number of traits with null effects increases, ASSET performed the best along with competitive specificity and sensitivity. With opposite directional effects, CPASSOC featured the first-rate power. However, caution is advised when using CPASSOC for studying genetically correlated traits with overlapping samples. We conclude with a discussion of unresolved issues and directions for future research.

  19. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

    DEFF Research Database (Denmark)

    Marshall, Christian R.; Howrigan, Daniel P.; Merico, Daniele

    2017-01-01

    Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline...

  20. Genome-wide analysis of Tol2 transposon reintegration in zebrafish.

    Science.gov (United States)

    Kondrychyn, Igor; Garcia-Lecea, Marta; Emelyanov, Alexander; Parinov, Sergey; Korzh, Vladimir

    2009-09-08

    Tol2, a member of the hAT family of transposons, has become a useful tool for genetic manipulation of model animals, but information about its interactions with vertebrate genomes is still limited. Furthermore, published reports on Tol2 have mainly been based on random integration of the transposon system after co-injection of a plasmid DNA harboring the transposon and a transposase mRNA. It is important to understand how Tol2 would behave upon activation after integration into the genome. We performed a large-scale enhancer trap (ET) screen and generated 338 insertions of the Tol2 transposon-based ET cassette into the zebrafish genome. These insertions were generated by remobilizing the transposon from two different donor sites in two transgenic lines. We found that 39% of Tol2 insertions occurred in transcription units, mostly into introns. Analysis of the transposon target sites revealed no strict specificity at the DNA sequence level. However, Tol2 was prone to target AT-rich regions with weak palindromic consensus sequences centered at the insertion site. Our systematic analysis of sequential remobilizations of the Tol2 transposon from two independent sites within a vertebrate genome has revealed properties such as a tendency to integrate into transcription units and into AT-rich palindrome-like sequences. This information will influence the development of various applications involving DNA transposons and Tol2 in particular.

  1. Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

    NARCIS (Netherlands)

    Fehringer, Gordon; Kraft, Peter; Pharoah, Paul D.; Eeles, Rosalind A.; Chatterjee, Nilanjan; Schumacher, Fredrick R.; Schildkraut, Joellen M.; Lindstrom, Sara; Brennan, Paul; Bickeboller, Heike; Houlston, Richard S.; Landi, Maria Teresa; Caporaso, Neil; Risch, Angela; Al Olama, Ali Amin; Berndt, Sonja I.; Giovannucci, Edward L.; Gronberg, Henrik; Kote-Jarai, Zsofia; Ma, Jing; Muir, Kenneth; Stampfer, Meir J.; Stevens, Victoria L.; Wiklund, Fredrik; Willett, Walter C.; Goode, Ellen L.; Permuth, Jennifer B.; Risch, Harvey A.; Reid, Brett M.; Bezieau, Stephane; Brenner, Hermann; Chan, Andrew T.; Chang-Claude, Jenny; Hudson, Thomas J.; Kocarnik, Jonathan K.; Newcomb, Polly A.; Schoen, Robert E.; Slattery, Martha L.; White, Emily; Adank, Muriel A.; Ahsan, Habibul; Aittomaki, Kristiina; Baglietto, Laura; Blomquist, Carl; Canzian, Federico; Czene, Kamila; dos-Santos-Silva, Isabel; Eliassen, A. Heather; Figueroa, Jonine D.; Timens, Wim

    2016-01-01

    Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820

  2. Cross-cancer genome-wide analysis of lung, ovary, breast, prostate, and colorectal cancer reveals novel pleiotropic associations

    NARCIS (Netherlands)

    Fehringer, Gordon; Kraft, Peter; Pharoah, Paul D.; Eeles, Rosalind A.; Chatterjee, Nilanjan; Schumacher, Fredrick R.; Schildkraut, Joellen M.; Lindström, Sara; Brennan, Paul; Bickeböller, Heike; Houlston, Richard S.; Landi, Maria Teresa; Caporaso, Neil; Risch, Angela; Al Olama, Ali Amin; Berndt, Sonja I.; Giovannucci, Edward L.; Grönberg, Henrik; Kote-Jarai, Zsofia; Ma, Jing; Muir, Kenneth; Stampfer, Meir J.; Stevens, Victoria L.; Wiklund, Fredrik; Willett, Walter C.; Goode, Ellen L.; Permuth, Jennifer B.; Risch, Harvey A.; Reid, Brett M.; Bezieau, Stephane; Brenner, Hermann; Chan, Andrew T.; Chang-Claude, Jenny; Hudson, Thomas J.; Kocarnik, Jonathan K.; Newcomb, Polly A.; Schoen, Robert E.; Slattery, Martha L.; White, Emily; Adank, Muriel A.; Ahsan, Habibul; Aittomäki, Kristiina; Baglietto, Laura; Blomquist, Carl; Canzian, Federico; Czene, Kamila; Dos-Santos-silva, Isabel; Eliassen, A. Heather; Figueroa, Jonine D.; Flesch-Janys, Dieter; Fletcher, Olivia; Garcia-Closas, Montserrat; Gaudet, Mia M.; Johnson, Nichola; Hall, Per; Hazra, Aditi; Hein, Rebecca; Hofman, Albert; Hopper, John L.; Irwanto, Astrid; Johansson, Mattias; Kaaks, Rudolf; Kibriya, Muhammad G.; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Meindl, Alfons; Müller-Myhsok, Bertram; Muranen, Taru A.; Nevanlinna, Heli; Peeters, Petra H.; Peto, Julian; Prentice, Ross L.; Rahman, Nazneen; Sanchez, Maria Jose; Schmidt, Daniel F.; Schmutzler, Rita K.; Southey, Melissa C.; Tamimi, Rulla; Travis, Ruth C.; Turnbull, Clare; Uitterlinden, Andre G.; Wang, Zhaoming; Whittemore, Alice S.; Yang, Xiaohong R.; Zheng, Wei; Buchanan, Daniel D.; Casey, Graham; Conti, David V.; Edlund, Christopher K.; Gallinger, Steven; Haile, Robert W.; Jenkins, Mark; Marchand, Loïcle; Li, Li; Lindor, Noralene M.; Schmit, Stephanie L.; Thibodeau, Stephen N.; Woods, Michael O.; Rafnar, Thorunn; Gudmundsson, Julius; Stacey, Simon N.; Stefansson, Kari; Sulem, Patrick; Chen, Y. Ann; Tyrer, Jonathan P.; Christiani, David C.; Wei, Yongyue; Shen, Hongbing; Hu, Zhibin; Shu, Xiao Ou; Shiraishi, Kouya; Takahashi, Atsushi; Bossé, Yohan; Obeidat, Ma'en; Nickle, David; Timens, Wim; Freedman, Matthew L.; Li, Qiyuan; Seminara, Daniela; Chanock, Stephen J.; Gong, Jian; Peters, Ulrike; Gruber, Stephen B.; Amos, Christopher I.; Sellers, Thomas A.; Easton, Douglas F.; Hunter, David J.; Haiman, Christopher A.; Henderson, Brian E.; Hung, Rayjean J.

    2016-01-01

    Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820

  3. GenoGAM: genome-wide generalized additive models for ChIP-Seq analysis.

    Science.gov (United States)

    Stricker, Georg; Engelhardt, Alexander; Schulz, Daniel; Schmid, Matthias; Tresch, Achim; Gagneur, Julien

    2017-08-01

    Chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) is a widely used approach to study protein-DNA interactions. Often, the quantities of interest are the differential occupancies relative to controls, between genetic backgrounds, treatments, or combinations thereof. Current methods for differential occupancy of ChIP-Seq data rely however on binning or sliding window techniques, for which the choice of the window and bin sizes are subjective. Here, we present GenoGAM (Genome-wide Generalized Additive Model), which brings the well-established and flexible generalized additive models framework to genomic applications using a data parallelism strategy. We model ChIP-Seq read count frequencies as products of smooth functions along chromosomes. Smoothing parameters are objectively estimated from the data by cross-validation, eliminating ad hoc binning and windowing needed by current approaches. GenoGAM provides base-level and region-level significance testing for full factorial designs. Application to a ChIP-Seq dataset in yeast showed increased sensitivity over existing differential occupancy methods while controlling for type I error rate. By analyzing a set of DNA methylation data and illustrating an extension to a peak caller, we further demonstrate the potential of GenoGAM as a generic statistical modeling tool for genome-wide assays. Software is available from Bioconductor: https://www.bioconductor.org/packages/release/bioc/html/GenoGAM.html . gagneur@in.tum.de. Supplementary information is available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  4. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption

    NARCIS (Netherlands)

    M. Cornelis (Marilyn); E.M. Byrne; T. Esko (Tõnu); M.A. Nalls (Michael); A. Ganna (Andrea); N.P. Paynter (Nina); K.L. Monda (Keri); N. Amin (Najaf); K. Fischer (Krista); F. Renström (Frida); J.S. Ngwa; V. Huikari (Ville); A. Cavadino (Alana); I.M. Nolte (Ilja M.); A. Teumer (Alexander); K. Yu; P. Marques-Vidal; R. Rawal; A. Manichaikul (Ani); M.K. Wojczynski (Mary ); J.M. Vink; J.H. Zhao (Jing Hua); G. Burlutsky (George); J. Lahti (Jari); V. Mikkilä (Vera); R.N. Lemaitre (Rozenn ); J. Eriksson; S. Musani (Solomon); T. Tanaka; F. Geller (Frank); J. Luan; J. Hui; R. Mägi (Reedik); M. Dimitriou (Maria); M. Garcia (Melissa); W.-K. Ho; M.J. Wright (Margaret); L.M. Rose (Lynda M.); P.K.E. Magnusson (Patrik K. E.); N.L. Pedersen (Nancy L.); D.J. Couper (David); B.A. Oostra (Ben); A. Hofman (Albert); M.A. Ikram (Arfan); H.W. Tiemeier (Henning); A.G. Uitterlinden (André); F.J.A. van Rooij (Frank); I. Barroso; I. Johansson (Ingegerd); L. Xue (Luting); M. Kaakinen (Marika); L. Milani (Lili); C. Power (Christine); H. Snieder (Harold); R.P. Stolk; S.E. Baumeister (Sebastian); R. Biffar; F. Gu; F. Bastardot (Francois); Z. Kutalik; D.R. Jacobs (David); N.G. Forouhi (Nita G.); E. Mihailov (Evelin); L. Lind (Lars); C. Lindgren; K. Michaëlsson; A.P. Morris (Andrew); M.K. Jensen (Majken K.); K.T. Khaw; R.N. Luben (Robert); J.J. Wang; S. Männistö (Satu); M.-M. Perälä; M. Kähönen (Mika); T. Lehtimäki (Terho); J. Viikari (Jorma); D. Mozaffarian; K. Mukamal (Kenneth); B.M. Psaty (Bruce); A. Döring; A.C. Heath (Andrew C.); G.W. Montgomery (Grant W.); N. Dahmen (N.); T. Carithers; K.L. Tucker; L. Ferrucci (Luigi); H.A. Boyd; M. Melbye (Mads); J.L. Treur; D. Mellström (Dan); J.J. Hottenga (Jouke Jan); I. Prokopenko (Inga); A. Tönjes (Anke); P. Deloukas (Panagiotis); S. Kanoni (Stavroula); M. Lorentzon (Mattias); D.K. Houston; Y. Liu; J. Danesh (John); A. Rasheed; M.A. Mason; A.B. Zonderman; L. Franke (Lude); B.S. Kristal; J. Karjalainen (Juha); D.R. Reed; H.-J. Westra; M.K. Evans; D. Saleheen; T.B. Harris (Tamara); G.V. Dedoussis (George V.); G.C. Curhan (Gary); M. Stumvoll (Michael); J. Beilby (John); L.R. Pasquale; B. Feenstra; S. Bandinelli; J.M. Ordovas; A.T. Chan; U. Peters (Ulrike); C. Ohlsson (Claes); C. Gieger (Christian); N.G. Martin (Nicholas); M. Waldenberger (Melanie); D.S. Siscovick (David); O. Raitakari (Olli); J.G. Eriksson (Johan G.); P. Mitchell (Paul); D. Hunter (David); P. Kraft (Peter); E.B. Rimm (Eric B.); D.I. Boomsma (Dorret); I.B. Borecki (Ingrid); R.J.F. Loos (Ruth); N.J. Wareham (Nick); P.K. Vollenweider (Peter K.); N. Caporaso; H.J. Grabe (Hans Jörgen); M.L. Neuhouser (Marian L.); B.H.R. Wolffenbuttel (Bruce H. R.); F.B. Hu (Frank); E. Hypponen (Elina); M.-R. Jarvelin (Marjo-Riitta); L.A. Cupples (Adrienne); P.W. Franks; P.M. Ridker (Paul); C.M. van Duijn (Cornelia); G. Heiss (Gerardo); A. Metspalu (Andres); K.E. North (Kari); E. Ingelsson (Erik); J.A. Nettleton; R.M. van Dam (Rob); D.I. Chasman (Daniel)

    2015-01-01

    textabstractCoffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day)

  5. Genome-wide linkage analysis of malaria infection intensity and mild disease.

    Directory of Open Access Journals (Sweden)

    Christian Timmann

    2007-03-01

    Full Text Available Although balancing selection with the sickle-cell trait and other red blood cell disorders has emphasized the interaction between malaria and human genetics, no systematic approach has so far been undertaken towards a comprehensive search for human genome variants influencing malaria. By screening 2,551 families in rural Ghana, West Africa, 108 nuclear families were identified who were exposed to hyperendemic malaria transmission and were homozygous wild-type for the established malaria resistance factors of hemoglobin (HbS, HbC, alpha(+ thalassemia, and glucose-6-phosphate-dehydrogenase deficiency. Of these families, 392 siblings aged 0.5-11 y were characterized for malaria susceptibility by closely monitoring parasite counts, malaria fever episodes, and anemia over 8 mo. An autosome-wide linkage analysis based on 10,000 single-nucleotide polymorphisms was conducted in 68 selected families including 241 siblings forming 330 sib pairs. Several regions were identified which showed evidence for linkage to the parasitological and clinical phenotypes studied, among them a prominent signal on Chromosome 10p15 obtained with malaria fever episodes (asymptotic z score = 4.37, empirical p-value = 4.0 x 10(-5, locus-specific heritability of 37.7%; 95% confidence interval, 15.7%-59.7%. The identification of genetic variants underlying the linkage signals may reveal as yet unrecognized pathways influencing human resistance to malaria.

  6. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

    DEFF Research Database (Denmark)

    Kato, Norihiro; Loh, Marie; Takeuchi, Fumihiko

    2015-01-01

    We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10...

  7. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

    NARCIS (Netherlands)

    Kato, Norihiro; Loh, Marie; Takeuchi, Fumihiko; Verweij, Niek; Wang, Xu; Zhang, Weihua; Kelly, Tanika N.; Saleheen, Danish; Lehne, Benjamin; Leach, Irene Mateo; Drong, Alexander W.; Abbott, James; Wahl, Simone; Tan, Sian-Tsung; Scott, William R.; Campanella, Gianluca; Chadeau-Hyam, Marc; Afzal, Uzma; Ahluwalia, Tarunveer S.; Bonder, Marc Jan; Chen, Peng; Dehghan, Abbas; Edwards, Todd L.; Esko, Tonu; Go, Min Jin; Harris, Sarah E.; Hartiala, Jaana; Kasela, Silva; Kasturiratne, Anuradhani; Khor, Chiea-Chuen; Kleber, Marcus E.; Li, Huaixing; Mok, Zuan Yu; Nakatochi, Masahiro; Sapari, Nur Sabrina; Saxena, Richa; Stewart, Alexandre F. R.; Stolk, Lisette; Tabara, Yasuharu; Teh, Ai Ling; Wu, Ying; Wu, Jer-Yuarn; Zhang, Yi; Aits, Imke; Alves, Alexessander Da Silva Couto; Das, Shikta; Dorajoo, Rajkumar; Hopewell, Jemma C.; Kim, Yun Kyoung; Koivula, Robert W.; Luan, Jian'an; Lyytikainen, Leo-Pekka; Nguyen, Quang N.; Pereira, Mark A.; Postmus, Iris; Raitakari, Olli T.; Bryan, Molly Scannell; Scott, Robert A.; Sorice, Rossella; Tragante, Vinicius; Traglia, Michela; White, Jon; Yamamoto, Ken; Zhang, Yonghong; Adair, Linda S.; Ahmed, Alauddin; Akiyama, Koichi; Asif, Rasheed; Aung, Tin; Barroso, Ines; Bjonnes, Andrew; Braun, Timothy R.; Cai, Hui; Chang, Li-Ching; Chen, Chien-Hsiun; Cheng, Ching-Yu; Chong, Yap-Seng; Collins, Rory; Courtney, Regina; Davies, Gail; Delgado, Graciela; Do, Loi D.; Doevendans, Pieter A.; Gansevoort, Ron T.; Gao, Yu-Tang; Grammer, Tanja B.; Grarup, Niels; Grewal, Jagvir; Gu, Dongfeng; Wander, Gurpreet S.; Hartikainen, Anna-Liisa; Hazen, Stanley L.; He, Jing; Heng, Chew-Kiat; Hixson, James E.; Hofman, Albert; Hsu, Chris; Huang, Wei; Husemoen, Lise L. N.; Hwang, Joo-Yeon; Ichihara, Sahoko; Igase, Michiya; Isono, Masato; Justesen, Johanne M.; Katsuy, Tomohiro; Kibriya, Muhammad G.; Kim, Young Jin; Kishimoto, Miyako; Koh, Woon-Puay; Kohara, Katsuhiko; Kumari, Meena; Kwek, Kenneth; Lee, Nanette R.; Lee, Jeannette; Liao, Jiemin; Lieb, Wolfgang; Liewald, David C. M.; Matsubara, Tatsuaki; Matsushita, Yumi; Meitinger, Thomas; Mihailov, Evelin; Milani, Lili; Mills, Rebecca; Mononen, Nina; Mueller-Nurasyid, Martina; Nabika, Toru; Nakashima, Eitaro; Ng, Hong Kiat; Nikus, Kjell; Nutile, Teresa; Ohkubo, Takayoshi; Ohnaka, Keizo; Parish, Sarah; Paternoster, Lavinia; Peng, Hao; Peters, Annette; Pham, Son T.; Pinidiyapathirage, Mohitha J.; Rahman, Mahfuzar; Rakugi, Hiromi; Rolandsson, Olov; Rozario, Michelle Ann; Ruggiero, Daniela; Sala, Cinzia F.; Sarju, Ralhan; Shimokawa, Kazuro; Snieder, Harold; Sparso, Thomas; Spiering, Wilko; Starr, John M.; Stott, David J.; Stram, Daniel O.; Sugiyama, Takao; Szymczak, Silke; Tang, W. H. Wilson; Tong, Lin; Trompet, Stella; Turjanmaa, Vaino; Ueshima, Hirotsugu; Uitterlinden, Andre G.; Umemura, Satoshi; Vaarasmaki, Marja; van Dam, Rob M.; van Gilst, Wiek H.; van Veldhuisen, Dirk J.; Viikari, Jorma S.; Waldenberger, Melanie; Wang, Yiqin; Wang, Aili; Wilson, Rory; Wong, Tien-Yin; Xiang, Yong-Bing; Yamaguchi, Shuhei; Ye, Xingwang; Young, Robin D.; Young, Terri L.; Yuan, Jian-Min; Zhou, Xueya; Asselbergs, Folkert W.; Ciullo, Marina; Clarke, Robert; Deloukas, Panos; Franke, Andre; Franks, Paul W.; Franks, Steve; Friedlander, Yechiel; Gross, Myron D.; Guo, Zhirong; Hansen, Torben; Jarvelin, Marjo-Riitta; Jorgensen, Torben; Jukema, J. Wouter; Kahonen, Mika; Kajio, Hiroshi; Kivimaki, Mika; Lee, Jong-Young; Lehtimaki, Terho; Linneberg, Allan; Miki, Tetsuro; Pedersen, Oluf; Samani, Nilesh J.; Sorensen, Thorkild I. A.; Takayanagi, Ryoichi; Toniolo, Daniela; Ahsan, Habibul; Allayee, Hooman; Chen, Yuan-Tsong; Danesh, John; Deary, Ian J.; Franco, Oscar H.; Franke, Lude; Heijman, Bastiaan T.; Holbrook, Joanna D.; Isaacs, Aaron; Kim, Bong-Jo; Lin, Xu; Liu, Jianjun; Maerz, Winfried; Metspalu, Andres; Mohlke, Karen L.; Sanghera, Dharambir K.; Shu, Xiao-Ou; van Meurs, Joyce B. J.; Vithana, Eranga; Wickremasinghe, Ananda R.; Wijmenga, Cisca; Wolffenbuttel, Bruce H. W.; Yokota, Mitsuhiro; Zheng, Wei; Zhu, Dingliang; Vineis, Paolo; Kyrtopoulos, Soterios A.; Kleinjans, Jos C. S.; McCarthy, Mark I.; Soong, Richie; Gieger, Christian; Scott, James; Teo, Yik-Ying; He, Jiang; Elliott, Paul; Tai, E. Shyong; van der Harst, Pim; Kooner, Jaspal S.; Chambers, John C.

    2015-01-01

    We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 x 10(-11) to 5.0 x

  8. A genome-wide association study of corneal astigmatism: The CREAM Consortium

    OpenAIRE

    Shah, Rupal L.; Li, Qing; Zhao, Wanting; Tedja, Milly S.; Tideman, J. Willem L.; Khawaja, Anthony P.; Fan, Qiao; Yazar, Seyhan; Williams, Katie M.; Verhoeven, Virginie J.M.; Xie, Jing; Wang, Ya Xing; Hess, Moritz; Nickels, Stefan; Lackner, Karl J.

    2018-01-01

    Purpose To identify genes and genetic markers associated with corneal astigmatism. Methods: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts we...

  9. A genome-wide association study of corneal astigmatism: The CREAM Consortium

    OpenAIRE

    Shah, Rupal L.; Li, Qing; Zhao, Wanting; Tedja, Milly S.; Tideman, J. Willem L.; Khawaja, Anthony P.; Fan, Qiao; Yazar, Seyhan; Williams, Katie M.; Verhoeven, Virginie J.M.; Xie, Jing; Wang, Ya Xing; Hess, Moritz; Nickels, Stefan; Lackner, Karl J.

    2018-01-01

    Purpose To identify genes and genetic markers associated with corneal astigmatism. Methods A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts wer...

  10. A genome-wide association study of corneal astigmatism: The CREAM Consortium.

    OpenAIRE

    Shah, Rupal L; Li, Qing; Zhao, Wanting; Tedja, Milly S; Tideman, J Willem L; Khawaja, Anthony P; Fan, Qiao; Yazar, Seyhan; Williams, Katie M; Verhoeven, Virginie J M; Xie, Jing; Wang, Ya Xing; Hess, Moritz; Nickels, Stefan; Lackner, Karl J

    2018-01-01

    Purpose To identify genes and genetic markers associated with corneal astigmatism. Methods A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry...

  11. A genome-wide association study of corneal astigmatism : The CREAM Consortium

    OpenAIRE

    Shah, Rupal L.; Li, Qing; Zhao, Wanting; Tedja, Milly S.; Tideman, J. Willem L.; Khawaja, Anthony P.; Fan, Qiao; Yazar, Seyhan; Williams, Katie M.; Verhoeven, Virginie J.M.; Xie, Jing; Wang, Ya Xing; Hess, Moritz; Nickels, Stefan; Lackner, Karl J.

    2018-01-01

    Purpose: To identify genes and genetic markers associated with corneal astigmatism. Methods: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohor...

  12. A genome-wide association study of corneal astigmatism:The CREAM consortium

    OpenAIRE

    Shah, Rupal L.; Li, Qing; Zhao, Wanting; Tedja, Milly S.; Tideman, J. Willem L.; Khawaja, Anthony P.; Fan, Qiao; Yazar, Seyhan; Williams, Katie M.; Verhoeven, Virginie J.M.; Xie, Jing; Wang, Ya Xing; Hess, Moritz; Nickels, Stefan; Lackner, Karl J.

    2018-01-01

    Purpose: To identify genes and genetic markers associated with corneal astigmatism. Methods: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohort...

  13. Genome-wide association analysis identifies 13 new risk loci for schizophrenia

    NARCIS (Netherlands)

    Ripke, S.; O'Dushlaine, C.; Chambert, K.; Moran, J.L.; Kähler, A.K.; Akterin, S.; Bergen, S.E.; Collins, A.L.; Crowley, J.J.; Fromer, M.; Kim, Y.; Lee, S.H.; Magnusson, P.K.; Sanchez, N.; Stahl, E.A.; Williams, S.; Wray, N.R.; Xia, K.; Bettella, F.; Borglum, A. D.; Bulik-Sullivan, B.K.; Cormican, P.; Craddock, N.; de Leeuw, C.A.; Durmishi, N.; Gill, M.; Golimbet, V.; Hamshere, M.L.; Holmans, P.; Hougaard, D. M.; Kendler, K.S.; Lin, K.; Morris, D. W.; Mors, O.; Mortensen, P.B.; Neale, B. M.; O'Neill, F. A.; Owen, M.J.; Milovancevic, M.P.; Posthuma, D.; Powell, J.; Richards, A.L.; Riley, B.P.; Ruderfer, D.; Rujescu, D.; Sigurdsson, E.; Silagadze, T.; Smit, A.B.; Stefansson, H.; Steinberg, S.; Suvisaari, J.; Tosato, S.; Verhage, M.; Walters, T.J.; Levinson, D.F.; Gejman, P.V.; Laurent, C.; Mowry, B. J.; O'Donovan, M.C.; Pulver, A. E.; Schwab, S.G.; Wildenauer, D. B.; Dudbridge, F.; Shi, J.; Albus, M.; Alexander, M.; Campion, D.; Cohen, D.; Dikeos, D.; Duan, J.; Eichhammer, P.; Godard, S.; Hansen, M.; Lerer, F.B.; Liang, K.Y.; Maier, W.; Mallet, J.; Nertney, D. A.; Nestadt, G.; Norton, N.; O'Neill, F.A.; Papadimitriou, G.N.; Ribble, R.; Sanders, A.R.; Silverman, J.M.; Wormley, B.; Arranz, M.J.; Bakker, S.; Bender, S.; Bramon, E.; Collier, D.; Crespo-Facorro, B.; Hall, J.; Iyegbe, C.; Jablensky, A.; Kahn, R.S.; Kalaydjieva, L.; Lawrie, S.M.; Lewis, C.M.; Linszen, D.H.; Mata, I.; McIntosh, A.; Murray, R.M.; Ophoff, R.A.; van Os, J.; Walshe, M.; Weisbrod, M.; Wiersma, D.; Donnely, P.; Barasso, I.; Blackwell, J.M.; Brown, M.A.; Casas, J.P.; Corvin, A.P.; Deloukas, P.; Duncanson, A.; Jankowski, J.; Markus, H.S.; Mathew, C.G.; Palmer, C.N.; Plomin, R.; Rautanen, A.; Sawcer, S.J.; Trembath, R.C.; Viswanathan, A.C.; Wood, N.W.; Spencer, C. C.; Band, G.; Bellenguez, C.; Freeman, C.; Hellenthal, G.; Giannoulatou, E.; Pirinen, M.; Pearson, R.D.; Strange, A.; Su, Z.; Vukcevic, D.; Langford, C.; Hunt, S.E.; Edkins, S.; Gwilliam, R.; Blackburn, H.; Bumpstead, S.; Dronov, S.; Gillman, M.; Gray, E.; Hammond, N.; Jayakumar, A.; McCann, O.T.; Liddle, J.; Potter, S.C.; Ravindrarajah, R.; Ricketts, M.; Tashakkori-Ghanbaria, A.; Waller, M.J.; Weston, P.; Widaa, S.; Whittaker, P.; Barrroso, I.; McCarthy, M.I.; Spencer, C.C.; Stefansson, K.; Scolnick, E.; Purcell, S.; McCarroll, S.A.; Sklar, P.; Hultman, C. M.; Sullivan, P.F.

    2013-01-01

    Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-Analysis with

  14. Genome-wide association analysis identifies 13 new risk loci for schizophrenia

    NARCIS (Netherlands)

    Ripke, Stephan; O'Dushlaine, Colm; Chambert, Kimberly; Moran, Jennifer L.; Kähler, Anna K.; Akterin, Susanne; Bergen, Sarah E.; Collins, Ann L.; Crowley, James J.; Fromer, Menachem; Kim, Yunjung; Lee, Sang Hong; Magnusson, Patrik K. E.; Sanchez, Nick; Stahl, Eli A.; Williams, Stephanie; Wray, Naomi R.; Xia, Kai; Bettella, Francesco; Borglum, Anders D.; Bulik-Sullivan, Brendan K.; Cormican, Paul; Craddock, Nick; de Leeuw, Christiaan; Durmishi, Naser; Gill, Michael; Golimbet, Vera; Hamshere, Marian L.; Holmans, Peter; Hougaard, David M.; Kendler, Kenneth S.; Lin, Kuang; Morris, Derek W.; Mors, Ole; Mortensen, Preben B.; Neale, Benjamin M.; O'Neill, Francis A.; Owen, Michael J.; Milovancevic, Milica Pejovic; Posthuma, Danielle; Powell, John; Richards, Alexander L.; Riley, Brien P.; Ruderfer, Douglas; Rujescu, Dan; Sigurdsson, Engilbert; Silagadze, Teimuraz; Smit, August B.; Stefansson, Hreinn; Steinberg, Stacy; Suvisaari, Jaana; Tosato, Sarah; Verhage, Matthijs; Walters, James T.; Levinson, Douglas F.; Gejman, Pablo V.; Laurent, Claudine; Mowry, Bryan J.; O'Donovan, Michael C.; Pulver, Ann E.; Schwab, Sibylle G.; Wildenauer, Dieter B.; Dudbridge, Frank; Shi, Jianxin; Albus, Margot; Alexander, Madeline; Campion, Dominique; Cohen, David; Dikeos, Dimitris; Duan, Jubao; Eichhammer, Peter; Godard, Stephanie; Hansen, Mark; Lerer, F. Bernard; Liang, Kung-Yee; Maier, Wolfgang; Mallet, Jacques; Nertney, Deborah A.; Nestadt, Gerald; Norton, Nadine; Papadimitriou, George N.; Ribble, Robert; Sanders, Alan R.; Silverman, Jeremy M.; Walsh, Dermot; Williams, Nigel M.; Wormley, Brandon; Arranz, Maria J.; Bakker, Steven; Bender, Stephan; Bramon, Elvira; Collier, David; Crespo-Facorro, Benedicto; Hall, Jeremy; Iyegbe, Conrad; Jablensky, Assen; Kahn, Rene S.; Kalaydjieva, Luba; Lawrie, Stephen; Lewis, Cathryn M.; Linszen, Don H.; Mata, Ignacio; McIntosh, Andrew; Murray, Robin M.; Ophoff, Roel A.; van Os, Jim; Walshe, Muriel; Weisbrod, Matthias; Wiersma, Durk; Donnelly, Peter; Barroso, Ines; Blackwell, Jenefer M.; Brown, Matthew A.; Casas, Juan P.; Corvin, Aiden P.; Deloukas, Panos; Duncanson, Audrey; Jankowski, Janusz; Markus, Hugh S.; Mathew, Christopher G.; Palmer, Colin N. A.; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J.; Trembath, Richard C.; Viswanathan, Ananth C.; Wood, Nicholas W.; Spencer, Chris C. A.; Band, Gavin; Bellenguez, Céline; Freeman, Colin; Hellenthal, Garrett; Giannoulatou, Eleni; Pirinen, Matti; Pearson, Richard D.; Strange, Amy; Su, Zhan; Vukcevic, Damjan; Langford, Cordelia; Hunt, Sarah E.; Edkins, Sarah; Gwilliam, Rhian; Blackburn, Hannah; Bumpstead, Suzannah J.; Dronov, Serge; Gillman, Matthew; Gray, Emma; Hammond, Naomi; Jayakumar, Alagurevathi; McCann, Owen T.; Liddle, Jennifer; Potter, Simon C.; Ravindrarajah, Radhi; Ricketts, Michelle; Tashakkori-Ghanbaria, Avazeh; Waller, Matthew J.; Weston, Paul; Widaa, Sara; Whittaker, Pamela; McCarthy, Mark I.; Stefansson, Kari; Scolnick, Edward; Purcell, Shaun; McCarroll, Steven A.; Sklar, Pamela; Hultman, Christina M.; Sullivan, Patrick F.

    2013-01-01

    Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with

  15. Stepwise Distributed Open Innovation Contests for Software Development: Acceleration of Genome-Wide Association Analysis.

    Science.gov (United States)

    Hill, Andrew; Loh, Po-Ru; Bharadwaj, Ragu B; Pons, Pascal; Shang, Jingbo; Guinan, Eva; Lakhani, Karim; Kilty, Iain; Jelinsky, Scott A

    2017-05-01

    The association of differing genotypes with disease-related phenotypic traits offers great potential to both help identify new therapeutic targets and support stratification of patients who would gain the greatest benefit from specific drug classes. Development of low-cost genotyping and sequencing has made collecting large-scale genotyping data routine in population and therapeutic intervention studies. In addition, a range of new technologies is being used to capture numerous new and complex phenotypic descriptors. As a result, genotype and phenotype datasets have grown exponentially. Genome-wide association studies associate genotypes and phenotypes using methods such as logistic regression. As existing tools for association analysis limit the efficiency by which value can be extracted from increasing volumes of data, there is a pressing need for new software tools that can accelerate association analyses on large genotype-phenotype datasets. Using open innovation (OI) and contest-based crowdsourcing, the logistic regression analysis in a leading, community-standard genetics software package (PLINK 1.07) was substantially accelerated. OI allowed us to do this in innovation, we achieved an end-to-end speedup of 591-fold for a data set size of 6678 subjects by 645 863 variants, compared to PLINK 1.07's logistic regression. This represents a reduction in run time from 4.8 hours to 29 seconds. Accelerated logistic regression code developed in this project has been incorporated into the PLINK2 project. Using iterative competition-based OI, we have developed a new, faster implementation of logistic regression for genome-wide association studies analysis. We present lessons learned and recommendations on running a successful OI process for bioinformatics. © The Author 2017. Published by Oxford University Press.

  16. Pooled genome wide association detects association upstream of FCRL3 with Graves' disease.

    Science.gov (United States)

    Khong, Jwu Jin; Burdon, Kathryn P; Lu, Yi; Laurie, Kate; Leonardos, Lefta; Baird, Paul N; Sahebjada, Srujana; Walsh, John P; Gajdatsy, Adam; Ebeling, Peter R; Hamblin, Peter Shane; Wong, Rosemary; Forehan, Simon P; Fourlanos, Spiros; Roberts, Anthony P; Doogue, Matthew; Selva, Dinesh; Montgomery, Grant W; Macgregor, Stuart; Craig, Jamie E

    2016-11-18

    Graves' disease is an autoimmune thyroid disease of complex inheritance. Multiple genetic susceptibility loci are thought to be involved in Graves' disease and it is therefore likely that these can be identified by genome wide association studies. This study aimed to determine if a genome wide association study, using a pooling methodology, could detect genomic loci associated with Graves' disease. Nineteen of the top ranking single nucleotide polymorphisms including HLA-DQA1 and C6orf10, were clustered within the Major Histo-compatibility Complex region on chromosome 6p21, with rs1613056 reaching genome wide significance (p = 5 × 10 -8 ). Technical validation of top ranking non-Major Histo-compatablity complex single nucleotide polymorphisms with individual genotyping in the discovery cohort revealed four single nucleotide polymorphisms with p ≤ 10 -4 . Rs17676303 on chromosome 1q23.1, located upstream of FCRL3, showed evidence of association with Graves' disease across the discovery, replication and combined cohorts. A second single nucleotide polymorphism rs9644119 downstream of DPYSL2 showed some evidence of association supported by finding in the replication cohort that warrants further study. Pooled genome wide association study identified a genetic variant upstream of FCRL3 as a susceptibility locus for Graves' disease in addition to those identified in the Major Histo-compatibility Complex. A second locus downstream of DPYSL2 is potentially a novel genetic variant in Graves' disease that requires further confirmation.

  17. The humankind genome: from genetic diversity to the origin of human diseases.

    Science.gov (United States)

    Belizário, Jose E

    2013-12-01

    Genome-wide association studies have failed to establish common variant risk for the majority of common human diseases. The underlying reasons for this failure are explained by recent studies of resequencing and comparison of over 1200 human genomes and 10 000 exomes, together with the delineation of DNA methylation patterns (epigenome) and full characterization of coding and noncoding RNAs (transcriptome) being transcribed. These studies have provided the most comprehensive catalogues of functional elements and genetic variants that are now available for global integrative analysis and experimental validation in prospective cohort studies. With these datasets, researchers will have unparalleled opportunities for the alignment, mining, and testing of hypotheses for the roles of specific genetic variants, including copy number variations, single nucleotide polymorphisms, and indels as the cause of specific phenotypes and diseases. Through the use of next-generation sequencing technologies for genotyping and standardized ontological annotation to systematically analyze the effects of genomic variation on humans and model organism phenotypes, we will be able to find candidate genes and new clues for disease's etiology and treatment. This article describes essential concepts in genetics and genomic technologies as well as the emerging computational framework to comprehensively search websites and platforms available for the analysis and interpretation of genomic data.

  18. Genome-wide associations of gene expression variation in humans.

    Directory of Open Access Journals (Sweden)

    Barbara E Stranger

    2005-12-01

    Full Text Available The exploration of quantitative variation in human populations has become one of the major priorities for medical genetics. The successful identification of variants that contribute to complex traits is highly dependent on reliable assays and genetic maps. We have performed a genome-wide quantitative trait analysis of 630 genes in 60 unrelated Utah residents with ancestry from Northern and Western Europe using the publicly available phase I data of the International HapMap project. The genes are located in regions of the human genome with elevated functional annotation and disease interest including the ENCODE regions spanning 1% of the genome, Chromosome 21 and Chromosome 20q12-13.2. We apply three different methods of multiple test correction, including Bonferroni, false discovery rate, and permutations. For the 374 expressed genes, we find many regions with statistically significant association of single nucleotide polymorphisms (SNPs with expression variation in lymphoblastoid cell lines after correcting for multiple tests. Based on our analyses, the signal proximal (cis- to the genes of interest is more abundant and more stable than distal and trans across statistical methodologies. Our results suggest that regulatory polymorphism is widespread in the human genome and show that the 5-kb (phase I HapMap has sufficient density to enable linkage disequilibrium mapping in humans. Such studies will significantly enhance our ability to annotate the non-coding part of the genome and interpret functional variation. In addition, we demonstrate that the HapMap cell lines themselves may serve as a useful resource for quantitative measurements at the cellular level.

  19. Genome-Wide Associations of Gene Expression Variation in Humans.

    Directory of Open Access Journals (Sweden)

    2005-12-01

    Full Text Available The exploration of quantitative variation in human populations has become one of the major priorities for medical genetics. The successful identification of variants that contribute to complex traits is highly dependent on reliable assays and genetic maps. We have performed a genome-wide quantitative trait analysis of 630 genes in 60 unrelated Utah residents with ancestry from Northern and Western Europe using the publicly available phase I data of the International HapMap project. The genes are located in regions of the human genome with elevated functional annotation and disease interest including the ENCODE regions spanning 1% of the genome, Chromosome 21 and Chromosome 20q12-13.2. We apply three different methods of multiple test correction, including Bonferroni, false discovery rate, and permutations. For the 374 expressed genes, we find many regions with statistically significant association of single nucleotide polymorphisms (SNPs with expression variation in lymphoblastoid cell lines after correcting for multiple tests. Based on our analyses, the signal proximal (cis- to the genes of interest is more abundant and more stable than distal and trans across statistical methodologies. Our results suggest that regulatory polymorphism is widespread in the human genome and show that the 5-kb (phase I HapMap has sufficient density to enable linkage disequilibrium mapping in humans. Such studies will significantly enhance our ability to annotate the non-coding part of the genome and interpret functional variation. In addition, we demonstrate that the HapMap cell lines themselves may serve as a useful resource for quantitative measurements at the cellular level.

  20. Evaluation of different sources of DNA for use in genome wide studies and forensic application.

    Science.gov (United States)

    Al Safar, Habiba S; Abidi, Fatima H; Khazanehdari, Kamal A; Dadour, Ian R; Tay, Guan K

    2011-02-01

    In the field of epidemiology, Genome-Wide Association Studies (GWAS) are commonly used to identify genetic predispositions of many human diseases. Large repositories housing biological specimens for clinical and genetic investigations have been established to store material and data for these studies. The logistics of specimen collection and sample storage can be onerous, and new strategies have to be explored. This study examines three different DNA sources (namely, degraded genomic DNA, amplified degraded genomic DNA and amplified extracted DNA from FTA card) for GWAS using the Illumina platform. No significant difference in call rate was detected between amplified degraded genomic DNA extracted from whole blood and amplified DNA retrieved from FTA™ cards. However, using unamplified-degraded genomic DNA reduced the call rate to a mean of 42.6% compared to amplified DNA extracted from FTA card (mean of 96.6%). This study establishes the utility of FTA™ cards as a viable storage matrix for cells from which DNA can be extracted to perform GWAS analysis.

  1. Balanced into array : genome-wide array analysis in 54 patients with an apparently balanced de novo chromosome rearrangement and a meta-analysis

    NARCIS (Netherlands)

    Feenstra, Ilse; Hanemaaijer, Nicolien; Sikkema-Raddatz, Birgit; Yntema, Helger; Dijkhuizen, Trijnie; Lugtenberg, Dorien; Verheij, Joke; Green, Andrew; Hordijk, Roel; Reardon, William; de Vries, Bert; Brunner, Han; Bongers, Ernie; de Leeuw, Nicole; van Ravenswaaij-Arts, Conny

    2011-01-01

    High-resolution genome-wide array analysis enables detailed screening for cryptic and submicroscopic imbalances of microscopically balanced de novo rearrangements in patients with developmental delay and/or congenital abnormalities. In this report, we added the results of genome-wide array analysis

  2. Use of modern tomato breeding germplasm for deciphering the genetic control of agronomical traits by Genome Wide Association study.

    Science.gov (United States)

    Bauchet, Guillaume; Grenier, Stéphane; Samson, Nicolas; Bonnet, Julien; Grivet, Laurent; Causse, Mathilde

    2017-05-01

    A panel of 300 tomato accessions including breeding materials was built and characterized with >11,000 SNP. A population structure in six subgroups was identified. Strong heterogeneity in linkage disequilibrium and recombination landscape among groups and chromosomes was shown. GWAS identified several associations for fruit weight, earliness and plant growth. Genome-wide association studies (GWAS) have become a method of choice in quantitative trait dissection. First limited to highly polymorphic and outcrossing species, it is now applied in horticultural crops, notably in tomato. Until now GWAS in tomato has been performed on panels of heirloom and wild accessions. Using modern breeding materials would be of direct interest for breeding purpose. To implement GWAS on a large panel of 300 tomato accessions including 168 breeding lines, this study assessed the genetic diversity and linkage disequilibrium decay and revealed the population structure and performed GWA experiment. Genetic diversity and population structure analyses were based on molecular markers (>11,000 SNP) covering the whole genome. Six genetic subgroups were revealed and associated to traits of agronomical interest, such as fruit weight and disease resistance. Estimates of linkage disequilibrium highlighted the heterogeneity of its decay among genetic subgroups. Haplotype definition allowed a fine characterization of the groups and their recombination landscape revealing the patterns of admixture along the genome. Selection footprints showed results in congruence with introgressions. Taken together, all these elements refined our knowledge of the genetic material included in this panel and allowed the identification of several associations for fruit weight, plant growth and earliness, deciphering the genetic architecture of these complex traits and identifying several new loci useful for tomato breeding.

  3. Genome-wide identification, functional and evolutionary analysis of terpene synthases in pineapple.

    Science.gov (United States)

    Chen, Xiaoe; Yang, Wei; Zhang, Liqin; Wu, Xianmiao; Cheng, Tian; Li, Guanglin

    2017-10-01

    Terpene synthases (TPSs) are vital for the biosynthesis of active terpenoids, which have important physiological, ecological and medicinal value. Although terpenoids have been reported in pineapple (Ananas comosus), genome-wide investigations of the TPS genes responsible for pineapple terpenoid synthesis are still lacking. By integrating pineapple genome and proteome data, twenty-one putative terpene synthase genes were found in pineapple and divided into five subfamilies. Tandem duplication is the cause of TPS gene family duplication. Furthermore, functional differentiation between each TPS subfamily may have occurred for several reasons. Sixty-two key amino acid sites were identified as being type-II functionally divergence between TPS-a and TPS-c subfamily. Finally, coevolution analysis indicated that multiple amino acid residues are involved in coevolutionary processes. In addition, the enzyme activity of two TPSs were tested. This genome-wide identification, functional and evolutionary analysis of pineapple TPS genes provide a new insight into understanding the roles of TPS family and lay the basis for further characterizing the function and evolution of TPS gene family. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption

    NARCIS (Netherlands)

    Cornelis, M. C.; Byrne, E. M.; Esko, T.; Nalls, M. A.; Ganna, A.; Paynter, N.; Monda, K. L.; Amin, N.; Fischer, K.; Renstrom, F.; Ngwa, J. S.; Huikari, V.; Cavadino, A.; Nolte, I. M.; Teumer, A.; Yu, K.; Marques-Vidal, P.; Rawal, R.; Manichaikul, A.; Wojczynski, M. K.; Vink, J. M.; Zhao, J. H.; Burlutsky, G.; Lahti, J.; Mikkila, V.; Lemaitre, R. N.; Eriksson, J.; Musani, S. K.; Tanaka, T.; Geller, F.; Luan, J.; Hui, J.; Maegi, R.; Dimitriou, M.; Garcia, M. E.; Ho, W-K; Wright, M. J.; Rose, L. M.; Magnusson, P. K. E.; Pedersen, N. L.; Couper, D.; Oostra, B. A.; Hofman, A.; Ikram, M. A.; Tiemeier, H. W.; Uitterlinden, A. G.; van Rooij, F. J. A.; Barroso, I.; Johansson, I.; Xue, L.; Kaakinen, M.; Milani, L.; Power, C.; Snieder, H.; Stolk, R. P.; Baumeister, S. E.; Biffar, R.; Gu, F.; Bastardot, F.; Kutalik, Z.; Jacobs, D. R.; Forouhi, N. G.; Mihailov, E.; Lind, L.; Lindgren, C.; Michaelsson, K.; Morris, A.; Jensen, M.; Khaw, K-T; Luben, R. N.; Wang, J. J.; Mannisto, S.; Perala, M-M; Kahonen, M.; Lehtimaki, T.; Viikari, J.; Mozaffarian, D.; Mukamal, K.; Psaty, B. M.; Doering, A.; Heath, A. C.; Montgomery, G. W.; Dahmen, N.; Carithers, T.; Tucker, K. L.; Ferrucci, L.; Boyd, H. A.; Melbye, M.; Treur, J. L.; Mellstrom, D.; Hottenga, J. J.; Prokopenko, I.; Toenjes, A.; Deloukas, P.; Kanoni, S.; Lorentzon, M.; Houston, D. K.; Liu, Y.; Danesh, J.; Rasheed, A.; Mason, M. A.; Zonderman, A. B.; Franke, L.; Kristal, B. S.; Karjalainen, J.; Reed, D. R.; Westra, H-J; Evans, M. K.; Saleheen, D.; Harris, T. B.; Dedoussis, G.; Curhan, G.; Stumvoll, M.; Beilby, J.; Pasquale, L. R.; Feenstra, B.; Bandinelli, S.; Ordovas, J. M.; Chan, A. T.; Peters, U.; Ohlsson, C.; Gieger, C.; Martin, N. G.; Waldenberger, M.; Siscovick, D. S.; Raitakari, O.; Eriksson, J. G.; Mitchell, P.; Hunter, D. J.; Kraft, P.; Rimm, E. B.; Boomsma, D. I.; Borecki, I. B.; Loos, R. J. F.; Wareham, N. J.; Vollenweider, P.; Caporaso, N.; Grabe, H. J.; Neuhouser, M. L.; Wolffenbuttel, B. H. R.; Hu, F. B.; Hyppoenen, E.; Jarvelin, M-R; Cupples, L. A.; Franks, P. W.; Ridker, P. M.; van Duijn, C. M.; Heiss, G.; Metspalu, A.; North, K. E.; Ingelsson, E.; Nettleton, J. A.; van Dam, R. M.; Chasman, D. I.

    Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to

  5. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption

    NARCIS (Netherlands)

    Cornelis, M. C.; Byrne, E. M.; Esko, T.; Nalls, M. A.; Ganna, A.; Paynter, N.; Monda, K. L.; Amin, N.; Fischer, K.; Renstrom, F.; Ngwa, J. S.; Huikari, V.; Cavadino, A.; Nolte, I. M.; Teumer, A.; Yu, K.; Marques-Vidal, P.; Rawal, R.; Manichaikul, A.; Wojczynski, M. K.; Vink, J. M.; Zhao, J. H.; Burlutsky, G.; Lahti, J.; Mikkilä, V.; Lemaitre, R. N.; Eriksson, J.; Musani, S. K.; Tanaka, T.; Geller, F.; Luan, J.; Hui, J.; Mägi, R.; Dimitriou, M.; Garcia, M. E.; Ho, W.-K.; Wright, M. J.; Rose, L. M.; Magnusson, P. K. E.; Pedersen, N. L.; Couper, D.; Oostra, B. A.; Hofman, A.; Ikram, M. A.; Tiemeier, H. W.; Uitterlinden, A. G.; van Rooij, F. J. A.; Barroso, I.; Johansson, I.; Xue, L.; Kaakinen, M.; Milani, L.; Power, C.; Snieder, H.; Stolk, R. P.; Baumeister, S. E.; Biffar, R.; Gu, F.; Bastardot, F.; Kutalik, Z.; Jacobs, D. R.; Forouhi, N. G.; Mihailov, E.; Lind, L.; Lindgren, C.; Michaëlsson, K.; Morris, A.; Jensen, M.; Khaw, K.-T.; Luben, R. N.; Wang, J. J.; Männistö, S.; Perälä, M.-M.; Kähönen, M.; Lehtimäki, T.; Viikari, J.; Mozaffarian, D.; Mukamal, K.; Psaty, B. M.; Döring, A.; Heath, A. C.; Montgomery, G. W.; Dahmen, N.; Carithers, T.; Tucker, K. L.; Ferrucci, L.; Boyd, H. A.; Melbye, M.; Treur, J. L.; Mellström, D.; Hottenga, J. J.; Prokopenko, I.; Tönjes, A.; Deloukas, P.; Kanoni, S.; Lorentzon, M.; Houston, D. K.; Liu, Y.; Danesh, J.; Rasheed, A.; Mason, M. A.; Zonderman, A. B.; Franke, L.; Kristal, B. S.; Karjalainen, J.; Reed, D. R.; Westra, H.-J.; Evans, M. K.; Saleheen, D.; Harris, T. B.; Dedoussis, G.; Curhan, G.; Stumvoll, M.; Beilby, J.; Pasquale, L. R.; Feenstra, B.; Bandinelli, S.; Ordovas, J. M.; Chan, A. T.; Peters, U.; Ohlsson, C.; Gieger, C.; Martin, N. G.; Waldenberger, M.; Siscovick, D. S.; Raitakari, O.; Eriksson, J. G.; Mitchell, P.; Hunter, D. J.; Kraft, P.; Rimm, E. B.; Boomsma, D. I.; Borecki, I. B.; Loos, R. J. F.; Wareham, N. J.; Vollenweider, P.; Caporaso, N.; Grabe, H. J.; Neuhouser, M. L.; Wolffenbuttel, B. H. R.; Hu, F. B.; Hyppönen, E.; Järvelin, M.-R.; Cupples, L. A.; Franks, P. W.; Ridker, P. M.; van Duijn, C. M.; Heiss, G.; Metspalu, A.; North, K. E.; Ingelsson, E.; Nettleton, J. A.; van Dam, R. M.; Chasman, D. I.; Nalls, Michael A.; Plagnol, Vincent; Hernandez, Dena G.; Sharma, Manu; Sheerin, Una-Marie; Saad, Mohamad; Simón-Sánchez, Javier; Schulte, Claudia; Lesage, Suzanne; Sveinbjörnsdóttir, Sigurlaug; Arepalli, Sampath; Barker, Roger; Ben-Shlomo, Yoav; Berendse, Henk W.; Berg, Daniela; Bhatia, Kailash; de Bie, Rob M. A.; Biffi, Alessandro; Bloem, Bas; Bochdanovits, Zoltan; Bonin, Michael; Bras, M.; Brockmann, Kathrin; Brooks, Janet; Burn, David J.; Charlesworth, Gavin; Chen, Honglei; Chinnery, Patrick F.; Chong, Sean; Clarke, Carl E.; Cookson, Mark R.; Cooper, J. Mark; Corvol, Jean Christophe; Counsell, Carl; Damier, Philippe; Dartigues, Jean-François; Deloukas, Panos; Deuschl, Günther; Dexter, David T.; van Dijk, Karin D.; Dillman, Allissa; Durif, Frank; Dürr, Alexandra; Edkins, Sarah; Evans, Jonathan R.; Foltynie, Thomas; Dong, Jing; Gardner, Michelle; Gibbs, J. Raphael; Goate, Alison; Gray, Emma; Guerreiro, Rita; Harris, Clare; van Hilten, Jacobus J.; Hofman, Albert; Hollenbeck, Albert; Holton, Janice; Hu, Michele; Huang, Xuemei; Hershey, Milton S.; Wurster, Isabel; Mätzler, Walter; Hudson, Gavin; Hunt, Sarah E.; Huttenlocher, Johanna; Illig, Thomas; München, Helmholtz Zentrum; Jónsson, Pálmi V.; Lambert, Jean-Charles; Langford, Cordelia; Lees, Andrew; Lichtner, Peter; Limousin, Patricia; Lopez, Grisel; Lorenz, Delia; McNeill, Alisdair; Moorby, Catriona; Moore, Matthew; Morris, Huw R.; Morrison, Karen E.; O' Sullivan, Sean S.; Pearson, Justin; Perlmutter, Joel S.; Pétursson, Hjörvar; Pollak, Pierre; Potter, Simon; Ravina, Bernard; Revesz, Tamas; Riess, Olaf; Rivadeneira, Fernando; Rizzu, Patrizia; Ryten, Mina; Sawcer, Stephen; Schapira, Anthony; Scheffer, Hans; Shaw, Karen; Sidransky, Ellen; Smith, Colin; Spencer, Chris C. A.; Stefánsson, Hreinn; Bettella, Francesco; Stockton, Joanna D.; Strange, Amy; Talbot, Kevin; Tanner, M.; Tashakkori-Ghanbaria, Avazeh; Tison, François; Trabzuni, Daniah; Traynor, Bryan J.; Uitterlinden, André G.; Velseboer, Daan; Vidailhet, Marie; Walker, Robert; van de Warrenburg, Bart; Wickremaratchi, Mirdhu; Williams, Nigel; Williams-Gray, Caroline H.; Winder-Rhodes, Sophie; Stefánsson, Kári; Martinez, Maria; Sabatier, Paul; Wood, Nicholas W.; Hardy, John; Heutink, Peter; Brice, Alexis; Gasser, Thomas; Singleton, Andrew B.; Singleton, Andrew; Cookson, Mark; Hernandez, Dena; Nalls, Michael; Zonderman, Alan; Ferrucci, Luigi; Johnson, Robert; Longo, Dan; O'Brien, Richard; Traynor, Bryan; Troncoso, Juan; van der Brug, Marcel; Zielke, Ronald; Weale, Michael; Ramasamy, Adaikalavan; Box, P. O.

    2015-01-01

    Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to

  6. Trends in genome-wide and region-specific genetic diversity in the Dutch-Flemish Holstein-Friesian breeding program from 1986 to 2015.

    Science.gov (United States)

    Doekes, Harmen P; Veerkamp, Roel F; Bijma, Piter; Hiemstra, Sipke J; Windig, Jack J

    2018-04-11

    In recent decades, Holstein-Friesian (HF) selection schemes have undergone profound changes, including the introduction of optimal contribution selection (OCS; around 2000), a major shift in breeding goal composition (around 2000) and the implementation of genomic selection (GS; around 2010). These changes are expected to have influenced genetic diversity trends. Our aim was to evaluate genome-wide and region-specific diversity in HF artificial insemination (AI) bulls in the Dutch-Flemish breeding program from 1986 to 2015. Pedigree and genotype data (~ 75.5 k) of 6280 AI-bulls were used to estimate rates of genome-wide inbreeding and kinship and corresponding effective population sizes. Region-specific inbreeding trends were evaluated using regions of homozygosity (ROH). Changes in observed allele frequencies were compared to those expected under pure drift to identify putative regions under selection. We also investigated the direction of changes in allele frequency over time. Effective population size estimates for the 1986-2015 period ranged from 69 to 102. Two major breakpoints were observed in genome-wide inbreeding and kinship trends. Around 2000, inbreeding and kinship levels temporarily dropped. From 2010 onwards, they steeply increased, with pedigree-based, ROH-based and marker-based inbreeding rates as high as 1.8, 2.1 and 2.8% per generation, respectively. Accumulation of inbreeding varied substantially across the genome. A considerable fraction of markers showed changes in allele frequency that were greater than expected under pure drift. Putative selected regions harboured many quantitative trait loci (QTL) associated to a wide range of traits. In consecutive 5-year periods, allele frequencies changed more often in the same direction than in opposite directions, except when comparing the 1996-2000 and 2001-2005 periods. Genome-wide and region-specific diversity trends reflect major changes in the Dutch-Flemish HF breeding program. Introduction of

  7. Genome-wide analysis of poly(A) site selection in Schizosaccharomyces pombe

    KAUST Repository

    Schlackow, M.

    2013-10-23

    Polyadenylation of pre-mRNAs, a critical step in eukaryotic gene expression, is mediated by cis elements collectively called the polyadenylation signal. Genome-wide analysis of such polyadenylation signals was missing in fission yeast, even though it is an important model organism. We demonstrate that the canonical AATAAA motif is the most frequent and functional polyadenylation signal in Schizosaccharomyces pombe. Using analysis of RNA-Seq data sets from cells grown under various physiological conditions, we identify 3\\' UTRs for nearly 90% of the yeast genes. Heterogeneity of cleavage sites is common, as is alternative polyadenylation within and between conditions. We validated the computationally identified sequence elements likely to promote polyadenylation by functional assays, including qRT-PCR and 3\\'RACE analysis. The biological importance of the AATAAA motif is underlined by functional analysis of the genes containing it. Furthermore, it has been shown that convergent genes require trans elements, like cohesin for efficient transcription termination. Here we show that convergent genes lacking cohesin (on chromosome 2) are generally associated with longer overlapping mRNA transcripts. Our bioinformatic and experimental genome-wide results are summarized and can be accessed and customized in a user-friendly database Pomb(A).

  8. Genome-wide analysis of poly(A) site selection in Schizosaccharomyces pombe

    KAUST Repository

    Schlackow, M.; Marguerat, S.; Proudfoot, N. J.; Bahler, J.; Erban, R.; Gullerova, M.

    2013-01-01

    Polyadenylation of pre-mRNAs, a critical step in eukaryotic gene expression, is mediated by cis elements collectively called the polyadenylation signal. Genome-wide analysis of such polyadenylation signals was missing in fission yeast, even though it is an important model organism. We demonstrate that the canonical AATAAA motif is the most frequent and functional polyadenylation signal in Schizosaccharomyces pombe. Using analysis of RNA-Seq data sets from cells grown under various physiological conditions, we identify 3' UTRs for nearly 90% of the yeast genes. Heterogeneity of cleavage sites is common, as is alternative polyadenylation within and between conditions. We validated the computationally identified sequence elements likely to promote polyadenylation by functional assays, including qRT-PCR and 3'RACE analysis. The biological importance of the AATAAA motif is underlined by functional analysis of the genes containing it. Furthermore, it has been shown that convergent genes require trans elements, like cohesin for efficient transcription termination. Here we show that convergent genes lacking cohesin (on chromosome 2) are generally associated with longer overlapping mRNA transcripts. Our bioinformatic and experimental genome-wide results are summarized and can be accessed and customized in a user-friendly database Pomb(A).

  9. Genome-wide analysis of E. coli cell-gene interactions.

    Science.gov (United States)

    Cardinale, S; Cambray, G

    2017-11-23

    The pursuit of standardization and reliability in synthetic biology has achieved, in recent years, a number of advances in the design of more predictable genetic parts for biological circuits. However, even with the development of high-throughput screening methods and whole-cell models, it is still not possible to predict reliably how a synthetic genetic construct interacts with all cellular endogenous systems. This study presents a genome-wide analysis of how the expression of synthetic genes is affected by systematic perturbations of cellular functions. We found that most perturbations modulate expression indirectly through an effect on cell size, putting forward the existence of a generic Size-Expression interaction in the model prokaryote Escherichia coli. The Size-Expression interaction was quantified by inserting a dual fluorescent reporter gene construct into each of the 3822 single-gene deletion strains comprised in the KEIO collection. Cellular size was measured for single cells via flow cytometry. Regression analyses were used to discriminate between expression-specific and gene-specific effects. Functions of the deleted genes broadly mapped onto three systems with distinct primary influence on the Size-Expression map. Perturbations in the Division and Biosynthesis (DB) system led to a large-cell and high-expression phenotype. In contrast, disruptions of the Membrane and Motility (MM) system caused small-cell and low-expression phenotypes. The Energy, Protein synthesis and Ribosome (EPR) system was predominantly associated with smaller cells and positive feedback on ribosome function. Feedback between cell growth and gene expression is widespread across cell systems. Even though most gene disruptions proximally affect one component of the Size-Expression interaction, the effect therefore ultimately propagates to both. More specifically, we describe the dual impact of growth on cell size and gene expression through cell division and ribosomal content

  10. Genome-Wide Interaction Analysis of Air Pollution Exposure and Childhood Asthma with Functional Follow-up.

    Science.gov (United States)

    Gref, Anna; Merid, Simon K; Gruzieva, Olena; Ballereau, Stéphane; Becker, Allan; Bellander, Tom; Bergström, Anna; Bossé, Yohan; Bottai, Matteo; Chan-Yeung, Moira; Fuertes, Elaine; Ierodiakonou, Despo; Jiang, Ruiwei; Joly, Stéphane; Jones, Meaghan; Kobor, Michael S; Korek, Michal; Kozyrskyj, Anita L; Kumar, Ashish; Lemonnier, Nathanaël; MacIntyre, Elaina; Ménard, Camille; Nickle, David; Obeidat, Ma'en; Pellet, Johann; Standl, Marie; Sääf, Annika; Söderhäll, Cilla; Tiesler, Carla M T; van den Berge, Maarten; Vonk, Judith M; Vora, Hita; Xu, Cheng-Jian; Antó, Josep M; Auffray, Charles; Brauer, Michael; Bousquet, Jean; Brunekreef, Bert; Gauderman, W James; Heinrich, Joachim; Kere, Juha; Koppelman, Gerard H; Postma, Dirkje; Carlsten, Christopher; Pershagen, Göran; Melén, Erik

    2017-05-15

    The evidence supporting an association between traffic-related air pollution exposure and incident childhood asthma is inconsistent and may depend on genetic factors. To identify gene-environment interaction effects on childhood asthma using genome-wide single-nucleotide polymorphism (SNP) data and air pollution exposure. Identified loci were further analyzed at epigenetic and transcriptomic levels. We used land use regression models to estimate individual air pollution exposure (represented by outdoor NO 2 levels) at the birth address and performed a genome-wide interaction study for doctors' diagnoses of asthma up to 8 years in three European birth cohorts (n = 1,534) with look-up for interaction in two separate North American cohorts, CHS (Children's Health Study) and CAPPS/SAGE (Canadian Asthma Primary Prevention Study/Study of Asthma, Genetics and Environment) (n = 1,602 and 186 subjects, respectively). We assessed expression quantitative trait locus effects in human lung specimens and blood, as well as associations among air pollution exposure, methylation, and transcriptomic patterns. In the European cohorts, 186 SNPs had an interaction P asthma development and provided supportive evidence for interaction with air pollution for ADCY2, B4GALT5, and DLG2.

  11. Multivariate Methods for Meta-Analysis of Genetic Association Studies.

    Science.gov (United States)

    Dimou, Niki L; Pantavou, Katerina G; Braliou, Georgia G; Bagos, Pantelis G

    2018-01-01

    Multivariate meta-analysis of genetic association studies and genome-wide association studies has received a remarkable attention as it improves the precision of the analysis. Here, we review, summarize and present in a unified framework methods for multivariate meta-analysis of genetic association studies and genome-wide association studies. Starting with the statistical methods used for robust analysis and genetic model selection, we present in brief univariate methods for meta-analysis and we then scrutinize multivariate methodologies. Multivariate models of meta-analysis for a single gene-disease association studies, including models for haplotype association studies, multiple linked polymorphisms and multiple outcomes are discussed. The popular Mendelian randomization approach and special cases of meta-analysis addressing issues such as the assumption of the mode of inheritance, deviation from Hardy-Weinberg Equilibrium and gene-environment interactions are also presented. All available methods are enriched with practical applications and methodologies that could be developed in the future are discussed. Links for all available software implementing multivariate meta-analysis methods are also provided.

  12. Genome-wide association study of serum selenium concentrations

    DEFF Research Database (Denmark)

    Gong, Jian; Hsu, Li; Harrison, Tabitha

    2013-01-01

    Selenium is an essential trace element and circulating selenium concentrations have been associated with a wide range of diseases. Candidate gene studies suggest that circulating selenium concentrations may be impacted by genetic variation; however, no study has comprehensively investigated...... this hypothesis. Therefore, we conducted a two-stage genome-wide association study to identify genetic variants associated with serum selenium concentrations in 1203 European descents from two cohorts: the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening and the Women’s Health Initiative (WHI). We...... tested association between 2,474,333 single nucleotide polymorphisms (SNPs) and serum selenium concentrations using linear regression models. In the first stage (PLCO) 41 SNPs clustered in 15 regions had p

  13. Genetic susceptibility markers for a breast-colorectal cancer phenotype: Exploratory results from genome-wide association studies

    Science.gov (United States)

    Joon, Aron; Brewster, Abenaa M.; Chen, Wei V.; Eng, Cathy; Shete, Sanjay; Casey, Graham; Schumacher, Fredrick; Lin, Yi; Harrison, Tabitha A.; White, Emily; Ahsan, Habibul; Andrulis, Irene L.; Whittemore, Alice S.; Ko Win, Aung; Schmidt, Daniel F.; Kapuscinski, Miroslaw K.; Ochs-Balcom, Heather M.; Gallinger, Steven; Jenkins, Mark A.; Newcomb, Polly A.; Lindor, Noralane M.; Peters, Ulrike; Amos, Christopher I.; Lynch, Patrick M.

    2018-01-01

    Background Clustering of breast and colorectal cancer has been observed within some families and cannot be explained by chance or known high-risk mutations in major susceptibility genes. Potential shared genetic susceptibility between breast and colorectal cancer, not explained by high-penetrance genes, has been postulated. We hypothesized that yet undiscovered genetic variants predispose to a breast-colorectal cancer phenotype. Methods To identify variants associated with a breast-colorectal cancer phenotype, we analyzed genome-wide association study (GWAS) data from cases and controls that met the following criteria: cases (n = 985) were women with breast cancer who had one or more first- or second-degree relatives with colorectal cancer, men/women with colorectal cancer who had one or more first- or second-degree relatives with breast cancer, and women diagnosed with both breast and colorectal cancer. Controls (n = 1769), were unrelated, breast and colorectal cancer-free, and age- and sex- frequency-matched to cases. After imputation, 6,220,060 variants were analyzed using the discovery set and variants associated with the breast-colorectal cancer phenotype at Pcolorectal cancer phenotype in the discovery and replication data (most significant; rs7430339, Pdiscovery = 1.2E-04; rs7429100, Preplication = 2.8E-03). In meta-analysis of the discovery and replication data, the most significant association remained at rs7429100 (P = 1.84E-06). Conclusion The results of this exploratory analysis did not find clear evidence for a susceptibility locus with a pleiotropic effect on hereditary breast and colorectal cancer risk, although the suggestive association of genetic variation in the region of ROBO1, a potential tumor suppressor gene, merits further investigation. PMID:29698419

  14. Hematopoietic transcriptional mechanisms: from locus-specific to genome-wide vantage points.

    Science.gov (United States)

    DeVilbiss, Andrew W; Sanalkumar, Rajendran; Johnson, Kirby D; Keles, Sunduz; Bresnick, Emery H

    2014-08-01

    Hematopoiesis is an exquisitely regulated process in which stem cells in the developing embryo and the adult generate progenitor cells that give rise to all blood lineages. Master regulatory transcription factors control hematopoiesis by integrating signals from the microenvironment and dynamically establishing and maintaining genetic networks. One of the most rudimentary aspects of cell type-specific transcription factor function, how they occupy a highly restricted cohort of cis-elements in chromatin, remains poorly understood. Transformative technologic advances involving the coupling of next-generation DNA sequencing technology with the chromatin immunoprecipitation assay (ChIP-seq) have enabled genome-wide mapping of factor occupancy patterns. However, formidable problems remain; notably, ChIP-seq analysis yields hundreds to thousands of chromatin sites occupied by a given transcription factor, and only a fraction of the sites appear to be endowed with critical, non-redundant function. It has become en vogue to map transcription factor occupancy patterns genome-wide, while using powerful statistical tools to establish correlations to inform biology and mechanisms. With the advent of revolutionary genome editing technologies, one can now reach beyond correlations to conduct definitive hypothesis testing. This review focuses on key discoveries that have emerged during the path from single loci to genome-wide analyses, specifically in the context of hematopoietic transcriptional mechanisms. Copyright © 2014 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  15. Integrating Nonadditive Genomic Relationship Matrices into the Study of Genetic Architecture of Complex Traits.

    Science.gov (United States)

    Nazarian, Alireza; Gezan, Salvador A

    2016-03-01

    The study of genetic architecture of complex traits has been dramatically influenced by implementing genome-wide analytical approaches during recent years. Of particular interest are genomic prediction strategies which make use of genomic information for predicting phenotypic responses instead of detecting trait-associated loci. In this work, we present the results of a simulation study to improve our understanding of the statistical properties of estimation of genetic variance components of complex traits, and of additive, dominance, and genetic effects through best linear unbiased prediction methodology. Simulated dense marker information was used to construct genomic additive and dominance matrices, and multiple alternative pedigree- and marker-based models were compared to determine if including a dominance term into the analysis may improve the genetic analysis of complex traits. Our results showed that a model containing a pedigree- or marker-based additive relationship matrix along with a pedigree-based dominance matrix provided the best partitioning of genetic variance into its components, especially when some degree of true dominance effects was expected to exist. Also, we noted that the use of a marker-based additive relationship matrix along with a pedigree-based dominance matrix had the best performance in terms of accuracy of correlations between true and estimated additive, dominance, and genetic effects. © The American Genetic Association 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  16. Genome-wide QTL and bulked transcriptomic analysis reveals new candidate genes for the control of tuber carotenoid content in potato (Solanum tuberosum L.).

    Science.gov (United States)

    Campbell, Raymond; Pont, Simon D A; Morris, Jenny A; McKenzie, Gaynor; Sharma, Sanjeev Kumar; Hedley, Pete E; Ramsay, Gavin; Bryan, Glenn J; Taylor, Mark A

    2014-09-01

    Genome-wide QTL analysis of potato tuber carotenoid content was investigated in populations of Solanum tuberosum Group Phureja that segregate for flesh colour, revealing a novel major QTL on chromosome 9. The carotenoid content of edible plant storage organs is a key nutritional and quality trait. Although the structural genes that encode the biosynthetic enzymes are well characterised, much less is known about the factors that determine overall storage organ content. In this study, genome-wide QTL mapping, in concert with an efficient 'genetical genomics' analysis using bulked samples, has been employed to investigate the genetic architecture of potato tuber carotenoid content. Two diploid populations of Solanum tuberosum Group Phureja were genotyped (AFLP, SSR and DArT markers) and analysed for their tuber carotenoid content over two growing seasons. Common to both populations were QTL that explained relatively small proportions of the variation in constituent carotenoids and a major QTL on chromosome 3 explaining up to 71 % of the variation in carotenoid content. In one of the populations (01H15), a second major carotenoid QTL was identified on chromosome 9, explaining up to 20 % of the phenotypic variation. Whereas the major chromosome 3 QTL was likely to be due to an allele of a gene encoding β-carotene hydroxylase, no known carotenoid biosynthetic genes are located in the vicinity of the chromosome 9 QTL. A unique expression profiling strategy using phenotypically distinct bulks comprised individuals with similar carotenoid content provided further support for the QTL mapping to chromosome 9. This study shows the potential of using the potato genome sequence to link genetic maps to data arising from eQTL approaches to enhance the discovery of candidate genes underlying QTLs.

  17. Genome-wide identification of genetic determinants for the cytotoxicity of perifosine

    Directory of Open Access Journals (Sweden)

    Zhang Wei

    2008-09-01

    Full Text Available Abstract Perifosine belongs to the class of alkylphospholipid analogues, which act primarily at the cell membrane, thereby targeting signal transduction pathways. In phase I/II clinical trials, perifosine has induced tumour regression and caused disease stabilisation in a variety of tumour types. The genetic determinants responsible for its cytotoxicity have not been comprehensively studied, however. We performed a genome-wide analysis to identify genes whose expression levels or genotypic variation were correlated with the cytotoxicity of perifosine, using public databases on the US National Cancer Institute (NCI-60 human cancer cell lines. For demonstrating drug specificity, the NCI Standard Agent Database (including 171 drugs acting through a variety of mechanisms was used as a control. We identified agents with similar cytotoxicity profiles to that of perifosine in compounds used in the NCI drug screen. Furthermore, Gene Ontology and pathway analyses were carried out on genes more likely to be perifosine specific. The results suggested that genes correlated with perifosine cytotoxicity are connected by certain known pathways that lead to the mitogen-activated protein kinase signalling pathway and apoptosis. Biological processes such as 'response to stress', 'inflammatory response' and 'ubiquitin cycle' were enriched among these genes. Three single nucleotide polymorphisms (SNPs located in CACNA2DI and EXOC4 were found to be correlated with perifosine cytotoxicity. Our results provided a manageable list of genes whose expression levels or genotypic variation were strongly correlated with the cytotoxcity of perifosine. These genes could be targets for further studies using candidate-gene approaches. The results also provided insights into the pharmacodynamics of perifosine.

  18. Genome-wide association between DNA methylation and alternative splicing in an invertebrate

    Directory of Open Access Journals (Sweden)

    Flores Kevin

    2012-09-01

    Full Text Available Abstract Background Gene bodies are the most evolutionarily conserved targets of DNA methylation in eukaryotes. However, the regulatory functions of gene body DNA methylation remain largely unknown. DNA methylation in insects appears to be primarily confined to exons. Two recent studies in Apis mellifera (honeybee and Nasonia vitripennis (jewel wasp analyzed transcription and DNA methylation data for one gene in each species to demonstrate that exon-specific DNA methylation may be associated with alternative splicing events. In this study we investigated the relationship between DNA methylation, alternative splicing, and cross-species gene conservation on a genome-wide scale using genome-wide transcription and DNA methylation data. Results We generated RNA deep sequencing data (RNA-seq to measure genome-wide mRNA expression at the exon- and gene-level. We produced a de novo transcriptome from this RNA-seq data and computationally predicted splice variants for the honeybee genome. We found that exons that are included in transcription are higher methylated than exons that are skipped during transcription. We detected enrichment for alternative splicing among methylated genes compared to unmethylated genes using fisher’s exact test. We performed a statistical analysis to reveal that the presence of DNA methylation or alternative splicing are both factors associated with a longer gene length and a greater number of exons in genes. In concordance with this observation, a conservation analysis using BLAST revealed that each of these factors is also associated with higher cross-species gene conservation. Conclusions This study constitutes the first genome-wide analysis exhibiting a positive relationship between exon-level DNA methylation and mRNA expression in the honeybee. Our finding that methylated genes are enriched for alternative splicing suggests that, in invertebrates, exon-level DNA methylation may play a role in the construction of splice

  19. Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

    NARCIS (Netherlands)

    Justice, Anne E; Winkler, Thomas W; Feitosa, Mary F; Graff, Misa; Fisher, Virginia A; Young, Kristin L; Barata, Llilda; Deng, Xuan; Czajkowski, Jacek; Hadley, David; Ngwa, Julius S; Ahluwalia, Tarunveer S; Chu, Audrey Y; Heard-Costa, Nancy L; Lim, Elise; Perez, Jeremiah; Eicher, John D; Kutalik, Zoltán; Xue, Luting; Mahajan, Anubha; Renström, Frida; Wu, Joseph; Qi, Qibin; Ahmad, Shafqat; Alfred, Tamuno; Amin, Najaf; Bielak, Lawrence F; Bonnefond, Amelie; Bragg-Gresham, Jennifer L; Cadby, Gemma; Chittani, Martina; Coggeshall, Scott; Corre, Tanguy; Direk, Nese; Eriksson, Joel; Fischer, Krista; Gorski, Mathias; Neergaard Harder, Marie; Horikoshi, Momoko; Huang, Tao; Huffman, Jennifer E; Jackson, Anne U; Justesen, Johanne Marie; Kanoni, Stavroula; Kinnunen, Leena; Kleber, Marcus E; Komulainen, Pirjo; Kumari, Meena; Lim, Unhee; Luan, Jian'an; Lyytikäinen, Leo-Pekka; Mangino, Massimo; Manichaikul, Ani; Marten, Jonathan; Middelberg, Rita P S; Müller-Nurasyid, Martina; Navarro, Pau; Pérusse, Louis; Pervjakova, Natalia; Sarti, Cinzia; Smith, Albert Vernon; Smith, Jennifer A; Stančáková, Alena; Strawbridge, Rona J; Stringham, Heather M; Sung, Yun Ju; Tanaka, Toshiko; Teumer, Alexander; Trompet, Stella; van der Laan, Sander W; van der Most, Peter J; van Vliet-Ostaptchouk, Jana V; Vedantam, Sailaja L; Verweij, Niek; Vink, Jacqueline M; Vitart, Veronique; Wu, Ying; Yengo, Loic; Zhang, Weihua; Hua Zhao, Jing; Zimmermann, Martina E; Zubair, Niha; Abecasis, Gonçalo R; Adair, Linda S; Afaq, Saima; Afzal, Uzma; Bakker, Stephan J L; Bartz, Traci M; Beilby, John; Bergman, Richard N; Bergmann, Sven; Biffar, Reiner; Blangero, John; Boerwinkle, Eric; Bonnycastle, Lori L; Bottinger, Erwin; Braga, Daniele; Buckley, Brendan M; Buyske, Steve; Campbell, Harry; Chambers, John C; Collins, Francis S; Curran, Joanne E; de Borst, Gert J; De Craen, Anton J M; de Geus, Eco J C; Dedoussis, George; Delgado, Graciela E; den Ruijter, Hester M; Eiriksdottir, Gudny; Eriksson, Anna L; Esko, Tõnu; Faul, Jessica D; Ford, Ian; Forrester, Terrence; Gertow, Karl; Gigante, Bruna; Glorioso, Nicola; Gong, Jian; Grallert, Harald; Grammer, Tanja B; Grarup, Niels; Haitjema, Saskia; Hallmans, Göran; Hamsten, Anders; Hansen, Torben; Harris, Tamara B; Hartman, Catharina A; Hassinen, Maija; Hastie, Nicholas D; Heath, Andrew C; Hernandez, Dena G; Hindorff, Lucia; Hocking, Lynne J; Hollensted, Mette; Holmen, Oddgeir L; Homuth, Georg; Huang, Jie; Hung, Joseph; Hutri-Kähönen, Nina; Ingelsson, Erik; James, Alan L; Jansson, John-Olov; Jarvelin, Marjo-Riitta; Jhun, Min A; Jørgensen, Marit E; Juonala, Markus; Kähönen, Mika; Karlsson, Magnus; Koistinen, Heikki A; Kolcic, Ivana; Kolovou, Genovefa; Kooperberg, Charles; Krämer, Bernhard K; Kuusisto, Johanna; Kvaløy, Kirsti; Lakka, Timo A; Langenberg, Claudia; Launer, Lenore J; Leander, Karin; Lee, Nanette R; Lind, Lars; Lindgren, Cecilia M; Linneberg, Allan; Lobbens, Stephane; Loh, Marie; Lorentzon, Mattias; Luben, Robert; Lubke, Gitta; Ludolph-Donislawski, Anja; Lupoli, Sara; Madden, Pamela A F; Männikkö, Reija; Marques-Vidal, Pedro M; Martin, Nicholas G; McKenzie, Colin A; McKnight, Barbara; Mellström, Dan; Menni, Cristina; Montgomery, Grant W; Musk, Aw Bill; Narisu, Narisu; Nauck, Matthias; Nolte, Ilja M; Oldehinkel, Albertine J; Olden, Matthias; Ong, Ken K; Padmanabhan, Sandosh; Peyser, Patricia A; Pisinger, Charlotta; Porteous, David J; Raitakari, Olli T; Rankinen, Tuomo; Rao, D.C.; Rasmussen-Torvik, Laura J; Rawal, Rajesh; Rice, Treva; Ridker, Paul M; Rose, Lynda M; Bien, Stephanie A; Rudan, Igor; Sanna, Serena; Sarzynski, Mark A; Sattar, Naveed; Savonen, Kai; Schlessinger, David; Scholtens, Salome; Schurmann, Claudia; Scott, Robert A; Sennblad, Bengt; Siemelink, Marten A; Silbernagel, Günther; Slagboom, P. Eline; Snieder, Harold; Staessen, Jan A; Stott, David J; Swertz, Morris a.; Swift, Amy J; Taylor, Kent D; Tayo, Bamidele O; Thorand, Barbara; Thuillier, Dorothee; Tuomilehto, Jaakko; Uitterlinden, Andre G; Vandenput, Liesbeth; Vohl, Marie-Claude; Völzke, Henry; Vonk, Judith M; Waeber, Gérard; Waldenberger, Melanie; Westendorp, R.G.J.; Wild, Sarah; Willemsen, Gonneke; Wolffenbuttel, Bruce H R; Wong, Andrew; Wright, Alan F; Zhao, Wei; Zillikens, M Carola; Baldassarre, Damiano; Balkau, Beverley; Bandinelli, Stefania; Böger, Carsten A; Boomsma, Dorret I; Bouchard, Claude; Bruinenberg, Marcel; Chasman, Daniel I; Chen, Yii-DerIda; Chines, Peter S; Cooper, Richard S; Cucca, Francesco; Cusi, Daniele; Faire, Ulf de; Ferrucci, Luigi; Franks, Paul W; Froguel, Philippe; Gordon-Larsen, Penny; Grabe, Hans-Jörgen; Gudnason, Vilmundur; Haiman, Christopher A; Hayward, Caroline; Hveem, Kristian; Johnson, Andrew D; Wouter Jukema, J; Kardia, Sharon L R; Kivimaki, Mika; Kooner, Jaspal S; Kuh, Diana; Laakso, Markku; Lehtimäki, Terho; Marchand, Loic Le; März, Winfried; McCarthy, Mark I; Metspalu, Andres; Morris, Andrew P; Ohlsson, Claes; Palmer, Lyle J; Pasterkamp, Gerard; Pedersen, Oluf; Peters, Annette; Peters, Ulrike; Polasek, Ozren; Psaty, Bruce M; Qi, Lu; Rauramaa, Rainer; Smith, Blair H; Sørensen, Thorkild I A; Strauch, Konstantin; Tiemeier, Henning; Tremoli, Elena; van der Harst, Pim; Vestergaard, Henrik; Vollenweider, Peter; Wareham, Nicholas J; Weir, David R; Whitfield, John B; Wilson, James F; Tyrrell, Jessica; Frayling, Timothy M; Barroso, Inês; Boehnke, Michael; Deloukas, Panagiotis; Fox, Caroline S; Hirschhorn, Joel N; Hunter, David J; Spector, Tim D; Strachan, David P; van Duijn, Cornelia M; Heid, Iris M; Mohlke, Karen L; Marchini, Jonathan; Loos, Ruth J F; Kilpeläinen, Tuomas O; Liu, Ching-Ti; Borecki, Ingrid B; North, Kari E; Cupples, L Adrienne; Hottenga, J.J.

    2017-01-01

    Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87%

  20. Genome-wide analysis of Tol2 transposon reintegration in zebrafish

    Directory of Open Access Journals (Sweden)

    Parinov Sergey

    2009-09-01

    Full Text Available Abstract Background Tol2, a member of the hAT family of transposons, has become a useful tool for genetic manipulation of model animals, but information about its interactions with vertebrate genomes is still limited. Furthermore, published reports on Tol2 have mainly been based on random integration of the transposon system after co-injection of a plasmid DNA harboring the transposon and a transposase mRNA. It is important to understand how Tol2 would behave upon activation after integration into the genome. Results We performed a large-scale enhancer trap (ET screen and generated 338 insertions of the Tol2 transposon-based ET cassette into the zebrafish genome. These insertions were generated by remobilizing the transposon from two different donor sites in two transgenic lines. We found that 39% of Tol2 insertions occurred in transcription units, mostly into introns. Analysis of the transposon target sites revealed no strict specificity at the DNA sequence level. However, Tol2 was prone to target AT-rich regions with weak palindromic consensus sequences centered at the insertion site. Conclusion Our systematic analysis of sequential remobilizations of the Tol2 transposon from two independent sites within a vertebrate genome has revealed properties such as a tendency to integrate into transcription units and into AT-rich palindrome-like sequences. This information will influence the development of various applications involving DNA transposons and Tol2 in particular.

  1. Genome-wide linkage analysis for human longevity

    DEFF Research Database (Denmark)

    Beekman, Marian; Blanché, Hélène; Perola, Markus

    2013-01-01

    Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian...

  2. Genetic Architecture of Aluminum Tolerance in Rice (Oryza sativa) Determined through Genome-Wide Association Analysis and QTL Mapping

    Science.gov (United States)

    Famoso, Adam N.; Zhao, Keyan; Clark, Randy T.; Tung, Chih-Wei; Wright, Mark H.; Bustamante, Carlos; Kochian, Leon V.; McCouch, Susan R.

    2011-01-01

    Aluminum (Al) toxicity is a primary limitation to crop productivity on acid soils, and rice has been demonstrated to be significantly more Al tolerant than other cereal crops. However, the mechanisms of rice Al tolerance are largely unknown, and no genes underlying natural variation have been reported. We screened 383 diverse rice accessions, conducted a genome-wide association (GWA) study, and conducted QTL mapping in two bi-parental populations using three estimates of Al tolerance based on root growth. Subpopulation structure explained 57% of the phenotypic variation, and the mean Al tolerance in Japonica was twice that of Indica. Forty-eight regions associated with Al tolerance were identified by GWA analysis, most of which were subpopulation-specific. Four of these regions co-localized with a priori candidate genes, and two highly significant regions co-localized with previously identified QTLs. Three regions corresponding to induced Al-sensitive rice mutants (ART1, STAR2, Nrat1) were identified through bi-parental QTL mapping or GWA to be involved in natural variation for Al tolerance. Haplotype analysis around the Nrat1 gene identified susceptible and tolerant haplotypes explaining 40% of the Al tolerance variation within the aus subpopulation, and sequence analysis of Nrat1 identified a trio of non-synonymous mutations predictive of Al sensitivity in our diversity panel. GWA analysis discovered more phenotype–genotype associations and provided higher resolution, but QTL mapping identified critical rare and/or subpopulation-specific alleles not detected by GWA analysis. Mapping using Indica/Japonica populations identified QTLs associated with transgressive variation where alleles from a susceptible aus or indica parent enhanced Al tolerance in a tolerant Japonica background. This work supports the hypothesis that selectively introgressing alleles across subpopulations is an efficient approach for trait enhancement in plant breeding programs and

  3. High-Resolution Genome-Wide Linkage Mapping Identifies Susceptibility Loci for BMI in the Chinese Population

    DEFF Research Database (Denmark)

    Zhang, Dong Feng; Pang, Zengchang; Li, Shuxia

    2012-01-01

    The genetic loci affecting the commonly used BMI have been intensively investigated using linkage approaches in multiple populations. This study aims at performing the first genome-wide linkage scan on BMI in the Chinese population in mainland China with hypothesis that heterogeneity in genetic...... linkage could exist in different ethnic populations. BMI was measured from 126 dizygotic twins in Qingdao municipality who were genotyped using high-resolution Affymetrix Genome-Wide Human SNP arrays containing about 1 million single-nucleotide polymorphisms (SNPs). Nonparametric linkage analysis...... in western countries. Multiple loci showing suggestive linkage were found on chromosome 1 (lod score 2.38 at 242 cM), chromosome 8 (2.48 at 95 cM), and chromosome 14 (2.2 at 89.4 cM). The strong linkage identified in the Chinese subjects that is consistent with that found in populations of European origin...

  4. Identification of novel risk genes associated with type 1 diabetes mellitus using a genome-wide gene-based association analysis.

    Science.gov (United States)

    Qiu, Ying-Hua; Deng, Fei-Yan; Li, Min-Jing; Lei, Shu-Feng

    2014-11-01

    Type 1 diabetes mellitus is a serious disorder characterized by destruction of pancreatic β-cells, culminating in absolute insulin deficiency. Genetic factors contribute to the susceptibility of type 1 diabetes mellitus. The aim of the present study was to identify more susceptibility genes of type 1 diabetes mellitus. We carried out an initial gene-based genome-wide association study in a total of 4,075 type 1 diabetes mellitus cases and 2,604 controls by using the Gene-based Association Test using Extended Simes procedure. Furthermore, we carried out replication studies, differential expression analysis and functional annotation clustering analysis to support the significance of the identified susceptibility genes. We identified 452 genes associated with type 1 diabetes mellitus, even after adapting the genome-wide threshold for significance (P diabetes mellitus, which were ignored in single-nucleotide polymorphism-based association analysis and were not previously reported. We found that 53 genes have supportive evidence from replication studies and/or differential expression studies. In particular, seven genes including four non-human leukocyte antigen (HLA) genes (RASIP1, STRN4, BCAR1 and MYL2) are replicated in at least one independent population and also differentially expressed in peripheral blood mononuclear cells or monocytes. Furthermore, the associated genes tend to enrich in immune-related pathways or Gene Ontology project terms. The present results suggest the high power of gene-based association analysis in detecting disease-susceptibility genes. Our findings provide more insights into the genetic basis of type 1 diabetes mellitus.

  5. Multilocus genetic models of handedness closely resemble single-locus models in explaining family data and are compatible with genome-wide association studies.

    Science.gov (United States)

    McManus, I C; Davison, Angus; Armour, John A L

    2013-06-01

    Right- and left-handedness run in families, show greater concordance in monozygotic than dizygotic twins, and are well described by single-locus Mendelian models. Here we summarize a large genome-wide association study (GWAS) that finds no significant associations with handedness and is consistent with a meta-analysis of GWASs. The GWAS had 99% power to detect a single locus using the conventional criterion of P < 5 × 10(-8) for the single locus models of McManus and Annett. The strong conclusion is that handedness is not controlled by a single genetic locus. A consideration of the genetic architecture of height, primary ciliary dyskinesia, and intelligence suggests that handedness inheritance can be explained by a multilocus variant of the McManus DC model, classical effects on family and twins being barely distinguishable from the single locus model. Based on the ENGAGE meta-analysis of GWASs, we estimate at least 40 loci are involved in determining handedness. © 2013 New York Academy of Sciences.

  6. Whole genome amplification in preimplantation genetic diagnosis*

    Science.gov (United States)

    Zheng, Ying-ming; Wang, Ning; Li, Lei; Jin, Fan

    2011-01-01

    Preimplantation genetic diagnosis (PGD) refers to a procedure for genetically analyzing embryos prior to implantation, improving the chance of conception for patients at high risk of transmitting specific inherited disorders. This method has been widely used for a large number of genetic disorders since the first successful application in the early 1990s. Polymerase chain reaction (PCR) and fluorescent in situ hybridization (FISH) are the two main methods in PGD, but there are some inevitable shortcomings limiting the scope of genetic diagnosis. Fortunately, different whole genome amplification (WGA) techniques have been developed to overcome these problems. Sufficient DNA can be amplified and multiple tasks which need abundant DNA can be performed. Moreover, WGA products can be analyzed as a template for multi-loci and multi-gene during the subsequent DNA analysis. In this review, we will focus on the currently available WGA techniques and their applications, as well as the new technical trends from WGA products. PMID:21194180

  7. Genome-wide association study identifies 74 loci associated with educational attainment

    Science.gov (United States)

    Okbay, Aysu; Beauchamp, Jonathan P.; Fontana, Mark A.; Lee, James J.; Pers, Tune H.; Rietveld, Cornelius A.; Turley, Patrick; Chen, Guo-Bo; Emilsson, Valur; Meddens, S. Fleur W.; Oskarsson, Sven; Pickrell, Joseph K.; Thom, Kevin; Timshel, Pascal; de Vlaming, Ronald; Abdellaoui, Abdel; Ahluwalia, Tarunveer S.; Bacelis, Jonas; Baumbach, Clemens; Bjornsdottir, Gyda; Brandsma, Johannes H.; Concas, Maria Pina; Derringer, Jaime; Furlotte, Nicholas A.; Galesloot, Tessel E.; Girotto, Giorgia; Gupta, Richa; Hall, Leanne M.; Harris, Sarah E.; Hofer, Edith; Horikoshi, Momoko; Huffman, Jennifer E.; Kaasik, Kadri; Kalafati, Ioanna P.; Karlsson, Robert; Kong, Augustine; Lahti, Jari; van der Lee, Sven J.; de Leeuw, Christiaan; Lind, Penelope A.; Lindgren, Karl-Oskar; Liu, Tian; Mangino, Massimo; Marten, Jonathan; Mihailov, Evelin; Miller, Michael B.; van der Most, Peter J.; Oldmeadow, Christopher; Payton, Antony; Pervjakova, Natalia; Peyrot, Wouter J.; Qian, Yong; Raitakari, Olli; Rueedi, Rico; Salvi, Erika; Schmidt, Börge; Schraut, Katharina E.; Shi, Jianxin; Smith, Albert V.; Poot, Raymond A.; Pourcain, Beate; Teumer, Alexander; Thorleifsson, Gudmar; Verweij, Niek; Vuckovic, Dragana; Wellmann, Juergen; Westra, Harm-Jan; Yang, Jingyun; Zhao, Wei; Zhu, Zhihong; Alizadeh, Behrooz Z.; Amin, Najaf; Bakshi, Andrew; Baumeister, Sebastian E.; Biino, Ginevra; Bønnelykke, Klaus; Boyle, Patricia A.; Campbell, Harry; Cappuccio, Francesco P.; Davies, Gail; De Neve, Jan-Emmanuel; Deloukas, Panos; Demuth, Ilja; Ding, Jun; Eibich, Peter; Eisele, Lewin; Eklund, Niina; Evans68, David M.; Faul, Jessica D.; Feitosa, Mary F.; Forstner, Andreas J.; Gandin, Ilaria; Gunnarsson, Bjarni; Halldórsson, Bjarni V.; Harris, Tamara B.; Heath, Andrew C.; Hocking, Lynne J.; Holliday, Elizabeth G.; Homuth, Georg; Horan, Michael A.; Hottenga, Jouke-Jan; de Jager, Philip L.; Joshi, Peter K.; Jugessur, Astanand; Kaakinen, Marika A.; Kähönen, Mika; Kanoni, Stavroula; Keltigangas-Järvinen, Liisa; Kiemeney, Lambertus A.L.M.; Kolcic, Ivana; Koskinen, Seppo; Kraja, Aldi T.; Kroh, Martin; Kutalik, Zoltan; Latvala, Antti; Launer, Lenore J.; Lebreton, Maël P.; Levinson, Douglas F.; Lichtenstein, Paul; Lichtner, Peter; Liewald, David C.M.; Loukola, Anu; Madden, Pamela A.; Mägi, Reedik; Mäki-Opas, Tomi; Marioni, Riccardo E.; Marques-Vidal, Pedro; Meddens, Gerardus A.; McMahon, George; Meisinger, Christa; Meitinger, Thomas; Milaneschi, Yusplitri; Milani, Lili; Montgomery, Grant W.; Myhre, Ronny; Nelson, Christopher P.; Nyholt, Dale R.; Ollier, William E.R.; Palotie, Aarno; Paternoster, Lavinia; Pedersen, Nancy L.; Petrovic, Katja E.; Porteous, David J.; Räikkönen, Katri; Ring, Susan M.; Robino, Antonietta; Rostapshova, Olga; Rudan, Igor; Rustichini, Aldo; Salomaa, Veikko; Sanders, Alan R.; Sarin, Antti-Pekka; Schmidt, Helena; Scott, Rodney J.; Smith, Blair H.; Smith, Jennifer A.; Staessen, Jan A.; Steinhagen-Thiessen, Elisabeth; Strauch, Konstantin; Terracciano, Antonio; Tobin, Martin D.; Ulivi, Sheila; Vaccargiu, Simona; Quaye, Lydia; van Rooij, Frank J.A.; Venturini, Cristina; Vinkhuyzen, Anna A.E.; Völker, Uwe; Völzke, Henry; Vonk, Judith M.; Vozzi, Diego; Waage, Johannes; Ware, Erin B.; Willemsen, Gonneke; Attia, John R.; Bennett, David A.; Berger, Klaus; Bertram, Lars; Bisgaard, Hans; Boomsma, Dorret I.; Borecki, Ingrid B.; Bultmann, Ute; Chabris, Christopher F.; Cucca, Francesco; Cusi, Daniele; Deary, Ian J.; Dedoussis, George V.; van Duijn, Cornelia M.; Eriksson, Johan G.; Franke, Barbara; Franke, Lude; Gasparini, Paolo; Gejman, Pablo V.; Gieger, Christian; Grabe, Hans-Jörgen; Gratten, Jacob; Groenen, Patrick J.F.; Gudnason, Vilmundur; van der Harst, Pim; Hayward, Caroline; Hinds, David A.; Hoffmann, Wolfgang; Hyppönen, Elina; Iacono, William G.; Jacobsson, Bo; Järvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L.R.; Lehtimäki, Terho; Lehrer, Steven F.; Magnusson, Patrik K.E.; Martin, Nicholas G.; McGue, Matt; Metspalu, Andres; Pendleton, Neil; Penninx, Brenda W.J.H.; Perola, Markus; Pirastu, Nicola; Pirastu, Mario; Polasek, Ozren; Posthuma, Danielle; Power, Christine; Province, Michael A.; Samani, Nilesh J.; Schlessinger, David; Schmidt, Reinhold; Sørensen, Thorkild I.A.; Spector, Tim D.; Stefansson, Kari; Thorsteinsdottir, Unnur; Thurik, A. Roy; Timpson, Nicholas J.; Tiemeier, Henning; Tung, Joyce Y.; Uitterlinden, André G.; Vitart, Veronique; Vollenweider, Peter; Weir, David R.; Wilson, James F.; Wright, Alan F.; Conley, Dalton C.; Krueger, Robert F.; Smith, George Davey; Hofman, Albert; Laibson, David I.; Medland, Sarah E.; Meyer, Michelle N.; Yang, Jian; Johannesson, Magnus; Visscher, Peter M.; Esko, Tõnu; Koellinger, Philipp D.; Cesarini, David; Benjamin, Daniel J.

    2016-01-01

    Summary Educational attainment (EA) is strongly influenced by social and other environmental factors, but genetic factors are also estimated to account for at least 20% of the variation across individuals1. We report the results of a genome-wide association study (GWAS) for EA that extends our earlier discovery sample1,2 of 101,069 individuals to 293,723 individuals, and a replication in an independent sample of 111,349 individuals from the UK Biobank. We now identify 74 genome-wide significant loci associated with number of years of schooling completed. Single-nucleotide polymorphisms (SNPs) associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioral phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because EA is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric disease. PMID:27225129

  8. Genome-Wide Association Study of Serum Selenium Concentrations

    Directory of Open Access Journals (Sweden)

    Ulrike Peters

    2013-05-01

    Full Text Available Selenium is an essential trace element and circulating selenium concentrations have been associated with a wide range of diseases. Candidate gene studies suggest that circulating selenium concentrations may be impacted by genetic variation; however, no study has comprehensively investigated this hypothesis. Therefore, we conducted a two-stage genome-wide association study to identify genetic variants associated with serum selenium concentrations in 1203 European descents from two cohorts: the Prostate, Lung, Colorectal, and Ovarian (PLCO Cancer Screening and the Women’s Health Initiative (WHI. We tested association between 2,474,333 single nucleotide polymorphisms (SNPs and serum selenium concentrations using linear regression models. In the first stage (PLCO 41 SNPs clustered in 15 regions had p < 1 × 10−5. None of these 41 SNPs reached the significant threshold (p = 0.05/15 regions = 0.003 in the second stage (WHI. Three SNPs had p < 0.05 in the second stage (rs1395479 and rs1506807 in 4q34.3/AGA-NEIL3; and rs891684 in 17q24.3/SLC39A11 and had p between 2.62 × 10−7 and 4.04 × 10−7 in the combined analysis (PLCO + WHI. Additional studies are needed to replicate these findings. Identification of genetic variation that impacts selenium concentrations may contribute to a better understanding of which genes regulate circulating selenium concentrations.

  9. A genomic background based method for association analysis in related individuals.

    Directory of Open Access Journals (Sweden)

    Najaf Amin

    Full Text Available BACKGROUND: Feasibility of genotyping of hundreds and thousands of single nucleotide polymorphisms (SNPs in thousands of study subjects have triggered the need for fast, powerful, and reliable methods for genome-wide association analysis. Here we consider a situation when study participants are genetically related (e.g. due to systematic sampling of families or because a study was performed in a genetically isolated population. Of the available methods that account for relatedness, the Measured Genotype (MG approach is considered the 'gold standard'. However, MG is not efficient with respect to time taken for the analysis of genome-wide data. In this context we proposed a fast two-step method called Genome-wide Association using Mixed Model and Regression (GRAMMAR for the analysis of pedigree-based quantitative traits. This method certainly overcomes the drawback of time limitation of the measured genotype (MG approach, but pays in power. One of the major drawbacks of both MG and GRAMMAR, is that they crucially depend on the availability of complete and correct pedigree data, which is rarely available. METHODOLOGY: In this study we first explore type 1 error and relative power of MG, GRAMMAR, and Genomic Control (GC approaches for genetic association analysis. Secondly, we propose an extension to GRAMMAR i.e. GRAMMAR-GC. Finally, we propose application of GRAMMAR-GC using the kinship matrix estimated through genomic marker data, instead of (possibly missing and/or incorrect genealogy. CONCLUSION: Through simulations we show that MG approach maintains high power across a range of heritabilities and possible pedigree structures, and always outperforms other contemporary methods. We also show that the power of our proposed GRAMMAR-GC approaches to that of the 'gold standard' MG for all models and pedigrees studied. We show that this method is both feasible and powerful and has correct type 1 error in the context of genome-wide association analysis

  10. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

    NARCIS (Netherlands)

    T.W. Winkler (Thomas W.); A.E. Justice (Anne); M.J. Graff (Maud J.L.); Barata, L. (Llilda); M.F. Feitosa (Mary Furlan); Chu, S. (Su); J. Czajkowski (Jacek); T. Esko (Tõnu); M. Fall (Magnus); T.O. Kilpeläinen (Tuomas); Y. Lu (Yingchang); R. Mägi (Reedik); E. Mihailov (Evelin); T.H. Pers (Tune); Rüeger, S. (Sina); A. Teumer (Alexander); G.B. Ehret (Georg); T. Ferreira (Teresa); N.L. Heard-Costa (Nancy); J. Karjalainen (Juha); V. Lagou (Vasiliki); A. Mahajan (Anubha); Neinast, M.D. (Michael D.); I. Prokopenko (Inga); J. Simino (Jeannette); T.M. Teslovich (Tanya M.); R. Jansen; H.J. Westra (Harm-Jan); C.C. White (Charles); D. Absher (Devin); T.S. Ahluwalia (Tarunveer Singh); S. Ahmad (Shafqat); E. Albrecht (Eva); A.C. Alves (Alexessander Couto); Bragg-Gresham, J.L. (Jennifer L.); A.J. de Craen (Anton); J.C. Bis (Joshua); A. Bonnefond (Amélie); G. Boucher (Gabrielle); G. Cadby (Gemma); Y.-C. Cheng (Yu-Ching); Chiang, C.W. (Charleston W K); G. Delgado; A. Demirkan (Ayşe); N. Dueker (Nicole); N. Eklund (Niina); G. Eiriksdottir (Gudny); J. Eriksson (Joel); B. Feenstra (Bjarke); K. Fischer (Krista); F. Frau (Francesca); T.E. Galesloot (Tessel); F. Geller (Frank); A. Goel (Anuj); M. Gorski (Mathias); T.B. Grammer (Tanja); S. Gustafsson (Stefan); Haitjema, S. (Saskia); J.J. Hottenga (Jouke Jan); J.E. Huffman (Jennifer); A.U. Jackson (Anne); K.B. Jacobs (Kevin); A. Johansson (Åsa); M. Kaakinen (Marika); M.E. Kleber (Marcus); J. Lahti (Jari); I.M. Leach (Irene Mateo); Lehne, B. (Benjamin); Liu, Y. (Youfang); K.S. Lo; M. Lorentzon (Mattias); J. Luan (Jian'An); P.A. Madden (Pamela); M. Mangino (Massimo); B. McKnight (Barbara); Medina-Gomez, C. (Carolina); K.L. Monda (Keri); M.E. Montasser (May E.); G. Müller (Gabriele); M. Müller-Nurasyid (Martina); I.M. Nolte (Ilja); Panoutsopoulou, K. (Kalliope); L. Pascoe (Laura); L. Paternoster (Lavinia); N.W. Rayner (Nigel William); F. Renström (Frida); Rizzi, F. (Federica); L.M. Rose (Lynda); Ryan, K.A. (Kathy A.); P. Salo (Perttu); S. Sanna (Serena); H. Scharnagl (Hubert); Shi, J. (Jianxin); A.V. Smith (Albert Vernon); L. Southam (Lorraine); A. Stancáková (Alena); V. Steinthorsdottir (Valgerdur); R.J. Strawbridge (Rona); Sung, Y.J. (Yun Ju); I. Tachmazidou (Ioanna); T. Tanaka (Toshiko); G. Thorleifsson (Gudmar); S. Trompet (Stella); N. Pervjakova (Natalia); J.P. Tyrer (Jonathan); L. Vandenput (Liesbeth); S.W. Van Der Laan (Sander W.); N. van der Velde (Nathalie); J. van Setten (Jessica); J.V. van Vliet-Ostaptchouk (Jana); N. Verweij (Niek); E. Vlachopoulou (Efthymia); L. Waite (Lindsay); S.R. Wang (Sophie); Z. Wang (Zhaoming); S.H. Wild (Sarah); C. Willenborg (Christina); J.F. Wilson (James); A. Wong (Andrew); Yang, J. (Jian); L. Yengo (Loic); L.M. Yerges-Armstrong (Laura); Yu, L. (Lei); W. Zhang (Weihua); Zhao, J.H. (Jing Hua); E.A. Andersson (Ehm Astrid); S.J.L. Bakker (Stephan); D. Baldassarre (Damiano); Banasik, K. (Karina); Barcella, M. (Matteo); Barlassina, C. (Cristina); C. Bellis (Claire); P. Benaglio (Paola); J. Blangero (John); M. Blüher (Matthias); Bonnet, F. (Fabrice); L.L. Bonnycastle (Lori); H.A. Boyd (Heather); M. Bruinenberg (M.); Buchman, A.S. (Aron S.); H. Campbell (Harry); Y.D. Chen (Y.); P.S. Chines (Peter); S. Claudi-Boehm (Simone); J.W. Cole (John W.); F.S. Collins (Francis); E.J.C. de Geus (Eco); L.C.P.G.M. de Groot (Lisette); M. Dimitriou (Maria); J. Duan (Jubao); S. Enroth (Stefan); E. Eury (Elodie); A.-E. Farmaki (Aliki-Eleni); N.G. Forouhi (Nita); N. Friedrich (Nele); P.V. Gejman (Pablo); B. Gigante (Bruna); N. Glorioso (Nicola); A. Go (Attie); R.F. Gottesman (Rebecca); J. Gräßler (Jürgen); H. Grallert (Harald); N. Grarup (Niels); Gu, Y.-M. (Yu-Mei); L. Broer (Linda); A.C. Ham (Annelies); T. Hansen (T.); T.B. Harris (Tamara); C.A. Hartman (Catharina A.); Hassinen, M. (Maija); N. Hastie (Nick); A.T. Hattersley (Andrew); A.C. Heath (Andrew); A.K. Henders (Anjali); D.G. Hernandez (Dena); H.L. Hillege (Hans); O.L. Holmen (Oddgeir); G.K. Hovingh (Kees); J. Hui (Jennie); Husemoen, L.L. (Lise L.); Hutri-Kähönen, N. (Nina); P.G. Hysi (Pirro); T. Illig (Thomas); P.L. de Jager (Philip); S. Jalilzadeh (Shapour); T. Jorgensen (Torben); J.W. Jukema (Jan Wouter); Juonala, M. (Markus); S. Kanoni (Stavroula); M. Karaleftheri (Maria); K.T. Khaw; L. Kinnunen (Leena); T. Kittner (Thomas); W. Koenig (Wolfgang); I. Kolcic (Ivana); P. Kovacs (Peter); Krarup, N.T. (Nikolaj T.); W. Kratzer (Wolfgang); Krüger, J. (Janine); Kuh, D. (Diana); M. Kumari (Meena); T. Kyriakou (Theodosios); C. Langenberg (Claudia); L. Lannfelt (Lars); C. Lanzani (Chiara); V. Lotay (Vaneet); L.J. Launer (Lenore); K. Leander (Karin); J. Lindström (Jaana); A. Linneberg (Allan); Liu, Y.-P. (Yan-Ping); S. Lobbens (Stéphane); R.N. Luben (Robert); V. Lyssenko (Valeriya); S. Männistö (Satu); P.K. Magnusson (Patrik); W.L. McArdle (Wendy); C. Menni (Cristina); S. Merger (Sigrun); L. Milani (Lili); Montgomery, G.W. (Grant W.); A.P. Morris (Andrew); N. Narisu (Narisu); M. Nelis (Mari); K.K. Ong (Ken); A. Palotie (Aarno); L. Perusse (Louis); I. Pichler (Irene); M.G. Pilia (Maria Grazia); A. Pouta (Anneli); Rheinberger, M. (Myriam); Ribel-Madsen, R. (Rasmus); Richards, M. (Marcus); K.M. Rice (Kenneth); T.K. Rice (Treva K.); C. Rivolta (Carlo); V. Salomaa (Veikko); A.R. Sanders (Alan); M.A. Sarzynski (Mark A.); S. Scholtens (Salome); R.A. Scott (Robert); W.R. Scott (William R.); S. Sebert (Sylvain); S. Sengupta (Sebanti); B. Sennblad (Bengt); T. Seufferlein (Thomas); A. Silveira (Angela); P.E. Slagboom (Eline); J.H. Smit (Jan); T. Sparsø (Thomas); K. Stirrups (Kathy); R.P. Stolk (Ronald); H.M. Stringham (Heather); Swertz, M.A. (Morris A.); A.J. Swift (Amy); A.C. Syvänen; S.-T. Tan (Sian-Tsung); B. Thorand (Barbara); A. Tönjes (Anke); Tremblay, A. (Angelo); E. Tsafantakis (Emmanouil); P.J. van der Most (Peter); U. Völker (Uwe); M.-C. Vohl (Marie-Claude); J.M. Vonk (Judith); M. Waldenberger (Melanie); Walker, R.W. (Ryan W.); R. Wennauer (Roman); E. Widen; G.A.H.M. Willemsen (Gonneke); T. Wilsgaard (Tom); A.F. Wright (Alan); M.C. Zillikens (Carola); S. Van Dijk (Suzanne); N.M. van Schoor (Natasja); F.W. Asselbergs (Folkert); P.I.W. de Bakker (Paul); J.S. Beckmann (Jacques); J.P. Beilby (John); D.A. Bennett (David A.); R.N. Bergman (Richard); S.M. Bergmann (Sven); C.A. Böger (Carsten); B.O. Boehm (Bernhard); E.A. Boerwinkle (Eric); D.I. Boomsma (Dorret); S.R. Bornstein (Stefan); E.P. Bottinger (Erwin); C. Bouchard (Claude); J.C. Chambers (John); S.J. Chanock (Stephen); D.I. Chasman (Daniel); F. Cucca (Francesco); D. Cusi (Daniele); G.V. Dedoussis (George); J. Erdmann (Jeanette); K. Hagen (Knut); D. Evans; U. de Faire (Ulf); M. Farrall (Martin); L. Ferrucci (Luigi); I. Ford (Ian); L. Franke (Lude); P.W. Franks (Paul); P. Froguel (Philippe); R.T. Gansevoort (Ron); C. Gieger (Christian); H. Grönberg (Henrik); V. Gudnason (Vilmundur); U. Gyllensten (Ulf); P. Hall (Per); A. Hamsten (Anders); P. van der Harst (Pim); C. Hayward (Caroline); M. Heliovaara (Markku); C. Hengstenberg (Christian); A.A. Hicks (Andrew); A. Hingorani (Aroon); A. Hofman (Albert); Hu, F. (Frank); H.V. Huikuri (Heikki); K. Hveem (Kristian); A. James (Alan); Jordan, J.M. (Joanne M.); A. Jula (Antti); M. Kähönen (Mika); E. Kajantie (Eero); S. Kathiresan (Sekar); L.A.L.M. Kiemeney (Bart); M. Kivimaki (Mika); P. Knekt; H. Koistinen (Heikki); J.S. Kooner (Jaspal S.); S. Koskinen (Seppo); J. Kuusisto (Johanna); W. Maerz (Winfried); N.G. Martin (Nicholas); M. Laakso (Markku); T.A. Lakka (Timo); T. Lehtimäki (Terho); G. Lettre (Guillaume); D.F. Levinson (Douglas); W.H.L. Kao (Wen); M.L. Lokki; Mäntyselkä, P. (Pekka); M. Melbye (Mads); A. Metspalu (Andres); B.D. Mitchell (Braxton); F.L. Moll (Frans); J.C. Murray (Jeffrey); A.W. Musk (Arthur); M.S. Nieminen (Markku); I. Njølstad (Inger); C. Ohlsson (Claes); A.J. Oldehinkel (Albertine); B.A. Oostra (Ben); C. Palmer (Cameron); J.S. Pankow (James); G. Pasterkamp (Gerard); N.L. Pedersen (Nancy); O. Pedersen (Oluf); B.W.J.H. Penninx (Brenda); M. Perola (Markus); A. Peters (Annette); O. Polasek (Ozren); P.P. Pramstaller (Peter Paul); Psaty, B.M. (Bruce M.); Qi, L. (Lu); T. Quertermous (Thomas); Raitakari, O.T. (Olli T.); T. Rankinen (Tuomo); R. Rauramaa (Rainer); P.M. Ridker (Paul); J.D. Rioux (John); F. Rivadeneira Ramirez (Fernando); J.I. Rotter (Jerome I.); I. Rudan (Igor); H.M. den Ruijter (Hester ); J. Saltevo (Juha); N. Sattar (Naveed); Schunkert, H. (Heribert); P.E.H. Schwarz (Peter); A.R. Shuldiner (Alan); J. Sinisalo (Juha); H. Snieder (Harold); T.I.A. Sørensen (Thorkild); T.D. Spector (Timothy); Staessen, J.A. (Jan A.); Stefania, B. (Bandinelli); U. Thorsteinsdottir (Unnur); M. Stumvoll (Michael); J.-C. Tardif (Jean-Claude); E. Tremoli (Elena); J. Tuomilehto (Jaakko); A.G. Uitterlinden (André); M. Uusitupa (Matti); A.L.M. Verbeek; S.H.H.M. Vermeulen (Sita); J. Viikari (Jorma); Vitart, V. (Veronique); H. Völzke (Henry); P. Vollenweider (Peter); G. Waeber (Gérard); M. Walker (Mark); H. Wallaschofski (Henri); N.J. Wareham (Nick); H. Watkins (Hugh); E. Zeggini (Eleftheria); A. Chakravarti (Aravinda); Clegg, D.J. (Deborah J.); L.A. Cupples (Adrienne); P. Gordon-Larsen (Penny); C.E. Jaquish (Cashell); D.C. Rao (Dabeeru C.); Abecasis, G.R. (Goncalo R.); T.L. Assimes (Themistocles); I.E. Barroso (Inês); S.I. Berndt (Sonja); M. Boehnke (Michael); P. Deloukas (Panagiotis); C.S. Fox (Caroline); L. Groop (Leif); D. Hunter (David); E. Ingelsson (Erik); R.C. Kaplan (Robert); McCarthy, M.I. (Mark I.); K.L. Mohlke (Karen); J.R. O´Connell; Schlessinger, D. (David); D.P. Strachan (David); J-A. Zwart (John-Anker); C.M. van Duijn (Cornelia); J.N. Hirschhorn (Joel); C.M. Lindgren (Cecilia M.); I.M. Heid (Iris); K.E. North (Kari); I.B. Borecki (Ingrid); Z. Kutalik (Zoltán); R.J.F. Loos (Ruth)

    2015-01-01

    textabstractGenome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ

  11. Incidental and clinically actionable genetic variants in 1005 whole exomes and genomes from Qatar

    Directory of Open Access Journals (Sweden)

    Abhinav Jain

    2017-10-01

    Full Text Available Next generation sequencing (NGS technologies such as whole genome and whole exome sequencing has enabled accurate diagnosis of genetic diseases through identification of variations at the genome wide level. While many large populations have been adequately covered in global sequencing efforts little is known on the genomic architecture of populations from Middle East, and South Asia and Africa. Incidental findings and their prevalence in populations have been extensively studied in populations of Caucasian descent. The recent emphasis on genomics and availability of genome-scale datasets in public domain for ethnic population in the Middle East prompted us to estimate the prevalence of incidental findings for this population. In this study, we used whole genome and exome data for a total 1005 non-related healthy individuals from Qatar population dataset which contained 20,930,177 variants. Systematic analysis of the variants in 59 genes recommended by the American College of Medical Genetics and Genomics for reporting of incidental findings revealed a total of 2 pathogenic and 2 likely pathogenic variants. Our analysis suggests the prevalence of incidental variants in population-scale datasets is approx. 0.6%, much lower than those reported for global populations. Our study underlines the essentiality to study population-scale genomes from ethnic groups to understand systematic differences in genetic variants associated with disease predisposition.

  12. Meta-analysis of genome-wide association from genomic prediction models

    Science.gov (United States)

    A limitation of many genome-wide association studies (GWA) in animal breeding is that there are many loci with small effect sizes; thus, larger sample sizes (N) are required to guarantee suitable power of detection. To increase sample size, results from different GWA can be combined in a meta-analys...

  13. Genome-Wide Association Study for Susceptibility to and Recoverability From Mastitis in Danish Holstein Cows

    Science.gov (United States)

    Welderufael, B. G.; Løvendahl, Peter; de Koning, Dirk-Jan; Janss, Lucas L. G.; Fikse, W. F.

    2018-01-01

    Because mastitis is very frequent and unavoidable, adding recovery information into the analysis for genetic evaluation of mastitis is of great interest from economical and animal welfare point of view. Here we have performed genome-wide association studies (GWAS) to identify associated single nucleotide polymorphisms (SNPs) and investigate the genetic background not only for susceptibility to – but also for recoverability from mastitis. Somatic cell count records from 993 Danish Holstein cows genotyped for a total of 39378 autosomal SNP markers were used for the association analysis. Single SNP regression analysis was performed using the statistical software package DMU. Substitution effect of each SNP was tested with a t-test and a genome-wide significance level of P-value mastitis were located in or very near to genes that have been reported for their role in the immune system. Genes involved in lymphocyte developments (e.g., MAST3 and STAB2) and genes involved in macrophage recruitment and regulation of inflammations (PDGFD and PTX3) were suggested as possible causal genes for susceptibility to – and recoverability from mastitis, respectively. However, this is the first GWAS study for recoverability from mastitis and our results need to be validated. The findings in the current study are, therefore, a starting point for further investigations in identifying causal genetic variants or chromosomal regions for both susceptibility to – and recoverability from mastitis. PMID:29755506

  14. Machine learning in genetics and genomics

    Science.gov (United States)

    Libbrecht, Maxwell W.; Noble, William Stafford

    2016-01-01

    The field of machine learning promises to enable computers to assist humans in making sense of large, complex data sets. In this review, we outline some of the main applications of machine learning to genetic and genomic data. In the process, we identify some recurrent challenges associated with this type of analysis and provide general guidelines to assist in the practical application of machine learning to real genetic and genomic data. PMID:25948244

  15. Nonlinear Analysis of Time Series in Genome-Wide Linkage Disequilibrium Data

    Science.gov (United States)

    Hernández-Lemus, Enrique; Estrada-Gil, Jesús K.; Silva-Zolezzi, Irma; Fernández-López, J. Carlos; Hidalgo-Miranda, Alfredo; Jiménez-Sánchez, Gerardo

    2008-02-01

    The statistical study of large scale genomic data has turned out to be a very important tool in population genetics. Quantitative methods are essential to understand and implement association studies in the biomedical and health sciences. Nevertheless, the characterization of recently admixed populations has been an elusive problem due to the presence of a number of complex phenomena. For example, linkage disequilibrium structures are thought to be more complex than their non-recently admixed population counterparts, presenting the so-called ancestry blocks, admixed regions that are not yet smoothed by the effect of genetic recombination. In order to distinguish characteristic features for various populations we have implemented several methods, some of them borrowed or adapted from the analysis of nonlinear time series in statistical physics and quantitative physiology. We calculate the main fractal dimensions (Kolmogorov's capacity, information dimension and correlation dimension, usually named, D0, D1 and D2). We also have made detrended fluctuation analysis and information based similarity index calculations for the probability distribution of correlations of linkage disequilibrium coefficient of six recently admixed (mestizo) populations within the Mexican Genome Diversity Project [1] and for the non-recently admixed populations in the International HapMap Project [2]. Nonlinear correlations showed up as a consequence of internal structure within the haplotype distributions. The analysis of these correlations as well as the scope and limitations of these procedures within the biomedical sciences are discussed.

  16. Genome-Wide Association Studies In Plant Pathosystems: Toward an Ecological Genomics Approach

    Directory of Open Access Journals (Sweden)

    Claudia Bartoli

    2017-05-01

    Full Text Available The emergence and re-emergence of plant pathogenic microorganisms are processes that imply perturbations in both host and pathogen ecological niches. Global change is largely assumed to drive the emergence of new etiological agents by altering the equilibrium of the ecological habitats which in turn places hosts more in contact with pathogen reservoirs. In this context, the number of epidemics is expected to increase dramatically in the next coming decades both in wild and crop plants. Under these considerations, the identification of the genetic variants underlying natural variation of resistance is a pre-requisite to estimate the adaptive potential of wild plant populations and to develop new breeding resistant cultivars. On the other hand, the prediction of pathogen's genetic determinants underlying disease emergence can help to identify plant resistance alleles. In the genomic era, whole genome sequencing combined with the development of statistical methods led to the emergence of Genome Wide Association (GWA mapping, a powerful tool for detecting genomic regions associated with natural variation of disease resistance in both wild and cultivated plants. However, GWA mapping has been less employed for the detection of genetic variants associated with pathogenicity in microbes. Here, we reviewed GWA studies performed either in plants or in pathogenic microorganisms (bacteria, fungi and oomycetes. In addition, we highlighted the benefits and caveats of the emerging joint GWA mapping approach that allows for the simultaneous identification of genes interacting between genomes of both partners. Finally, based on co-evolutionary processes in wild populations, we highlighted a phenotyping-free joint GWA mapping approach as a promising tool for describing the molecular landscape underlying plant - microbe interactions.

  17. Genome-wide association meta-analysis of fish and EPA+DHA consumption in 17 US and European cohorts.

    Directory of Open Access Journals (Sweden)

    Dariush Mozaffarian

    Full Text Available Regular fish and omega-3 consumption may have several health benefits and are recommended by major dietary guidelines. Yet, their intakes remain remarkably variable both within and across populations, which could partly owe to genetic influences.To identify common genetic variants that influence fish and dietary eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA consumption.We conducted genome-wide association (GWA meta-analysis of fish (n = 86,467 and EPA+DHA (n = 62,265 consumption in 17 cohorts of European descent from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium Nutrition Working Group. Results from cohort-specific GWA analyses (additive model for fish and EPA+DHA consumption were adjusted for age, sex, energy intake, and population stratification, and meta-analyzed separately using fixed-effect meta-analysis with inverse variance weights (METAL software. Additionally, heritability was estimated in 2 cohorts.Heritability estimates for fish and EPA+DHA consumption ranged from 0.13-0.24 and 0.12-0.22, respectively. A significant GWA for fish intake was observed for rs9502823 on chromosome 6: each copy of the minor allele (FreqA = 0.015 was associated with 0.029 servings/day (~1 serving/month lower fish consumption (P = 1.96x10-8. No significant association was observed for EPA+DHA, although rs7206790 in the obesity-associated FTO gene was among top hits (P = 8.18x10-7. Post-hoc calculations demonstrated 95% statistical power to detect a genetic variant associated with effect size of 0.05% for fish and 0.08% for EPA+DHA.These novel findings suggest that non-genetic personal and environmental factors are principal determinants of the remarkable variation in fish consumption, representing modifiable targets for increasing intakes among all individuals. Genes underlying the signal at rs72838923 and mechanisms for the association warrant further investigation.

  18. PEPIS: A Pipeline for Estimating Epistatic Effects in Quantitative Trait Locus Mapping and Genome-Wide Association Studies.

    Directory of Open Access Journals (Sweden)

    Wenchao Zhang

    2016-05-01

    Full Text Available The term epistasis refers to interactions between multiple genetic loci. Genetic epistasis is important in regulating biological function and is considered to explain part of the 'missing heritability,' which involves marginal genetic effects that cannot be accounted for in genome-wide association studies. Thus, the study of epistasis is of great interest to geneticists. However, estimating epistatic effects for quantitative traits is challenging due to the large number of interaction effects that must be estimated, thus significantly increasing computing demands. Here, we present a new web server-based tool, the Pipeline for estimating EPIStatic genetic effects (PEPIS, for analyzing polygenic epistatic effects. The PEPIS software package is based on a new linear mixed model that has been used to predict the performance of hybrid rice. The PEPIS includes two main sub-pipelines: the first for kinship matrix calculation, and the second for polygenic component analyses and genome scanning for main and epistatic effects. To accommodate the demand for high-performance computation, the PEPIS utilizes C/C++ for mathematical matrix computing. In addition, the modules for kinship matrix calculations and main and epistatic-effect genome scanning employ parallel computing technology that effectively utilizes multiple computer nodes across our networked cluster, thus significantly improving the computational speed. For example, when analyzing the same immortalized F2 rice population genotypic data examined in a previous study, the PEPIS returned identical results at each analysis step with the original prototype R code, but the computational time was reduced from more than one month to about five minutes. These advances will help overcome the bottleneck frequently encountered in genome wide epistatic genetic effect analysis and enable accommodation of the high computational demand. The PEPIS is publically available at http://bioinfo.noble.org/PolyGenic_QTL/.

  19. PEPIS: A Pipeline for Estimating Epistatic Effects in Quantitative Trait Locus Mapping and Genome-Wide Association Studies.

    Science.gov (United States)

    Zhang, Wenchao; Dai, Xinbin; Wang, Qishan; Xu, Shizhong; Zhao, Patrick X

    2016-05-01

    The term epistasis refers to interactions between multiple genetic loci. Genetic epistasis is important in regulating biological function and is considered to explain part of the 'missing heritability,' which involves marginal genetic effects that cannot be accounted for in genome-wide association studies. Thus, the study of epistasis is of great interest to geneticists. However, estimating epistatic effects for quantitative traits is challenging due to the large number of interaction effects that must be estimated, thus significantly increasing computing demands. Here, we present a new web server-based tool, the Pipeline for estimating EPIStatic genetic effects (PEPIS), for analyzing polygenic epistatic effects. The PEPIS software package is based on a new linear mixed model that has been used to predict the performance of hybrid rice. The PEPIS includes two main sub-pipelines: the first for kinship matrix calculation, and the second for polygenic component analyses and genome scanning for main and epistatic effects. To accommodate the demand for high-performance computation, the PEPIS utilizes C/C++ for mathematical matrix computing. In addition, the modules for kinship matrix calculations and main and epistatic-effect genome scanning employ parallel computing technology that effectively utilizes multiple computer nodes across our networked cluster, thus significantly improving the computational speed. For example, when analyzing the same immortalized F2 rice population genotypic data examined in a previous study, the PEPIS returned identical results at each analysis step with the original prototype R code, but the computational time was reduced from more than one month to about five minutes. These advances will help overcome the bottleneck frequently encountered in genome wide epistatic genetic effect analysis and enable accommodation of the high computational demand. The PEPIS is publically available at http://bioinfo.noble.org/PolyGenic_QTL/.

  20. Genetics, genomes and cloning the biotechnology revolution

    CERN Document Server

    CERN. Geneva

    1999-01-01

    As this century draws to a close, spectacular advances in the fields of genomics and genetics are opening up dramatic new horizons for medicine. For much of the 20th century, genetic research has focused on rare diseases caused by mutations in a particular gene. However, more recently it has been realised that common genetic variations (polymorphisms), interacting with the environment, can influence an individual's susceptibility to diseases widely represented in our populations (e.g. mental illness and asthma), redefining the term "genetic disease". Officially starting in 1990, the Human Genome Project was a $3-billion, 15-year program to find the estimated 80,000 human genes and determine the sequence of the 3 billion DNA building blocks that underlie all of human biology and its diversity. The resulting boom in genetic information and technologies, not only from humans, but from many other organisms, means that we now have new tools to understand and treat normal and disease states. This information is bei...

  1. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits.

    Directory of Open Access Journals (Sweden)

    Angelo Scuteri

    2007-07-01

    Full Text Available The obesity epidemic is responsible for a substantial economic burden in developed countries and is a major risk factor for type 2 diabetes and cardiovascular disease. The disease is the result not only of several environmental risk factors, but also of genetic predisposition. To take advantage of recent advances in gene-mapping technology, we executed a genome-wide association scan to identify genetic variants associated with obesity-related quantitative traits in the genetically isolated population of Sardinia. Initial analysis suggested that several SNPs in the FTO and PFKP genes were associated with increased BMI, hip circumference, and weight. Within the FTO gene, rs9930506 showed the strongest association with BMI (p = 8.6 x10(-7, hip circumference (p = 3.4 x 10(-8, and weight (p = 9.1 x 10(-7. In Sardinia, homozygotes for the rare "G" allele of this SNP (minor allele frequency = 0.46 were 1.3 BMI units heavier than homozygotes for the common "A" allele. Within the PFKP gene, rs6602024 showed very strong association with BMI (p = 4.9 x 10(-6. Homozygotes for the rare "A" allele of this SNP (minor allele frequency = 0.12 were 1.8 BMI units heavier than homozygotes for the common "G" allele. To replicate our findings, we genotyped these two SNPs in the GenNet study. In European Americans (N = 1,496 and in Hispanic Americans (N = 839, we replicated significant association between rs9930506 in the FTO gene and BMI (p-value for meta-analysis of European American and Hispanic American follow-up samples, p = 0.001, weight (p = 0.001, and hip circumference (p = 0.0005. We did not replicate association between rs6602024 and obesity-related traits in the GenNet sample, although we found that in European Americans, Hispanic Americans, and African Americans, homozygotes for the rare "A" allele were, on average, 1.0-3.0 BMI units heavier than homozygotes for the more common "G" allele. In summary, we have completed a whole genome-association scan for

  2. Genome-Wide Analysis of Microsatellite Markers Based on Sequenced Database in Chinese Spring Wheat (Triticum aestivum L..

    Directory of Open Access Journals (Sweden)

    Bin Han

    Full Text Available Microsatellites or simple sequence repeats (SSRs are distributed across both prokaryotic and eukaryotic genomes and have been widely used for genetic studies and molecular marker-assisted breeding in crops. Though an ordered draft sequence of hexaploid bread wheat have been announced, the researches about systemic analysis of SSRs for wheat still have not been reported so far. In the present study, we identified 364,347 SSRs from among 10,603,760 sequences of the Chinese spring wheat (CSW genome, which were present at a density of 36.68 SSR/Mb. In total, we detected 488 types of motifs ranging from di- to hexanucleotides, among which dinucleotide repeats dominated, accounting for approximately 42.52% of the genome. The density of tri- to hexanucleotide repeats was 24.97%, 4.62%, 3.25% and 24.65%, respectively. AG/CT, AAG/CTT, AGAT/ATCT, AAAAG/CTTTT and AAAATT/AATTTT were the most frequent repeats among di- to hexanucleotide repeats. Among the 21 chromosomes of CSW, the density of repeats was highest on chromosome 2D and lowest on chromosome 3A. The proportions of di-, tri-, tetra-, penta- and hexanucleotide repeats on each chromosome, and even on the whole genome, were almost identical. In addition, 295,267 SSR markers were successfully developed from the 21 chromosomes of CSW, which cover the entire genome at a density of 29.73 per Mb. All of the SSR markers were validated by reverse electronic-Polymerase Chain Reaction (re-PCR; 70,564 (23.9% were found to be monomorphic and 224,703 (76.1% were found to be polymorphic. A total of 45 monomorphic markers were selected randomly for validation purposes; 24 (53.3% amplified one locus, 8 (17.8% amplified multiple identical loci, and 13 (28.9% did not amplify any fragments from the genomic DNA of CSW. Then a dendrogram was generated based on the 24 monomorphic SSR markers among 20 wheat cultivars and three species of its diploid ancestors showing that monomorphic SSR markers represented a promising

  3. Genome-wide association studies in asthma: progress and pitfalls

    Directory of Open Access Journals (Sweden)

    March ME

    2015-01-01

    Full Text Available Michael E March,1 Patrick MA Sleiman,1,2 Hakon Hakonarson1,2 1Center for Applied Genomics, Children's Hospital of Philadelphia Research Institute, 2Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Abstract: Genetic studies of asthma have revealed that there is considerable heritability to the phenotype. An extensive history of candidate-gene studies has identified a long list of genes associated with immune function that are potentially involved in asthma pathogenesis. However, many of the results of candidate-gene studies have failed to be replicated, leaving in question the true impact of the implicated biological pathways on asthma. With the advent of genome-wide association studies, geneticists are able to examine the association of hundreds of thousands of genetic markers with a phenotype, allowing the hypothesis-free identification of variants associated with disease. Many such studies examining asthma or related phenotypes have been published, and several themes have begun to emerge regarding the biological pathways underpinning asthma. The results of many genome-wide association studies have currently not been replicated, and the large sample sizes required for this experimental strategy invoke difficulties with sample stratification and phenotypic heterogeneity. Recently, large collaborative groups of researchers have formed consortia focused on asthma, with the goals of sharing material and data and standardizing diagnosis and experimental methods. Additionally, research has begun to focus on genetic variants that affect the response to asthma medications and on the biology that generates the heterogeneity in the asthma phenotype. As this work progresses, it will move asthma patients closer to more specific, personalized medicine. Keywords: asthma, genetics, GWAS, pharmacogenetics, biomarkers

  4. Genome-wide methylation study of diploid and triploid brown trout (Salmo trutta L.).

    Science.gov (United States)

    Covelo-Soto, L; Leunda, P M; Pérez-Figueroa, A; Morán, P

    2015-06-01

    The induction of triploidization in fish is a very common practice in aquaculture. Although triploidization has been applied successfully in many salmonid species, little is known about the epigenetic mechanisms implicated in the maintenance of the normal functions of the new polyploid genome. By means of methylation-sensitive amplified polymorphism (MSAP) techniques, genome-wide methylation changes associated with triploidization were assessed in DNA samples obtained from diploid and triploid siblings of brown trout (Salmo trutta). Simple comparative body measurements showed that the triploid trout used in the study were statistically bigger, however, not heavier than their diploid counterparts. The statistical analysis of the MSAP data showed no significant differences between diploid and triploid brown trout in respect to brain, gill, heart, liver, kidney or muscle samples. Nonetheless, local analysis pointed to the possibility of differences in connection with concrete loci. This is the first study that has investigated DNA methylation alterations associated with triploidization in brown trout. Our results set the basis for new studies to be undertaken and provide a new approach concerning triploidization effects of the salmonid genome while also contributing to the better understanding of the genome-wide methylation processes. © 2015 Stichting International Foundation for Animal Genetics.

  5. Genotyping-By-Sequencing for Plant Genetic Diversity Analysis: A Lab Guide for SNP Genotyping

    Directory of Open Access Journals (Sweden)

    Gregory W. Peterson

    2014-10-01

    Full Text Available Genotyping-by-sequencing (GBS has recently emerged as a promising genomic approach for exploring plant genetic diversity on a genome-wide scale. However, many uncertainties and challenges remain in the application of GBS, particularly in non-model species. Here, we present a GBS protocol we developed and use for plant genetic diversity analysis. It uses two restriction enzymes to reduce genome complexity, applies Illumina multiplexing indexes for barcoding and has a custom bioinformatics pipeline for genotyping. This genetic diversity-focused GBS (gd-GBS protocol can serve as an easy-to-follow lab guide to assist a researcher through every step of a GBS application with five main components: sample preparation, library assembly, sequencing, SNP calling and diversity analysis. Specifically, in this presentation, we provide a brief overview of the GBS approach, describe the gd-GBS procedures, illustrate it with an application to analyze genetic diversity in 20 flax (Linum usitatissimum L. accessions and discuss related issues in GBS application. Following these lab bench procedures and using the custom bioinformatics pipeline, one could generate genome-wide SNP genotype data for a conventional genetic diversity analysis of a non-model plant species.

  6. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease

    NARCIS (Netherlands)

    Nalls, Mike A.; Pankratz, Nathan; Lill, Christina M.; Do, Chuong B.; Hernandez, Dena G.; Saad, Mohamad; DeStefano, Anita L.; Kara, Eleanna; Bras, Jose; Sharma, Manu; Schulte, Claudia; Keller, Margaux F.; Arepalli, Sampath; Letson, Christopher; Edsall, Connor; Stefansson, Hreinn; Liu, Xinmin; Pliner, Hannah; Lee, Joseph H.; Cheng, Rong; Ikram, M. Arfan; Ioannidis, John P. A.; Hadjigeorgiou, Georgios M.; Bis, Joshua C.; Martinez, Maria; Perlmutter, Joel S.; Goate, Alison; Marder, Karen; Fiske, Brian; Sutherland, Margaret; Xiromerisiou, Georgia; Myers, Richard H.; Clark, Lorraine N.; Stefansson, Kari; Hardy, John A.; Heutink, Peter; Chen, Honglei; Wood, Nicholas W.; Houlden, Henry; Payami, Haydeh; Brice, Alexis; Scott, William K.; Gasser, Thomas; Bertram, Lars; Eriksson, Nicholas; Foroud, Tatiana; Singleton, Andrew B.; Plagnol, Vincent; Sheerin, Una-Marie; Simón-Sánchez, Javier; Lesage, Suzanne; Sveinbjörnsdóttir, Sigurlaug; Barker, Roger; Ben-Shlomo, Yoav; Berendse, Henk W.; Berg, Daniela; Bhatia, Kailash; de Bie, Rob M. A.; Biffi, Alessandro; Bloem, Bas; Bochdanovits, Zoltan; Bonin, Michael; Bras, Jose M.; Brockmann, Kathrin; Brooks, Janet; Burn, David J.; Charlesworth, Gavin; Chinnery, Patrick F.; Chong, Sean; Clarke, Carl E.; Cookson, Mark R.; Cooper, J. Mark; Corvol, Jean Christophe; Counsell, Carl; Damier, Philippe; Dartigues, Jean-François; Deloukas, Panos; Deuschl, Günther; Dexter, David T.; van Dijk, Karin D.; Dillman, Allissa; Durif, Frank; Dürr, Alexandra; Edkins, Sarah; Evans, Jonathan R.; Foltynie, Thomas; Dong, Jing; Gardner, Michelle; Gibbs, J. Raphael; Gray, Emma; Guerreiro, Rita; Harris, Clare; van Hilten, Jacobus J.; Hofman, Albert; Hollenbeck, Albert; Holton, Janice; Hu, Michele; Huang, Xuemei; Wurster, Isabel; Mätzler, Walter; Hudson, Gavin; Hunt, Sarah E.; Huttenlocher, Johanna; Illig, Thomas; Jónsson, Pálmi V.; Lambert, Jean-Charles; Langford, Cordelia; Lees, Andrew; Lichtner, Peter; Limousin, Patricia; Lopez, Grisel; Lorenz, Delia; McNeill, Alisdair; Moorby, Catriona; Moore, Matthew; Morris, Huw R.; Morrison, Karen E.; Mudanohwo, Ese; O'Sullivan, Sean S.; Pearson, Justin; Pétursson, Hjörvar; Pollak, Pierre; Post, Bart; Potter, Simon; Ravina, Bernard; Revesz, Tamas; Riess, Olaf; Rivadeneira, Fernando; Rizzu, Patrizia; Ryten, Mina; Sawcer, Stephen; Schapira, Anthony; Scheffer, Hans; Shaw, Karen; Shoulson, Ira; Sidransky, Ellen; Smith, Colin; Spencer, Chris C. A.; Stefánsson, Hreinn; Bettella, Francesco; Stockton, Joanna D.; Strange, Amy; Talbot, Kevin; Tanner, Carlie M.; Tashakkori-Ghanbaria, Avazeh; Tison, François; Trabzuni, Daniah; Traynor, Bryan J.; Uitterlinden, André G.; Velseboer, Daan; Vidailhet, Marie; Walker, Robert; van de Warrenburg, Bart; Wickremaratchi, Mirdhu; Williams, Nigel; Williams-Gray, Caroline H.; Winder-Rhodes, Sophie; Stefánsson, Kári; Hardy, John; Factor, S.; Higgins, D.; Evans, S.; Shill, H.; Stacy, M.; Danielson, J.; Marlor, L.; Williamson, K.; Jankovic, J.; Hunter, C.; Simon, D.; Ryan, P.; Scollins, L.; Saunders-Pullman, R.; Boyar, K.; Costan-Toth, C.; Ohmann, E.; Sudarsky, L.; Joubert, C.; Friedman, J.; Chou, K.; Fernandez, H.; Lannon, M.; Galvez-Jimenez, N.; Podichetty, A.; Thompson, K.; Lewitt, P.; Deangelis, M.; O'Brien, C.; Seeberger, L.; Dingmann, C.; Judd, D.; Marder, K.; Fraser, J.; Harris, J.; Bertoni, J.; Peterson, C.; Rezak, M.; Medalle, G.; Chouinard, S.; Panisset, M.; Hall, J.; Poiffaut, H.; Calabrese, V.; Roberge, P.; Wojcieszek, J.; Belden, J.; Jennings, D.; Marek, K.; Mendick, S.; Reich, S.; Dunlop, B.; Jog, M.; Horn, C.; Uitti, R.; Turk, M.; Ajax, T.; Mannetter, J.; Sethi, K.; Carpenter, J.; Dill, B.; Hatch, L.; Ligon, K.; Narayan, S.; Blindauer, K.; Abou-Samra, K.; Petit, J.; Elmer, L.; Aiken, E.; Davis, K.; Schell, C.; Wilson, S.; Velickovic, M.; Koller, W.; Phipps, S.; Feigin, A.; Gordon, M.; Hamann, J.; Licari, E.; Marotta-Kollarus, M.; Shannon, B.; Winnick, R.; Simuni, T.; Videnovic, A.; Kaczmarek, A.; Williams, K.; Wolff, M.; Rao, J.; Cook, M.; Fernandez, M.; Kostyk, S.; Hubble, J.; Campbell, A.; Reider, C.; Seward, A.; Camicioli, R.; Carter, J.; Nutt, J.; Andrews, P.; Morehouse, S.; Stone, C.; Mendis, T.; Grimes, D.; Alcorn-Costa, C.; Gray, P.; Haas, K.; Vendette, J.; Sutton, J.; Hutchinson, B.; Young, J.; Rajput, A.; Klassen, L.; Shirley, T.; Manyam, B.; Simpson, P.; Whetteckey, J.; Wulbrecht, B.; Truong, D.; Pathak, M.; Frei, K.; Luong, N.; Tra, T.; Tran, A.; Vo, J.; Lang, A.; Kleiner- Fisman, G.; Nieves, A.; Johnston, L.; So, J.; Podskalny, G.; Giffin, L.; Atchison, P.; Allen, C.; Martin, W.; Wieler, M.; Suchowersky, O.; Furtado, S.; Klimek, M.; Hermanowicz, N.; Niswonger, S.; Shults, C.; Fontaine, D.; Aminoff, M.; Christine, C.; Diminno, M.; Hevezi, J.; Dalvi, A.; Kang, U.; Richman, J.; Uy, S.; Sahay, A.; Gartner, M.; Schwieterman, D.; Hall, D.; Leehey, M.; Culver, S.; Derian, T.; Demarcaida, T.; Thurlow, S.; Rodnitzky, R.; Dobson, J.; Lyons, K.; Pahwa, R.; Gales, T.; Thomas, S.; Shulman, L.; Weiner, W.; Dustin, K.; Singer, C.; Zelaya, L.; Tuite, P.; Hagen, V.; Rolandelli, S.; Schacherer, R.; Kosowicz, J.; Gordon, P.; Werner, J.; Serrano, C.; Roque, S.; Kurlan, R.; Berry, D.; Gardiner, I.; Hauser, R.; Sanchez-Ramos, J.; Zesiewicz, T.; Delgado, H.; Price, K.; Rodriguez, P.; Wolfrath, S.; Pfeiffer, R.; Davis, L.; Pfeiffer, B.; Dewey, R.; Hayward, B.; Johnson, A.; Meacham, M.; Estes, B.; Walker, F.; Hunt, V.; O'Neill, C.; Racette, B.; Swisher, L.; Dijamco, Cheri; Conley, Emily Drabant; Dorfman, Elizabeth; Tung, Joyce Y.; Hinds, David A.; Mountain, Joanna L.; Wojcicki, Anne; Lew, M.; Klein, C.; Golbe, L.; Growdon, J.; Wooten, G. F.; Watts, R.; Guttman, M.; Goldwurm, S.; Saint-Hilaire, M. H.; Baker, K.; Litvan, I.; Nicholson, G.; Nance, M.; Drasby, E.; Isaacson, S.; Burn, D.; Pramstaller, P.; Al-hinti, J.; Moller, A.; Sherman, S.; Roxburgh, R.; Slevin, J.; Perlmutter, J.; Mark, M. H.; Huggins, N.; Pezzoli, G.; Massood, T.; Itin, I.; Corbett, A.; Chinnery, P.; Ostergaard, K.; Snow, B.; Cambi, F.; Kay, D.; Samii, A.; Agarwal, P.; Roberts, J. W.; Higgins, D. S.; Molho, Eric; Rosen, Ami; Montimurro, J.; Martinez, E.; Griffith, A.; Kusel, V.; Yearout, D.; Zabetian, C.; Clark, L. N.; Liu, X.; Lee, J. H.; Taub, R. Cheng; Louis, E. D.; Cote, L. J.; Waters, C.; Ford, B.; Fahn, S.; Vance, Jeffery M.; Beecham, Gary W.; Martin, Eden R.; Nuytemans, Karen; Pericak-Vance, Margaret A.; Haines, Jonathan L.; DeStefano, Anita; Seshadri, Sudha; Choi, Seung Hoan; Frank, Samuel; Psaty, Bruce M.; Rice, Kenneth; Longstreth, W. T.; Ton, Thanh G. N.; Jain, Samay; van Duijn, Cornelia M.; Verlinden, Vincent J.; Koudstaal, Peter J.; Singleton, Andrew; Cookson, Mark; Hernandez, Dena; Nalls, Michael; Zonderman, Alan; Ferrucci, Luigi; Johnson, Robert; Longo, Dan; O'Brien, Richard; Traynor, Bryan; Troncoso, Juan; van der Brug, Marcel; Zielke, Ronald; Weale, Michael; Ramasamy, Adaikalavan; Dardiotis, Efthimios; Tsimourtou, Vana; Spanaki, Cleanthe; Plaitakis, Andreas; Bozi, Maria; Stefanis, Leonidas; Vassilatis, Dimitris; Koutsis, Georgios; Panas, Marios; Lunnon, Katie; Lupton, Michelle; Powell, John; Parkkinen, Laura; Ansorge, Olaf

    2014-01-01

    We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were

  7. Genetic diversity analysis of two commercial breeds of pigs using genomic and pedigree data.

    Science.gov (United States)

    Zanella, Ricardo; Peixoto, Jane O; Cardoso, Fernando F; Cardoso, Leandro L; Biegelmeyer, Patrícia; Cantão, Maurício E; Otaviano, Antonio; Freitas, Marcelo S; Caetano, Alexandre R; Ledur, Mônica C

    2016-03-30

    Genetic improvement in livestock populations can be achieved without significantly affecting genetic diversity if mating systems and selection decisions take genetic relationships among individuals into consideration. The objective of this study was to examine the genetic diversity of two commercial breeds of pigs. Genotypes from 1168 Landrace (LA) and 1094 Large White (LW) animals from a commercial breeding program in Brazil were obtained using the Illumina PorcineSNP60 Beadchip. Inbreeding estimates based on pedigree (F x) and genomic information using runs of homozygosity (F ROH) and the single nucleotide polymorphisms (SNP) by SNP inbreeding coefficient (F SNP) were obtained. Linkage disequilibrium (LD), correlation of linkage phase (r) and effective population size (N e ) were also estimated. Estimates of inbreeding obtained with pedigree information were lower than those obtained with genomic data in both breeds. We observed that the extent of LD was slightly larger at shorter distances between SNPs in the LW population than in the LA population, which indicates that the LW population was derived from a smaller N e . Estimates of N e based on genomic data were equal to 53 and 40 for the current populations of LA and LW, respectively. The correlation of linkage phase between the two breeds was equal to 0.77 at distances up to 50 kb, which suggests that genome-wide association and selection should be performed within breed. Although selection intensities have been stronger in the LA breed than in the LW breed, levels of genomic and pedigree inbreeding were lower for the LA than for the LW breed. The use of genomic data to evaluate population diversity in livestock animals can provide new and more precise insights about the effects of intense selection for production traits. Resulting information and knowledge can be used to effectively increase response to selection by appropriately managing the rate of inbreeding, minimizing negative effects of inbreeding

  8. Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene

    NARCIS (Netherlands)

    Kayser, Manfred; Liu, Fan; Janssens, A. Cecile J. W.; Rivadeneira, Fernando; Lao, Oscar; van Duijn, Kate; Vermeulen, Mark; Arp, Pascal; Jhamai, Mila M.; van Ijcken, Wilfred F. J.; den Dunnen, Johan T.; Heath, Simon; Zelenika, Diana; Despriet, Dominiek D. G.; Klaver, Caroline C. W.; Vingerling, Johannes R.; de Jong, Paulus T. V. M.; Hofman, Albert; Aulchenko, Yurii S.; Uitterlinden, Andre G.; Oostra, Ben A.; van Duijn, Cornelia M.

    2008-01-01

    Human iris color was one of the first traits for which Mendelian segregation was established. To date, the genetics of iris color is still not fully understood and is of interest, particularly in view of forensic applications. In three independent genome-wide association (GWA) studies of a total of

  9. Genome wide association study identifies KCNMA1 contributing to human obesity

    DEFF Research Database (Denmark)

    Jiao, Hong; Arner, Peter; Hoffstedt, Johan

    2011-01-01

    Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population....... Thus many genetic variants controlling obesity remain to be identified. The aim of this study was to use GWA followed by multiple stepwise validations to identify additional genes associated with obesity....

  10. Genome wide study of maternal and parent-of-origin effects on the etiology of orofacial clefts

    DEFF Research Database (Denmark)

    Shi, Min; Murray, Jeff; Marazita, Mary L

    2012-01-01

    We performed a genome wide association analysis of maternally-mediated genetic effects and parent-of-origin (POO) effects on risk of orofacial clefting (OC) using over 2,000 case-parent triads collected through an international cleft consortium. We used log-linear regression models to test indivi...... individual SNPs. For SNPs with a P-value...

  11. Genome-wide search for gene-gene interactions in colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Shuo Jiao

    Full Text Available Genome-wide association studies (GWAS have successfully identified a number of single-nucleotide polymorphisms (SNPs associated with colorectal cancer (CRC risk. However, these susceptibility loci known today explain only a small fraction of the genetic risk. Gene-gene interaction (GxG is considered to be one source of the missing heritability. To address this, we performed a genome-wide search for pair-wise GxG associated with CRC risk using 8,380 cases and 10,558 controls in the discovery phase and 2,527 cases and 2,658 controls in the replication phase. We developed a simple, but powerful method for testing interaction, which we term the Average Risk Due to Interaction (ARDI. With this method, we conducted a genome-wide search to identify SNPs showing evidence for GxG with previously identified CRC susceptibility loci from 14 independent regions. We also conducted a genome-wide search for GxG using the marginal association screening and examining interaction among SNPs that pass the screening threshold (p<10(-4. For the known locus rs10795668 (10p14, we found an interacting SNP rs367615 (5q21 with replication p = 0.01 and combined p = 4.19×10(-8. Among the top marginal SNPs after LD pruning (n = 163, we identified an interaction between rs1571218 (20p12.3 and rs10879357 (12q21.1 (nominal combined p = 2.51×10(-6; Bonferroni adjusted p = 0.03. Our study represents the first comprehensive search for GxG in CRC, and our results may provide new insight into the genetic etiology of CRC.

  12. Genetic variants associated with subjective well-being, depressive symptoms and neuroticism identified through genome-wide analyses

    Science.gov (United States)

    Derringer, Jaime; Gratten, Jacob; Lee, James J; Liu, Jimmy Z; de Vlaming, Ronald; Ahluwalia, Tarunveer S; Buchwald, Jadwiga; Cavadino, Alana; Frazier-Wood, Alexis C; Davies, Gail; Furlotte, Nicholas A; Garfield, Victoria; Geisel, Marie Henrike; Gonzalez, Juan R; Haitjema, Saskia; Karlsson, Robert; van der Laan, Sander W; Ladwig, Karl-Heinz; Lahti, Jari; van der Lee, Sven J; Miller, Michael B; Lind, Penelope A; Liu, Tian; Matteson, Lindsay; Mihailov, Evelin; Minica, Camelia C; Nolte, Ilja M; Mook-Kanamori, Dennis O; van der Most, Peter J; Oldmeadow, Christopher; Qian, Yong; Raitakari, Olli; Rawal, Rajesh; Realo, Anu; Rueedi, Rico; Schmidt, Börge; Smith, Albert V; Stergiakouli, Evie; Tanaka, Toshiko; Taylor, Kent; Thorleifsson, Gudmar; Wedenoja, Juho; Wellmann, Juergen; Westra, Harm-Jan; Willems, Sara M; Zhao, Wei; Amin, Najaf; Bakshi, Andrew; Bergmann, Sven; Bjornsdottir, Gyda; Boyle, Patricia A; Cherney, Samantha; Cox, Simon R; Davis, Oliver S P; Ding, Jun; Direk, Nese; Eibich, Peter; Emeny, Rebecca T; Fatemifar, Ghazaleh; Faul, Jessica D; Ferrucci, Luigi; Forstner, Andreas J; Gieger, Christian; Gupta, Richa; Harris, Tamara B; Harris, Juliette M; Holliday, Elizabeth G; Hottenga, Jouke-Jan; De Jager, Philip L; Kaakinen, Marika A; Kajantie, Eero; Karhunen, Ville; Kolcic, Ivana; Kumari, Meena; Launer, Lenore J; Franke, Lude; Li-Gao, Ruifang; Liewald, David C; Koini, Marisa; Loukola, Anu; Marques-Vidal, Pedro; Montgomery, Grant W; Mosing, Miriam A; Paternoster, Lavinia; Pattie, Alison; Petrovic, Katja E; Pulkki-Råback, Laura; Quaye, Lydia; Räikkönen, Katri; Rudan, Igor; Scott, Rodney J; Smith, Jennifer A; Sutin, Angelina R; Trzaskowski, Maciej; Vinkhuyzen, Anna E; Yu, Lei; Zabaneh, Delilah; Attia, John R; Bennett, David A; Berger, Klaus; Bertram, Lars; Boomsma, Dorret I; Snieder, Harold; Chang, Shun-Chiao; Cucca, Francesco; Deary, Ian J; van Duijn, Cornelia M; Eriksson, Johan G; Bültmann, Ute; de Geus, Eco J C; Groenen, Patrick J F; Gudnason, Vilmundur; Hansen, Torben; Hartman, Catharine A; Haworth, Claire M A; Hayward, Caroline; Heath, Andrew C; Hinds, David A; Hyppönen, Elina; Iacono, William G; Järvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L R; Keltikangas-Järvinen, Liisa; Kraft, Peter; Kubzansky, Laura D; Lehtimäki, Terho; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; Metspalu, Andres; Mills, Melinda; de Mutsert, Renée; Oldehinkel, Albertine J; Pasterkamp, Gerard; Pedersen, Nancy L; Plomin, Robert; Polasek, Ozren; Power, Christine; Rich, Stephen S; Rosendaal, Frits R; den Ruijter, Hester M; Schlessinger, David; Schmidt, Helena; Svento, Rauli; Schmidt, Reinhold; Alizadeh, Behrooz Z; Sørensen, Thorkild I A; Spector, Tim D; Starr, John M; Stefansson, Kari; Steptoe, Andrew; Terracciano, Antonio; Thorsteinsdottir, Unnur; Thurik, A Roy; Timpson, Nicholas J; Tiemeier, Henning; Uitterlinden, André G; Vollenweider, Peter; Wagner, Gert G; Weir, David R; Yang, Jian; Conley, Dalton C; Smith, George Davey; Hofman, Albert; Johannesson, Magnus; Laibson, David I; Medland, Sarah E; Meyer, Michelle N; Pickrell, Joseph K; Esko, Tõnu; Krueger, Robert F; Beauchamp, Jonathan P; Koellinger, Philipp D; Benjamin, Daniel J; Bartels, Meike; Cesarini, David

    2016-01-01

    We conducted genome-wide association studies of three phenotypes: subjective well-being (N = 298,420), depressive symptoms (N = 161,460), and neuroticism (N = 170,910). We identified three variants associated with subjective well-being, two with depressive symptoms, and eleven with neuroticism, including two inversion polymorphisms. The two depressive symptoms loci replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings, and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal/pancreas tissues are strongly enriched for association. PMID:27089181

  13. Moving into a new era of periodontal genetic studies: relevance of large case-control samples using severe phenotypes for genome-wide association studies.

    Science.gov (United States)

    Vaithilingam, R D; Safii, S H; Baharuddin, N A; Ng, C C; Cheong, S C; Bartold, P M; Schaefer, A S; Loos, B G

    2014-12-01

    Studies to elucidate the role of genetics as a risk factor for periodontal disease have gone through various phases. In the majority of cases, the initial 'hypothesis-dependent' candidate-gene polymorphism studies did not report valid genetic risk loci. Following a large-scale replication study, these initially positive results are believed to be caused by type 1 errors. However, susceptibility genes, such as CDKN2BAS (Cyclin Dependend KiNase 2B AntiSense RNA; alias ANRIL [ANtisense Rna In the Ink locus]), glycosyltransferase 6 domain containing 1 (GLT6D1) and cyclooxygenase 2 (COX2), have been reported as conclusive risk loci of periodontitis. The search for genetic risk factors accelerated with the advent of 'hypothesis-free' genome-wide association studies (GWAS). However, despite many different GWAS being performed for almost all human diseases, only three GWAS on periodontitis have been published - one reported genome-wide association of GLT6D1 with aggressive periodontitis (a severe phenotype of periodontitis), whereas the remaining two, which were performed on patients with chronic periodontitis, were not able to find significant associations. This review discusses the problems faced and the lessons learned from the search for genetic risk variants of periodontitis. Current and future strategies for identifying genetic variance in periodontitis, and the importance of planning a well-designed genetic study with large and sufficiently powered case-control samples of severe phenotypes, are also discussed. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Genome-wide patterns of copy number variation in the diversified chicken genomes using next-generation sequencing.

    Science.gov (United States)

    Yi, Guoqiang; Qu, Lujiang; Liu, Jianfeng; Yan, Yiyuan; Xu, Guiyun; Yang, Ning

    2014-11-07

    Copy number variation (CNV) is important and widespread in the genome, and is a major cause of disease and phenotypic diversity. Herein, we performed a genome-wide CNV analysis in 12 diversified chicken genomes based on whole genome sequencing. A total of 8,840 CNV regions (CNVRs) covering 98.2 Mb and representing 9.4% of the chicken genome were identified, ranging in size from 1.1 to 268.8 kb with an average of 11.1 kb. Sequencing-based predictions were confirmed at a high validation rate by two independent approaches, including array comparative genomic hybridization (aCGH) and quantitative PCR (qPCR). The Pearson's correlation coefficients between sequencing and aCGH results ranged from 0.435 to 0.755, and qPCR experiments revealed a positive validation rate of 91.71% and a false negative rate of 22.43%. In total, 2,214 (25.0%) predicted CNVRs span 2,216 (36.4%) RefSeq genes associated with specific biological functions. Besides two previously reported copy number variable genes EDN3 and PRLR, we also found some promising genes with potential in phenotypic variation. Two genes, FZD6 and LIMS1, related to disease susceptibility/resistance are covered by CNVRs. The highly duplicated SOCS2 may lead to higher bone mineral density. Entire or partial duplication of some genes like POPDC3 may have great economic importance in poultry breeding. Our results based on extensive genetic diversity provide a more refined chicken CNV map and genome-wide gene copy number estimates, and warrant future CNV association studies for important traits in chickens.

  15. Genome-wide single-generation signatures of local selection in the panmictic European eel

    DEFF Research Database (Denmark)

    Pujolar, J. M.; Jacobsen, M. W.; Als, Thomas Damm

    2014-01-01

    Next-generation sequencing and the collection of genome-wide data allow identifying adaptive variation and footprints of directional selection. Using a large SNP data set from 259 RAD-sequenced European eel individuals (glass eels) from eight locations between 34 and 64oN, we examined the patterns...... of genome-wide genetic diversity across locations. We tested for local selection by searching for increased population differentiation using FST-based outlier tests and by testing for significant associations between allele frequencies and environmental variables. The overall low genetic differentiation...... with single-generation signatures of spatially varying selection acting on glass eels. After screening 50 354 SNPs, a total of 754 potentially locally selected SNPs were identified. Candidate genes for local selection constituted a wide array of functions, including calcium signalling, neuroactive ligand...

  16. A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure

    NARCIS (Netherlands)

    Sung, Yun J.; Winkler, Thomas W.; de las Fuentes, Lisa; Bentley, Amy R.; Brown, Michael R.; Kraja, Aldi T.; Schwander, Karen; Ntalla, Ioanna; Guo, Xiuqing; Franceschini, Nora; Lu, Yingchang; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Marten, Jonathan; Musani, Solomon K.; Li, Changwei; Feitosa, Mary F.; Kilpelainen, Tuomas O.; Richard, Melissa A.; Noordam, Raymond; Aslibekyan, Stella; Aschard, Hugues; Bartz, Traci M.; Dorajoo, Rajkumar; Liu, Yongmei; Manning, Alisa K.; Rankinen, Tuomo; Smith, Albert Vernon; Tajuddin, Salman M.; Tayo, Bamidele O.; Warren, Helen R.; Zhao, Wei; Zhou, Yanhua; Matoba, Nana; Sofer, Tamar; Alver, Maris; Amini, Marzyeh; Boissel, Mathilde; Chai, Jin Fang; Chen, Xu; Divers, Jasmin; Gandin, Ilaria; Gao, Chuan; Giulianini, Franco; Goel, Anuj; Harris, Sarah E.; Hartwig, Fernando Pires; Horimoto, Andrea R. V. R.; Hsu, Fang-Chi; Jackson, Anne U.; Kahonen, Mika; Kasturiratne, Anuradhani; Kuhnel, Brigitte; Leander, Karin; Lee, Wen-Jane; Lin, Keng-Hung; Luan, Jian' an; McKenzie, Colin A.; He Meian,; Nelson, Christopher P.; Rauramaa, Rainer; Schupf, Nicole; Scott, Robert A.; Sheu, Wayne H. H.; Stancakova, Alena; Takeuchi, Fumihiko; van der Most, Peter J.; Varga, Tibor V.; Wang, Heming; Wang, Yajuan; Ware, Erin B.; Weiss, Stefan; Wen, Wanqing; Yanek, Lisa R.; Zhang, Weihua; Zhao, Jing Hua; Afaq, Saima; Alfred, Tamuno; Amin, Najaf; Arking, Dan; Aung, Tin; Barr, R. Graham; Bielak, Lawrence F.; Boerwinkle, Eric; Bottinger, Erwin P.; Braund, Peter S.; Brody, Jennifer A.; Broeckel, Ulrich; Cabrera, Claudia P.; Cade, Brian; Yu Caizheng,; Campbell, Archie; Canouil, Mickael; Chakravarti, Aravinda; Chauhan, Ganesh; Christensen, Kaare; Cocca, Massimiliano; Collins, Francis S.; Connell, John M.; de Mutsert, Renee; de Silva, H. Janaka; Debette, Stephanie; Dorr, Marcus; Duan, Qing; Eaton, Charles B.; Ehret, Georg; Evangelou, Evangelos; Faul, Jessica D.; Fisher, Virginia A.; Forouhi, Nita G.; Franco, Oscar H.; Friedlander, Yechiel; Gao, He; Gigante, Bruna; Graff, Misa; Gu, C. Charles; Gu, Dongfeng; Gupta, Preeti; Hagenaars, Saskia P.; Harris, Tamara B.; He, Jiang; Heikkinen, Sami; Heng, Chew-Kiat; Hirata, Makoto; Hofman, Albert; Howard, Barbara V.; Hunt, Steven; Irvin, Marguerite R.; Jia, Yucheng; Joehanes, Roby; Justice, Anne E.; Katsuya, Tomohiro; Kaufman, Joel; Kerrison, Nicola D.; Khor, Chiea Chuen; Koh, Woon-Puay; Koistinen, Heikki A.; Komulainen, Pirjo; Kooperberg, Charles; Krieger, Jose E.; Kubo, Michiaki; Kuusisto, Johanna; Langefeld, Carl D.; Langenberg, Claudia; Launer, Lenore J.; Lehne, Benjamin; Lewis, Cora E.; Li, Yize; Lim, Sing Hui; Lin, Shiow; Liu, Ching-Ti; Liu, Jianjun; Liu, Jingmin; Liu, Kiang; Liu, Yeheng; Loh, Marie; Lohman, Kurt K.; Long, Jirong; Louie, Tin; Magi, Reedik; Mahajan, Anubha; Meitinger, Thomas; Metspalu, Andres; Milani, Lili; Momozawa, Yukihide; Morris, Andrew P.; Mosley, Thomas H.; Munson, Peter; Murray, Alison D.; Nalls, Mike A.; Nasri, Ubaydah; Norris, Jill M.; North, Kari; Ogunniyi, Adesola; Padmanabhan, Sandosh; Palmas, Walter R.; Palmer, Nicholette D.; Pankow, James S.; Pedersen, Nancy L.; Peters, Annette; Peyser, Patricia A.; Polasek, Ozren; Raitakari, Olli T.; Renstrom, Frida; Rice, Treva K.; Ridker, Paul M.; Robino, Antonietta; Robinson, Jennifer G.; Rose, Lynda M.; Rudan, Igor; Sabanayagam, Charumathi; Salako, Babatunde L.; Sandow, Kevin; Schmidt, Carsten O.; Schreiner, Pamela J.; Scott, William R.; Seshadri, Sudha; Sever, Peter; Sitlani, Colleen M.; Smith, Jennifer A.; Snieder, Harold; Starr, John M.; Strauch, Konstantin; Tang, Hua; Taylor, Kent D.; Teo, Yik Ying; Tham, Yih Chung; Ultterlinden, Andre G.; Waldenberger, Melanie; Wang, Lihua; Wang, Ya X.; Bin Wei, Wen; Williams, Christine; Wilson, Gregory; Wojczynski, Mary K.; Yao, Jie; Yuan, Jian-Min; Zonderman, Alan B.; Becker, Diane M.; Boehnke, Michael; Bowden, Donald W.; Chambers, John C.; Chen, Yii-Der Ida; de Faire, Ulf; Deary, Ian J.; Esko, Tonu; Farrall, Martin; Forrester, Terrence; Franks, Paul W.; Freedman, Barry I.; Froguel, Philippe; Gasparini, Paolo; Gieger, Christian; Horta, Bernardo Lessa; Hung, Yi-Jen; Jonas, Jost B.; Kato, Norihiro; Kooner, Jaspal S.; Laakso, Markku; Lehtimaki, Terho; Liang, Kae-Woei; Magnusson, Patrik K. E.; Newman, Anne B.; Oldehinkel, Albertine J.; Pereira, Alexandre C.; Redline, Susan; Rettig, Rainer; Samani, Nilesh J.; Scott, James; Shu, Xiao-Ou; van der Harst, Pim; Wagenknecht, Lynne E.; Wareham, Nicholas J.; Watkins, Hugh; Weir, David R.; Wickremasinghe, Ananda R.; Wu, Tangchun; Zheng, Wei; Kamatani, Yoichiro; Laurie, Cathy C.; Bouchard, Claude; Cooper, Richard S.; Evans, Michele K.; Gudnason, Vilmundur; Kardia, Sharon L. R.; Kritchevsky, Stephen B.; Levy, Daniel; O'Connell, Jeff R.; Psaty, Bruce M.; van Dam, Rob M.; Sims, Mario; Arnett, Donna K.; Mook-Kanamori, Dennis O.; Kelly, Tanika N.; Fox, Ervin R.; Hayward, Caroline; Fornage, Myriam; Rotimi, Charles N.; Province, Michael A.; van Duijn, Cornelia M.; Tai, E. Shyong; Wong, Tien Yin; Loos, Ruth J. F.; Reiner, Alex P.; Rotter, Jerome I.; Zhu, Xiaofeng; Bierut, Laura J.; Gauderman, W. James; Caulfield, Mark J.; Elliott, Paul; Rice, Kenneth; Munroe, Patricia B.; Morrison, Alanna C.; Cupples, L. Adrienne; Rao, Dabeeru C.; Chasman, Daniel I.; Study, Lifelines Cohort

    2018-01-01

    Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed

  17. Patterns of Genome-Wide Variation in Glossina fuscipes fuscipes Tsetse Flies from Uganda

    Directory of Open Access Journals (Sweden)

    Andrea Gloria-Soria

    2016-06-01

    Full Text Available The tsetse fly Glossina fuscipes fuscipes (Gff is the insect vector of the two forms of Human African Trypanosomiasis (HAT that exist in Uganda. Understanding Gff population dynamics, and the underlying genetics of epidemiologically relevant phenotypes is key to reducing disease transmission. Using ddRAD sequence technology, complemented with whole-genome sequencing, we developed a panel of ∼73,000 single-nucleotide polymorphisms (SNPs distributed across the Gff genome that can be used for population genomics and to perform genome-wide-association studies. We used these markers to estimate genomic patterns of linkage disequilibrium (LD in Gff, and used the information, in combination with outlier-locus detection tests, to identify candidate regions of the genome under selection. LD in individual populations decays to half of its maximum value (r2max/2 between 1359 and 2429 bp. The overall LD estimated for the species reaches r2max/2 at 708 bp, an order of magnitude slower than in Drosophila. Using 53 infected (Trypanosoma spp. and uninfected flies from four genetically distinct Ugandan populations adapted to different environmental conditions, we were able to identify SNPs associated with the infection status of the fly and local environmental adaptation. The extent of LD in Gff likely facilitated the detection of loci under selection, despite the small sample size. Furthermore, it is probable that LD in the regions identified is much higher than the average genomic LD due to strong selection. Our results show that even modest sample sizes can reveal significant genetic associations in this species, which has implications for future studies given the difficulties of collecting field specimens with contrasting phenotypes for association analysis.

  18. Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

    Directory of Open Access Journals (Sweden)

    Mariaelisa Graff

    2017-04-01

    Full Text Available Physical activity (PA may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423 or other ancestry (n = 20,029. We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

  19. Genome-wide Studies of Mycolic Acid Bacteria: Computational Identification and Analysis of a Minimal Genome

    KAUST Repository

    Kamanu, Frederick Kinyua

    2012-12-01

    The mycolic acid bacteria are a distinct suprageneric group of asporogenous Grampositive, high GC-content bacteria, distinguished by the presence of mycolic acids in their cell envelope. They exhibit great diversity in their cell and morphology; although primarily non-pathogens, this group contains three major pathogens Mycobacterium leprae, Mycobacterium tuberculosis complex, and Corynebacterium diphtheria. Although the mycolic acid bacteria are a clearly defined group of bacteria, the taxonomic relationships between its constituent genera and species are less well defined. Two approaches were tested for their suitability in describing the taxonomy of the group. First, a Multilocus Sequence Typing (MLST) experiment was assessed and found to be superior to monophyletic (16S small ribosomal subunit) in delineating a total of 52 mycolic acid bacterial species. Phylogenetic inference was performed using the neighbor-joining method. To further refine phylogenetic analysis and to take advantage of the widespread availability of bacterial genome data, a computational framework that simulates DNA-DNA hybridisation was developed and validated using multiscale bootstrap resampling. The tool classifies microbial genomes based on whole genome DNA, and was deployed as a web-application using PHP and Javascript. It is accessible online at http://cbrc.kaust.edu.sa/dna_hybridization/ A third study was a computational and statistical methods in the identification and analysis of a putative minimal mycolic acid bacterial genome so as to better understand (1) the genomic requirements to encode a mycolic acid bacterial cell and (2) the role and type of genes and genetic elements that lead to the massive increase in genome size in environmental mycolic acid bacteria. Using a reciprocal comparison approach, a total of 690 orthologous gene clusters forming a putative minimal genome were identified across 24 mycolic acid bacterial species. In order to identify new potential drug

  20. Circadian pathway genetic variation and cancer risk: evidence from genome-wide association studies.

    Science.gov (United States)

    Mocellin, Simone; Tropea, Saveria; Benna, Clara; Rossi, Carlo Riccardo

    2018-02-19

    Dysfunction of the circadian clock and single polymorphisms of some circadian genes have been linked to cancer susceptibility, although data are scarce and findings inconsistent. We aimed to investigate the association between circadian pathway genetic variation and risk of developing common cancers based on the findings of genome-wide association studies (GWASs). Single nucleotide polymorphisms (SNPs) of 17 circadian genes reported by three GWAS meta-analyses dedicated to breast (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Consortium; cases, n = 15,748; controls, n = 18,084), prostate (Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium; cases, n = 14,160; controls, n = 12,724) and lung carcinoma (Transdisciplinary Research In Cancer of the Lung (TRICL) Consortium; cases, n = 12,160; controls, n = 16,838) in patients of European ancestry were utilized to perform pathway analysis by means of the adaptive rank truncated product (ARTP) method. Data were also available for the following subgroups: estrogen receptor negative breast cancer, aggressive prostate cancer, squamous lung carcinoma and lung adenocarcinoma. We found a highly significant statistical association between circadian pathway genetic variation and the risk of breast (pathway P value = 1.9 × 10 -6 ; top gene RORA, gene P value = 0.0003), prostate (pathway P value = 4.1 × 10 -6 ; top gene ARNTL, gene P value = 0.0002) and lung cancer (pathway P value = 6.9 × 10 -7 ; top gene RORA, gene P value = 2.0 × 10 -6 ), as well as all their subgroups. Out of 17 genes investigated, 15 were found to be significantly associated with the risk of cancer: four genes were shared by all three malignancies (ARNTL, CLOCK, RORA and RORB), two by breast and lung cancer (CRY1 and CRY2) and three by prostate and lung cancer (NPAS2, NR1D1 and PER3), whereas four genes were specific for lung cancer

  1. Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes.

    Science.gov (United States)

    Ruth, Katherine S; Campbell, Purdey J; Chew, Shelby; Lim, Ee Mun; Hadlow, Narelle; Stuckey, Bronwyn G A; Brown, Suzanne J; Feenstra, Bjarke; Joseph, John; Surdulescu, Gabriela L; Zheng, Hou Feng; Richards, J Brent; Murray, Anna; Spector, Tim D; Wilson, Scott G; Perry, John R B

    2016-02-01

    Genetic factors contribute strongly to sex hormone levels, yet knowledge of the regulatory mechanisms remains incomplete. Genome-wide association studies (GWAS) have identified only a small number of loci associated with sex hormone levels, with several reproductive hormones yet to be assessed. The aim of the study was to identify novel genetic variants contributing to the regulation of sex hormones. We performed GWAS using genotypes imputed from the 1000 Genomes reference panel. The study used genotype and phenotype data from a UK twin register. We included 2913 individuals (up to 294 males) from the Twins UK study, excluding individuals receiving hormone treatment. Phenotypes were standardised for age, sex, BMI, stage of menstrual cycle and menopausal status. We tested 7,879,351 autosomal SNPs for association with levels of dehydroepiandrosterone sulphate (DHEAS), oestradiol, free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, progesterone, sex hormone-binding globulin and testosterone. Eight independent genetic variants reached genome-wide significance (P<5 × 10(-8)), with minor allele frequencies of 1.3-23.9%. Novel signals included variants for progesterone (P=7.68 × 10(-12)), oestradiol (P=1.63 × 10(-8)) and FAI (P=1.50 × 10(-8)). A genetic variant near the FSHB gene was identified which influenced both FSH (P=1.74 × 10(-8)) and LH (P=3.94 × 10(-9)) levels. A separate locus on chromosome 7 was associated with both DHEAS (P=1.82 × 10(-14)) and progesterone (P=6.09 × 10(-14)). This study highlights loci that are relevant to reproductive function and suggests overlap in the genetic basis of hormone regulation.

  2. Multiple Genes Related to Muscle Identified through a Joint Analysis of a Two-stage Genome-wide Association Study for Racing Performance of 1,156 Thoroughbreds

    Directory of Open Access Journals (Sweden)

    Dong-Hyun Shin

    2015-06-01

    Full Text Available Thoroughbred, a relatively recent horse breed, is best known for its use in horse racing. Although myostatin (MSTN variants have been reported to be highly associated with horse racing performance, the trait is more likely to be polygenic in nature. The purpose of this study was to identify genetic variants strongly associated with racing performance by using estimated breeding value (EBV for race time as a phenotype. We conducted a two-stage genome-wide association study to search for genetic variants associated with the EBV. In the first stage of genome-wide association study, a relatively large number of markers (~54,000 single-nucleotide polymorphisms, SNPs were evaluated in a small number of samples (240 horses. In the second stage, a relatively small number of markers identified to have large effects (170 SNPs were evaluated in a much larger number of samples (1,156 horses. We also validated the SNPs related to MSTN known to have large effects on racing performance and found significant associations in the stage two analysis, but not in stage one. We identified 28 significant SNPs related to 17 genes. Among these, six genes have a function related to myogenesis and five genes are involved in muscle maintenance. To our knowledge, these genes are newly reported for the genetic association with racing performance of Thoroughbreds. It complements a recent horse genome-wide association studies of racing performance that identified other SNPs and genes as the most significant variants. These results will help to expand our knowledge of the polygenic nature of racing performance in Thoroughbreds.

  3. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

    NARCIS (Netherlands)

    S.I. Berndt (Sonja); S. Gustafsson (Stefan); R. Mägi (Reedik); A. Ganna (Andrea); E. Wheeler (Eleanor); M.F. Feitosa (Mary Furlan); A.E. Justice (Anne); K.L. Monda (Keri); D.C. Croteau-Chonka (Damien); F.R. Day (Felix); T. Esko (Tõnu); M. Fall (Magnus); T. Ferreira (Teresa); D. Gentilini (Davide); A.U. Jackson (Anne); J. Luan; J.C. Randall (Joshua); S. Vedantam (Sailaja); C.J. Willer (Cristen); T.W. Winkler (Thomas); A.R. Wood (Andrew); T. Workalemahu (Tsegaselassie); Y.-J. Hu (Yi-Juan); S.H. Lee (Sang Hong); L. Liang (Liming); D.Y. Lin (Dan); J. Min (Josine); B.M. Neale (Benjamin); G. Thorleifsson (Gudmar); J. Yang (Jian); E. Albrecht (Eva); N. Amin (Najaf); J.L. Bragg-Gresham (Jennifer L.); G. Cadby (Gemma); M. den Heijer (Martin); N. Eklund (Niina); K. Fischer (Krista); A. Goel (Anuj); J.J. Hottenga (Jouke Jan); J.E. Huffman (Jennifer); I. Jarick (Ivonne); A. Johansson (Åsa); T. Johnson (Toby); S. Kanoni (Stavroula); M.E. Kleber (Marcus); I.R. König (Inke); K. Kristiansson (Kati); Z. Kutalik (Zoltán); C. Lamina (Claudia); C. Lecoeur (Cécile); G. Li (Guo); M. Mangino (Massimo); W.L. McArdle (Wendy); M.C. Medina-Gomez (Carolina); M. Müller-Nurasyid (Martina); J.S. Ngwa; I.M. Nolte (Ilja); L. Paternoster (Lavinia); S. Pechlivanis (Sonali); M. Perola (Markus); M.J. Peters (Marjolein); M. Preuss (Michael); L.M. Rose (Lynda); J. Shi (Jianxin); D. Shungin (Dmitry); G.D. Smith; R.J. Strawbridge (Rona); I. Surakka (Ida); A. Teumer (Alexander); M.D. Trip (Mieke); J.P. Tyrer (Jonathan); J.V. van Vliet-Ostaptchouk (Jana); L. Vandenput (Liesbeth); L. Waite (Lindsay); J.H. Zhao (Jing Hua); D. Absher (Devin); F.W. Asselbergs (Folkert); M. Atalay (Mustafa); A.P. Attwood (Antony); A.J. Balmforth (Anthony); D.C.G. Basart (Dick); J.P. Beilby (John); L.L. Bonnycastle (Lori); P. Brambilla (Paolo); M. Bruinenberg (M.); H. Campbell (Harry); D.I. Chasman (Daniel); P.S. Chines (Peter); F.S. Collins (Francis); J. Connell (John); W. O Cookson (William); U. de Faire (Ulf); F. de Vegt (Femmie); M. Dei (Mariano); M. Dimitriou (Maria); T. Edkins (Ted); K. Estrada Gil (Karol); D.M. Evans (David); M. Farrall (Martin); F. Ferrario (Franco); J. Ferrières (Jean); L. Franke (Lude); F. Frau (Francesca); P.V. Gejman (Pablo); H. Grallert (Harald); H. Grönberg (Henrik); V. Gudnason (Vilmundur); A. Hall (Anne); A.S. Hall (Alistair); A.L. Hartikainen; C. Hayward (Caroline); N.L. Heard-Costa (Nancy); A.C. Heath (Andrew); J. Hebebrand (Johannes); G. Homuth (Georg); F.B. Hu (Frank); S.E. Hunt (Sarah); E. Hyppönen (Elina); C. Iribarren (Carlos); K.B. Jacobs (Kevin); J.-O. Jansson (John-Olov); A. Jula (Antti); M. Kähönen (Mika); S. Kathiresan (Sekar); F. Kee (F.); K-T. Khaw (Kay-Tee); M. Kivimaki (Mika); W. Koenig (Wolfgang); A. Kraja (Aldi); M. Kumari (Meena); K. Kuulasmaa (Kari); J. Kuusisto (Johanna); J. Laitinen (Jaana); T.A. Lakka (Timo); C. Langenberg (Claudia); L.J. Launer (Lenore); L. Lind (Lars); J. Lindstrom (Jaana); J. Liu (Jianjun); A. Liuzzi (Antonio); M.L. Lokki; M. Lorentzon (Mattias); P.A. Madden (Pamela); P.K. Magnusson (Patrik); P. Manunta (Paolo); D. Marek (Diana); W. März (Winfried); I.M. Leach (Irene Mateo); B. McKnight (Barbara); S.E. Medland (Sarah Elizabeth); E. Mihailov (Evelin); L. Milani (Lili); G.W. Montgomery (Grant); V. Mooser (Vincent); T.W. Mühleisen (Thomas); P. Munroe (Patricia); A.W. Musk (Arthur); N. Narisu (Narisu); G. Navis (Gerjan); G. Nicholson (Ggeorge); C. Nohr (Christian); K. Ong (Ken); B.A. Oostra (Ben); C.N.A. Palmer (Colin); A. Palotie (Aarno); J. Peden (John); N. Pedersen; A. Peters (Annette); O. Polasek (Ozren); A. Pouta (Anneli); P.P. Pramstaller (Peter Paul); I. Prokopenko (Inga); C. Pütter (Carolin); A. Radhakrishnan (Aparna); O. Raitakari (Olli); A. Rendon (Augusto); F. Rivadeneira Ramirez (Fernando); I. Rudan (Igor); T. Saaristo (Timo); J.G. Sambrook (Jennifer); A.R. Sanders (Alan); S. Sanna (Serena); J. Saramies (Jouko); S. Schipf (Sabine); S. Schreiber (Stefan); H. Schunkert (Heribert); S.-Y. Shin; S. Signorini (Stefano); J. Sinisalo (Juha); B. Skrobek (Boris); N. Soranzo (Nicole); A. Stancáková (Alena); K. Stark (Klaus); J. Stephens (Jonathan); K. Stirrups (Kathy); R.P. Stolk (Ronald); M. Stumvoll (Michael); A.J. Swift (Amy); E.V. Theodoraki (Eirini); B. Thorand (Barbara); D.-A. Tregouet (David-Alexandre); E. Tremoli (Elena); M.M. van der Klauw (Melanie); J.B.J. van Meurs (Joyce); S.H.H.M. Vermeulen (Sita); J. Viikari (Jorma); J. Virtamo (Jarmo); V. Vitart (Veronique); G. Waeber (Gérard); Z. Wang (Zhaoming); E. Widen (Elisabeth); S.H. Wild (Sarah); G.A.H.M. Willemsen (Gonneke); B. Winkelmann; J.C.M. Witteman (Jacqueline); B.H.R. Wolffenbuttel (Bruce); A. Wong (Andrew); A.F. Wright (Alan); M.C. Zillikens (Carola); P. Amouyel (Philippe); B.O. Boehm (Bernhard); E.A. Boerwinkle (Eric); D.I. Boomsma (Dorret); M. Caulfield (Mark); S.J. Chanock (Stephen); L.A. Cupples (Adrienne); D. Cusi (Daniele); G.V. Dedoussis (George); J. Erdmann (Jeanette); J.G. Eriksson (Johan); P.W. Franks (Paul); P. Froguel (Philippe); C. Gieger (Christian); U. Gyllensten (Ulf); A. Hamsten (Anders); T.B. Harris (Tamara); C. Hengstenberg (Christian); A.A. Hicks (Andrew); A. Hingorani (Aroon); A. Hinney (Anke); A. Hofman (Albert); G.K. Hovingh (Kees); K. Hveem (Kristian); T. Illig (Thomas); M.-R. Jarvelin (Marjo-Riitta); K.-H. Jöckel (Karl-Heinz); S. Keinanen-Kiukaanniemi (Sirkka); L.A.L.M. Kiemeney (Bart); D. Kuh (Diana); M. Laakso (Markku); T. Lehtimäki (Terho); D.F. Levinson (Douglas); N.G. Martin (Nicholas); A. Metspalu (Andres); A.D. Morris (Andrew); M.S. Nieminen (Markku); I. Njølstad (Inger); C. Ohlsson (Claes); A.J. Oldehinkel (Albertine); W.H. Ouwehand (Willem); C. Palmer (Cameron); B.W.J.H. Penninx (Brenda); C. Power (Christopher); M.A. Province (Mike); B.M. Psaty (Bruce); L. Qi (Lu); R. Rauramaa (Rainer); P.M. Ridker (Paul); S. Ripatti (Samuli); V. Salomaa (Veikko); N.J. Samani (Nilesh); H. Snieder (Harold); H.G. Sorensen; T.D. Spector (Timothy); J-A. Zwart (John-Anker); A. Tönjes (Anke); J. Tuomilehto (Jaakko); A.G. Uitterlinden (André); M. Uusitupa (Matti); P. van der Harst (Pim); P. Vollenweider (Peter); H. Wallaschofski (Henri); N.J. Wareham (Nick); H. Watkins (Hugh); H.E. Wichmann (Heinz Erich); J.F. Wilson (James F); G.R. Abecasis (Gonçalo); T.L. Assimes (Themistocles); I.E. Barroso (Inês); M. Boehnke (Michael); I.B. Borecki (Ingrid); P. Deloukas (Panagiotis); C. Fox (Craig); T.M. Frayling (Timothy); L. Groop (Leif); T. Haritunian (Talin); I.M. Heid (Iris); D. Hunter (David); R.C. Kaplan (Robert); F. Karpe (Fredrik); M.F. Moffatt (Miriam); K.L. Mohlke (Karen); J.R. O´Connell; Y. Pawitan (Yudi); E.E. Schadt (Eric); D. Schlessinger (David); V. Steinthorsdottir (Valgerdur); D.P. Strachan (David); U. Thorsteinsdottir (Unnur); C.M. van Duijn (Cornelia); P.M. Visscher (Peter); A.M. Di Blasio (Anna Maria); J.N. Hirschhorn (Joel); C.M. Lindgren (Cecilia); A.D. Morris (Andrew); D. Meyre (David); A. Scherag (Andre); M.I. McCarthy (Mark); E.K. Speliotes (Elizabeth); K.E. North (Kari); R.J.F. Loos (Ruth); E. Ingelsson (Erik)

    2013-01-01

    textabstractApproaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of

  4. Human genetics and genomics a decade after the release of the draft sequence of the human genome

    Science.gov (United States)

    2011-01-01

    Substantial progress has been made in human genetics and genomics research over the past ten years since the publication of the draft sequence of the human genome in 2001. Findings emanating directly from the Human Genome Project, together with those from follow-on studies, have had an enormous impact on our understanding of the architecture and function of the human genome. Major developments have been made in cataloguing genetic variation, the International HapMap Project, and with respect to advances in genotyping technologies. These developments are vital for the emergence of genome-wide association studies in the investigation of complex diseases and traits. In parallel, the advent of high-throughput sequencing technologies has ushered in the 'personal genome sequencing' era for both normal and cancer genomes, and made possible large-scale genome sequencing studies such as the 1000 Genomes Project and the International Cancer Genome Consortium. The high-throughput sequencing and sequence-capture technologies are also providing new opportunities to study Mendelian disorders through exome sequencing and whole-genome sequencing. This paper reviews these major developments in human genetics and genomics over the past decade. PMID:22155605

  5. Integrative Analysis of Genetic, Genomic, and Phenotypic Data for Ethanol Behaviors: A Network-Based Pipeline for Identifying Mechanisms and Potential Drug Targets.

    Science.gov (United States)

    Bogenpohl, James W; Mignogna, Kristin M; Smith, Maren L; Miles, Michael F

    2017-01-01

    Complex behavioral traits, such as alcohol abuse, are caused by an interplay of genetic and environmental factors, producing deleterious functional adaptations in the central nervous system. The long-term behavioral consequences of such changes are of substantial cost to both the individual and society. Substantial progress has been made in the last two decades in understanding elements of brain mechanisms underlying responses to ethanol in animal models and risk factors for alcohol use disorder (AUD) in humans. However, treatments for AUD remain largely ineffective and few medications for this disease state have been licensed. Genome-wide genetic polymorphism analysis (GWAS) in humans, behavioral genetic studies in animal models and brain gene expression studies produced by microarrays or RNA-seq have the potential to produce nonbiased and novel insight into the underlying neurobiology of AUD. However, the complexity of such information, both statistical and informational, has slowed progress toward identifying new targets for intervention in AUD. This chapter describes one approach for integrating behavioral, genetic, and genomic information across animal model and human studies. The goal of this approach is to identify networks of genes functioning in the brain that are most relevant to the underlying mechanisms of a complex disease such as AUD. We illustrate an example of how genomic studies in animal models can be used to produce robust gene networks that have functional implications, and to integrate such animal model genomic data with human genetic studies such as GWAS for AUD. We describe several useful analysis tools for such studies: ComBAT, WGCNA, and EW_dmGWAS. The end result of this analysis is a ranking of gene networks and identification of their cognate hub genes, which might provide eventual targets for future therapeutic development. Furthermore, this combined approach may also improve our understanding of basic mechanisms underlying gene x

  6. Case-control genome-wide association study of attention-deficit/hyperactivity disorder.

    NARCIS (Netherlands)

    Neale, B.M.; Medland, S.; Ripke, S.; Anney, R.J.; Asherson, P.; Buitelaar, J.K.; Franke, B.; Gill, M.; Kent, L.; Holmans, P.; Middleton, F.; Thapar, A.; Lesch, K.P.; Faraone, S.V.; Daly, M.; Nguyen, T.T.; Schafer, H.; Steinhausen, H.C.; Reif, A.; Renner, T.J.; Romanos, M.; Romanos, J.; Warnke, A.; Walitza, S.; Freitag, C.; Meyer, J.; Palmason, H.; Rothenberger, A.; Hawi, Z.; Sergeant, J.A.; Roeyers, H.; Mick, E.; Biederman, J.

    2010-01-01

    OBJECTIVE: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. Thus additional genomewide association studies (GWAS) are needed.

  7. Review:Whole genome amplification in preimplantation genetic diagnosis

    Institute of Scientific and Technical Information of China (English)

    Ying-ming ZHENG; Ning WANG; Lei LI; Fan JIN

    2011-01-01

    Preimplantation genetic diagnosis(PGD)refers to a procedure for genetically analyzing embryos prior to implantation,improving the chance of conception for patients at high risk of transmitting specific inherited disorders.This method has been widely used for a large number of genetic disorders since the first successful application in the early 1990s.Polymerase chain reaction(PCR)and fluorescent in situ hybridization(FISH)are the two main methods in PGD,but there are some inevitable shortcomings limiting the scope of genetic diagnosis.Fortunately,different whole genome amplification(WGA)techniques have been developed to overcome these problems.Sufficient DNA can be amplified and multiple tasks which need abundant DNA can be performed.Moreover,WGA products can be analyzed as a template for multi-loci and multi-gene during the subsequent DNA analysis.In this review,we will focus on the currently available WGA techniques and their applications,as well as the new technical trends from WGA products.

  8. Genome-wide association mapping identifies the genetic basis of discrete and quantitative variation in sexual weaponry in a wild sheep population.

    Science.gov (United States)

    Johnston, Susan E; McEwan, John C; Pickering, Natalie K; Kijas, James W; Beraldi, Dario; Pilkington, Jill G; Pemberton, Josephine M; Slate, Jon

    2011-06-01

    Understanding the genetic architecture of phenotypic variation in natural populations is a fundamental goal of evolutionary genetics. Wild Soay sheep (Ovis aries) have an inherited polymorphism for horn morphology in both sexes, controlled by a single autosomal locus, Horns. The majority of males have large normal horns, but a small number have vestigial, deformed horns, known as scurs; females have either normal horns, scurs or no horns (polled). Given that scurred males and polled females have reduced fitness within each sex, it is counterintuitive that the polymorphism persists within the population. Therefore, identifying the genetic basis of horn type will provide a vital foundation for understanding why the different morphs are maintained in the face of natural selection. We conducted a genome-wide association study using ∼36000 single nucleotide polymorphisms (SNPs) and determined the main candidate for Horns as RXFP2, an autosomal gene with a known involvement in determining primary sex characters in humans and mice. Evidence from additional SNPs in and around RXFP2 supports a new model of horn-type inheritance in Soay sheep, and for the first time, sheep with the same horn phenotype but different underlying genotypes can be identified. In addition, RXFP2 was shown to be an additive quantitative trait locus (QTL) for horn size in normal-horned males, accounting for up to 76% of additive genetic variation in this trait. This finding contrasts markedly from genome-wide association studies of quantitative traits in humans and some model species, where it is often observed that mapped loci only explain a modest proportion of the overall genetic variation. © 2011 Blackwell Publishing Ltd.

  9. The influence of age and sex on genetic associations with adult body size and shape: a large-scale genome-wide interaction study

    OpenAIRE

    Winkler, Thomas W.; Heid, Iris M.; Gorski, Mathias

    2015-01-01

    Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of Eur...

  10. Population and genomic lessons from genetic analysis of two Indian populations.

    Science.gov (United States)

    Juyal, Garima; Mondal, Mayukh; Luisi, Pierre; Laayouni, Hafid; Sood, Ajit; Midha, Vandana; Heutink, Peter; Bertranpetit, Jaume; Thelma, B K; Casals, Ferran

    2014-10-01

    Indian demographic history includes special features such as founder effects, interpopulation segregation, complex social structure with a caste system and elevated frequency of consanguineous marriages. It also presents a higher frequency for some rare mendelian disorders and in the last two decades increased prevalence of some complex disorders. Despite the fact that India represents about one-sixth of the human population, deep genetic studies from this terrain have been scarce. In this study, we analyzed high-density genotyping and whole-exome sequencing data of a North and a South Indian population. Indian populations show higher differentiation levels than those reported between populations of other continents. In this work, we have analyzed its consequences, by specifically assessing the transferability of genetic markers from or to Indian populations. We show that there is limited genetic marker portability from available genetic resources such as HapMap or the 1,000 Genomes Project to Indian populations, which also present an excess of private rare variants. Conversely, tagSNPs show a high level of portability between the two Indian populations, in contrast to the common belief that North and South Indian populations are genetically very different. By estimating kinship from mates and consanguinity in our data from trios, we also describe different patterns of assortative mating and inbreeding in the two populations, in agreement with distinct mating preferences and social structures. In addition, this analysis has allowed us to describe genomic regions under recent adaptive selection, indicating differential adaptive histories for North and South Indian populations. Our findings highlight the importance of considering demography for design and analysis of genetic studies, as well as the need for extending human genetic variation catalogs to new populations and particularly to those with particular demographic histories.

  11. GRIMP: A web- and grid-based tool for high-speed analysis of large-scale genome-wide association using imputed data.

    NARCIS (Netherlands)

    K. Estrada Gil (Karol); A. Abuseiris (Anis); F.G. Grosveld (Frank); A.G. Uitterlinden (André); T.A. Knoch (Tobias); F. Rivadeneira Ramirez (Fernando)

    2009-01-01

    textabstractThe current fast growth of genome-wide association studies (GWAS) combined with now common computationally expensive imputation requires the online access of large user groups to high-performance computing resources capable of analyzing rapidly and efficiently millions of genetic

  12. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

    NARCIS (Netherlands)

    Berndt, Sonja I; Gustafsson, Stefan; Mägi, Reedik; Ganna, Andrea; Wheeler, Eleanor; Feitosa, Mary F; Justice, Anne E; Monda, Keri L; Croteau-Chonka, Damien C; Day, Felix R; Esko, Tõnu; Fall, Tove; Ferreira, Teresa; Gentilini, Davide; Jackson, Anne U; Luan, Jian'an; Randall, Joshua C; Vedantam, Sailaja; Willer, Cristen J; Winkler, Thomas W; Wood, Andrew R; Workalemahu, Tsegaselassie; Hu, Yi-Juan; Lee, Sang Hong; Liang, Liming; Lin, Dan-Yu; Min, Josine L; Neale, Benjamin M; Thorleifsson, Gudmar; Yang, Jian; Albrecht, Eva; Amin, Najaf; Bragg-Gresham, Jennifer L; Cadby, Gemma; den Heijer, Martin; Eklund, Niina; Fischer, Krista; Goel, Anuj; Hottenga, Jouke-Jan; Huffman, Jennifer E; Jarick, Ivonne; Johansson, Åsa; Johnson, Toby; Kanoni, Stavroula; Kleber, Marcus E; König, Inke R; Kristiansson, Kati; Kutalik, Zoltán; Lamina, Claudia; Lecoeur, Cecile; Li, Guo; Mangino, Massimo; McArdle, Wendy L; Medina-Gomez, Carolina; Müller-Nurasyid, Martina; Ngwa, Julius S; Nolte, Ilja M; Paternoster, Lavinia; Pechlivanis, Sonali; Perola, Markus; Peters, Marjolein J; Preuss, Michael; Rose, Lynda M; Shi, Jianxin; Shungin, Dmitry; Smith, Albert Vernon; Strawbridge, Rona J; Surakka, Ida; Teumer, Alexander; Trip, Mieke D; Tyrer, Jonathan; Van Vliet-Ostaptchouk, Jana V; Vandenput, Liesbeth; Waite, Lindsay L; Zhao, Jing Hua; Absher, Devin; Asselbergs, Folkert W; Atalay, Mustafa; Attwood, Antony P; Balmforth, Anthony J; Basart, Hanneke; Beilby, John; Bonnycastle, Lori L; Brambilla, Paolo; Bruinenberg, Marcel; Campbell, Harry; Chasman, Daniel I; Chines, Peter S; Collins, Francis S; Connell, John M; Cookson, William O; de Faire, Ulf; de Vegt, Femmie; Dei, Mariano; Dimitriou, Maria; Edkins, Sarah; Estrada, Karol; Evans, David M; Farrall, Martin; Ferrario, Marco M; Ferrières, Jean; Franke, Lude; Frau, Francesca; Gejman, Pablo V; Grallert, Harald; Grönberg, Henrik; Gudnason, Vilmundur; Hall, Alistair S; Hall, Per; Hartikainen, Anna-Liisa; Hayward, Caroline; Heard-Costa, Nancy L; Heath, Andrew C; Hebebrand, Johannes; Homuth, Georg; Hu, Frank B; Hunt, Sarah E; Hyppönen, Elina; Iribarren, Carlos; Jacobs, Kevin B; Jansson, John-Olov; Jula, Antti; Kähönen, Mika; Kathiresan, Sekar; Kee, Frank; Khaw, Kay-Tee; Kivimäki, Mika; Koenig, Wolfgang; Kraja, Aldi T; Kumari, Meena; Kuulasmaa, Kari; Kuusisto, Johanna; Laitinen, Jaana H; Lakka, Timo A; Langenberg, Claudia; Launer, Lenore J; Lind, Lars; Lindström, Jaana; Liu, Jianjun; Liuzzi, Antonio; Lokki, Marja-Liisa; Lorentzon, Mattias; Madden, Pamela A; Magnusson, Patrik K; Manunta, Paolo; Marek, Diana; März, Winfried; Mateo Leach, Irene; McKnight, Barbara; Medland, Sarah E; Mihailov, Evelin; Milani, Lili; Montgomery, Grant W; Mooser, Vincent; Mühleisen, Thomas W; Munroe, Patricia B; Musk, Arthur W; Narisu, Narisu; Navis, Gerjan; Nicholson, George; Nohr, Ellen A; Ong, Ken K; Oostra, Ben A; Palmer, Colin N A; Palotie, Aarno; Peden, John F; Pedersen, Nancy; Peters, Annette; Polasek, Ozren; Pouta, Anneli; Pramstaller, Peter P; Prokopenko, Inga; Pütter, Carolin; Radhakrishnan, Aparna; Raitakari, Olli; Rendon, Augusto; Rivadeneira, Fernando; Rudan, Igor; Saaristo, Timo E; Sambrook, Jennifer G; Sanders, Alan R; Sanna, Serena; Saramies, Jouko; Schipf, Sabine; Schreiber, Stefan; Schunkert, Heribert; Shin, So-Youn; Signorini, Stefano; Sinisalo, Juha; Skrobek, Boris; Soranzo, Nicole; Stančáková, Alena; Stark, Klaus; Stephens, Jonathan C; Stirrups, Kathleen; Stolk, Ronald P; Stumvoll, Michael; Swift, Amy J; Theodoraki, Eirini V; Thorand, Barbara; Tregouet, David-Alexandre; Tremoli, Elena; Van der Klauw, Melanie M; van Meurs, Joyce B J; Vermeulen, Sita H; Viikari, Jorma; Virtamo, Jarmo; Vitart, Veronique; Waeber, Gérard; Wang, Zhaoming; Widén, Elisabeth; Wild, Sarah H; Willemsen, Gonneke; Winkelmann, Bernhard R; Witteman, Jacqueline C M; Wolffenbuttel, Bruce H R; Wong, Andrew; Wright, Alan F; Zillikens, M Carola; Amouyel, Philippe; Boehm, Bernhard O; Boerwinkle, Eric; Boomsma, Dorret I; Caulfield, Mark J; Chanock, Stephen J; Cupples, L Adrienne; Cusi, Daniele; Dedoussis, George V; Erdmann, Jeanette; Eriksson, Johan G; Franks, Paul W; Froguel, Philippe; Gieger, Christian; Gyllensten, Ulf; Hamsten, Anders; Harris, Tamara B; Hengstenberg, Christian; Hicks, Andrew A; Hingorani, Aroon; Hinney, Anke; Hofman, Albert; Hovingh, Kees G; Hveem, Kristian; Illig, Thomas; Jarvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Keinanen-Kiukaanniemi, Sirkka M; Kiemeney, Lambertus A; Kuh, Diana; Laakso, Markku; Lehtimäki, Terho; Levinson, Douglas F; Martin, Nicholas G; Metspalu, Andres; Morris, Andrew D; Nieminen, Markku S; Njølstad, Inger; Ohlsson, Claes; Oldehinkel, Albertine J; Ouwehand, Willem H; Palmer, Lyle J; Penninx, Brenda; Power, Chris; Province, Michael A; Psaty, Bruce M; Qi, Lu; Rauramaa, Rainer; Ridker, Paul M; Ripatti, Samuli; Salomaa, Veikko; Samani, Nilesh J; Snieder, Harold; Sørensen, Thorkild I A; Spector, Timothy D; Stefansson, Kari; Tönjes, Anke; Tuomilehto, Jaakko; Uitterlinden, André G; Uusitupa, Matti; van der Harst, Pim; Vollenweider, Peter; Wallaschofski, Henri; Wareham, Nicholas J; Watkins, Hugh; Wichmann, H-Erich; Wilson, James F; Abecasis, Goncalo R; Assimes, Themistocles L; Barroso, Inês; Boehnke, Michael; Borecki, Ingrid B; Deloukas, Panos; Fox, Caroline S; Frayling, Timothy; Groop, Leif C; Haritunian, Talin; Heid, Iris M; Hunter, David; Kaplan, Robert C; Karpe, Fredrik; Moffatt, Miriam F; Mohlke, Karen L; O'Connell, Jeffrey R; Pawitan, Yudi; Schadt, Eric E; Schlessinger, David; Steinthorsdottir, Valgerdur; Strachan, David P; Thorsteinsdottir, Unnur; van Duijn, Cornelia M; Visscher, Peter M; Di Blasio, Anna Maria; Hirschhorn, Joel N; Lindgren, Cecilia M; Morris, Andrew P; Meyre, David; Scherag, André; McCarthy, Mark I; Speliotes, Elizabeth K; North, Kari E; Loos, Ruth J F; Ingelsson, Erik

    Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass

  13. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

    NARCIS (Netherlands)

    Berndt, Sonja I.; Gustafsson, Stefan; Mägi, Reedik; Ganna, Andrea; Wheeler, Eleanor; Feitosa, Mary F.; Justice, Anne E.; Monda, Keri L.; Croteau-Chonka, Damien C.; Day, Felix R.; Esko, Tõnu; Fall, Tove; Ferreira, Teresa; Gentilini, Davide; Jackson, Anne U.; Luan, Jian'an; Randall, Joshua C.; Vedantam, Sailaja; Willer, Cristen J.; Winkler, Thomas W.; Wood, Andrew R.; Workalemahu, Tsegaselassie; Hu, Yi-Juan; Lee, Sang Hong; Liang, Liming; Lin, Dan-Yu; Min, Josine L.; Neale, Benjamin M.; Thorleifsson, Gudmar; Yang, Jian; Albrecht, Eva; Amin, Najaf; Bragg-Gresham, Jennifer L.; Cadby, Gemma; den Heijer, Martin; Eklund, Niina; Fischer, Krista; Goel, Anuj; Hottenga, Jouke-Jan; Huffman, Jennifer E.; Jarick, Ivonne; Johansson, Asa; Johnson, Toby; Kanoni, Stavroula; Kleber, Marcus E.; König, Inke R.; Kristiansson, Kati; Kutalik, Zoltán; Lamina, Claudia; Lecoeur, Cecile; Li, Guo; Mangino, Massimo; McArdle, Wendy L.; Medina-Gomez, Carolina; Müller-Nurasyid, Martina; Ngwa, Julius S.; Nolte, Ilja M.; Paternoster, Lavinia; Pechlivanis, Sonali; Perola, Markus; Peters, Marjolein J.; Preuss, Michael; Rose, Lynda M.; Shi, Jianxin; Shungin, Dmitry; Smith, Albert Vernon; Strawbridge, Rona J.; Surakka, Ida; Teumer, Alexander; Trip, Mieke D.; Tyrer, Jonathan; van Vliet-Ostaptchouk, Jana V.; Vandenput, Liesbeth; Waite, Lindsay L.; Zhao, Jing Hua; Absher, Devin; Asselbergs, Folkert W.; Atalay, Mustafa; Attwood, Antony P.; Balmforth, Anthony J.; Basart, Hanneke; Beilby, John; Bonnycastle, Lori L.; Brambilla, Paolo; Bruinenberg, Marcel; Campbell, Harry; Chasman, Daniel I.; Chines, Peter S.; Collins, Francis S.; Connell, John M.; Cookson, William O.; de Faire, Ulf; de Vegt, Femmie; dei, Mariano; Dimitriou, Maria; Edkins, Sarah; Estrada, Karol; Evans, David M.; Farrall, Martin; Ferrario, Marco M.; Ferrières, Jean; Franke, Lude; Frau, Francesca; Gejman, Pablo V.; Grallert, Harald; Grönberg, Henrik; Gudnason, Vilmundur; Hall, Alistair S.; Hall, Per; Hartikainen, Anna-Liisa; Hayward, Caroline; Heard-Costa, Nancy L.; Heath, Andrew C.; Hebebrand, Johannes; Homuth, Georg; Hu, Frank B.; Hunt, Sarah E.; Hyppönen, Elina; Iribarren, Carlos; Jacobs, Kevin B.; Jansson, John-Olov; Jula, Antti; Kähönen, Mika; Kathiresan, Sekar; Kee, Frank; Khaw, Kay-Tee; Kivimäki, Mika; Koenig, Wolfgang; Kraja, Aldi T.; Kumari, Meena; Kuulasmaa, Kari; Kuusisto, Johanna; Laitinen, Jaana H.; Lakka, Timo A.; Langenberg, Claudia; Launer, Lenore J.; Lind, Lars; Lindström, Jaana; Liu, Jianjun; Liuzzi, Antonio; Lokki, Marja-Liisa; Lorentzon, Mattias; Madden, Pamela A.; Magnusson, Patrik K.; Manunta, Paolo; Marek, Diana; März, Winfried; Mateo Leach, Irene; McKnight, Barbara; Medland, Sarah E.; Mihailov, Evelin; Milani, Lili; Montgomery, Grant W.; Mooser, Vincent; Mühleisen, Thomas W.; Munroe, Patricia B.; Musk, Arthur W.; Narisu, Narisu; Navis, Gerjan; Nicholson, George; Nohr, Ellen A.; Ong, Ken K.; Oostra, Ben A.; Palmer, Colin N. A.; Palotie, Aarno; Peden, John F.; Pedersen, Nancy; Peters, Annette; Polasek, Ozren; Pouta, Anneli; Pramstaller, Peter P.; Prokopenko, Inga; Pütter, Carolin; Radhakrishnan, Aparna; Raitakari, Olli; Rendon, Augusto; Rivadeneira, Fernando; Rudan, Igor; Saaristo, Timo E.; Sambrook, Jennifer G.; Sanders, Alan R.; Sanna, Serena; Saramies, Jouko; Schipf, Sabine; Schreiber, Stefan; Schunkert, Heribert; Shin, So-Youn; Signorini, Stefano; Sinisalo, Juha; Skrobek, Boris; Soranzo, Nicole; Stančáková, Alena; Stark, Klaus; Stephens, Jonathan C.; Stirrups, Kathleen; Stolk, Ronald P.; Stumvoll, Michael; Swift, Amy J.; Theodoraki, Eirini V.; Thorand, Barbara; Tregouet, David-Alexandre; Tremoli, Elena; van der Klauw, Melanie M.; van Meurs, Joyce B. J.; Vermeulen, Sita H.; Viikari, Jorma; Virtamo, Jarmo; Vitart, Veronique; Waeber, Gérard; Wang, Zhaoming; Widén, Elisabeth; Wild, Sarah H.; Willemsen, Gonneke; Winkelmann, Bernhard R.; Witteman, Jacqueline C. M.; Wolffenbuttel, Bruce H. R.; Wong, Andrew; Wright, Alan F.; Zillikens, M. Carola; Amouyel, Philippe; Boehm, Bernhard O.; Boerwinkle, Eric; Boomsma, Dorret I.; Caulfield, Mark J.; Chanock, Stephen J.; Cupples, L. Adrienne; Cusi, Daniele; Dedoussis, George V.; Erdmann, Jeanette; Eriksson, Johan G.; Franks, Paul W.; Froguel, Philippe; Gieger, Christian; Gyllensten, Ulf; Hamsten, Anders; Harris, Tamara B.; Hengstenberg, Christian; Hicks, Andrew A.; Hingorani, Aroon; Hinney, Anke; Hofman, Albert; Hovingh, Kees G.; Hveem, Kristian; Illig, Thomas; Jarvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Keinanen-Kiukaanniemi, Sirkka M.; Kiemeney, Lambertus A.; Kuh, Diana; Laakso, Markku; Lehtimäki, Terho; Levinson, Douglas F.; Martin, Nicholas G.; Metspalu, Andres; Morris, Andrew D.; Nieminen, Markku S.; Njølstad, Inger; Ohlsson, Claes; Oldehinkel, Albertine J.; Ouwehand, Willem H.; Palmer, Lyle J.; Penninx, Brenda; Power, Chris; Province, Michael A.; Psaty, Bruce M.; Qi, Lu; Rauramaa, Rainer; Ridker, Paul M.; Ripatti, Samuli; Salomaa, Veikko; Samani, Nilesh J.; Snieder, Harold; Sørensen, Thorkild I. A.; Spector, Timothy D.; Stefansson, Kari; Tönjes, Anke; Tuomilehto, Jaakko; Uitterlinden, André G.; Uusitupa, Matti; van der Harst, Pim; Vollenweider, Peter; Wallaschofski, Henri; Wareham, Nicholas J.; Watkins, Hugh; Wichmann, H.-Erich; Wilson, James F.; Abecasis, Goncalo R.; Assimes, Themistocles L.; Barroso, Inês; Boehnke, Michael; Borecki, Ingrid B.; Deloukas, Panos; Fox, Caroline S.; Frayling, Timothy; Groop, Leif C.; Haritunian, Talin; Heid, Iris M.; Hunter, David; Kaplan, Robert C.; Karpe, Fredrik; Moffatt, Miriam F.; Mohlke, Karen L.; O'Connell, Jeffrey R.; Pawitan, Yudi; Schadt, Eric E.; Schlessinger, David; Steinthorsdottir, Valgerdur; Strachan, David P.; Thorsteinsdottir, Unnur; van Duijn, Cornelia M.; Visscher, Peter M.; Di Blasio, Anna Maria; Hirschhorn, Joel N.; Lindgren, Cecilia M.; Morris, Andrew P.; Meyre, David; Scherag, André; McCarthy, Mark I.; Speliotes, Elizabeth K.; North, Kari E.; Loos, Ruth J. F.; Ingelsson, Erik

    2013-01-01

    Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass

  14. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

    DEFF Research Database (Denmark)

    Berndt, Sonja I; Gustafsson, Stefan; Mägi, Reedik

    2013-01-01

    Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass ...

  15. Genome wide study of maternal and parent-of-origin effects on the etiology of orofacial clefts

    Science.gov (United States)

    Shi, Min; Murray, Jeffrey C; Marazita, Mary L; Munger, Ronald G; Ruczinski, Ingo; Hetmanski, Jacqueline B; Wu, Tao; Murray, Tanda; Redett, Richard J; Wilcox, Allen J; Lie, Rolv T; Jabs, Ethylin Wang; Wu-Chou, Yah Huei; Chen, Philip K; Wang, Hong; Ye, Xiaoqian; Yeow, Vincent; Chong, Samuel S; Shi, Bing; Christensen, Kaare; Scott, Alan F; Patel, Poorav; Cheah, Felicia; Beaty, Terri H

    2013-01-01

    We performed a genome wide association analysis of maternally-mediated genetic effects and parent-of-origin effects on risk of orofacial clefting using over 2,000 case-parent triads collected through an international cleft consortium. We used log-linear regression models to test individual SNPs. For SNPs with a p-value <10−5 for maternal genotypic effects, we also applied a haplotype-based method, TRIMM, to extract potential information from clusters of correlated SNPs. None of the SNPs were significant at the genome wide level. Our results suggest neither maternal genome nor parent of origin effects play major roles in the etiology of orofacial clefting in our sample. This finding is consistent with previous genetic studies and recent population-based cohort studies in Norway and Denmark, which showed no apparent difference between mother-to-offspring and father-to-offspring recurrence of clefting. We, however, cannot completely rule out maternal genome or parent of origin effects as risk factors because very small effects might not be detectable with our sample size, they may influence risk through interactions with environmental exposures or may act through a more complex network of interacting genes. Thus the most promising SNPs identified by this study may still be worth further investigation. PMID:22419666

  16. Genome-wide screening and identification of antigens for rickettsial vaccine development

    Science.gov (United States)

    The capacity to identify immunogens for vaccine development by genome-wide screening has been markedly enhanced by the availability of complete microbial genome sequences coupled to rapid proteomic and bioinformatic analysis. Critical to this genome-wide screening is in vivo testing in the context o...

  17. Whole genome SNP discovery and analysis of genetic diversity in Turkey (Meleagris gallopavo)

    Science.gov (United States)

    2012-01-01

    Background The turkey (Meleagris gallopavo) is an important agricultural species and the second largest contributor to the world’s poultry meat production. Genetic improvement is attributed largely to selective breeding programs that rely on highly heritable phenotypic traits, such as body size and breast muscle development. Commercial breeding with small effective population sizes and epistasis can result in loss of genetic diversity, which in turn can lead to reduced individual fitness and reduced response to selection. The presence of genomic diversity in domestic livestock species therefore, is of great importance and a prerequisite for rapid and accurate genetic improvement of selected breeds in various environments, as well as to facilitate rapid adaptation to potential changes in breeding goals. Genomic selection requires a large number of genetic markers such as e.g. single nucleotide polymorphisms (SNPs) the most abundant source of genetic variation within the genome. Results Alignment of next generation sequencing data of 32 individual turkeys from different populations was used for the discovery of 5.49 million SNPs, which subsequently were used for the analysis of genetic diversity among the different populations. All of the commercial lines branched from a single node relative to the heritage varieties and the South Mexican turkey population. Heterozygosity of all individuals from the different turkey populations ranged from 0.17-2.73 SNPs/Kb, while heterozygosity of populations ranged from 0.73-1.64 SNPs/Kb. The average frequency of heterozygous SNPs in individual turkeys was 1.07 SNPs/Kb. Five genomic regions with very low nucleotide variation were identified in domestic turkeys that showed state of fixation towards alleles different than wild alleles. Conclusion The turkey genome is much less diverse with a relatively low frequency of heterozygous SNPs as compared to other livestock species like chicken and pig. The whole genome SNP discovery

  18. Whole genome SNP discovery and analysis of genetic diversity in Turkey (Meleagris gallopavo

    Directory of Open Access Journals (Sweden)

    Aslam Muhammad L

    2012-08-01

    Full Text Available Abstract Background The turkey (Meleagris gallopavo is an important agricultural species and the second largest contributor to the world’s poultry meat production. Genetic improvement is attributed largely to selective breeding programs that rely on highly heritable phenotypic traits, such as body size and breast muscle development. Commercial breeding with small effective population sizes and epistasis can result in loss of genetic diversity, which in turn can lead to reduced individual fitness and reduced response to selection. The presence of genomic diversity in domestic livestock species therefore, is of great importance and a prerequisite for rapid and accurate genetic improvement of selected breeds in various environments, as well as to facilitate rapid adaptation to potential changes in breeding goals. Genomic selection requires a large number of genetic markers such as e.g. single nucleotide polymorphisms (SNPs the most abundant source of genetic variation within the genome. Results Alignment of next generation sequencing data of 32 individual turkeys from different populations was used for the discovery of 5.49 million SNPs, which subsequently were used for the analysis of genetic diversity among the different populations. All of the commercial lines branched from a single node relative to the heritage varieties and the South Mexican turkey population. Heterozygosity of all individuals from the different turkey populations ranged from 0.17-2.73 SNPs/Kb, while heterozygosity of populations ranged from 0.73-1.64 SNPs/Kb. The average frequency of heterozygous SNPs in individual turkeys was 1.07 SNPs/Kb. Five genomic regions with very low nucleotide variation were identified in domestic turkeys that showed state of fixation towards alleles different than wild alleles. Conclusion The turkey genome is much less diverse with a relatively low frequency of heterozygous SNPs as compared to other livestock species like chicken and pig. The

  19. A novel genome-wide microsatellite resource for species of Eucalyptus with linkage-to-physical correspondence on the reference genome sequence.

    Science.gov (United States)

    Grattapaglia, Dario; Mamani, Eva M C; Silva-Junior, Orzenil B; Faria, Danielle A

    2015-03-01

    Keystone species in their native ranges, eucalypts, are ecologically and genetically very diverse, growing naturally along extensive latitudinal and altitudinal ranges and variable environments. Besides their ecological importance, eucalypts are also the most widely planted trees for sustainable forestry in the world. We report the development of a novel collection of 535 microsatellites for species of Eucalyptus, 494 designed from ESTs and 41 from genomic libraries. A selected subset of 223 was evaluated for individual identification, parentage testing, and ancestral information content in the two most extensively studied species, Eucalyptus grandis and Eucalyptus globulus. Microsatellites showed high transferability and overlapping allele size range, suggesting they have arisen still in their common ancestor and confirming the extensive genome conservation between these two species. A consensus linkage map with 437 microsatellites, the most comprehensive microsatellite-only genetic map for Eucalyptus, was built by assembling segregation data from three mapping populations and anchored to the Eucalyptus genome. An overall colinearity between recombination-based and physical positioning of 84% of the mapped microsatellites was observed, with some ordering discrepancies and sporadic locus duplications, consistent with the recently described whole genome duplication events in Eucalyptus. The linkage map covered 95.2% of the 605.8-Mbp assembled genome sequence, placing one microsatellite every 1.55 Mbp on average, and an overall estimate of physical to recombination distance of 618 kbp/cM. The genetic parameters estimates together with linkage and physical position data for this large set of microsatellites should assist marker choice for genome-wide population genetics and comparative mapping in Eucalyptus. © 2014 John Wiley & Sons Ltd.

  20. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity

    DEFF Research Database (Denmark)

    Thorleifsson, Gudmar; Walters, G Bragi; Gudbjartsson, Daniel F

    2009-01-01

    Obesity results from the interaction of genetic and environmental factors. To search for sequence variants that affect variation in two common measures of obesity, weight and body mass index (BMI), both of which are highly heritable, we performed a genome-wide association (GWA) study with 305......,846 SNPs typed in 25,344 Icelandic, 2,998 Dutch, 1,890 European Americans and 1,160 African American subjects and combined the results with previously published results from the Diabetes Genetics Initiative (DGI) on 3,024 Scandinavians. We selected 43 variants in 19 regions for follow-up in 5,586 Danish...... individuals and compared the results to a genome-wide study on obesity-related traits from the GIANT consortium. In total, 29 variants, some correlated, in 11 chromosomal regions reached a genome-wide significance threshold of P

  1. Genome-wide association analysis of pain severity in dysmenorrhea identifies association at chromosome 1p13.2, near the nerve growth factor locus.

    Science.gov (United States)

    Jones, Amy V; Hockley, James R F; Hyde, Craig; Gorman, Donal; Sredic-Rhodes, Ana; Bilsland, James; McMurray, Gordon; Furlotte, Nicholas A; Hu, Youna; Hinds, David A; Cox, Peter J; Scollen, Serena

    2016-11-01

    Dysmenorrhea is a common chronic pelvic pain syndrome affecting women of childbearing potential. Family studies suggest that genetic background influences the severity of dysmenorrhea, but genetic predisposition and molecular mechanisms underlying dysmenorrhea are not understood. In this study, we conduct the first genome-wide association study to identify genetic factors associated with dysmenorrhea pain severity. A cohort of females of European descent (n = 11,891) aged 18 to 45 years rated their average dysmenorrhea pain severity. We used a linear regression model adjusting for age and body mass index, identifying one genome-wide significant (P dysmenorrhea pain were more likely to report being positive for endometriosis, polycystic ovarian syndrome, depression, and other psychiatric disorders. Our results indicate that dysmenorrhea pain severity is partly genetically determined. NGF already has an established role in chronic pain disorders, and our findings suggest that NGF may be an important mediator for gynaecological/pelvic pain in the viscera.

  2. Novel probabilistic models of spatial genetic ancestry with applications to stratification correction in genome-wide association studies.

    Science.gov (United States)

    Bhaskar, Anand; Javanmard, Adel; Courtade, Thomas A; Tse, David

    2017-03-15

    Genetic variation in human populations is influenced by geographic ancestry due to spatial locality in historical mating and migration patterns. Spatial population structure in genetic datasets has been traditionally analyzed using either model-free algorithms, such as principal components analysis (PCA) and multidimensional scaling, or using explicit spatial probabilistic models of allele frequency evolution. We develop a general probabilistic model and an associated inference algorithm that unify the model-based and data-driven approaches to visualizing and inferring population structure. Our spatial inference algorithm can also be effectively applied to the problem of population stratification in genome-wide association studies (GWAS), where hidden population structure can create fictitious associations when population ancestry is correlated with both the genotype and the trait. Our algorithm Geographic Ancestry Positioning (GAP) relates local genetic distances between samples to their spatial distances, and can be used for visually discerning population structure as well as accurately inferring the spatial origin of individuals on a two-dimensional continuum. On both simulated and several real datasets from diverse human populations, GAP exhibits substantially lower error in reconstructing spatial ancestry coordinates compared to PCA. We also develop an association test that uses the ancestry coordinates inferred by GAP to accurately account for ancestry-induced correlations in GWAS. Based on simulations and analysis of a dataset of 10 metabolic traits measured in a Northern Finland cohort, which is known to exhibit significant population structure, we find that our method has superior power to current approaches. Our software is available at https://github.com/anand-bhaskar/gap . abhaskar@stanford.edu or ajavanma@usc.edu. Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved

  3. Creative Activities in Music--A Genome-Wide Linkage Analysis.

    Science.gov (United States)

    Oikkonen, Jaana; Kuusi, Tuire; Peltonen, Petri; Raijas, Pirre; Ukkola-Vuoti, Liisa; Karma, Kai; Onkamo, Päivi; Järvelä, Irma

    2016-01-01

    Creative activities in music represent a complex cognitive function of the human brain, whose biological basis is largely unknown. In order to elucidate the biological background of creative activities in music we performed genome-wide linkage and linkage disequilibrium (LD) scans in musically experienced individuals characterised for self-reported composing, arranging and non-music related creativity. The participants consisted of 474 individuals from 79 families, and 103 sporadic individuals. We found promising evidence for linkage at 16p12.1-q12.1 for arranging (LOD 2.75, 120 cases), 4q22.1 for composing (LOD 2.15, 103 cases) and Xp11.23 for non-music related creativity (LOD 2.50, 259 cases). Surprisingly, statistically significant evidence for linkage was found for the opposite phenotype of creative activity in music (neither composing nor arranging; NCNA) at 18q21 (LOD 3.09, 149 cases), which contains cadherin genes like CDH7 and CDH19. The locus at 4q22.1 overlaps the previously identified region of musical aptitude, music perception and performance giving further support for this region as a candidate region for broad range of music-related traits. The other regions at 18q21 and 16p12.1-q12.1 are also adjacent to the previously identified loci with musical aptitude. Pathway analysis of the genes suggestively associated with composing suggested an overrepresentation of the cerebellar long-term depression pathway (LTD), which is a cellular model for synaptic plasticity. The LTD also includes cadherins and AMPA receptors, whose component GSG1L was linked to arranging. These results suggest that molecular pathways linked to memory and learning via LTD affect music-related creative behaviour. Musical creativity is a complex phenotype where a common background with musicality and intelligence has been proposed. Here, we implicate genetic regions affecting music-related creative behaviour, which also include genes with neuropsychiatric associations. We also propose

  4. Creative Activities in Music--A Genome-Wide Linkage Analysis.

    Directory of Open Access Journals (Sweden)

    Jaana Oikkonen

    Full Text Available Creative activities in music represent a complex cognitive function of the human brain, whose biological basis is largely unknown. In order to elucidate the biological background of creative activities in music we performed genome-wide linkage and linkage disequilibrium (LD scans in musically experienced individuals characterised for self-reported composing, arranging and non-music related creativity. The participants consisted of 474 individuals from 79 families, and 103 sporadic individuals. We found promising evidence for linkage at 16p12.1-q12.1 for arranging (LOD 2.75, 120 cases, 4q22.1 for composing (LOD 2.15, 103 cases and Xp11.23 for non-music related creativity (LOD 2.50, 259 cases. Surprisingly, statistically significant evidence for linkage was found for the opposite phenotype of creative activity in music (neither composing nor arranging; NCNA at 18q21 (LOD 3.09, 149 cases, which contains cadherin genes like CDH7 and CDH19. The locus at 4q22.1 overlaps the previously identified region of musical aptitude, music perception and performance giving further support for this region as a candidate region for broad range of music-related traits. The other regions at 18q21 and 16p12.1-q12.1 are also adjacent to the previously identified loci with musical aptitude. Pathway analysis of the genes suggestively associated with composing suggested an overrepresentation of the cerebellar long-term depression pathway (LTD, which is a cellular model for synaptic plasticity. The LTD also includes cadherins and AMPA receptors, whose component GSG1L was linked to arranging. These results suggest that molecular pathways linked to memory and learning via LTD affect music-related creative behaviour. Musical creativity is a complex phenotype where a common background with musicality and intelligence has been proposed. Here, we implicate genetic regions affecting music-related creative behaviour, which also include genes with neuropsychiatric associations. We

  5. Genome-wide association study and biological pathway analysis of the Eimeria maxima response in broilers.

    Science.gov (United States)

    Hamzić, Edin; Buitenhuis, Bart; Hérault, Frédéric; Hawken, Rachel; Abrahamsen, Mitchel S; Servin, Bertrand; Elsen, Jean-Michel; Pinard-van der Laan, Marie-Hélène; Bed'Hom, Bertrand

    2015-11-25

    Coccidiosis is the most common and costly disease in the poultry industry and is caused by protozoans of the Eimeria genus. The current control of coccidiosis, based on the use of anticoccidial drugs and vaccination, faces serious obstacles such as drug resistance and the high costs for the development of efficient vaccines, respectively. Therefore, the current control programs must be expanded with complementary approaches such as the use of genetics to improve the host response to Eimeria infections. Recently, we have performed a large-scale challenge study on Cobb500 broilers using E. maxima for which we investigated variability among animals in response to the challenge. As a follow-up to this challenge study, we performed a genome-wide association study (GWAS) to identify genomic regions underlying variability of the measured traits in the response to Eimeria maxima in broilers. Furthermore, we conducted a post-GWAS functional analysis to increase our biological understanding of the underlying response to Eimeria maxima challenge. In total, we identified 22 single nucleotide polymorphisms (SNPs) with q value Eimeria maxima in broilers. Furthermore, the post-GWAS functional analysis indicates that biological pathways and networks involved in tissue proliferation and repair along with the primary innate immune response may play the most important role during the early stage of Eimeria maxima infection in broilers.

  6. A genome-wide association study of bipolar disorder with comorbid eating disorder replicates the SOX2-OT region.

    Science.gov (United States)

    Liu, Xiaohua; Kelsoe, John R; Greenwood, Tiffany A

    2016-01-01

    Bipolar disorder is a heterogeneous mood disorder associated with several important clinical comorbidities, such as eating disorders. This clinical heterogeneity complicates the identification of genetic variants contributing to bipolar susceptibility. Here we investigate comorbidity of eating disorders as a subphenotype of bipolar disorder to identify genetic variation that is common and unique to both disorders. We performed a genome-wide association analysis contrasting 184 bipolar subjects with eating disorder comorbidity against both 1370 controls and 2006 subjects with bipolar disorder only from the Bipolar Genome Study (BiGS). The most significant genome-wide finding was observed bipolar with comorbid eating disorder vs. controls within SOX2-OT (p=8.9×10(-8) for rs4854912) with a secondary peak in the adjacent FXR1 gene (p=1.2×10(-6) for rs1805576) on chromosome 3q26.33. This region was also the most prominent finding in the case-only analysis (p=3.5×10(-7) and 4.3×10(-6), respectively). Several regions of interest containing genes involved in neurodevelopment and neuroprotection processes were also identified. While our primary finding did not quite reach genome-wide significance, likely due to the relatively limited sample size, these results can be viewed as a replication of a recent study of eating disorders in a large cohort. These findings replicate the prior association of SOX2-OT with eating disorders and broadly support the involvement of neurodevelopmental/neuroprotective mechanisms in the pathophysiology of both disorders. They further suggest that different clinical manifestations of bipolar disorder may reflect differential genetic contributions and argue for the utility of clinical subphenotypes in identifying additional molecular pathways leading to illness. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Pantoea ananatis Genetic Diversity Analysis Reveals Limited Genomic Diversity as Well as Accessory Genes Correlated with Onion Pathogenicity

    Directory of Open Access Journals (Sweden)

    Shaun P. Stice

    2018-02-01

    Full Text Available Pantoea ananatis is a member of the family Enterobacteriaceae and an enigmatic plant pathogen with a broad host range. Although P. ananatis strains can be aggressive on onion causing foliar necrosis and onion center rot, previous genomic analysis has shown that P. ananatis lacks the primary virulence secretion systems associated with other plant pathogens. We assessed a collection of fifty P. ananatis strains collected from Georgia over three decades to determine genetic factors that correlated with onion pathogenic potential. Previous genetic analysis studies have compared strains isolated from different hosts with varying diseases potential and isolation sources. Strains varied greatly in their pathogenic potential and aggressiveness on different cultivated Allium species like onion, leek, shallot, and chive. Using multi-locus sequence analysis (MLSA and repetitive extragenic palindrome repeat (rep-PCR techniques, we did not observe any correlation between onion pathogenic potential and genetic diversity among strains. Whole genome sequencing and pan-genomic analysis of a sub-set of 10 strains aided in the identification of a novel series of genetic regions, likely plasmid borne, and correlating with onion pathogenicity observed on single contigs of the genetic assemblies. We named these loci Onion Virulence Regions (OVR A-D. The OVR loci contain genes involved in redox regulation as well as pectate lyase and rhamnogalacturonase genes. Previous studies have not identified distinct genetic loci or plasmids correlating with onion foliar pathogenicity or pathogenicity on a single host pathosystem. The lack of focus on a single host system for this phytopathgenic disease necessitates the pan-genomic analysis performed in this study.

  8. Genome-wide association study identifies 74 loci associated with educational attainment

    NARCIS (Netherlands)

    A. Okbay (Aysu); J.P. Beauchamp (Jonathan); Fontana, M.A. (Mark Alan); J.J. Lee (James J.); T.H. Pers (Tune); Rietveld, C.A. (Cornelius A.); P. Turley (Patrick); Chen, G.-B. (Guo-Bo); V. Emilsson (Valur); Meddens, S.F.W. (S. Fleur W.); Oskarsson, S. (Sven); Pickrell, J.K. (Joseph K.); Thom, K. (Kevin); Timshel, P. (Pascal); R. de Vlaming (Ronald); A. Abdellaoui (Abdel); T.S. Ahluwalia (Tarunveer Singh); J. Bacelis (Jonas); C. Baumbach (Clemens); Bjornsdottir, G. (Gyda); J.H. Brandsma (Johan); Pina Concas, M. (Maria); J. Derringer; Furlotte, N.A. (Nicholas A.); T.E. Galesloot (Tessel); S. Girotto; Gupta, R. (Richa); L.M. Hall (Leanne M.); S.E. Harris (Sarah); E. Hofer; Horikoshi, M. (Momoko); J.E. Huffman (Jennifer E.); Kaasik, K. (Kadri); I.-P. Kalafati (Ioanna-Panagiota); R. Karlsson (Robert); A. Kong (Augustine); J. Lahti (Jari); S.J. van der Lee (Sven); Deleeuw, C. (Christiaan); P.A. Lind (Penelope); Lindgren, K.-O. (Karl-Oskar); Liu, T. (Tian); M. Mangino (Massimo); J. Marten (Jonathan); E. Mihailov (Evelin); M. Miller (Mike); P.J. van der Most (Peter); C. Oldmeadow (Christopher); A. Payton (Antony); N. Pervjakova (Natalia); W.J. Peyrot (Wouter ); Qian, Y. (Yong); O. Raitakari (Olli); Rueedi, R. (Rico); Salvi, E. (Erika); Schmidt, B. (Börge); Schraut, K.E. (Katharina E.); Shi, J. (Jianxin); A.V. Smith (Albert Vernon); R.A. Poot (Raymond); B. St Pourcain (Beate); A. Teumer (Alexander); G. Thorleifsson (Gudmar); N. Verweij (Niek); D. Vuckovic (Dragana); Wellmann, J. (Juergen); H.J. Westra (Harm-Jan); Yang, J. (Jingyun); Zhao, W. (Wei); Zhu, Z. (Zhihong); B.Z. Alizadeh (Behrooz); N. Amin (Najaf); Bakshi, A. (Andrew); S.E. Baumeister (Sebastian); G. Biino (Ginevra); K. Bønnelykke (Klaus); P.A. Boyle (Patricia); H. Campbell (Harry); Cappuccio, F.P. (Francesco P.); G. Davies (Gail); J.E. de Neve (Jan-Emmanuel); P. Deloukas (Panagiotis); I. Demuth (Ilja); Ding, J. (Jun); Eibich, P. (Peter); Eisele, L. (Lewin); N. Eklund (Niina); D.M. Evans (David); J.D. Faul (Jessica D.); M.F. Feitosa (Mary Furlan); A.J. Forstner (Andreas); I. Gandin (Ilaria); Gunnarsson, B. (Bjarni); B.V. Halldorsson (Bjarni); T.B. Harris (Tamara); E.G. Holliday (Elizabeth); A.C. Heath (Andrew C.); L.J. Hocking; G. Homuth (Georg); M. Horan (Mike); J.J. Hottenga (Jouke Jan); P.L. de Jager (Philip); P.K. Joshi (Peter); A. Juqessur (Astanand); M. Kaakinen (Marika); M. Kähönen (Mika); S. Kanoni (Stavroula); Keltigangas-Järvinen, L. (Liisa); L.A.L.M. Kiemeney (Bart); I. Kolcic (Ivana); Koskinen, S. (Seppo); A. Kraja (Aldi); Kroh, M. (Martin); Z. Kutalik (Zoltán); A. Latvala (Antti); L.J. Launer (Lenore); Lebreton, M.P. (Maël P.); D.F. Levinson (Douglas F.); P. Lichtenstein (Paul); P. Lichtner (Peter); D.C. Liewald (David C.); A. Loukola (Anu); P.A. Madden (Pamela); R. Mägi (Reedik); Mäki-Opas, T. (Tomi); R.E. Marioni (Riccardo); P. Marques-Vidal; Meddens, G.A. (Gerardus A.); G. Mcmahon (George); C. Meisinger (Christa); T. Meitinger (Thomas); Milaneschi, Y. (Yusplitri); L. Milani (Lili); G.W. Montgomery (Grant); R. Myhre (Ronny); C.P. Nelson (Christopher P.); D.R. Nyholt (Dale); W.E.R. Ollier (William); A. Palotie (Aarno); L. Paternoster (Lavinia); N.L. Pedersen (Nancy); K. Petrovic (Katja); D.J. Porteous (David J.); K. Räikkönen (Katri); Ring, S.M. (Susan M.); A. Robino (Antonietta); O. Rostapshova (Olga); I. Rudan (Igor); A. Rustichini (Aldo); V. Salomaa (Veikko); Sanders, A.R. (Alan R.); A.-P. Sarin; R. Schmidt (Reinhold); R.J. Scott (Rodney); B.H. Smith (Blair); J.A. Smith (Jennifer A); J.A. Staessen (Jan); E. Steinhagen-Thiessen (Elisabeth); K. Strauch (Konstantin); A. Terracciano; M.D. Tobin (Martin); S. Ulivi (Shelia); S. Vaccargiu (Simona); L. Quaye (Lydia); F.J.A. van Rooij (Frank); C. Venturini (Cristina); A.A.E. Vinkhuyzen (Anna A.); U. Völker (Uwe); Völzke, H. (Henry); J.M. Vonk (Judith); D. Vozzi (Diego); J. Waage (Johannes); E.B. Ware (Erin B.); G.A.H.M. Willemsen (Gonneke); J. Attia (John); D.A. Bennett (David A.); Berger, K. (Klaus); L. Bertram (Lars); H. Bisgaard (Hans); D.I. Boomsma (Dorret); I.B. Borecki (Ingrid); U. Bültmann (Ute); C.F. Chabris (Christopher F.); F. Cucca (Francesco); D. Cusi (Daniele); I.J. Deary (Ian J.); G.V. Dedoussis (George); C.M. van Duijn (Cornelia); K. Hagen (Knut); B. Franke (Barbara); L. Franke (Lude); P. Gasparini (Paolo); P.V. Gejman (Pablo); C. Gieger (Christian); H.J. Grabe (Hans Jörgen); J. Gratten (Jacob); P.J.F. Groenen (Patrick); V. Gudnason (Vilmundur); P. van der Harst (Pim); C. Hayward (Caroline); D.A. Hinds (David A.); W. Hoffmann (Wolfgang); E. Hypponen (Elina); W.G. Iacono (William); B. Jacobsson (Bo); M.-R. Jarvelin (Marjo-Riitta); K.-H. JöCkel (Karl-Heinz); J. Kaprio (Jaakko); S.L.R. Kardia (Sharon); T. Lehtimäki (Terho); Lehrer, S.F. (Steven F.); P.K. Magnusson (Patrik); N.G. Martin (Nicholas); M. McGue (Matt); A. Metspalu (Andres); N. Pendleton (Neil); B.W.J.H. Penninx (Brenda); M. Perola (Markus); N. Pirastu (Nicola); M. Pirastu (Mario); O. Polasek (Ozren); D. Posthuma (Danielle); C. Power (Christopher); M.A. Province (Mike); N.J. Samani (Nilesh); Schlessinger, D. (David); R. Schmidt (Reinhold); T.I.A. Sørensen (Thorkild); T.D. Spector (Timothy); J-A. Zwart (John-Anker); U. Thorsteinsdottir (Unnur); A.R. Thurik (Roy); Timpson, N.J. (Nicholas J.); H.W. Tiemeier (Henning); J.Y. Tung (Joyce Y.); A.G. Uitterlinden (André); Vitart, V. (Veronique); P. Vollenweider (Peter); D.R. Weir (David); J.F. Wilson (James F.); A.F. Wright (Alan); Conley, D.C. (Dalton C.); R.F. Krueger; G.D. Smith; Hofman, A. (Albert); D. Laibson (David); S.E. Medland (Sarah Elizabeth); M.N. Meyer (Michelle N.); J. Yang (Joanna); M. Johannesson (Magnus); P.M. Visscher (Peter); T. Esko (Tõnu); Ph.D. Koellinger (Philipp); D. Cesarini (David); D.J. Benjamin (Daniel J.)

    2016-01-01

    textabstractEducational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that

  9. Genome-wide association study identifies 74 loci associated with educational attainment

    NARCIS (Netherlands)

    Okbay, A.; Beauchamp, J.; Fontana, M.A.; Lee, J.J.; Pers, T.H.; Rietveld, C.A.; Turley, P.; Chen, G.B.; Emilsson, V.; Meddens, S.F.W.; de Vlaming, R.; Abdellaoui, A.; Peyrot, W.; Vinkhuyzen, A.A.E.; Hottenga, J.J.; Willemsen, G.; Boomsma, D.I.; Penninx, B.W.J.H.; Laibson, D.; Medland, S.E.; Meyer, M.N.; Yang, J.; Johannesson, M.; Visscher, P.M.; Esko, T.; Koellinger, P.D.; Cesarini, D.; Benjamin, D.J.

    2016-01-01

    Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our

  10. Genome-wide association study identifies 74 loci associated with educational attainment

    NARCIS (Netherlands)

    Okbay, Aysu; Beauchamp, Jonathan P.; Fontana, Mark Alan; Lee, James J.; Pers, Tune H.; Rietveld, Cornelius A.; Turley, Patrick; Chen, Guo-Bo; Emilsson, Valur; Meddens, S. Fleur W.; Oskarsson, Sven; Pickrell, Joseph K.; Thom, Kevin; Timshel, Pascal; de Vlaming, Ronald; Abdellaoui, Abdel; Ahluwalia, Tarunveer S.; Bacelis, Jonas; Baumbach, Clemens; Bjornsdottir, Gyda; Brandsma, Johannes H.; Concas, Maria Pina; Derringer, Jaime; Furlotte, Nicholas A.; Galesloot, Tessel E.; Girotto, Giorgia; Gupta, Richa; Hall, Leanne M.; Harris, Sarah E.; Hofer, Edith; Horikoshi, Momoko; Huffman, Jennifer E.; Kaasik, Kadri; Kalafati, Ioanna P.; Karlsson, Robert; Kong, Augustine; Lahti, Jari; van der Lee, Sven J.; de Leeuw, Christiaan; Lind, Penelope A.; Lindgren, Karl-Oskar; Liu, Tian; van der Most, Peter J.; Verweij, Niek; Alizadeh, Behrooz Z.; Vonk, Judith M.; Bultmann, Ute; Franke, Lude; van der Harst, Pim; Penninx, Brenda W. J. H.

    2016-01-01

    Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals(1). Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends

  11. A systematic review of genome-wide research on psychotic experiences and negative symptom traits: New revelations and implications for psychiatry.

    Science.gov (United States)

    Ronald, Angelica; Pain, Oliver

    2018-05-08

    We present a systematic review of genome-wide research on psychotic experience and negative symptom traits (PENS) in the community. We integrate these new findings, most of which have emerged over the last four years, with more established behaviour genetic and epidemiological research. The review includes the first genome-wide association studies of PENS, including a recent meta-analysis, and the first SNP heritability estimates. Sample sizes of < 10,000 participants mean that no genome-wide significant variants have yet been replicated. Importantly, however, in the most recent and well-powered studies, polygenic risk score prediction and linkage disequilibrium (LD) score regression analyses show that all types of PENS share genetic influences with diagnosed schizophrenia and that negative symptom traits also share genetic influences with major depression. These genetic findings corroborate other evidence in supporting a link between PENS in the community and psychiatric conditions. Beyond the systematic review, we highlight recent work on gene-environment correlation, which appears to be a relevant process for psychotic experiences. Genes that influence risk factors such as tobacco use and stressful life events are likely to be harbouring 'hits' that also influence PENS. We argue for the acceptance of PENS within the mainstream, as heritable traits in the same vein as other subclinical psychopathology and personality styles such as neuroticism. While acknowledging some mixed findings, new evidence shows genetic overlap between PENS and psychiatric conditions. In sum, normal variations in adolescent and adult thinking styles, such as feeling paranoid, are heritable and show genetic associations with schizophrenia and major depression.

  12. A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing.

    Science.gov (United States)

    Davies, G; Harris, S E; Reynolds, C A; Payton, A; Knight, H M; Liewald, D C; Lopez, L M; Luciano, M; Gow, A J; Corley, J; Henderson, R; Murray, C; Pattie, A; Fox, H C; Redmond, P; Lutz, M W; Chiba-Falek, O; Linnertz, C; Saith, S; Haggarty, P; McNeill, G; Ke, X; Ollier, W; Horan, M; Roses, A D; Ponting, C P; Porteous, D J; Tenesa, A; Pickles, A; Starr, J M; Whalley, L J; Pedersen, N L; Pendleton, N; Visscher, P M; Deary, I J

    2014-01-01

    Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP--rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)--had a genome-wide significant association with cognitive ageing (P=2.5 × 10(-8)). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10(-6)). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10(-8); females, P=1.66 × 10(-11); males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10(-11)) and TOMM40 (rs11556505; P=2.45 × 10(-8)) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.

  13. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies

    DEFF Research Database (Denmark)

    Bulik-Sullivan, Brendan K.; Loh, Po-Ru; Finucane, Hilary K.

    2015-01-01

    Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from...

  14. Genome-wide association study of the four-constitution medicine.

    Science.gov (United States)

    Yin, Chang Shik; Park, Hi Joon; Chung, Joo-Ho; Lee, Hye-Jung; Lee, Byung-Cheol

    2009-12-01

    Four-constitution medicine (FCM), also known as Sasang constitutional medicine, and the heritage of the long history of individualized acupuncture medicine tradition, is one of the holistic and traditional systems of constitution to appraise and categorize individual differences into four major types. This study first reports a genome-wide association study on FCM, to explore the genetic basis of FCM and facilitate the integration of FCM with conventional individual differences research. Healthy individuals of the Korean population were classified into the four constitutional types (FCTs). A total of 353,202 single nucleotide polymorphisms (SNPs) were typed using whole genome amplified samples, and six-way comparison of FCM types provided lists of significantly differential SNPs. In one-to-one FCT comparisons, 15,944 SNPs were significantly differential, and 5 SNPs were commonly significant in all of the three comparisons. In one-to-two FCT comparisons, 22,616 SNPs were significantly differential, and 20 SNPs were commonly significant in all of the three comparison groups. This study presents the association between genome-wide SNP profiles and the categorization of the FCM, and it could further provide a starting point of genome-based identification and research of the constitutions of FCM.

  15. Integrative Functional Genomics for Systems Genetics in GeneWeaver.org.

    Science.gov (United States)

    Bubier, Jason A; Langston, Michael A; Baker, Erich J; Chesler, Elissa J

    2017-01-01

    The abundance of existing functional genomics studies permits an integrative approach to interpreting and resolving the results of diverse systems genetics studies. However, a major challenge lies in assembling and harmonizing heterogeneous data sets across species for facile comparison to the positional candidate genes and coexpression networks that come from systems genetic studies. GeneWeaver is an online database and suite of tools at www.geneweaver.org that allows for fast aggregation and analysis of gene set-centric data. GeneWeaver contains curated experimental data together with resource-level data such as GO annotations, MP annotations, and KEGG pathways, along with persistent stores of user entered data sets. These can be entered directly into GeneWeaver or transferred from widely used resources such as GeneNetwork.org. Data are analyzed using statistical tools and advanced graph algorithms to discover new relations, prioritize candidate genes, and generate function hypotheses. Here we use GeneWeaver to find genes common to multiple gene sets, prioritize candidate genes from a quantitative trait locus, and characterize a set of differentially expressed genes. Coupling a large multispecies repository curated and empirical functional genomics data to fast computational tools allows for the rapid integrative analysis of heterogeneous data for interpreting and extrapolating systems genetics results.

  16. Microsatellite genotyping and genome-wide single nucleotide polymorphism-based indices of Plasmodium falciparum diversity within clinical infections.

    Science.gov (United States)

    Murray, Lee; Mobegi, Victor A; Duffy, Craig W; Assefa, Samuel A; Kwiatkowski, Dominic P; Laman, Eugene; Loua, Kovana M; Conway, David J

    2016-05-12

    In regions where malaria is endemic, individuals are often infected with multiple distinct parasite genotypes, a situation that may impact on evolution of parasite virulence and drug resistance. Most approaches to studying genotypic diversity have involved analysis of a modest number of polymorphic loci, although whole genome sequencing enables a broader characterisation of samples. PCR-based microsatellite typing of a panel of ten loci was performed on Plasmodium falciparum in 95 clinical isolates from a highly endemic area in the Republic of Guinea, to characterize within-isolate genetic diversity. Separately, single nucleotide polymorphism (SNP) data from genome-wide short-read sequences of the same samples were used to derive within-isolate fixation indices (F ws), an inverse measure of diversity within each isolate compared to overall local genetic diversity. The latter indices were compared with the microsatellite results, and also with indices derived by randomly sampling modest numbers of SNPs. As expected, the number of microsatellite loci with more than one allele in each isolate was highly significantly inversely correlated with the genome-wide F ws fixation index (r = -0.88, P 10 % had high correlation (r > 0.90) with the index derived using all SNPs. Different types of data give highly correlated indices of within-infection diversity, although PCR-based analysis detects low-level minority genotypes not apparent in bulk sequence analysis. When whole-genome data are not obtainable, quantitative assay of ten or more SNPs can yield a reasonably accurate estimate of the within-infection fixation index (F ws).

  17. Time-Resolved Transposon Insertion Sequencing Reveals Genome-Wide Fitness Dynamics during Infection.

    Science.gov (United States)

    Yang, Guanhua; Billings, Gabriel; Hubbard, Troy P; Park, Joseph S; Yin Leung, Ka; Liu, Qin; Davis, Brigid M; Zhang, Yuanxing; Wang, Qiyao; Waldor, Matthew K

    2017-10-03

    Transposon insertion sequencing (TIS) is a powerful high-throughput genetic technique that is transforming functional genomics in prokaryotes, because it enables genome-wide mapping of the determinants of fitness. However, current approaches for analyzing TIS data assume that selective pressures are constant over time and thus do not yield information regarding changes in the genetic requirements for growth in dynamic environments (e.g., during infection). Here, we describe structured analysis of TIS data collected as a time series, termed pattern analysis of conditional essentiality (PACE). From a temporal series of TIS data, PACE derives a quantitative assessment of each mutant's fitness over the course of an experiment and identifies mutants with related fitness profiles. In so doing, PACE circumvents major limitations of existing methodologies, specifically the need for artificial effect size thresholds and enumeration of bacterial population expansion. We used PACE to analyze TIS samples of Edwardsiella piscicida (a fish pathogen) collected over a 2-week infection period from a natural host (the flatfish turbot). PACE uncovered more genes that affect E. piscicida 's fitness in vivo than were detected using a cutoff at a terminal sampling point, and it identified subpopulations of mutants with distinct fitness profiles, one of which informed the design of new live vaccine candidates. Overall, PACE enables efficient mining of time series TIS data and enhances the power and sensitivity of TIS-based analyses. IMPORTANCE Transposon insertion sequencing (TIS) enables genome-wide mapping of the genetic determinants of fitness, typically based on observations at a single sampling point. Here, we move beyond analysis of endpoint TIS data to create a framework for analysis of time series TIS data, termed pattern analysis of conditional essentiality (PACE). We applied PACE to identify genes that contribute to colonization of a natural host by the fish pathogen

  18. Genome-wide association study of PR interval in Hispanics/Latinos identifies novel locus at ID2.

    Science.gov (United States)

    Seyerle, Amanda A; Lin, Henry J; Gogarten, Stephanie M; Stilp, Adrienne; Méndez Giráldez, Raul; Soliman, Elsayed; Baldassari, Antoine; Graff, Mariaelisa; Heckbert, Susan; Kerr, Kathleen F; Kooperberg, Charles; Rodriguez, Carlos; Guo, Xiuqing; Yao, Jie; Sotoodehnia, Nona; Taylor, Kent D; Whitsel, Eric A; Rotter, Jerome I; Laurie, Cathy C; Avery, Christy L

    2017-11-10

    PR interval (PR) is a heritable electrocardiographic measure of atrial and atrioventricular nodal conduction. Changes in PR duration may be associated with atrial fibrillation, heart failure and all-cause mortality. Hispanic/Latino populations have high burdens of cardiovascular morbidity and mortality, are highly admixed and represent exceptional opportunities for novel locus identification. However, they remain chronically understudied. We present the first genome-wide association study (GWAS) of PR in 14 756 participants of Hispanic/Latino ancestry from three studies. Study-specific summary results of the association between 1000 Genomes Phase 1 imputed single-nucleotide polymorphisms (SNPs) and PR assumed an additive genetic model and were adjusted for global ancestry, study centre/region and clinical covariates. Results were combined using fixed-effects, inverse variance weighted meta-analysis. Sequential conditional analyses were used to identify independent signals. Replication of novel loci was performed in populations of Asian, African and European descent. ENCODE and RoadMap data were used to annotate results. We identified a novel genome-wide association (PPR at ID2 (rs6730558), which replicated in Asian and European populations (PPR loci to Hispanics/Latinos. Bioinformatics annotation provided evidence for regulatory function in cardiac tissue. Further, for six loci that generalised, the Hispanic/Latino index SNP was genome-wide significant and identical to (or in high linkage disequilibrium with) the previously identified GWAS lead SNP. Our results suggest that genetic determinants of PR are consistent across race/ethnicity, but extending studies to admixed populations can identify novel associations, underscoring the importance of conducting genetic studies in diverse populations. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise

  19. The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position Statement of the Canadian College of Medical Geneticists

    OpenAIRE

    Boycott, Kym; Hartley, Taila; Adam, Shelin; Bernier, Francois; Chong, Karen; Fernandez, Bridget A; Friedman, Jan M; Geraghty, Michael T; Hume, Stacey; Knoppers, Bartha M; Laberge, Anne-Marie; Majewski, Jacek; Mendoza-Londono, Roberto; Meyn, M Stephen; Michaud, Jacques L

    2015-01-01

    Purpose and scope The aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it...

  20. Genome-wide distribution comparative and composition analysis of the SSRs in Poaceae.

    Science.gov (United States)

    Wang, Yi; Yang, Chao; Jin, Qiaojun; Zhou, Dongjie; Wang, Shuangshuang; Yu, Yuanjie; Yang, Long

    2015-02-15

    The Poaceae family is of great importance to human beings since it comprises the cereal grasses which are the main sources for human food and animal feed. With the rapid growth of genomic data from Poaceae members, comparative genomics becomes a convinent method to study genetics of diffierent species. The SSRs (Simple Sequence Repeats) are widely used markers in the studies of Poaceae for their high abundance and stability. In this study, using the genomic sequences of 9 Poaceae species, we detected 11,993,943 SSR loci and developed 6,799,910 SSR primer pairs. The results show that SSRs are distributed on all the genomic elements in grass. Hexamer is the most frequent motif and AT/TA is the most frequent motif in dimer. The abundance of the SSRs has a positive linear relationship with the recombination rate. SSR sequences in the coding regions involve a higher GC content in the Poaceae than that in the other species. SSRs of 70-80 bp in length showed the highest AT/GC base ratio among all of these loci. The result shows the highest polymorphism rate belongs to the SSRs ranged from 30 bp to 40 bp. Using all the SSR primers of Japonica, nineteen universal primers were selected and located on the genome of the grass family. The information of SSR loci, the SSR primers and the tools of mining and analyzing SSR are provided in the PSSRD (Poaceae SSR Database, http://biodb.sdau.edu.cn/pssrd/). Our study and the PSSRD database provide a foundation for the comparative study in the Poaceae and it will accelerate the study on markers application, gene mapping and molecular breeding.

  1. Genome-wide association analysis identifies three new risk loci for gout arthritis in Han Chinese

    Science.gov (United States)

    Li, Changgui; Li, Zhiqiang; Liu, Shiguo; Wang, Can; Han, Lin; Cui, Lingling; Zhou, Jingguo; Zou, Hejian; Liu, Zhen; Chen, Jianhua; Cheng, Xiaoyu; Zhou, Zhaowei; Ding, Chengcheng; Wang, Meng; Chen, Tong; Cui, Ying; He, Hongmei; Zhang, Keke; Yin, Congcong; Wang, Yunlong; Xing, Shichao; Li, Baojie; Ji, Jue; Jia, Zhaotong; Ma, Lidan; Niu, Jiapeng; Xin, Ying; Liu, Tian; Chu, Nan; Yu, Qing; Ren, Wei; Wang, Xuefeng; Zhang, Aiqing; Sun, Yuping; Wang, Haili; Lu, Jie; Li, Yuanyuan; Qing, Yufeng; Chen, Gang; Wang, Yangang; Zhou, Li; Niu, Haitao; Liang, Jun; Dong, Qian; Li, Xinde; Mi, Qing-Sheng; Shi, Yongyong

    2015-01-01

    Gout is one of the most common types of inflammatory arthritis, caused by the deposition of monosodium urate crystals in and around the joints. Previous genome-wide association studies (GWASs) have identified many genetic loci associated with raised serum urate concentrations. However, hyperuricemia alone is not sufficient for the development of gout arthritis. Here we conduct a multistage GWAS in Han Chinese using 4,275 male gout patients and 6,272 normal male controls (1,255 cases and 1,848 controls were genome-wide genotyped), with an additional 1,644 hyperuricemic controls. We discover three new risk loci, 17q23.2 (rs11653176, P=1.36 × 10−13, BCAS3), 9p24.2 (rs12236871, P=1.48 × 10−10, RFX3) and 11p15.5 (rs179785, P=1.28 × 10−8, KCNQ1), which contain inflammatory candidate genes. Our results suggest that these loci are most likely related to the progression from hyperuricemia to inflammatory gout, which will provide new insights into the pathogenesis of gout arthritis. PMID:25967671

  2. Genome-wide association analysis identifies three new risk loci for gout arthritis in Han Chinese.

    Science.gov (United States)

    Li, Changgui; Li, Zhiqiang; Liu, Shiguo; Wang, Can; Han, Lin; Cui, Lingling; Zhou, Jingguo; Zou, Hejian; Liu, Zhen; Chen, Jianhua; Cheng, Xiaoyu; Zhou, Zhaowei; Ding, Chengcheng; Wang, Meng; Chen, Tong; Cui, Ying; He, Hongmei; Zhang, Keke; Yin, Congcong; Wang, Yunlong; Xing, Shichao; Li, Baojie; Ji, Jue; Jia, Zhaotong; Ma, Lidan; Niu, Jiapeng; Xin, Ying; Liu, Tian; Chu, Nan; Yu, Qing; Ren, Wei; Wang, Xuefeng; Zhang, Aiqing; Sun, Yuping; Wang, Haili; Lu, Jie; Li, Yuanyuan; Qing, Yufeng; Chen, Gang; Wang, Yangang; Zhou, Li; Niu, Haitao; Liang, Jun; Dong, Qian; Li, Xinde; Mi, Qing-Sheng; Shi, Yongyong

    2015-05-13

    Gout is one of the most common types of inflammatory arthritis, caused by the deposition of monosodium urate crystals in and around the joints. Previous genome-wide association studies (GWASs) have identified many genetic loci associated with raised serum urate concentrations. However, hyperuricemia alone is not sufficient for the development of gout arthritis. Here we conduct a multistage GWAS in Han Chinese using 4,275 male gout patients and 6,272 normal male controls (1,255 cases and 1,848 controls were genome-wide genotyped), with an additional 1,644 hyperuricemic controls. We discover three new risk loci, 17q23.2 (rs11653176, P=1.36 × 10(-13), BCAS3), 9p24.2 (rs12236871, P=1.48 × 10(-10), RFX3) and 11p15.5 (rs179785, P=1.28 × 10(-8), KCNQ1), which contain inflammatory candidate genes. Our results suggest that these loci are most likely related to the progression from hyperuricemia to inflammatory gout, which will provide new insights into the pathogenesis of gout arthritis.

  3. Genome-wide physical activity interactions in adiposity ― A meta-analysis of 200,452 adults

    Science.gov (United States)

    Feitosa, Mary F.; Barata, Llilda; Chu, Audrey Y.; Mahajan, Anubha; Hadley, David; Xue, Luting; Workalemahu, Tsegaselassie; den Hoed, Marcel; Ahluwalia, Tarunveer S.; Qi, Qibin; Ngwa, Julius S.; Quaye, Lydia; Eicher, John D.; Hayes, James E.; Cornelis, Marilyn; Kutalik, Zoltan; Lim, Elise; Luan, Jian’an; Huffman, Jennifer E.; Zhang, Weihua; Zhao, Wei; Griffin, Paula J.; Haller, Toomas; Ahmad, Shafqat; Marques-Vidal, Pedro M.; Bien, Stephanie; Yengo, Loic; Teumer, Alexander; Smith, Albert Vernon; Kumari, Meena; Harder, Marie Neergaard; Justesen, Johanne Marie; Kleber, Marcus E.; Hollensted, Mette; Lohman, Kurt; Rivera, Natalia V.; Whitfield, John B.; Zhao, Jing Hua; Stringham, Heather M.; Lyytikäinen, Leo-Pekka; Huppertz, Charlotte; Willemsen, Gonneke; Peyrot, Wouter J.; Wu, Ying; Kristiansson, Kati; Demirkan, Ayse; Fornage, Myriam; Hassinen, Maija; Bielak, Lawrence F.; Cadby, Gemma; Tanaka, Toshiko; Mägi, Reedik; van der Most, Peter J.; Jackson, Anne U.; Bragg-Gresham, Jennifer L.; Vitart, Veronique; Marten, Jonathan; Navarro, Pau; Bellis, Claire; Pasko, Dorota; Johansson, Åsa; Snitker, Søren; Cheng, Yu-Ching; Eriksson, Joel; Lim, Unhee; Aadahl, Mette; Adair, Linda S.; Amin, Najaf; Balkau, Beverley; Auvinen, Juha; Beilby, John; Bergman, Richard N.; Bergmann, Sven; Bertoni, Alain G.; Blangero, John; Bonnefond, Amélie; Bonnycastle, Lori L.; Borja, Judith B.; Brage, Søren; Busonero, Fabio; Buyske, Steve; Campbell, Harry; Chines, Peter S.; Collins, Francis S.; Corre, Tanguy; Smith, George Davey; Delgado, Graciela E.; Dueker, Nicole; Dörr, Marcus; Ebeling, Tapani; Eiriksdottir, Gudny; Esko, Tõnu; Faul, Jessica D.; Fu, Mao; Færch, Kristine; Gieger, Christian; Gläser, Sven; Gong, Jian; Gordon-Larsen, Penny; Grallert, Harald; Grammer, Tanja B.; Grarup, Niels; van Grootheest, Gerard; Harald, Kennet; Hastie, Nicholas D.; Havulinna, Aki S.; Hernandez, Dena; Hindorff, Lucia; Hocking, Lynne J.; Holmens, Oddgeir L.; Holzapfel, Christina; Hottenga, Jouke Jan; Huang, Jie; Huang, Tao; Hui, Jennie; Huth, Cornelia; Hutri-Kähönen, Nina; James, Alan L.; Jansson, John-Olov; Jhun, Min A.; Juonala, Markus; Kinnunen, Leena; Koistinen, Heikki A.; Kolcic, Ivana; Komulainen, Pirjo; Kuusisto, Johanna; Kvaløy, Kirsti; Kähönen, Mika; Lakka, Timo A.; Launer, Lenore J.; Lehne, Benjamin; Lindgren, Cecilia M.; Lorentzon, Mattias; Luben, Robert; Marre, Michel; Milaneschi, Yuri; Monda, Keri L.; Montgomery, Grant W.; De Moor, Marleen H. M.; Mulas, Antonella; Müller-Nurasyid, Martina; Musk, A. W.; Männikkö, Reija; Männistö, Satu; Narisu, Narisu; Nauck, Matthias; Nettleton, Jennifer A.; Nolte, Ilja M.; Oldehinkel, Albertine J.; Olden, Matthias; Ong, Ken K.; Padmanabhan, Sandosh; Paternoster, Lavinia; Perez, Jeremiah; Perola, Markus; Peters, Annette; Peters, Ulrike; Peyser, Patricia A.; Prokopenko, Inga; Puolijoki, Hannu; Raitakari, Olli T.; Rankinen, Tuomo; Rasmussen-Torvik, Laura J.; Rawal, Rajesh; Ridker, Paul M.; Rose, Lynda M.; Rudan, Igor; Sarti, Cinzia; Sarzynski, Mark A.; Savonen, Kai; Scott, William R.; Sanna, Serena; Shuldiner, Alan R.; Sidney, Steve; Silbernagel, Günther; Smith, Blair H.; Smith, Jennifer A.; Snieder, Harold; Stančáková, Alena; Sternfeld, Barbara; Swift, Amy J.; Tammelin, Tuija; Tan, Sian-Tsung; Thorand, Barbara; Thuillier, Dorothée; Vandenput, Liesbeth; Vestergaard, Henrik; van Vliet-Ostaptchouk, Jana V.; Vohl, Marie-Claude; Völker, Uwe; Waeber, Gérard; Walker, Mark; Wild, Sarah; Wong, Andrew; Wright, Alan F.; Zillikens, M. Carola; Zubair, Niha; Haiman, Christopher A.; Lemarchand, Loic; Gyllensten, Ulf; Ohlsson, Claes; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, André G.; Pérusse, Louis; Wilson, James F.; Hayward, Caroline; Polasek, Ozren; Cucca, Francesco; Hveem, Kristian; Hartman, Catharina A.; Tönjes, Anke; Bandinelli, Stefania; Palmer, Lyle J.; Kardia, Sharon L. R.; Rauramaa, Rainer; Sørensen, Thorkild I. A.; Tuomilehto, Jaakko; Salomaa, Veikko; Penninx, Brenda W. J. H.; de Geus, Eco J. C.; Boomsma, Dorret I.; Lehtimäki, Terho; Mangino, Massimo; Laakso, Markku; Bouchard, Claude; Martin, Nicholas G.; Kuh, Diana; Liu, Yongmei; Linneberg, Allan; März, Winfried; Strauch, Konstantin; Kivimäki, Mika; Harris, Tamara B.; Gudnason, Vilmundur; Völzke, Henry; Qi, Lu; Järvelin, Marjo-Riitta; Chambers, John C.; Kooner, Jaspal S.; Froguel, Philippe; Kooperberg, Charles; Vollenweider, Peter; Hallmans, Göran; Hansen, Torben; Pedersen, Oluf; Metspalu, Andres; Wareham, Nicholas J.; Langenberg, Claudia; Weir, David R.; Porteous, David J.; Boerwinkle, Eric; Chasman, Daniel I.; Abecasis, Gonçalo R.; McCarthy, Mark I.; Frayling, Timothy M.; O’Connell, Jeffrey R.; van Duijn, Cornelia M.; Boehnke, Michael; Heid, Iris M.; Mohlke, Karen L.; Fox, Caroline S.; Hirschhorn, Joel N.; Johnson, Andrew D.; Borecki, Ingrid B.; Franks, Paul W.; North, Kari E.; Cupples, L. Adrienne; Loos, Ruth J. F.; Kilpeläinen, Tuomas O.

    2017-01-01

    Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery. PMID:28448500

  4. An evaluation of the genetic-matched pair study design using genome-wide SNP data from the European population

    DEFF Research Database (Denmark)

    Lu, Timothy Tehua; Lao, Oscar; Nothnagel, Michael

    2009-01-01

    of cases (76.0%), the BOM of a given individual, based on the complete marker set, came from a different recruitment site than the individual itself. A second marker set, specifically selected for ancestry sensitivity using singular value decomposition, performed even more poorly and was no more capable......Genetic matching potentially provides a means to alleviate the effects of incomplete Mendelian randomization in population-based gene-disease association studies. We therefore evaluated the genetic-matched pair study design on the basis of genome-wide SNP data (309,790 markers; Affymetrix Gene......Chip Human Mapping 500K Array) from 2457 individuals, sampled at 23 different recruitment sites across Europe. Using pair-wise identity-by-state (IBS) as a matching criterion, we tried to derive a subset of markers that would allow identification of the best overall matching (BOM) partner for a given...

  5. Genome-Wide Analysis of Simple Sequence Repeats in Bitter Gourd (Momordica charantia

    Directory of Open Access Journals (Sweden)

    Junjie Cui

    2017-06-01

    Full Text Available Bitter gourd (Momordica charantia is widely cultivated as a vegetable and medicinal herb in many Asian and African countries. After the sequencing of the cucumber (Cucumis sativus, watermelon (Citrullus lanatus, and melon (Cucumis melo genomes, bitter gourd became the fourth cucurbit species whose whole genome was sequenced. However, a comprehensive analysis of simple sequence repeats (SSRs in bitter gourd, including a comparison with the three aforementioned cucurbit species has not yet been published. Here, we identified a total of 188,091 and 167,160 SSR motifs in the genomes of the bitter gourd lines ‘Dali-11’ and ‘OHB3-1,’ respectively. Subsequently, the SSR content, motif lengths, and classified motif types were characterized for the bitter gourd genomes and compared among all the cucurbit genomes. Lastly, a large set of 138,727 unique in silico SSR primer pairs were designed for bitter gourd. Among these, 71 primers were selected, all of which successfully amplified SSRs from the two bitter gourd lines ‘Dali-11’ and ‘K44’. To further examine the utilization of unique SSR primers, 21 SSR markers were used to genotype a collection of 211 bitter gourd lines from all over the world. A model-based clustering method and phylogenetic analysis indicated a clear separation among the geographic groups. The genomic SSR markers developed in this study have considerable potential value in advancing bitter gourd research.

  6. GBOOST: a GPU-based tool for detecting gene-gene interactions in genome-wide case control studies.

    Science.gov (United States)

    Yung, Ling Sing; Yang, Can; Wan, Xiang; Yu, Weichuan

    2011-05-01

    Collecting millions of genetic variations is feasible with the advanced genotyping technology. With a huge amount of genetic variations data in hand, developing efficient algorithms to carry out the gene-gene interaction analysis in a timely manner has become one of the key problems in genome-wide association studies (GWAS). Boolean operation-based screening and testing (BOOST), a recent work in GWAS, completes gene-gene interaction analysis in 2.5 days on a desktop computer. Compared with central processing units (CPUs), graphic processing units (GPUs) are highly parallel hardware and provide massive computing resources. We are, therefore, motivated to use GPUs to further speed up the analysis of gene-gene interactions. We implement the BOOST method based on a GPU framework and name it GBOOST. GBOOST achieves a 40-fold speedup compared with BOOST. It completes the analysis of Wellcome Trust Case Control Consortium Type 2 Diabetes (WTCCC T2D) genome data within 1.34 h on a desktop computer equipped with Nvidia GeForce GTX 285 display card. GBOOST code is available at http://bioinformatics.ust.hk/BOOST.html#GBOOST.

  7. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

    DEFF Research Database (Denmark)

    O'Dushlaine, Colm; Rossin, Lizzy; Lee, Phil H.

    2015-01-01

    Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from ...

  8. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

    NARCIS (Netherlands)

    O'Dushlaine, Colm; Rossin, Lizzy; Lee, Phil H.; Duncan, Laramie; Parikshak, Neelroop N.; Newhouse, Stephen; Ripke, Stephan; Neale, Benjamin M.; Purcell, Shaun M.; Posthuma, Danielle; Nurnberger, John I.; Lee, S. Hong; Faraone, Stephen V.; Perlis, Roy H.; Mowry, Bryan J.; Thapar, Anita; Goddard, Michael E.; Witte, John S.; Absher, Devin; Agartz, Ingrid; Akil, Huda; Amin, Farooq; Andreassen, Ole A.; Anjorin, Adebayo; Anney, Richard; Anttila, Verneri; Arking, Dan E.; Asherson, Philip; Azevedo, Maria H.; Backlund, Lena; Badner, Judith A.; Bailey, Anthony J.; Banaschewski, Tobias; Barchas, Jack D.; Barnes, Michael R.; Barrett, Thomas B.; Bass, Nicholas; Battaglia, Agatino; Bauer, Michael; Bayes, Monica; Bellivier, Frank; Bergen, Sarah E.; Berrettini, Wade; Betancur, Catalina; Bettecken, Thomas; Biederman, Joseph; Binder, Elisabeth B.; Bruggeman, Richard; Nolen, Willem A.; Penninx, Brenda W.

    Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from

  9. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

    NARCIS (Netherlands)

    O'Dushlaine, Colm; Rossin, Lizzy; Lee, Phil H.; Duncan, Laramie; Parikshak, Neelroop N.; Newhouse, Stephen; Ripke, Stephan; Neale, Benjamin M.; Purcell, Shaun M.; Posthuma, Danielle; Nurnberger, John I.; Lee, S. Hong; Faraone, Stephen V.; Perlis, Roy H.; Mowry, Bryan J.; Thapar, Anita; Goddard, Michael E.; Witte, John S.; Absher, Devin; Agartz, Ingrid; Akil, Huda; Amin, Farooq; Andreassen, Ole A.; Anjorin, Adebayo; Anney, Richard; Anttila, Verneri; Arking, Dan E.; Asherson, Philip; Azevedo, Maria H.; Backlund, Lena; Badner, Judith A.; Bailey, Anthony J.; Banaschewski, Tobias; Barchas, Jack D.; Barnes, Michael R.; Barrett, Thomas B.; Bass, Nicholas; Battaglia, Agatino; Bauer, Michael; Bayés, Mònica; Bellivier, Frank; Bergen, Sarah E.; Berrettini, Wade; Betancur, Catalina; Bettecken, Thomas; Biederman, Joseph; Binder, Elisabeth B.; Black, Donald W.; de Haan, Lieuwe; Linszen, Don H.

    2015-01-01

    Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from

  10. Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity

    NARCIS (Netherlands)

    Joshi, Peter K; Pirastu, Nicola; Kentistou, Katherine A; Fischer, Krista; Hofer, Edith; Schraut, Katharina E; Clark, David W; Nutile, Teresa; Barnes, Catriona L K; Timmers, Paul R H J; Shen, Xia; Gandin, Ilaria; McDaid, Aaron F; Hansen, Thomas Folkmann; Gordon, Scott D; Giulianini, Franco; Boutin, Thibaud S; Abdellaoui, Abdel; Zhao, Wei; Medina-Gomez, Carolina; Bartz, Traci M; Trompet, Stella; Lange, Leslie A; Raffield, Laura; van der Spek, Ashley; Galesloot, Tessel E; Proitsi, Petroula; Yanek, Lisa R; Bielak, Lawrence F; Payton, Antony; Murgia, Federico; Concas, Maria Pina; Biino, Ginevra; Tajuddin, Salman M; Seppälä, Ilkka; Amin, Najaf; Boerwinkle, Eric; Børglum, Anders D; Campbell, Archie; Demerath, Ellen W; Demuth, Ilja; Faul, Jessica D; Ford, Ian; Gialluisi, Alessandro; Gögele, Martin; Graff, MariaElisa; Hingorani, Aroon; Hottenga, Jouke-Jan; Hougaard, David M; Hurme, Mikko A; Ikram, M Arfan; Jylhä, Marja; Kuh, Diana; Ligthart, Lannie; Lill, Christina M; Lindenberger, Ulman; Lumley, Thomas; Mägi, Reedik; Marques-Vidal, Pedro; Medland, Sarah E; Milani, Lili; Nagy, Reka; Ollier, William E R; Peyser, Patricia A; Pramstaller, Peter P; Ridker, Paul M; Rivadeneira, Fernando; Ruggiero, Daniela; Saba, Yasaman; Schmidt, Reinhold; Schmidt, Helena; Slagboom, P Eline; Smith, Blair H; Smith, Jennifer A; Sotoodehnia, Nona; Steinhagen-Thiessen, Elisabeth; van Rooij, Frank J A; Verbeek, André L; Vermeulen, Sita H; Vollenweider, Peter; Wang, Yunpeng; Werge, Thomas; Whitfield, John B; Zonderman, Alan B; Lehtimäki, Terho; Evans, Michele K; Pirastu, Mario; Fuchsberger, Christian; Bertram, Lars; Pendleton, Neil; Kardia, Sharon L R; Ciullo, Marina; Becker, Diane M; Wong, Andrew; Psaty, Bruce M; van Duijn, Cornelia M; Wilson, James G; Jukema, J Wouter; Kiemeney, Lambertus; Uitterlinden, André G; Franceschini, Nora; North, Kari E; Weir, David R; Metspalu, Andres; Boomsma, Dorret I; Hayward, Caroline; Chasman, Daniel; Martin, Nicholas G; Sattar, Naveed; Campbell, Harry; Esko, Tōnu; Kutalik, Zoltán; Wilson, James F

    2017-01-01

    Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE,

  11. Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity

    NARCIS (Netherlands)

    P.K. Joshi (Peter); N. Pirastu (Nicola); Kentistou, K.A. (Katherine A.); K. Fischer (Krista); E. Hofer (Edith); Schraut, K.E. (Katharina E.); Clark, D.W. (David W.); Nutile, T. (Teresa); Barnes, C.L.K. (Catriona L. K.); Timmers, P.R.H.J. (Paul R. H. J.); Shen, X. (Xia); I. Gandin (Ilaria); McDaid, A.F. (Aaron F.); Hansen, T.F. (Thomas Folkmann); S.D. Gordon (Scott D.); F. Giulianini (Franco); T. Boutin (Thibaud); A. Abdellaoui (Abdel); W. Zhao (Wei); M.C. Medina-Gomez (Carolina); T.M. Bartz (Traci M.); S. Trompet (Stella); L.A. Lange (Leslie); Raffield, L. (Laura); A. van der Spek (Ashley); T.E. Galesloot (Tessel); Proitsi, P. (Petroula); L.R. Yanek (Lisa); L.F. Bielak (Lawrence F.); A. Payton (Antony); D. Murgia (Daniela); M.P. Concas (Maria Pina); G. Biino (Ginevra); Tajuddin, S.M. (Salman M.); I. Seppälä (Ilkka); Amin, N. (Najaf); Boerwinkle, E. (Eric); Børglum, A.D. (Anders D.); A. Campbell (Archie); E.W. Demerath (Ellen); I. Demuth (Ilja); J.D. Faul (Jessica D.); I. Ford (Ian); Gialluisi, A. (Alessandro); M. Gögele (Martin); M.J. Graff (Maud J.L.); A. Hingorani (Aroon); J.J. Hottenga (Jouke Jan); D.M. Hougaard (David); Hurme, M.A. (Mikko A.); M.K. Ikram (Kamran); Jylhä, M. (Marja); Kuh, D. (Diana); L. Ligthart (Lannie); C.M. Lill (Christina); U. Lindenberger (Ulman); T. Lumley (Thomas); R. Mägi (Reedik); P. Marques-Vidal (Pedro); S.E. Medland (Sarah Elizabeth); L. Milani (Lili); Nagy, R. (Reka); W.E.R. Ollier (William); P.A. Peyser (Patricia A.); P.P. Pramstaller (Peter Paul); P.M. Ridker (Paul); Rivadeneira, F. (Fernando); D. Ruggiero; Y. Saba (Yasaman); R. Schmidt (Reinhold); H. Schmidt (Helena); P.E. Slagboom (Eline); B.H. Smith; J.A. Smith (Jennifer A); N. Sotoodehnia (Nona); E. Steinhagen-Thiessen (Elisabeth); F.J.A. van Rooij (Frank); A.L.M. Verbeek; S.H.H.M. Vermeulen (Sita); P. Vollenweider (Peter); Wang, Y. (Yunpeng); T.M. Werge (Thomas); J.B. Whitfield (John B.); A.B. Zonderman; T. Lehtimäki (Terho); M. Evans (Michele); M. Pirastu (Mario); C. Fuchsberger (Christian); L. Bertram (Lars); N. Pendleton (Neil); Kardia, S.L.R. (Sharon L. R.); Ciullo, M. (Marina); D.M. Becker (Diane); Wong, A. (Andrew); B.M. Psaty (Bruce M.); C.M. van Duijn (Cornelia); J.F. Wilson (James); J.W. Jukema (Jan Wouter); L.A.L.M. Kiemeney (Bart); A.G. Uitterlinden (André); N. Franceschini (Nora); K.E. North (Kari); Weir, D.R. (David R.); Metspalu, A. (Andres); D.I. Boomsma (Dorret); C. Hayward (Caroline); D.I. Chasman (Daniel); Martin, N.G. (Nicholas G.); N. Sattar (Naveed); H. Campbell (Harry); T. Esko (Tõnu); Z. Kutalik (Zoltán); J.F. Wilson (James)

    2017-01-01

    textabstractGenomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions

  12. Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity

    DEFF Research Database (Denmark)

    Joshi, Peter K; Pirastu, Nicola; Kentistou, Katherine A

    2017-01-01

    Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, ...

  13. Common genetic variants associated with disease from genome-wide association studies are mutually exclusive in prostate cancer and rheumatoid arthritis.

    Science.gov (United States)

    Orozco, Gisela; Goh, Chee L; Al Olama, Ali Amin; Benlloch-Garcia, Sara; Govindasami, Koveela; Guy, Michelle; Muir, Kenneth R; Giles, Graham G; Severi, Gianluca; Neal, David E; Hamdy, Freddie C; Donovan, Jenny L; Kote-Jarai, Zsofia; Easton, Douglas F; Eyre, Steve; Eeles, Rosalind A

    2013-06-01

    WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The link between inflammation and cancer has long been reported and inflammation is thought to play a role in the pathogenesis of many cancers, including prostate cancer (PrCa). Over the last 5 years, genome-wide association studies (GWAS) have reported numerous susceptibility loci that predispose individuals to many different traits. The present study aims to ascertain if there are common genetic risk profiles that might predispose individuals to both PrCa and the autoimmune inflammatory condition, rheumatoid arthritis. These results could have potential public heath impact in terms of screening and chemoprevention. To investigate if potential common pathways exist for the pathogenesis of autoimmune disease and prostate cancer (PrCa). To ascertain if the single nucleotide polymorphisms (SNPs) reported by genome-wide association studies (GWAS) as being associated with susceptibility to PrCa are also associated with susceptibility to the autoimmune disease rheumatoid arthritis (RA). The original Wellcome Trust Case Control Consortium (WTCCC) UK RA GWAS study was expanded to include a total of 3221 cases and 5272 controls. In all, 37 germline autosomal SNPs at genome-wide significance associated with PrCa risk were identified from a UK/Australian PrCa GWAS. Allele frequencies were compared for these 37 SNPs between RA cases and controls using a chi-squared trend test and corrected for multiple testing (Bonferroni). In all, 33 SNPs were able to be analysed in the RA dataset. Proxies could not be located for the SNPs in 3q26, 5p15 and for two SNPs in 17q12. After applying a Bonferroni correction for the number of SNPs tested, the SNP mapping to CCHCR1 (rs130067) retained statistically significant evidence for association (P = 6 × 10(-4) ; odds ratio [OR] = 1.15, 95% CI: 1.06-1.24); this has also been associated with psoriasis. However, further analyses showed that the association of this allele was due to

  14. Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE.

    Science.gov (United States)

    Bertram, Lars; Lange, Christoph; Mullin, Kristina; Parkinson, Michele; Hsiao, Monica; Hogan, Meghan F; Schjeide, Brit M M; Hooli, Basavaraj; Divito, Jason; Ionita, Iuliana; Jiang, Hongyu; Laird, Nan; Moscarillo, Thomas; Ohlsen, Kari L; Elliott, Kathryn; Wang, Xin; Hu-Lince, Diane; Ryder, Marie; Murphy, Amy; Wagner, Steven L; Blacker, Deborah; Becker, K David; Tanzi, Rudolph E

    2008-11-01

    Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. To date four genes have been established to either cause early-onset autosomal-dominant AD (APP, PSEN1, and PSEN2(1-4)) or to increase susceptibility for late-onset AD (APOE5). However, the heritability of late-onset AD is as high as 80%, (6) and much of the phenotypic variance remains unexplained to date. We performed a genome-wide association (GWA) analysis using 484,522 single-nucleotide polymorphisms (SNPs) on a large (1,376 samples from 410 families) sample of AD families of self-reported European descent. We identified five SNPs showing either significant or marginally significant genome-wide association with a multivariate phenotype combining affection status and onset age. One of these signals (p = 5.7 x 10(-14)) was elicited by SNP rs4420638 and probably reflects APOE-epsilon4, which maps 11 kb proximal (r2 = 0.78). The other four signals were tested in three additional independent AD family samples composed of nearly 2700 individuals from almost 900 families. Two of these SNPs showed significant association in the replication samples (combined p values 0.007 and 0.00002). The SNP (rs11159647, on chromosome 14q31) with the strongest association signal also showed evidence of association with the same allele in GWA data generated in an independent sample of approximately 1,400 AD cases and controls (p = 0.04). Although the precise identity of the underlying locus(i) remains elusive, our study provides compelling evidence for the existence of at least one previously undescribed AD gene that, like APOE-epsilon4, primarily acts as a modifier of onset age.

  15. Genome-Wide Footprints of Pig Domestication and Selection Revealed through Massive Parallel Sequencing of Pooled DNA

    NARCIS (Netherlands)

    Amaral, A.J.; Ferretti, L.; Megens, H.J.W.C.; Crooijmans, R.P.M.A.; Nie, H.; Ramos-Onsins, S.E.; Perez-Enciso, M.; Schook, L.B.; Groenen, M.A.M.

    2011-01-01

    Background Artificial selection has caused rapid evolution in domesticated species. The identification of selection footprints across domesticated genomes can contribute to uncover the genetic basis of phenotypic diversity. Methodology/Main Findings Genome wide footprints of pig domestication and

  16. Genome-wide analysis of tandem repeats in plants and green algae

    Science.gov (United States)

    Zhixin Zhao; Cheng Guo; Sreeskandarajan Sutharzan; Pei Li; Craig Echt; Jie Zhang; Chun Liang

    2014-01-01

    Tandem repeats (TRs) extensively exist in the genomes of prokaryotes and eukaryotes. Based on the sequenced genomes and gene annotations of 31 plant and algal species in Phytozome version 8.0 (http://www.phytozome.net/), we examined TRs in a genome-wide scale, characterized their distributions and motif features, and explored their putative biological functions. Among...

  17. Correcting systematic inflation in genetic association tests that consider interaction effects: application to a genome-wide association study of posttraumatic stress disorder.

    Science.gov (United States)

    Almli, Lynn M; Duncan, Richard; Feng, Hao; Ghosh, Debashis; Binder, Elisabeth B; Bradley, Bekh; Ressler, Kerry J; Conneely, Karen N; Epstein, Michael P

    2014-12-01

    Genetic association studies of psychiatric outcomes often consider interactions with environmental exposures and, in particular, apply tests that jointly consider gene and gene-environment interaction effects for analysis. Using a genome-wide association study (GWAS) of posttraumatic stress disorder (PTSD), we report that heteroscedasticity (defined as variability in outcome that differs by the value of the environmental exposure) can invalidate traditional joint tests of gene and gene-environment interaction. To identify the cause of bias in traditional joint tests of gene and gene-environment interaction in a PTSD GWAS and determine whether proposed robust joint tests are insensitive to this problem. The PTSD GWAS data set consisted of 3359 individuals (978 men and 2381 women) from the Grady Trauma Project (GTP), a cohort study from Atlanta, Georgia. The GTP performed genome-wide genotyping of participants and collected environmental exposures using the Childhood Trauma Questionnaire and Trauma Experiences Inventory. We performed joint interaction testing of the Beck Depression Inventory and modified PTSD Symptom Scale in the GTP GWAS. We assessed systematic bias in our interaction analyses using quantile-quantile plots and genome-wide inflation factors. Application of the traditional joint interaction test to the GTP GWAS yielded systematic inflation across different outcomes and environmental exposures (inflation-factor estimates ranging from 1.07 to 1.21), whereas application of the robust joint test to the same data set yielded no such inflation (inflation-factor estimates ranging from 1.01 to 1.02). Simulated data further revealed that the robust joint test is valid in different heteroscedasticity models, whereas the traditional joint test is invalid. The robust joint test also has power similar to the traditional joint test when heteroscedasticity is not an issue. We believe the robust joint test should be used in candidate-gene studies and GWASs of

  18. Genome-wide analysis of EgEVE_1, a transcriptionally active endogenous viral element associated to small RNAs in Eucalyptus genomes

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    Helena Sanches Marcon

    2017-02-01

    Full Text Available Abstract Endogenous viral elements (EVEs are the result of heritable horizontal gene transfer from viruses to hosts. In the last years, several EVE integration events were reported in plants by the exponential availability of sequenced genomes. Eucalyptus grandis is a forest tree species with a sequenced genome that is poorly studied in terms of evolution and mobile genetic elements composition. Here we report the characterization of E. grandis endogenous viral element 1 (EgEVE_1, a transcriptionally active EVE with a size of 5,664 bp. Phylogenetic analysis and genomic distribution demonstrated that EgEVE_1 is a newly described member of the Caulimoviridae family, distinct from the recently characterized plant Florendoviruses. Genomic distribution of EgEVE_1 and Florendovirus is also distinct. EgEVE_1 qPCR quantification in Eucalyptus urophylla suggests that this genome has more EgEVE_1 copies than E. grandis. EgEVE_1 transcriptional activity was demonstrated by RT-qPCR in five Eucalyptus species and one intrageneric hybrid. We also identified that Eucalyptus EVEs can generate small RNAs (sRNAs,that might be involved in de novo DNA methylation and virus resistance. Our data suggest that EVE families in Eucalyptus have distinct properties, and we provide the first comparative analysis of EVEs in Eucalyptus genomes.

  19. Genome-Wide Interactions with Dairy Intake for Body Mass Index in Adults of European Descent

    DEFF Research Database (Denmark)

    Smith, Caren E; Follis, Jack L; Dashti, Hassan S

    2018-01-01

    SCOPE: Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption. METHODS AND RESULTS: A genome-wide interaction study to discover genetic variants that account for variati...

  20. Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci

    NARCIS (Netherlands)

    A.D. Børglum; D. Demontis; J. Grove (Jakob); J. Pallesen (J.); M.V. Hollegaard (Mads V); C.B. Pedersen (C.); A. Hedemand (A.); M. Mattheisen (Manuel); A.G. Uitterlinden (André); M. Nyegaard (M.); T.F. Orntoft (Torben); C. Wiuf (Carsten); M. Didriksen (Michael); M. Nordentoft (M.); M.M. Nö then (M.); M. Rietschel (Marcella); R.A. Ophoff (Roel); S. Cichon (Sven); R.H. Yolken (Robert); D.M. Hougaard (David); P.B. Mortensen; O. Mors

    2014-01-01

    textabstractGenetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all

  1. Genome-wide survey and analysis of microsatellites in giant panda (Ailuropoda melanoleuca), with a focus on the applications of a novel microsatellite marker system.

    Science.gov (United States)

    Huang, Jie; Li, Yu-Zhi; Du, Lian-Ming; Yang, Bo; Shen, Fu-Jun; Zhang, He-Min; Zhang, Zhi-He; Zhang, Xiu-Yue; Yue, Bi-Song

    2015-02-07

    The giant panda (Ailuropoda melanoleuca) is a critically endangered species endemic to China. Microsatellites have been preferred as the most popular molecular markers and proven effective in estimating population size, paternity test, genetic diversity for the critically endangered species. The availability of the giant panda complete genome sequences provided the opportunity to carry out genome-wide scans for all types of microsatellites markers, which now opens the way for the analysis and development of microsatellites in giant panda. By screening the whole genome sequence of giant panda in silico mining, we identified microsatellites in the genome of giant panda and analyzed their frequency and distribution in different genomic regions. Based on our search criteria, a repertoire of 855,058 SSRs was detected, with mono-nucleotides being the most abundant. SSRs were found in all genomic regions and were more abundant in non-coding regions than coding regions. A total of 160 primer pairs were designed to screen for polymorphic microsatellites using the selected tetranucleotide microsatellite sequences. The 51 novel polymorphic tetranucleotide microsatellite loci were discovered based on genotyping blood DNA from 22 captive giant pandas in this study. Finally, a total of 15 markers, which showed good polymorphism, stability, and repetition in faecal samples, were used to establish the novel microsatellite marker system for giant panda. Meanwhile, a genotyping database for Chengdu captive giant pandas (n = 57) were set up using this standardized system. What's more, a universal individual identification method was established and the genetic diversity were analysed in this study as the applications of this marker system. The microsatellite abundance and diversity were characterized in giant panda genomes. A total of 154,677 tetranucleotide microsatellites were identified and 15 of them were discovered as the polymorphic and stable loci. The individual

  2. Genetic Dissection of Maize Embryonic Callus Regenerative Capacity Using Multi-Locus Genome-Wide Association Studies

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    Langlang Ma

    2018-04-01

    Full Text Available The regenerative capacity of the embryonic callus, a complex quantitative trait, is one of the main limiting factors for maize transformation. This trait was decomposed into five traits, namely, green callus rate (GCR, callus differentiating rate (CDR, callus plantlet number (CPN, callus rooting rate (CRR, and callus browning rate (CBR. To dissect the genetic foundation of maize transformation, in this study multi-locus genome-wide association studies (GWAS for the five traits were performed in a population of 144 inbred lines genotyped with 43,427 SNPs. Using the phenotypic values in three environments and best linear unbiased prediction (BLUP values, as a result, a total of 127, 56, 160, and 130 significant quantitative trait nucleotides (QTNs were identified by mrMLM, FASTmrEMMA, ISIS EM-BLASSO, and pLARmEB, respectively. Of these QTNs, 63 QTNs were commonly detected, including 15 across multiple environments and 58 across multiple methods. Allele distribution analysis showed that the proportion of superior alleles for 36 QTNs was <50% in 31 elite inbred lines. Meanwhile, these superior alleles had obviously additive effect on the regenerative capacity. This indicates that the regenerative capacity-related traits can be improved by proper integration of the superior alleles using marker-assisted selection. Moreover, a total of 40 candidate genes were found based on these common QTNs. Some annotated genes were previously reported to relate with auxin transport, cell fate, seed germination, or embryo development, especially, GRMZM2G108933 (WOX2 was found to promote maize transgenic embryonic callus regeneration. These identified candidate genes will contribute to a further understanding of the genetic foundation of maize embryonic callus regeneration.

  3. Simultaneous analysis of all SNPs in genome-wide and re-sequencing association studies.

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    Clive J Hoggart

    2008-07-01

    Full Text Available Testing one SNP at a time does not fully realise the potential of genome-wide association studies to identify multiple causal variants, which is a plausible scenario for many complex diseases. We show that simultaneous analysis of the entire set of SNPs from a genome-wide study to identify the subset that best predicts disease outcome is now feasible, thanks to developments in stochastic search methods. We used a Bayesian-inspired penalised maximum likelihood approach in which every SNP can be considered for additive, dominant, and recessive contributions to disease risk. Posterior mode estimates were obtained for regression coefficients that were each assigned a prior with a sharp mode at zero. A non-zero coefficient estimate was interpreted as corresponding to a significant SNP. We investigated two prior distributions and show that the normal-exponential-gamma prior leads to improved SNP selection in comparison with single-SNP tests. We also derived an explicit approximation for type-I error that avoids the need to use permutation procedures. As well as genome-wide analyses, our method is well-suited to fine mapping with very dense SNP sets obtained from re-sequencing and/or imputation. It can accommodate quantitative as well as case-control phenotypes, covariate adjustment, and can be extended to search for interactions. Here, we demonstrate the power and empirical type-I error of our approach using simulated case-control data sets of up to 500 K SNPs, a real genome-wide data set of 300 K SNPs, and a sequence-based dataset, each of which can be analysed in a few hours on a desktop workstation.

  4. Genome-wide Association Study Implicates PARD3B-based AIDS Restriction

    Science.gov (United States)

    Nelson, George W.; Lautenberger, James A.; Chinn, Leslie; McIntosh, Carl; Johnson, Randall C.; Sezgin, Efe; Kessing, Bailey; Malasky, Michael; Hendrickson, Sher L.; Pontius, Joan; Tang, Minzhong; An, Ping; Winkler, Cheryl A.; Limou, Sophie; Le Clerc, Sigrid; Delaneau, Olivier; Zagury, Jean-François; Schuitemaker, Hanneke; van Manen, Daniëlle; Bream, Jay H.; Gomperts, Edward D.; Buchbinder, Susan; Goedert, James J.; Kirk, Gregory D.; O'Brien, Stephen J.

    2011-01-01

    Background. Host genetic variation influences human immunodeficiency virus (HIV) infection and progression to AIDS. Here we used clinically well-characterized subjects from 5 pretreatment HIV/AIDS cohorts for a genome-wide association study to identify gene associations with rate of AIDS progression. Methods.  European American HIV seroconverters (n = 755) were interrogated for single-nucleotide polymorphisms (SNPs) (n = 700,022) associated with progression to AIDS 1987 (Cox proportional hazards regression analysis, co-dominant model). Results.  Association with slower progression was observed for SNPs in the gene PARD3B. One of these, rs11884476, reached genome-wide significance (relative hazard = 0.3; P =3. 370 × 10−9) after statistical correction for 700,022 SNPs and contributes 4.52% of the overall variance in AIDS progression in this study. Nine of the top-ranked SNPs define a PARD3B haplotype that also displays significant association with progression to AIDS (hazard ratio, 0.3; P = 3.220 × 10−8). One of these SNPs, rs10185378, is a predicted exonic splicing enhancer; significant alteration in the expression profile of PARD3B splicing transcripts was observed in B cell lines with alternate rs10185378 genotypes. This SNP was typed in European cohorts of rapid progressors and was found to be protective for AIDS 1993 definition (odds ratio, 0.43, P = .025). Conclusions. These observations suggest a potential unsuspected pathway of host genetic influence on the dynamics of AIDS progression. PMID:21502085

  5. Analysis of the genome-wide variations among multiple strains of the plant pathogenic bacterium Xylella fastidiosa

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    Walker M Andrew

    2006-09-01

    Full Text Available Abstract Background The Gram-negative, xylem-limited phytopathogenic bacterium Xylella fastidiosa is responsible for causing economically important diseases in grapevine, citrus and many other plant species. Despite its economic impact, relatively little is known about the genomic variations among strains isolated from different hosts and their influence on the population genetics of this pathogen. With the availability of genome sequence information for four strains, it is now possible to perform genome-wide analyses to identify and categorize such DNA variations and to understand their influence on strain functional divergence. Results There are 1,579 genes and 194 non-coding homologous sequences present in the genomes of all four strains, representing a 76. 2% conservation of the sequenced genome. About 60% of the X. fastidiosa unique sequences exist as tandem gene clusters of 6 or more genes. Multiple alignments identified 12,754 SNPs and 14,449 INDELs in the 1528 common genes and 20,779 SNPs and 10,075 INDELs in the 194 non-coding sequences. The average SNP frequency was 1.08 × 10-2 per base pair of DNA and the average INDEL frequency was 2.06 × 10-2 per base pair of DNA. On an average, 60.33% of the SNPs were synonymous type while 39.67% were non-synonymous type. The mutation frequency, primarily in the form of external INDELs was the main type of sequence variation. The relative similarity between the strains was discussed according to the INDEL and SNP differences. The number of genes unique to each strain were 60 (9a5c, 54 (Dixon, 83 (Ann1 and 9 (Temecula-1. A sub-set of the strain specific genes showed significant differences in terms of their codon usage and GC composition from the native genes suggesting their xenologous origin. Tandem repeat analysis of the genomic sequences of the four strains identified associations of repeat sequences with hypothetical and phage related functions. Conclusion INDELs and strain specific genes

  6. Genome-Wide Association Studies of a Broad Spectrum of Antisocial Behavior.

    Science.gov (United States)

    Tielbeek, Jorim J; Johansson, Ada; Polderman, Tinca J C; Rautiainen, Marja-Riitta; Jansen, Philip; Taylor, Michelle; Tong, Xiaoran; Lu, Qing; Burt, Alexandra S; Tiemeier, Henning; Viding, Essi; Plomin, Robert; Martin, Nicholas G; Heath, Andrew C; Madden, Pamela A F; Montgomery, Grant; Beaver, Kevin M; Waldman, Irwin; Gelernter, Joel; Kranzler, Henry R; Farrer, Lindsay A; Perry, John R B; Munafò, Marcus; LoParo, Devon; Paunio, Tiina; Tiihonen, Jari; Mous, Sabine E; Pappa, Irene; de Leeuw, Christiaan; Watanabe, Kyoko; Hammerschlag, Anke R; Salvatore, Jessica E; Aliev, Fazil; Bigdeli, Tim B; Dick, Danielle; Faraone, Stephen V; Popma, Arne; Medland, Sarah E; Posthuma, Danielle

    2017-12-01

    Antisocial behavior (ASB) places a large burden on perpetrators, survivors, and society. Twin studies indicate that half of the variation in this trait is genetic. Specific causal genetic variants have, however, not been identified. To estimate the single-nucleotide polymorphism-based heritability of ASB; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to reevaluate the candidate gene era data through the Broad Antisocial Behavior Consortium. Genome-wide association data from 5 large population-based cohorts and 3 target samples with genome-wide genotype and ASB data were used for meta-analysis from March 1, 2014, to May 1, 2016. All data sets used quantitative phenotypes, except for the Finnish Crime Study, which applied a case-control design (370 patients and 5850 control individuals). This study adopted relatively broad inclusion criteria to achieve a quantitative measure of ASB derived from multiple measures, maximizing the sample size over different age ranges. The discovery samples comprised 16 400 individuals, whereas the target samples consisted of 9381 individuals (all individuals were of European descent), including child and adult samples (mean age range, 6.7-56.1 years). Three promising loci with sex-discordant associations were found (8535 female individuals, chromosome 1: rs2764450, chromosome 11: rs11215217; 7772 male individuals, chromosome X, rs41456347). Polygenic risk score analyses showed prognostication of antisocial phenotypes in an independent Finnish Crime Study (2536 male individuals and 3684 female individuals) and shared genetic origin with conduct problems in a population-based sample (394 male individuals and 431 female individuals) but not with conduct disorder in a substance-dependent sample (950 male individuals and 1386 female individuals) (R2 = 0.0017 in the most optimal model, P = 0.03). Significant inverse genetic correlation

  7. Genome-wide association study of triglyceride response to a high-fat meal among participants of the NHLBI Genetics of Lipid Lowering Drugs and Diet Network (GOLDN).

    Science.gov (United States)

    Wojczynski, Mary K; Parnell, Laurence D; Pollin, Toni I; Lai, Chao Q; Feitosa, Mary F; O'Connell, Jeff R; Frazier-Wood, Alexis C; Gibson, Quince; Aslibekyan, Stella; Ryan, Kathy A; Province, Michael A; Tiwari, Hemant K; Ordovas, Jose M; Shuldiner, Alan R; Arnett, Donna K; Borecki, Ingrid B

    2015-10-01

    The triglyceride (TG) response to a high-fat meal (postprandial lipemia, PPL) affects cardiovascular disease risk and is influenced by genes and environment. Genes involved in lipid metabolism have dominated genetic studies of PPL TG response. We sought to elucidate common genetic variants through a genome-wide association (GWA) study in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN). The GOLDN GWAS discovery sample consisted of 872 participants within families of European ancestry. Genotypes for 2,543,887 variants were measured or imputed from HapMap. Replication of our top results was performed in the Heredity and Phenotype Intervention (HAPI) Heart Study (n = 843). PPL TG response phenotypes were constructed from plasma TG measured at baseline (fasting, 0 hour), 3.5 and 6 hours after a high-fat meal, using a random coefficient regression model. Association analyses were adjusted for covariates and principal components, as necessary, in a linear mixed model using the kinship matrix; additional models further adjusted for fasting TG were also performed. Meta-analysis of the discovery and replication studies (n = 1715) was performed on the top SNPs from GOLDN. GOLDN revealed 111 suggestive (p 5E-08). Of the two significant SNPs, rs964184 demonstrated evidence of replication (p = 1.20E-03) in the HAPI Heart Study and in a joint analysis, was GWA significant (p = 1.26E-09). Rs964184 has been associated with fasting lipids (TG and HDL) and is near ZPR1 (formerly ZNF259), close to the APOA1/C3/A4/A5 cluster. This association was attenuated upon additional adjustment for fasting TG. This is the first report of a genome-wide significant association with replication for a novel phenotype, namely PPL TG response. Future investigation into response phenotypes is warranted using pathway analyses, or newer genetic technologies such as metabolomics. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Genomic consequences of selection and genome-wide association mapping in soybean.

    Science.gov (United States)

    Wen, Zixiang; Boyse, John F; Song, Qijian; Cregan, Perry B; Wang, Dechun

    2015-09-03

    Crop improvement always involves selection of specific alleles at genes controlling traits of agronomic importance, likely resulting in detectable signatures of selection within the genome of modern soybean (Glycine max L. Merr.). The identification of these signatures of selection is meaningful from the perspective of evolutionary biology and for uncovering the genetic architecture of agronomic traits. To this end, two populations of soybean, consisting of 342 landraces and 1062 improved lines, were genotyped with the SoySNP50K Illumina BeadChip containing 52,041 single nucleotide polymorphisms (SNPs), and systematically phenotyped for 9 agronomic traits. A cross-population composite likelihood ratio (XP-CLR) method was used to screen the signals of selective sweeps. A total of 125 candidate selection regions were identified, many of which harbored genes potentially involved in crop improvement. To further investigate whether these candidate regions were in fact enriched for genes affected by selection, genome-wide association studies (GWAS) were conducted on 7 selection traits targeted in soybean breeding (grain yield, plant height, lodging, maturity date, seed coat color, seed protein and oil content) and 2 non-selection traits (pubescence and flower color). Major genomic regions associated with selection traits overlapped with candidate selection regions, whereas no overlap of this kind occurred for the non-selection traits, suggesting that the selection sweeps identified are associated with traits of agronomic importance. Multiple novel loci and refined map locations of known loci related to these traits were also identified. These findings illustrate that comparative genomic analyses, especially when combined with GWAS, are a promising approach to dissect the genetic architecture of complex traits.

  9. A genome-wide systems analysis reveals strong link between colorectal cancer and trimethylamine N-oxide (TMAO), a gut microbial metabolite of dietary meat and fat.

    Science.gov (United States)

    Xu, Rong; Wang, QuanQiu; Li, Li

    2015-01-01

    Dietary intakes of red meat and fat are established risk factors for both colorectal cancer (CRC) and cardiovascular disease (CVDs). Recent studies have shown a mechanistic link between TMAO, an intestinal microbial metabolite of red meat and fat, and risk of CVDs. Data linking TMAO directly to CRC is, however, lacking. Here, we present an unbiased data-driven network-based systems approach to uncover a potential genetic relationship between TMAO and CRC. We constructed two different epigenetic interaction networks (EINs) using chemical-gene, disease-gene and protein-protein interaction data from multiple large-scale data resources. We developed a network-based ranking algorithm to ascertain TMAO-related diseases from EINs. We systematically analyzed disease categories among TMAO-related diseases at different ranking cutoffs. We then determined which genetic pathways were associated with both TMAO and CRC. We show that CVDs and their major risk factors were ranked highly among TMAO-related diseases, confirming the newly discovered mechanistic link between CVDs and TMAO, and thus validating our algorithms. CRC was ranked highly among TMAO-related disease retrieved from both EINs (top 0.02%, #1 out of 4,372 diseases retrieved based on Mendelian genetics and top 10.9% among 882 diseases based on genome-wide association genetics), providing strong supporting evidence for our hypothesis that TMAO is genetically related to CRC. We have also identified putative genetic pathways that may link TMAO to CRC, which warrants further investigation. Through systematic disease enrichment analysis, we also demonstrated that TMAO is related to metabolic syndromes and cancers in general. Our genome-wide analysis demonstrates that systems approaches to studying the epigenetic interactions among diet, microbiome metabolisms, and disease genetics hold promise for understanding disease pathogenesis. Our results show that TMAO is genetically associated with CRC. This study suggests that

  10. Global DNA Methylation in the Chestnut Blight Fungus Cryphonectria parasitica and Genome-Wide Changes in DNA Methylation Accompanied with Sectorization

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    Kum-Kang So

    2018-02-01

    Full Text Available Mutation in CpBck1, an ortholog of the cell wall integrity mitogen-activated protein kinase kinase kinase (MAPKKK of Saccharomyces cerevisiae, in the chestnut blight fungus Cryphonectria parasitica resulted in a sporadic sectorization as culture proceeded. The progeny from the sectored area maintained the characteristics of the sector, showing a massive morphogenetic change, including robust mycelial growth without differentiation. Epigenetic changes were investigated as the genetic mechanism underlying this sectorization. Quantification of DNA methylation and whole-genome bisulfite sequencing revealed genome-wide DNA methylation of the wild-type at each nucleotide level and changes in DNA methylation of the sectored progeny. Compared to the wild-type, the sectored progeny exhibited marked genome-wide DNA hypomethylation but increased methylation sites. Expression analysis of two DNA methyltransferases, including two representative types of DNA methyltransferase (DNMTase, demonstrated that both were significantly down-regulated in the sectored progeny. However, functional analysis using mutant phenotypes of corresponding DNMTases demonstrated that a mutant of CpDmt1, an ortholog of RID of Neurospora crassa, resulted in the sectored phenotype but the CpDmt2 mutant did not, suggesting that the genetic basis of fungal sectorization is more complex. The present study revealed that a mutation in a signaling pathway component resulted in sectorization accompanied with changes in genome-wide DNA methylation, which suggests that this signal transduction pathway is important for epigenetic control of sectorization via regulation of genes involved in DNA methylation.

  11. Introns Protect Eukaryotic Genomes from Transcription-Associated Genetic Instability.

    Science.gov (United States)

    Bonnet, Amandine; Grosso, Ana R; Elkaoutari, Abdessamad; Coleno, Emeline; Presle, Adrien; Sridhara, Sreerama C; Janbon, Guilhem; Géli, Vincent; de Almeida, Sérgio F; Palancade, Benoit

    2017-08-17

    Transcription is a source of genetic instability that can notably result from the formation of genotoxic DNA:RNA hybrids, or R-loops, between the nascent mRNA and its template. Here we report an unexpected function for introns in counteracting R-loop accumulation in eukaryotic genomes. Deletion of endogenous introns increases R-loop formation, while insertion of an intron into an intronless gene suppresses R-loop accumulation and its deleterious impact on transcription and recombination in yeast. Recruitment of the spliceosome onto the mRNA, but not splicing per se, is shown to be critical to attenuate R-loop formation and transcription-associated genetic instability. Genome-wide analyses in a number of distant species differing in their intron content, including human, further revealed that intron-containing genes and the intron-richest genomes are best protected against R-loop accumulation and subsequent genetic instability. Our results thereby provide a possible rationale for the conservation of introns throughout the eukaryotic lineage. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Does parental expressed emotion moderate genetic effects in ADHD? An exploration using a genome wide association scan

    NARCIS (Netherlands)

    Sonuga-Barke, E.; Lasky-Su, J.; Neale, B.; Oades, R.D.; Chen, W.; Franke, B.; Buitelaar, J.K.; Banaschewski, T.; Ebstein, R.; Gill, M.; Anney, R.J.; Miranda, A.; Mulas, F.; Roeyers, H.; Rothenberger, A.; Sergeant, J.A.; Steinhausen, H.C.; Thompson, M.; Asherson, P.; Faraone, S.V.

    2008-01-01

    Studies of gene x environment (G x E) interaction in ADHD have previously focused on known risk genes for ADHD and environmentally mediated biological risk. Here we use G x E analysis in the context of a genome-wide association scan to identify novel genes whose effects on ADHD symptoms and comorbid

  13. Does parental expressed emotion moderate genetic effects in ADHD? An exploration using a genome wide association scan.

    NARCIS (Netherlands)

    Sonuga-Barke, E.J.S.; Lasky-Su, J.; Neale, B.; Oades, R.D.; Chen, W.; Franke, B.; Buitelaar, J.K.; Banaschewski, T.; Ebstein, R.P.; Gill, M.; Anney, R.; Miranda, A.; Mulas, F.; Roeyers, H.; Rothenberger, A.; Sergeant, J.A.; Steinhausen, H.C.; Thompson, M.; Asherson, P.; Faraone, S.V.

    2008-01-01

    Studies of gene x environment (G x E) interaction in ADHD have previously focused on known risk genes for ADHD and environmentally mediated biological risk. Here we use G x E analysis in the context of a genome-wide association scan to identify novel genes whose effects on ADHD symptoms and comorbid

  14. Genome-wide identification of specific oligonucleotides using artificial neural network and computational genomic analysis

    Directory of Open Access Journals (Sweden)

    Chen Jiun-Ching

    2007-05-01

    Full Text Available Abstract Background Genome-wide identification of specific oligonucleotides (oligos is a computationally-intensive task and is a requirement for designing microarray probes, primers, and siRNAs. An artificial neural network (ANN is a machine learning technique that can effectively process complex and high noise data. Here, ANNs are applied to process the unique subsequence distribution for prediction of specific oligos. Results We present a novel and efficient algorithm, named the integration of ANN and BLAST (IAB algorithm, to identify specific oligos. We establish the unique marker database for human and rat gene index databases using the hash table algorithm. We then create the input vectors, via the unique marker database, to train and test the ANN. The trained ANN predicted the specific oligos with high efficiency, and these oligos were subsequently verified by BLAST. To improve the prediction performance, the ANN over-fitting issue was avoided by early stopping with the best observed error and a k-fold validation was also applied. The performance of the IAB algorithm was about 5.2, 7.1, and 6.7 times faster than the BLAST search without ANN for experimental results of 70-mer, 50-mer, and 25-mer specific oligos, respectively. In addition, the results of polymerase chain reactions showed that the primers predicted by the IAB algorithm could specifically amplify the corresponding genes. The IAB algorithm has been integrated into a previously published comprehensive web server to support microarray analysis and genome-wide iterative enrichment analysis, through which users can identify a group of desired genes and then discover the specific oligos of these genes. Conclusion The IAB algorithm has been developed to construct SpecificDB, a web server that provides a specific and valid oligo database of the probe, siRNA, and primer design for the human genome. We also demonstrate the ability of the IAB algorithm to predict specific oligos through

  15. A genome-wide metabolic QTL analysis in Europeans implicates two loci shaped by recent positive selection.

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    George Nicholson

    2011-09-01

    Full Text Available We have performed a metabolite quantitative trait locus (mQTL study of the (1H nuclear magnetic resonance spectroscopy ((1H NMR metabolome in humans, building on recent targeted knowledge of genetic drivers of metabolic regulation. Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by (1H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs. Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10(-11genetic region (hence we report a total of three implicated genomic regions. Two of the three hit regions lie within haplotype blocks (at 2p13.1 and 10q24.2 that carry the genetic signature of strong, recent, positive selection in European populations. Genes NAT8 and PYROXD2, both with relatively uncharacterized functional roles, are good candidates for mediating the corresponding mQTL associations. The study's longitudinal twin design allowed detailed variance-components analysis of the sources of population variation in metabolite levels. The mQTLs explained 40%-64% of biological population variation in the corresponding metabolites' concentrations. These effect sizes are stronger than those reported in a recent, targeted mQTL study of metabolites in serum using the targeted-metabolomics Biocrates platform. By re-analysing our plasma samples using the Biocrates platform, we replicated the mQTL findings of the previous study and discovered a previously uncharacterized yet substantial familial component of variation in metabolite levels in addition to the heritability contribution from

  16. A possible mechanism behind autoimmune disorders discovered by genome-wide linkage and association analysis in celiac disease.

    Directory of Open Access Journals (Sweden)

    Malin Östensson

    Full Text Available Celiac disease is a common autoimmune disorder characterized by an intestinal inflammation triggered by gluten, a storage protein found in wheat, rye and barley. Similar to other autoimmune diseases such as type 1 diabetes, psoriasis and rheumatoid arthritis, celiac disease is the result of an immune response to self-antigens leading to tissue destruction and production of autoantibodies. Common diseases like celiac disease have a complex pattern of inheritance with inputs from both environmental as well as additive and non-additive genetic factors. In the past few years, Genome Wide Association Studies (GWAS have been successful in finding genetic risk variants behind many common diseases and traits. To complement and add to the previous findings, we performed a GWAS including 206 trios from 97 nuclear Swedish and Norwegian families affected with celiac disease. By stratifying for HLA-DQ, we identified a new genome-wide significant risk locus covering the DUSP10 gene. To further investigate the associations from the GWAS we performed pathway analyses and two-locus interaction analyses. These analyses showed an over-representation of genes involved in type 2 diabetes and identified a set of candidate mechanisms and genes of which some were selected for mRNA expression analysis using small intestinal biopsies from 98 patients. Several genes were expressed differently in the small intestinal mucosa from patients with celiac autoimmunity compared to intestinal mucosa from control patients. From top-scoring regions we identified susceptibility genes in several categories: 1 polarity and epithelial cell functionality; 2 intestinal smooth muscle; 3 growth and energy homeostasis, including proline and glutamine metabolism; and finally 4 innate and adaptive immune system. These genes and pathways, including specific functions of DUSP10, together reveal a new potential biological mechanism that could influence the genesis of celiac disease, and possibly

  17. No evidence from genome-wide data of a Khazar origin for the Ashkenazi Jews.

    Science.gov (United States)

    Behar, Doron M; Metspalu, Mait; Baran, Yael; Kopelman, Naama M; Yunusbayev, Bayazit; Gladstein, Ariella; Tzur, Shay; Sahakyan, Hovhannes; Bahmanimehr, Ardeshir; Yepiskoposyan, Levon; Tambets, Kristina; Khusnutdinova, Elza K; Kushniarevich, Alena; Balanovsky, Oleg; Balanovsky, Elena; Kovacevic, Lejla; Marjanovic, Damir; Mihailov, Evelin; Kouvatsi, Anastasia; Triantaphyllidis, Costas; King, Roy J; Semino, Ornella; Torroni, Antonio; Hammer, Michael F; Metspalu, Ene; Skorecki, Karl; Rosset, Saharon; Halperin, Eran; Villems, Richard; Rosenberg, Noah A

    2013-12-01

    The origin and history of the Ashkenazi Jewish population have long been of great interest, and advances in high-throughput genetic analysis have recently provided a new approach for investigating these topics. We and others have argued on the basis of genome-wide data that the Ashkenazi Jewish population derives its ancestry from a combination of sources tracing to both Europe and the Middle East. It has been claimed, however, through a reanalysis of some of our data, that a large part of the ancestry of the Ashkenazi population originates with the Khazars, a Turkic-speaking group that lived to the north of the Caucasus region ~1,000 years ago. Because the Khazar population has left no obvious modern descendants that could enable a clear test for a contribution to Ashkenazi Jewish ancestry, the Khazar hypothesis has been difficult to examine using genetics. Furthermore, because only limited genetic data have been available from the Caucasus region, and because these data have been concentrated in populations that are genetically close to populations from the Middle East, the attribution of any signal of Ashkenazi-Caucasus genetic similarity to Khazar ancestry rather than shared ancestral Middle Eastern ancestry has been problematic. Here, through integration of genotypes from newly collected samples with data from several of our past studies, we have assembled the largest data set available to date for assessment of Ashkenazi Jewish genetic origins. This data set contains genome-wide single-nucleotide polymorphisms in 1,774 samples from 106 Jewish and non-Jewish populations that span the possible regions of potential Ashkenazi ancestry: Europe, the Middle East, and the region historically associated with the Khazar Khaganate. The data set includes 261 samples from 15 populations from the Caucasus region and the region directly to its north, samples that have not previously been included alongside Ashkenazi Jewish samples in genomic studies. Employing a variety of

  18. Accounting for genetic architecture improves sequence based genomic prediction for a Drosophila fitness trait.

    Science.gov (United States)

    Ober, Ulrike; Huang, Wen; Magwire, Michael; Schlather, Martin; Simianer, Henner; Mackay, Trudy F C

    2015-01-01

    The ability to predict quantitative trait phenotypes from molecular polymorphism data will revolutionize evolutionary biology, medicine and human biology, and animal and plant breeding. Efforts to map quantitative trait loci have yielded novel insights into the biology of quantitative traits, but the combination of individually significant quantitative trait loci typically has low predictive ability. Utilizing all segregating variants can give good predictive ability in plant and animal breeding populations, but gives little insight into trait biology. Here, we used the Drosophila Genetic Reference Panel to perform both a genome wide association analysis and genomic prediction for the fitness-related trait chill coma recovery time. We found substantial total genetic variation for chill coma recovery time, with a genetic architecture that differs between males and females, a small number of molecular variants with large main effects, and evidence for epistasis. Although the top additive variants explained 36% (17%) of the genetic variance among lines in females (males), the predictive ability using genomic best linear unbiased prediction and a relationship matrix using all common segregating variants was very low for females and zero for males. We hypothesized that the low predictive ability was due to the mismatch between the infinitesimal genetic architecture assumed by the genomic best linear unbiased prediction model and the true genetic architecture of chill coma recovery time. Indeed, we found that the predictive ability of the genomic best linear unbiased prediction model is markedly improved when we combine quantitative trait locus mapping with genomic prediction by only including the top variants associated with main and epistatic effects in the relationship matrix. This trait-associated prediction approach has the advantage that it yields biologically interpretable prediction models.

  19. Genome-wide SNP detection, validation, and development of an 8K SNP array for apple.

    Directory of Open Access Journals (Sweden)

    David Chagné

    Full Text Available As high-throughput genetic marker screening systems are essential for a range of genetics studies and plant breeding applications, the International RosBREED SNP Consortium (IRSC has utilized the Illumina Infinium® II system to develop a medium- to high-throughput SNP screening tool for genome-wide evaluation of allelic variation in apple (Malus×domestica breeding germplasm. For genome-wide SNP discovery, 27 apple cultivars were chosen to represent worldwide breeding germplasm and re-sequenced at low coverage with the Illumina Genome Analyzer II. Following alignment of these sequences to the whole genome sequence of 'Golden Delicious', SNPs were identified using SoapSNP. A total of 2,113,120 SNPs were detected, corresponding to one SNP to every 288 bp of the genome. The Illumina GoldenGate® assay was then used to validate a subset of 144 SNPs with a range of characteristics, using a set of 160 apple accessions. This validation assay enabled fine-tuning of the final subset of SNPs for the Illumina Infinium® II system. The set of stringent filtering criteria developed allowed choice of a set of SNPs that not only exhibited an even distribution across the apple genome and a range of minor allele frequencies to ensure utility across germplasm, but also were located in putative exonic regions to maximize genotyping success rate. A total of 7867 apple SNPs was established for the IRSC apple 8K SNP array v1, of which 5554 were polymorphic after evaluation in segregating families and a germplasm collection. This publicly available genomics resource will provide an unprecedented resolution of SNP haplotypes, which will enable marker-locus-trait association discovery, description of the genetic architecture of quantitative traits, investigation of genetic variation (neutral and functional, and genomic selection in apple.

  20. Genome-Wide SNP Detection, Validation, and Development of an 8K SNP Array for Apple

    Science.gov (United States)

    Chagné, David; Crowhurst, Ross N.; Troggio, Michela; Davey, Mark W.; Gilmore, Barbara; Lawley, Cindy; Vanderzande, Stijn; Hellens, Roger P.; Kumar, Satish; Cestaro, Alessandro; Velasco, Riccardo; Main, Dorrie; Rees, Jasper D.; Iezzoni, Amy; Mockler, Todd; Wilhelm, Larry; Van de Weg, Eric; Gardiner, Susan E.; Bassil, Nahla; Peace, Cameron

    2012-01-01

    As high-throughput genetic marker screening systems are essential for a range of genetics studies and plant breeding applications, the International RosBREED SNP Consortium (IRSC) has utilized the Illumina Infinium® II system to develop a medium- to high-throughput SNP screening tool for genome-wide evaluation of allelic variation in apple (Malus×domestica) breeding germplasm. For genome-wide SNP discovery, 27 apple cultivars were chosen to represent worldwide breeding germplasm and re-sequenced at low coverage with the Illumina Genome Analyzer II. Following alignment of these sequences to the whole genome sequence of ‘Golden Delicious’, SNPs were identified using SoapSNP. A total of 2,113,120 SNPs were detected, corresponding to one SNP to every 288 bp of the genome. The Illumina GoldenGate® assay was then used to validate a subset of 144 SNPs with a range of characteristics, using a set of 160 apple accessions. This validation assay enabled fine-tuning of the final subset of SNPs for the Illumina Infinium® II system. The set of stringent filtering criteria developed allowed choice of a set of SNPs that not only exhibited an even distribution across the apple genome and a range of minor allele frequencies to ensure utility across germplasm, but also were located in putative exonic regions to maximize genotyping success rate. A total of 7867 apple SNPs was established for the IRSC apple 8K SNP array v1, of which 5554 were polymorphic after evaluation in segregating families and a germplasm collection. This publicly available genomics resource will provide an unprecedented resolution of SNP haplotypes, which will enable marker-locus-trait association discovery, description of the genetic architecture of quantitative traits, investigation of genetic variation (neutral and functional), and genomic selection in apple. PMID:22363718

  1. Identification of Promising Mutants Associated with Egg Production Traits Revealed by Genome-Wide Association Study.

    Directory of Open Access Journals (Sweden)

    Jingwei Yuan

    Full Text Available Egg number (EN, egg laying rate (LR and age at first egg (AFE are important production traits related to egg production in poultry industry. To better understand the knowledge of genetic architecture of dynamic EN during the whole laying cycle and provide the precise positions of associated variants for EN, LR and AFE, laying records from 21 to 72 weeks of age were collected individually for 1,534 F2 hens produced by reciprocal crosses between White Leghorn and Dongxiang Blue-shelled chicken, and their genotypes were assayed by chicken 600 K Affymetrix high density genotyping arrays. Subsequently, pedigree and SNP-based genetic parameters were estimated and a genome-wide association study (GWAS was conducted on EN, LR and AFE. The heritability estimates were similar between pedigree and SNP-based estimates varying from 0.17 to 0.36. In the GWA analysis, we identified nine genome-wide significant loci associated with EN of the laying periods from 21 to 26 weeks, 27 to 36 weeks and 37 to 72 weeks. Analysis of GTF2A1 and CLSPN suggested that they influenced the function of ovary and uterus, and may be considered as relevant candidates. The identified SNP rs314448799 for accumulative EN from 21 to 40 weeks on chromosome 5 created phenotypic differences of 6.86 eggs between two homozygous genotypes, which could be potentially applied to the molecular breeding for EN selection. Moreover, our finding showed that LR was a moderate polygenic trait. The suggestive significant region on chromosome 16 for AFE suggested the relationship between sex maturity and immune in the current population. The present study comprehensively evaluates the role of genetic variants in the development of egg laying. The findings will be helpful to investigation of causative genes function and future marker-assisted selection and genomic selection in chickens.

  2. Novel genetic loci underlying human intracranial volume identified through genome-wide association

    NARCIS (Netherlands)

    Adams, Hieab H H; Hibar, Derrek P; Chouraki, Vincent; Stein, Jason L; Nyquist, Paul A; Rentería, Miguel E; Trompet, Stella; Arias-Vasquez, Alejandro; Seshadri, Sudha; Desrivières, Sylvane; Beecham, Ashley H; Jahanshad, Neda; Wittfeld, Katharina; Van der Lee, Sven J; Abramovic, Lucija; Alhusaini, Saud; Amin, Najaf; Andersson, Micael; Arfanakis, Konstantinos; Aribisala, Benjamin S; Armstrong, Nicola J; Athanasiu, Lavinia; Axelsson, Tomas; Beiser, Alexa; Bernard, Manon; Bis, Joshua C; Blanken, Laura M E; Blanton, Susan H; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brickman, Adam M; Carmichael, Owen; Chakravarty, M Mallar; Chauhan, Ganesh; Chen, Qiang; Ching, Christopher R K; Cuellar-Partida, Gabriel; Braber, Anouk Den; Doan, Nhat Trung; Ehrlich, Stefan; Filippi, Irina; Ge, Tian; Giddaluru, Sudheer; Goldman, Aaron L; Gottesman, Rebecca F; Greven, Corina U; Grimm, Oliver; Griswold, Michael E; Guadalupe, Tulio; Hass, Johanna; Haukvik, Unn K; Hilal, Saima; Hofer, Edith; Hoehn, David; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kasperaviciute, Dalia; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Liao, Jiemin; Liewald, David C M; Lopez, Lorna M; Luciano, Michelle; Macare, Christine; Marquand, Andre; Matarin, Mar; Mather, Karen A; Mattheisen, Manuel; Mazoyer, Bernard; McKay, David R; McWhirter, Rebekah; Milaneschi, Yuri; Mirza-Schreiber, Nazanin; Muetzel, Ryan L; Maniega, Susana Muñoz; Nho, Kwangsik; Nugent, Allison C; Loohuis, Loes M Olde; Oosterlaan, Jaap; Papmeyer, Martina; Pappa, Irene; Pirpamer, Lukas; Pudas, Sara; Pütz, Benno; Rajan, Kumar B; Ramasamy, Adaikalavan; Richards, Jennifer S; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rommelse, Nanda; Rose, Emma J; Royle, Natalie A; Rundek, Tatjana; Sämann, Philipp G; Satizabal, Claudia L; Schmaal, Lianne; Schork, Andrew J; Shen, Li; Shin, Jean; Shumskaya, Elena; Smith, Albert V; Sprooten, Emma; Strike, Lachlan T; Teumer, Alexander; Thomson, Russell; Tordesillas-Gutierrez, Diana; Toro, Roberto; Trabzuni, Daniah; Vaidya, Dhananjay; Van der Grond, Jeroen; Van der Meer, Dennis; Van Donkelaar, Marjolein M J; Van Eijk, Kristel R; Van Erp, Theo G M; Van Rooij, Daan; Walton, Esther; Westlye, Lars T; Whelan, Christopher D; Windham, Beverly G; Winkler, Anderson M; Woldehawariat, Girma; Wolf, Christiane; Wolfers, Thomas; Xu, Bing; Yanek, Lisa R; Yang, Jingyun; Zijdenbos, Alex; Zwiers, Marcel P; Agartz, Ingrid; Aggarwal, Neelum T; Almasy, Laura; Ames, David; Amouyel, Philippe; Andreassen, Ole A; Arepalli, Sampath; Assareh, Amelia A; Barral, Sandra; Bastin, Mark E; Becker, Diane M; Becker, James T; Bennett, David A; Blangero, John; van Bokhoven, Hans; Boomsma, Dorret I; Brodaty, Henry; Brouwer, Rachel M; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Bulayeva, Kazima B; Cahn, Wiepke; Calhoun, Vince D; Cannon, Dara M; Cavalleri, Gianpiero L; Chen, Christopher; Cheng, Ching-Yu; Cichon, Sven; Cookson, Mark R; Corvin, Aiden; Crespo-Facorro, Benedicto; Curran, Joanne E; Czisch, Michael; Dale, Anders M; Davies, Gareth E; De Geus, Eco J C; De Jager, Philip L; de Zubicaray, Greig I; Delanty, Norman; Depondt, Chantal; DeStefano, Anita L; Dillman, Allissa; Djurovic, Srdjan; Donohoe, Gary; Drevets, Wayne C; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Espeseth, Thomas; Evans, Denis A; Fedko, Iryna O; Fernández, Guillén; Ferrucci, Luigi; Fisher, Simon E; Fleischman, Debra A; Ford, Ian; Foroud, Tatiana M; Fox, Peter T; Francks, Clyde; Fukunaga, Masaki; Gibbs, J Raphael; Glahn, David C; Gollub, Randy L; Göring, Harald H H; Grabe, Hans J; Green, Robert C; Gruber, Oliver; Gudnason, Vilmundur; Guelfi, Sebastian; Hansell, Narelle K; Hardy, John; Hartman, Catharina A; Hashimoto, Ryota; Hegenscheid, Katrin; Heinz, Andreas; Le Hellard, Stephanie; Hernandez, Dena G; Heslenfeld, Dirk J; Ho, Beng-Choon; Hoekstra, Pieter J; Hoffmann, Wolfgang; Hofman, Albert; Holsboer, Florian; Homuth, Georg; Hosten, Norbert; Hottenga, Jouke-Jan; Pol, Hilleke E Hulshoff; Ikeda, Masashi; Ikram, M Kamran; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Jönsson, Erik G; Jukema, J Wouter; Kahn, René S; Kanai, Ryota; Kloszewska, Iwona; Knopman, David S; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Lemaître, Hervé; Liu, Xinmin; Longo, Dan L; Longstreth, W T; Lopez, Oscar L; Lovestone, Simon; Martinez, Oliver; Martinot, Jean-Luc; Mattay, Venkata S; McDonald, Colm; McIntosh, Andrew M; McMahon, Katie L; McMahon, Francis J; Mecocci, Patrizia; Melle, Ingrid; Meyer-Lindenberg, Andreas; Mohnke, Sebastian; Montgomery, Grant W; Morris, Derek W; Mosley, Thomas H; Mühleisen, Thomas W; Müller-Myhsok, Bertram; Nalls, Michael A; Nauck, Matthias; Nichols, Thomas E; Niessen, Wiro J; Nöthen, Markus M; Nyberg, Lars; Ohi, Kazutaka; Olvera, Rene L; Ophoff, Roel A; Pandolfo, Massimo; Paus, Tomas; Pausova, Zdenka; Penninx, Brenda W J H; Pike, G Bruce; Potkin, Steven G; Psaty, Bruce M; Reppermund, Simone; Rietschel, Marcella; Roffman, Joshua L; Romanczuk-Seiferth, Nina; Rotter, Jerome I; Ryten, Mina; Sacco, Ralph L; Sachdev, Perminder S; Saykin, Andrew J; Schmidt, Reinhold; Schofield, Peter R; Sigurdsson, Sigurdur; Simmons, Andy; Singleton, Andrew; Sisodiya, Sanjay M; Smith, Colin; Smoller, Jordan W; Soininen, Hilkka; Srikanth, Velandai; Steen, Vidar M; Stott, David J; Sussmann, Jessika E; Thalamuthu, Anbupalam; Tiemeier, Henning; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Turner, Jessica A; Tzourio, Christophe; Uitterlinden, Andre G; Hernández, Maria C Valdés; Van der Brug, Marcel; Van der Lugt, Aad; Van der Wee, Nic J A; Van Duijn, Cornelia M; Van Haren, Neeltje E M; Van T Ent, Dennis; Van Tol, Marie-Jose; Vardarajan, Badri N; Veltman, Dick J; Vernooij, Meike W; Völzke, Henry; Walter, Henrik; Wardlaw, Joanna M; Wassink, Thomas H; Weale, Michael E; Weinberger, Daniel R; Weiner, Michael W; Wen, Wei; Westman, Eric; White, Tonya; Wong, Tien Y; Wright, Clinton B; Zielke, H Ronald; Zonderman, Alan B; Deary, Ian J; DeCarli, Charles; Schmidt, Helena; Martin, Nicholas G; De Craen, Anton J M; Wright, Margaret J; Launer, Lenore J; Schumann, Gunter; Fornage, Myriam; Franke, Barbara; Debette, Stéphanie; Medland, Sarah E; Ikram, M Arfan; Thompson, Paul M

    2016-01-01

    Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously

  3. Genome-Wide Analysis Provides Evidence on the Genetic Relatedness of the Emergent Xylella fastidiosa Genotype in Italy to Isolates from Central America.

    Science.gov (United States)

    Giampetruzzi, Annalisa; Saponari, Maria; Loconsole, Giuliana; Boscia, Donato; Savino, Vito Nicola; Almeida, Rodrigo P P; Zicca, Stefania; Landa, Blanca B; Chacón-Diaz, Carlos; Saldarelli, Pasquale

    2017-07-01

    Xylella fastidiosa is a plant-pathogenic bacterium recently introduced in Europe that is causing decline in olive trees in the South of Italy. Genetic studies have consistently shown that the bacterial genotype recovered from infected olive trees belongs to the sequence type ST53 within subspecies pauca. This genotype, ST53, has also been reported to occur in Costa Rica. The ancestry of ST53 was recently clarified, showing it contains alleles that are monophyletic with those of subsp. pauca in South America. To more robustly determine the phylogenetic placement of ST53 within X. fastidiosa, we performed a comparative analysis based on single nucleotide polymorphisms (SNPs) and the study of the pan-genome of the 27 currently public available whole genome sequences of X. fastidiosa. The resulting maximum-parsimony and maximum likelihood trees constructed using the SNPs and the pan-genome analysis are consistent with previously described X. fastidiosa taxonomy, distinguishing the subsp. fastidiosa, multiplex, pauca, sandyi, and morus. Within the subsp. pauca, the Italian and three Costa Rican isolates, all belonging to ST53, formed a compact phylotype in a clade divergent from the South American pauca isolates, also distinct from the recently described coffee isolate CFBP8072 imported into Europe from Ecuador. These findings were also supported by the gene characterization of a conjugative plasmid shared by all the four ST53 isolates. Furthermore, isolates of the ST53 clade possess an exclusive locus encoding a putative ATP-binding protein belonging to the family of histidine kinase-like ATPase gene, which is not present in isolates from the subspecies multiplex, sandyi, and pauca, but was detected in ST21 isolates of the subspecies fastidiosa from Costa Rica. The clustering and distinctiveness of the ST53 isolates supports the hypothesis of their common origin, and the limited genetic diversity among these isolates suggests this is an emerging clade within subsp

  4. Genome-wide association study identifies 74 loci associated with educational attainment

    DEFF Research Database (Denmark)

    Okbay, Aysu; P. Beauchamp, Jonathan; Alan Fontana, Mark

    2016-01-01

    -nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural......Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals1. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends...... development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals...

  5. Genome-association analysis of Korean Holstein milk traits using genomic estimated breeding value

    Directory of Open Access Journals (Sweden)

    Donghyun Shin

    2017-03-01

    Full Text Available Objective Holsteins are known as the world’s highest-milk producing dairy cattle. The purpose of this study was to identify genetic regions strongly associated with milk traits (milk production, fat, and protein using Korean Holstein data. Methods This study was performed using single nucleotide polymorphism (SNP chip data (Illumina BovineSNP50 Beadchip of 911 Korean Holstein individuals. We inferred each genomic estimated breeding values based on best linear unbiased prediction (BLUP and ridge regression using BLUPF90 and R. We then performed a genome-wide association study and identified genetic regions related to milk traits. Results We identified 9, 6, and 17 significant genetic regions related to milk production, fat and protein, respectively. These genes are newly reported in the genetic association with milk traits of Holstein. Conclusion This study complements a recent Holstein genome-wide association studies that identified other SNPs and genes as the most significant variants. These results will help to expand the knowledge of the polygenic nature of milk production in Holsteins.

  6. Ubiquitous polygenicity of human complex traits: genome-wide analysis of 49 traits in Koreans.

    Directory of Open Access Journals (Sweden)

    Jian Yang

    Full Text Available Recent studies in population of European ancestry have shown that 30% ~ 50% of heritability for human complex traits such as height and body mass index, and common diseases such as schizophrenia and rheumatoid arthritis, can be captured by common SNPs and that genetic variation attributed to chromosomes are in proportion to their length. Using genome-wide estimation and partitioning approaches, we analysed 49 human quantitative traits, many of which are relevant to human diseases, in 7,170 unrelated Korean individuals genotyped on 326,262 SNPs. For 43 of the 49 traits, we estimated a nominally significant (P<0.05 proportion of variance explained by all SNPs on the Affymetrix 5.0 genotyping array ([Formula: see text]. On average across 47 of the 49 traits for which the estimate of h(G(2 is non-zero, common SNPs explain approximately one-third (range of 7.8% to 76.8% of narrow sense heritability. The estimate of h(G(2 is highly correlated with the proportion of SNPs with association P<0.031 (r(2 = 0.92. Longer genomic segments tend to explain more phenotypic variation, with a correlation of 0.78 between the estimate of variance explained by individual chromosomes and their physical length, and 1% of the genome explains approximately 1% of the genetic variance. Despite the fact that there are a few SNPs with large effects for some traits, these results suggest that polygenicity is ubiquitous for most human complex traits and that a substantial proportion of the "missing heritability" is captured by common SNPs.

  7. A genome-wide association study in chronic obstructive pulmonary disease (COPD: identification of two major susceptibility loci.

    Directory of Open Access Journals (Sweden)

    Sreekumar G Pillai

    2009-03-01

    Full Text Available There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD. The only known genetic risk factor is severe deficiency of alpha(1-antitrypsin, which is present in 1-2% of individuals with COPD. We conducted a genome-wide association study (GWAS in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls and evaluated the top 100 single nucleotide polymorphisms (SNPs in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT and 472 controls from the Normative Aging Study (NAS and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the alpha-nicotinic acetylcholine receptor (CHRNA 3/5 locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48 x 10(-10, (rs8034191 and 5.74 x 10(-10 (rs1051730. Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article

  8. Improving Genetic Gain with Genomic Selection in Autotetraploid Potato

    Directory of Open Access Journals (Sweden)

    Anthony T. Slater

    2016-11-01

    Full Text Available Potato ( L. breeders consider a large number of traits during cultivar development and progress in conventional breeding can be slow. There is accumulating evidence that some of these traits, such as yield, are affected by a large number of genes with small individual effects. Recently, significant efforts have been applied to the development of genomic resources to improve potato breeding, culminating in a draft genome sequence and the identification of a large number of single nucleotide polymorphisms (SNPs. The availability of these genome-wide SNPs is a prerequisite for implementing genomic selection for improvement of polygenic traits such as yield. In this review, we investigate opportunities for the application of genomic selection to potato, including novel breeding program designs. We have considered a number of factors that will influence this process, including the autotetraploid and heterozygous genetic nature of potato, the rate of decay of linkage disequilibrium, the number of required markers, the design of a reference population, and trait heritability. Based on estimates of the effective population size derived from a potato breeding program, we have calculated the expected accuracy of genomic selection for four key traits of varying heritability and propose that it will be reasonably accurate. We compared the expected genetic gain from genomic selection with the expected gain from phenotypic and pedigree selection, and found that genetic gain can be substantially improved by using genomic selection.

  9. Genome-Wide Prediction of the Performance of Three-Way Hybrids in Barley

    Directory of Open Access Journals (Sweden)

    Zuo Li

    2017-03-01

    Full Text Available Predicting the grain yield performance of three-way hybrids is challenging. Three-way crosses are relevant for hybrid breeding in barley ( L. and maize ( L. adapted to East Africa. The main goal of our study was to implement and evaluate genome-wide prediction approaches of the performance of three-way hybrids using data of single-cross hybrids for a scenario in which parental lines of the three-way hybrids originate from three genetically distinct subpopulations. We extended the ridge regression best linear unbiased prediction (RRBLUP and devised a genomic selection model allowing for subpopulation-specific marker effects (GSA-RRBLUP: general and subpopulation-specific additive RRBLUP. Using an empirical barley data set, we showed that applying GSA-RRBLUP tripled the prediction ability of three-way hybrids from 0.095 to 0.308 compared with RRBLUP, modeling one additive effect for all three subpopulations. The experimental findings were further substantiated with computer simulations. Our results emphasize the potential of GSA-RRBLUP to improve genome-wide hybrid prediction of three-way hybrids for scenarios of genetically diverse parental populations. Because of the advantages of the GSA-RRBLUP model in dealing with hybrids from different parental populations, it may also be a promising approach to boost the prediction ability for hybrid breeding programs based on genetically diverse heterotic groups.

  10. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study.

    Science.gov (United States)

    Pottier, Cyril; Zhou, Xiaolai; Perkerson, Ralph B; Baker, Matt; Jenkins, Gregory D; Serie, Daniel J; Ghidoni, Roberta; Benussi, Luisa; Binetti, Giuliano; López de Munain, Adolfo; Zulaica, Miren; Moreno, Fermin; Le Ber, Isabelle; Pasquier, Florence; Hannequin, Didier; Sánchez-Valle, Raquel; Antonell, Anna; Lladó, Albert; Parsons, Tammee M; Finch, NiCole A; Finger, Elizabeth C; Lippa, Carol F; Huey, Edward D; Neumann, Manuela; Heutink, Peter; Synofzik, Matthis; Wilke, Carlo; Rissman, Robert A; Slawek, Jaroslaw; Sitek, Emilia; Johannsen, Peter; Nielsen, Jørgen E; Ren, Yingxue; van Blitterswijk, Marka; DeJesus-Hernandez, Mariely; Christopher, Elizabeth; Murray, Melissa E; Bieniek, Kevin F; Evers, Bret M; Ferrari, Camilla; Rollinson, Sara; Richardson, Anna; Scarpini, Elio; Fumagalli, Giorgio G; Padovani, Alessandro; Hardy, John; Momeni, Parastoo; Ferrari, Raffaele; Frangipane, Francesca; Maletta, Raffaele; Anfossi, Maria; Gallo, Maura; Petrucelli, Leonard; Suh, EunRan; Lopez, Oscar L; Wong, Tsz H; van Rooij, Jeroen G J; Seelaar, Harro; Mead, Simon; Caselli, Richard J; Reiman, Eric M; Noel Sabbagh, Marwan; Kjolby, Mads; Nykjaer, Anders; Karydas, Anna M; Boxer, Adam L; Grinberg, Lea T; Grafman, Jordan; Spina, Salvatore; Oblak, Adrian; Mesulam, M-Marsel; Weintraub, Sandra; Geula, Changiz; Hodges, John R; Piguet, Olivier; Brooks, William S; Irwin, David J; Trojanowski, John Q; Lee, Edward B; Josephs, Keith A; Parisi, Joseph E; Ertekin-Taner, Nilüfer; Knopman, David S; Nacmias, Benedetta; Piaceri, Irene; Bagnoli, Silvia; Sorbi, Sandro; Gearing, Marla; Glass, Jonathan; Beach, Thomas G; Black, Sandra E; Masellis, Mario; Rogaeva, Ekaterina; Vonsattel, Jean-Paul; Honig, Lawrence S; Kofler, Julia; Bruni, Amalia C; Snowden, Julie; Mann, David; Pickering-Brown, Stuart; Diehl-Schmid, Janine; Winkelmann, Juliane; Galimberti, Daniela; Graff, Caroline; Öijerstedt, Linn; Troakes, Claire; Al-Sarraj, Safa; Cruchaga, Carlos; Cairns, Nigel J; Rohrer, Jonathan D; Halliday, Glenda M; Kwok, John B; van Swieten, John C; White, Charles L; Ghetti, Bernardino; Murell, Jill R; Mackenzie, Ian R A; Hsiung, Ging-Yuek R; Borroni, Barbara; Rossi, Giacomina; Tagliavini, Fabrizio; Wszolek, Zbigniew K; Petersen, Ronald C; Bigio, Eileen H; Grossman, Murray; Van Deerlin, Vivianna M; Seeley, William W; Miller, Bruce L; Graff-Radford, Neill R; Boeve, Bradley F; Dickson, Dennis W; Biernacka, Joanna M; Rademakers, Rosa

    2018-06-01

    Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p<1 × 10 -5 ) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin. Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited

  11. An Open Access Database of Genome-wide Association Results

    Directory of Open Access Journals (Sweden)

    Johnson Andrew D

    2009-01-01

    Full Text Available Abstract Background The number of genome-wide association studies (GWAS is growing rapidly leading to the discovery and replication of many new disease loci. Combining results from multiple GWAS datasets may potentially strengthen previous conclusions and suggest new disease loci, pathways or pleiotropic genes. However, no database or centralized resource currently exists that contains anywhere near the full scope of GWAS results. Methods We collected available results from 118 GWAS articles into a database of 56,411 significant SNP-phenotype associations and accompanying information, making this database freely available here. In doing so, we met and describe here a number of challenges to creating an open access database of GWAS results. Through preliminary analyses and characterization of available GWAS, we demonstrate the potential to gain new insights by querying a database across GWAS. Results Using a genomic bin-based density analysis to search for highly associated regions of the genome, positive control loci (e.g., MHC loci were detected with high sensitivity. Likewise, an analysis of highly repeated SNPs across GWAS identified replicated loci (e.g., APOE, LPL. At the same time we identified novel, highly suggestive loci for a variety of traits that did not meet genome-wide significant thresholds in prior analyses, in some cases with strong support from the primary medical genetics literature (SLC16A7, CSMD1, OAS1, suggesting these genes merit further study. Additional adjustment for linkage disequilibrium within most regions with a high density of GWAS associations did not materially alter our findings. Having a centralized database with standardized gene annotation also allowed us to examine the representation of functional gene categories (gene ontologies containing one or more associations among top GWAS results. Genes relating to cell adhesion functions were highly over-represented among significant associations (p -14, a finding

  12. Global insights into acetic acid resistance mechanisms and genetic stability of Acetobacter pasteurianus strains by comparative genomics

    Science.gov (United States)

    Wang, Bin; Shao, Yanchun; Chen, Tao; Chen, Wanping; Chen, Fusheng

    2015-12-01

    Acetobacter pasteurianus (Ap) CICC 20001 and CGMCC 1.41 are two acetic acid bacteria strains that, because of their strong abilities to produce and tolerate high concentrations of acetic acid, have been widely used to brew vinegar in China. To globally understand the fermentation characteristics, acid-tolerant mechanisms and genetic stabilities, their genomes were sequenced. Genomic comparisons with 9 other sequenced Ap strains revealed that their chromosomes were evolutionarily conserved, whereas the plasmids were unique compared with other Ap strains. Analysis of the acid-tolerant metabolic pathway at the genomic level indicated that the metabolism of some amino acids and the known mechanisms of acetic acid tolerance, might collaboratively contribute to acetic acid resistance in Ap strains. The balance of instability factors and stability factors in the genomes of Ap CICC 20001 and CGMCC 1.41 strains might be the basis for their genetic stability, consistent with their stable industrial performances. These observations provide important insights into the acid resistance mechanism and the genetic stability of Ap strains and lay a foundation for future genetic manipulation and engineering of these two strains.

  13. Genome-Wide Fine-Scale Recombination Rate Variation in Drosophila melanogaster

    Science.gov (United States)

    Song, Yun S.

    2012-01-01

    Estimating fine-scale recombination maps of Drosophila from population genomic data is a challenging problem, in particular because of the high background recombination rate. In this paper, a new computational method is developed to address this challenge. Through an extensive simulation study, it is demonstrated that the method allows more accurate inference, and exhibits greater robustness to the effects of natural selection and noise, compared to a well-used previous method developed for studying fine-scale recombination rate variation in the human genome. As an application, a genome-wide analysis of genetic variation data is performed for two Drosophila melanogaster populations, one from North America (Raleigh, USA) and the other from Africa (Gikongoro, Rwanda). It is shown that fine-scale recombination rate variation is widespread throughout the D. melanogaster genome, across all chromosomes and in both populations. At the fine-scale, a conservative, systematic search for evidence of recombination hotspots suggests the existence of a handful of putative hotspots each with at least a tenfold increase in intensity over the background rate. A wavelet analysis is carried out to compare the estimated recombination maps in the two populations and to quantify the extent to which recombination rates are conserved. In general, similarity is observed at very broad scales, but substantial differences are seen at fine scales. The average recombination rate of the X chromosome appears to be higher than that of the autosomes in both populations, and this pattern is much more pronounced in the African population than the North American population. The correlation between various genomic features—including recombination rates, diversity, divergence, GC content, gene content, and sequence quality—is examined using the wavelet analysis, and it is shown that the most notable difference between D. melanogaster and humans is in the correlation between recombination and

  14. Using a higher criticism statistic to detect modest effects in a genome-wide study of rheumatoid arthritis

    Science.gov (United States)

    2009-01-01

    In high-dimensional studies such as genome-wide association studies, the correction for multiple testing in order to control total type I error results in decreased power to detect modest effects. We present a new analytical approach based on the higher criticism statistic that allows identification of the presence of modest effects. We apply our method to the genome-wide study of rheumatoid arthritis provided in the Genetic Analysis Workshop 16 Problem 1 data set. There is evidence for unknown bias in this study that could be explained by the presence of undetected modest effects. We compared the asymptotic and empirical thresholds for the higher criticism statistic. Using the asymptotic threshold we detected the presence of modest effects genome-wide. We also detected modest effects using 90th percentile of the empirical null distribution as a threshold; however, there is no such evidence when the 95th and 99th percentiles were used. While the higher criticism method suggests that there is some evidence for modest effects, interpreting individual single-nucleotide polymorphisms with significant higher criticism statistics is of undermined value. The goal of higher criticism is to alert the researcher that genetic effects remain to be discovered and to promote the use of more targeted and powerful studies to detect the remaining effects. PMID:20018032

  15. Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.

    Directory of Open Access Journals (Sweden)

    Eleanor Wheeler

    2017-09-01

    Full Text Available Glycated hemoglobin (HbA1c is used to diagnose type 2 diabetes (T2D and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits or glycemic (associated with other glucose-related traits. In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E or glycemic variants (GS-G were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241. Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29; whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60. In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in

  16. Genome-Wide SNP Detection, Validation, and Development of an 8K SNP Array for Apple

    NARCIS (Netherlands)

    Chagné, D.; Crowhurst, R.N.; Troggio, M.; Davey, M.W.; Gilmore, B.; Lawley, C.; Vanderzande, S.; Hellens, R.P.; Kumar, S.; Cestaro, A.; Velasco, R.; Main, D.; Rees, J.D.; Iezzoni, A.F.; Mockler, T.; Wilhelm, L.; Weg, van de W.E.; Gardiner, S.E.; Bassil, N.; Peace, C.

    2012-01-01

    As high-throughput genetic marker screening systems are essential for a range of genetics studies and plant breeding applications, the International RosBREED SNP Consortium (IRSC) has utilized the Illumina Infinium® II system to develop a medium- to high-throughput SNP screening tool for genome-wide

  17. Fine mapping of a Phytophthora-resistance gene RpsWY in soybean (Glycine max L.) by high-throughput genome-wide sequencing.

    Science.gov (United States)

    Cheng, Yanbo; Ma, Qibin; Ren, Hailong; Xia, Qiuju; Song, Enliang; Tan, Zhiyuan; Li, Shuxian; Zhang, Gengyun; Nian, Hai

    2017-05-01

    Using a combination of phenotypic screening, genetic and statistical analyses, and high-throughput genome-wide sequencing, we have finely mapped a dominant Phytophthora resistance gene in soybean cultivar Wayao. Phytophthora root rot (PRR) caused by Phytophthora sojae is one of the most important soil-borne diseases in many soybean-production regions in the world. Identification of resistant gene(s) and incorporating them into elite varieties are an effective way for breeding to prevent soybean from being harmed by this disease. Two soybean populations of 191 F 2 individuals and 196 F 7:8 recombinant inbred lines (RILs) were developed to map Rps gene by crossing a susceptible cultivar Huachun 2 with the resistant cultivar Wayao. Genetic analysis of the F 2 population indicated that PRR resistance in Wayao was controlled by a single dominant gene, temporarily named RpsWY, which was mapped on chromosome 3. A high-density genetic linkage bin map was constructed using 3469 recombination bins of the RILs to explore the candidate genes by the high-throughput genome-wide sequencing. The results of genotypic analysis showed that the RpsWY gene was located in bin 401 between 4466230 and 4502773 bp on chromosome 3 through line 71 and 100 of the RILs. Four predicted genes (Glyma03g04350, Glyma03g04360, Glyma03g04370, and Glyma03g04380) were found at the narrowed region of 36.5 kb in bin 401. These results suggest that the high-throughput genome-wide resequencing is an effective method to fine map PRR candidate genes.

  18. Genome-wide methylation analysis identifies genes silenced in non-seminoma cell lines.

    Science.gov (United States)

    Noor, Dzul Azri Mohamed; Jeyapalan, Jennie N; Alhazmi, Safiah; Carr, Matthew; Squibb, Benjamin; Wallace, Claire; Tan, Christopher; Cusack, Martin; Hughes, Jaime; Reader, Tom; Shipley, Janet; Sheer, Denise; Scotting, Paul J

    2016-01-01

    Silencing of genes by DNA methylation is a common phenomenon in many types of cancer. However, the genome-wide effect of DNA methylation on gene expression has been analysed in relatively few cancers. Germ cell tumours (GCTs) are a complex group of malignancies. They are unique in developing from a pluripotent progenitor cell. Previous analyses have suggested that non-seminomas exhibit much higher levels of DNA methylation than seminomas. The genomic targets that are methylated, the extent to which this results in gene silencing and the identity of the silenced genes most likely to play a role in the tumours' biology have not yet been established. In this study, genome-wide methylation and expression analysis of GCT cell lines was combined with gene expression data from primary tumours to address this question. Genome methylation was analysed using the Illumina infinium HumanMethylome450 bead chip system and gene expression was analysed using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Regulation by methylation was confirmed by demethylation using 5-aza-2-deoxycytidine and reverse transcription-quantitative PCR. Large differences in the level of methylation of the CpG islands of individual genes between tumour cell lines correlated well with differential gene expression. Treatment of non-seminoma cells with 5-aza-2-deoxycytidine verified that methylation of all genes tested played a role in their silencing in yolk sac tumour cells and many of these genes were also differentially expressed in primary tumours. Genes silenced by methylation in the various GCT cell lines were identified. Several pluripotency-associated genes were identified as a major functional group of silenced genes.

  19. Genome-Wide Analysis of Corynespora cassiicola Leaf Fall Disease Putative Effectors.

    Science.gov (United States)

    Lopez, David; Ribeiro, Sébastien; Label, Philippe; Fumanal, Boris; Venisse, Jean-Stéphane; Kohler, Annegret; de Oliveira, Ricardo R; Labutti, Kurt; Lipzen, Anna; Lail, Kathleen; Bauer, Diane; Ohm, Robin A; Barry, Kerrie W; Spatafora, Joseph; Grigoriev, Igor V; Martin, Francis M; Pujade-Renaud, Valérie

    2018-01-01

    Corynespora cassiicola is an Ascomycetes fungus with a broad host range and diverse life styles. Mostly known as a necrotrophic plant pathogen, it has also been associated with rare cases of human infection. In the rubber tree, this fungus causes the Corynespora leaf fall (CLF) disease, which increasingly affects natural rubber production in Asia and Africa. It has also been found as an endophyte in South American rubber plantations where no CLF outbreak has yet occurred. The C. cassiicola species is genetically highly diverse, but no clear relationship has been evidenced between phylogenetic lineage and pathogenicity. Cassiicolin, a small glycosylated secreted protein effector, is thought to be involved in the necrotrophic interaction with the rubber tree but some virulent C. cassiicola isolates do not have a cassiicolin gene. This study set out to identify other putative effectors involved in CLF. The genome of a highly virulent C. cassiicola isolate from the rubber tree (CCP) was sequenced and assembled. In silico prediction revealed 2870 putative effectors, comprising CAZymes, lipases, peptidases, secreted proteins and enzymes associated with secondary metabolism. Comparison with the genomes of 44 other fungal species, focusing on effector content, revealed a striking proximity with phylogenetically unrelated species ( Colletotrichum acutatum, Colletotrichum gloesporioides, Fusarium oxysporum, nectria hematococca , and Botrosphaeria dothidea ) sharing life style plasticity and broad host range. Candidate effectors involved in the compatible interaction with the rubber tree were identified by transcriptomic analysis. Differentially expressed genes included 92 putative effectors, among which cassiicolin and two other secreted singleton proteins. Finally, the genomes of 35 C. cassiicola isolates representing the genetic diversity of the species were sequenced and assembled, and putative effectors identified. At the intraspecific level, effector

  20. Genome-Wide Analysis of Corynespora cassiicola Leaf Fall Disease Putative Effectors

    Directory of Open Access Journals (Sweden)

    David Lopez

    2018-03-01

    Full Text Available Corynespora cassiicola is an Ascomycetes fungus with a broad host range and diverse life styles. Mostly known as a necrotrophic plant pathogen, it has also been associated with rare cases of human infection. In the rubber tree, this fungus causes the Corynespora leaf fall (CLF disease, which increasingly affects natural rubber production in Asia and Africa. It has also been found as an endophyte in South American rubber plantations where no CLF outbreak has yet occurred. The C. cassiicola species is genetically highly diverse, but no clear relationship has been evidenced between phylogenetic lineage and pathogenicity. Cassiicolin, a small glycosylated secreted protein effector, is thought to be involved in the necrotrophic interaction with the rubber tree but some virulent C. cassiicola isolates do not have a cassiicolin gene. This study set out to identify other putative effectors involved in CLF. The genome of a highly virulent C. cassiicola isolate from the rubber tree (CCP was sequenced and assembled. In silico prediction revealed 2870 putative effectors, comprising CAZymes, lipases, peptidases, secreted proteins and enzymes associated with secondary metabolism. Comparison with the genomes of 44 other fungal species, focusing on effector content, revealed a striking proximity with phylogenetically unrelated species (Colletotrichum acutatum, Colletotrichum gloesporioides, Fusarium oxysporum, nectria hematococca, and Botrosphaeria dothidea sharing life style plasticity and broad host range. Candidate effectors involved in the compatible interaction with the rubber tree were identified by transcriptomic analysis. Differentially expressed genes included 92 putative effectors, among which cassiicolin and two other secreted singleton proteins. Finally, the genomes of 35 C. cassiicola isolates representing the genetic diversity of the species were sequenced and assembled, and putative effectors identified. At the intraspecific level, effector