An efficient Bayesian meta-analysis approach for studying cross-phenotype genetic associations.

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Arunabha Majumdar

2018-02-01

Full Text Available Simultaneous analysis of genetic associations with multiple phenotypes may reveal shared genetic susceptibility across traits (pleiotropy. For a locus exhibiting overall pleiotropy, it is important to identify which specific traits underlie this association. We propose a Bayesian meta-analysis approach (termed CPBayes that uses summary-level data across multiple phenotypes to simultaneously measure the evidence of aggregate-level pleiotropic association and estimate an optimal subset of traits associated with the risk locus. This method uses a unified Bayesian statistical framework based on a spike and slab prior. CPBayes performs a fully Bayesian analysis by employing the Markov Chain Monte Carlo (MCMC technique Gibbs sampling. It takes into account heterogeneity in the size and direction of the genetic effects across traits. It can be applied to both cohort data and separate studies of multiple traits having overlapping or non-overlapping subjects. Simulations show that CPBayes can produce higher accuracy in the selection of associated traits underlying a pleiotropic signal than the subset-based meta-analysis ASSET. We used CPBayes to undertake a genome-wide pleiotropic association study of 22 traits in the large Kaiser GERA cohort and detected six independent pleiotropic loci associated with at least two phenotypes. This includes a locus at chromosomal region 1q24.2 which exhibits an association simultaneously with the risk of five different diseases: Dermatophytosis, Hemorrhoids, Iron Deficiency, Osteoporosis and Peripheral Vascular Disease. We provide an R-package 'CPBayes' implementing the proposed method.

Using Y-Chromosomal Haplogroups in Genetic Association Studies and Suggested Implications.

Science.gov (United States)

Erzurumluoglu, A Mesut; Baird, Denis; Richardson, Tom G; Timpson, Nicholas J; Rodriguez, Santiago

2018-01-22

Y-chromosomal (Y-DNA) haplogroups are more widely used in population genetics than in genetic epidemiology, although associations between Y-DNA haplogroups and several traits, including cardiometabolic traits, have been reported. In apparently homogeneous populations defined by principal component analyses, there is still Y-DNA haplogroup variation which will result from population history. Therefore, hidden stratification and/or differential phenotypic effects by Y-DNA haplogroups could exist. To test this, we hypothesised that stratifying individuals according to their Y-DNA haplogroups before testing for associations between autosomal single nucleotide polymorphisms (SNPs) and phenotypes will yield difference in association. For proof of concept, we derived Y-DNA haplogroups from 6537 males from two epidemiological cohorts, Avon Longitudinal Study of Parents and Children (ALSPAC) ( n = 5080; 816 Y-DNA SNPs) and the 1958 Birth Cohort ( n = 1457; 1849 Y-DNA SNPs), and studied the robust associations between 32 SNPs and body mass index (BMI), including SNPs in or near Fat Mass and Obesity-associated protein ( FTO ) which yield the strongest effects. Overall, no association was replicated in both cohorts when Y-DNA haplogroups were considered and this suggests that, for BMI at least, there is little evidence of differences in phenotype or SNP association by Y-DNA structure. Further studies using other traits, phenome-wide association studies (PheWAS), other haplogroups and/or autosomal SNPs are required to test the generalisability and utility of this approach.

On coding genotypes for genetic markers with multiple alleles in genetic association study of quantitative traits

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Wang Tao

2011-09-01

Full Text Available Abstract Background In genetic association study of quantitative traits using F∞ models, how to code the marker genotypes and interpret the model parameters appropriately is important for constructing hypothesis tests and making statistical inferences. Currently, the coding of marker genotypes in building F∞ models has mainly focused on the biallelic case. A thorough work on the coding of marker genotypes and interpretation of model parameters for F∞ models is needed especially for genetic markers with multiple alleles. Results In this study, we will formulate F∞ genetic models under various regression model frameworks and introduce three genotype coding schemes for genetic markers with multiple alleles. Starting from an allele-based modeling strategy, we first describe a regression framework to model the expected genotypic values at given markers. Then, as extension from the biallelic case, we introduce three coding schemes for constructing fully parameterized one-locus F∞ models and discuss the relationships between the model parameters and the expected genotypic values. Next, under a simplified modeling framework for the expected genotypic values, we consider several reduced one-locus F∞ models from the three coding schemes on the estimability and interpretation of their model parameters. Finally, we explore some extensions of the one-locus F∞ models to two loci. Several fully parameterized as well as reduced two-locus F∞ models are addressed. Conclusions The genotype coding schemes provide different ways to construct F∞ models for association testing of multi-allele genetic markers with quantitative traits. Which coding scheme should be applied depends on how convenient it can provide the statistical inferences on the parameters of our research interests. Based on these F∞ models, the standard regression model fitting tools can be used to estimate and test for various genetic effects through statistical contrasts with the

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

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

Defining the genetic susceptibility to cervical neoplasia-A genome-wide association study.

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Paul J Leo

2017-08-01

Full Text Available A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4% of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately >7.1% risk, and those in the highest 5% have approximately >21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods.

STrengthening the REporting of Genetic Association Studies (STREGA – An Extension of the STROBE Statement

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Julian Little

2009-09-01

Full Text Available Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA initiative builds on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modelling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.

Autism and genetics: Clinical approach and association study with two markers of HRAS gene

Energy Technology Data Exchange (ETDEWEB)

Herault, J.; Petit, E.; Cherpi, C. [Laboratoire de Biochimie Medicale, Tours (France)] [and others

1995-08-14

Twin studies and familial aggregation studies indicate that genetic factors could play a role in infantile autism. In an earlier study, we identified a possible positive association between autism and a c-Harvey-ras (HRAS) oncogene marker at the 3{prime} end of the coding region. In an attempt to confirm this finding, we studied a larger population, well-characterized clinically and genetically. We report a positive association between autism and two HRAS markers, the 3{prime} marker used in the initial study and an additional marker in exon 1. 46 refs., 1 fig., 2 tabs.

Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry : A genome-wide association study

NARCIS (Netherlands)

Allen, Richard J; Porte, Joanne; Braybrooke, Rebecca; Flores, Carlos; Fingerlin, Tasha E; Oldham, Justin M; Guillen-Guio, Beatriz; Ma, Shwu-Fan; Okamoto, Tsukasa; John, Alison E; Obeidat, Ma'en; Yang, Ivana V; Henry, Amanda; Hubbard, Richard B; Navaratnam, Vidya; Saini, Gauri; Thompson, Norma; Booth, Helen L; Hart, Simon P; Hill, Mike R; Hirani, Nik; Maher, Toby M; McAnulty, Robin J; Millar, Ann B; Molyneaux, Philip L; Parfrey, Helen; Rassl, Doris M; Whyte, Moira K B; Fahy, William A; Marshall, Richard P; Oballa, Eunice; Bossé, Yohan; Nickle, David C; Sin, Don D; Timens, Wim; Shrine, Nick; Sayers, Ian; Hall, Ian P; Noth, Imre; Schwartz, David A; Tobin, Martin D; Wain, Louise V; Jenkins, R Gisli

2017-01-01

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high mortality, uncertain cause, and few treatment options. Studies have identified a significant genetic risk associated with the development of IPF; however, mechanisms by which genetic risk factors promote

Heritability and confirmation of genetic association studies for childhood asthma in twins.

Science.gov (United States)

Ullemar, V; Magnusson, P K E; Lundholm, C; Zettergren, A; Melén, E; Lichtenstein, P; Almqvist, C

2016-02-01

Although the genetics of asthma has been extensively studied using both quantitative and molecular genetic analysis methods, both approaches lack studies specific to the childhood phenotype and including other allergic diseases. This study aimed to give specific estimates for the heritability of childhood asthma and other allergic diseases, to attempt to replicate findings from genomewide association studies (GWAS) for childhood asthma and to test the same variants against other allergic diseases. In a cohort of 25 306 Swedish twins aged 9 or 12 years, data on asthma were available from parental interviews and population-based registers. The interviews also inquired about wheeze, hay fever, eczema, and food allergy. Through structural equation modeling, the heritability of all phenotypes was calculated. A subset of 10 075 twins was genotyped for 16 single nucleotide polymorphisms (SNPs) selected from previous GWAS; these were first tested for association with asthma and significant findings also against the other allergic diseases. The heritability of any childhood asthma was 0.82 (95% CI 0.79-0.85). For the other allergic diseases, the range was approximately 0.60-0.80. Associations for six SNPs with asthma were replicated, including rs2305480 in the GSDMB gene (OR 0.80, 95% CI 0.74-0.86, P = 1.5*10(-8) ; other significant associations all below P = 3.5*10(-4) ). Of these, only rs3771180 in IL1RL1 was associated with any other allergic disease (for hay fever, OR 0.64, 95% CI 0.53-0.77, P = 2.5*10(-6) ). Asthma and allergic diseases of childhood are highly heritable, and these high-risk genetic variants associated specifically with childhood asthma, except for one SNP shared with hay fever. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A strategy analysis for genetic association studies with known inbreeding

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del Giacco Stefano

2011-07-01

Full Text Available Abstract Background Association studies consist in identifying the genetic variants which are related to a specific disease through the use of statistical multiple hypothesis testing or segregation analysis in pedigrees. This type of studies has been very successful in the case of Mendelian monogenic disorders while it has been less successful in identifying genetic variants related to complex diseases where the insurgence depends on the interactions between different genes and the environment. The current technology allows to genotype more than a million of markers and this number has been rapidly increasing in the last years with the imputation based on templates sets and whole genome sequencing. This type of data introduces a great amount of noise in the statistical analysis and usually requires a great number of samples. Current methods seldom take into account gene-gene and gene-environment interactions which are fundamental especially in complex diseases. In this paper we propose to use a non-parametric additive model to detect the genetic variants related to diseases which accounts for interactions of unknown order. Although this is not new to the current literature, we show that in an isolated population, where the most related subjects share also most of their genetic code, the use of additive models may be improved if the available genealogical tree is taken into account. Specifically, we form a sample of cases and controls with the highest inbreeding by means of the Hungarian method, and estimate the set of genes/environmental variables, associated with the disease, by means of Random Forest. Results We have evidence, from statistical theory, simulations and two applications, that we build a suitable procedure to eliminate stratification between cases and controls and that it also has enough precision in identifying genetic variants responsible for a disease. This procedure has been successfully used for the beta-thalassemia, which is

Recommendations for using standardised phenotypes in genetic association studies

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Naylor Melissa G

2009-07-01

Full Text Available Abstract Genetic association studies of complex traits often rely on standardised quantitative phenotypes, such as percentage of predicted forced expiratory volume and body mass index to measure an underlying trait of interest (eg lung function, obesity. These phenotypes are appealing because they provide an easy mechanism for comparing subjects, although such standardisations may not be the best way to control for confounders and other covariates. We recommend adjusting raw or standardised phenotypes within the study population via regression. We illustrate through simulation that optimal power in both population- and family-based association tests is attained by using the residuals from within-study adjustment as the complex trait phenotype. An application of family-based association analysis of forced expiratory volume in one second, and obesity in the Childhood Asthma Management Program data, illustrates that power is maintained or increased when adjusted phenotype residuals are used instead of typical standardised quantitative phenotypes.

Power assessment for genetic association study of human longevity using offspring of long-lived subjects

DEFF Research Database (Denmark)

Tan, Qihua; Zhao, Jing Hua; Li, Shuxia

2010-01-01

and the proportional hazard model for generating individual lifespan. Family genotype data is generated using a genetic linkage program for given SNP allele frequency. Power is estimated by setting the type I error rate at 0.05 and by calculating the Armitage's chi-squared test statistic for 200 replicate samples...... the direct approach. It also has low power in detecting non-additive effect genes. Indirect genetic association using offspring from families with both parents as nonagenarians is nearly as powerful as using offspring from families with one centenarian parent. In conclusion, the indirect design can be a good......Recently, an indirect genetic association approach that compares genotype frequencies in offspring of long-lived subjects and offspring from random families has been introduced to study gene-longevity associations. Although the indirect genetic association has certain advantages over the direct...

Genetics in psychiatry: common variant association studies

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Buxbaum Joseph D

2010-03-01

Full Text Available Abstract Many psychiatric conditions and traits are associated with significant heritability. Genetic risk for psychiatric conditions encompass rare variants, identified due to major effect, as well as common variants, the latter analyzed by association analyses. We review guidelines for common variant association analyses, undertaking after assessing evidence of heritability. We highlight the importance of: suitably large sample sizes; an experimental design that controls for ancestry; careful data cleaning; correction for multiple testing; small P values for positive findings; assessment of effect size for positive findings; and, inclusion of an independent replication sample. We also note the importance of a critical discussion of any prior findings, biological follow-up where possible, and a means of accessing the raw data.

Capturing the spectrum of interaction effects in genetic association studies by simulated evaporative cooling network analysis.

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Brett A McKinney

2009-03-01

Full Text Available Evidence from human genetic studies of several disorders suggests that interactions between alleles at multiple genes play an important role in influencing phenotypic expression. Analytical methods for identifying Mendelian disease genes are not appropriate when applied to common multigenic diseases, because such methods investigate association with the phenotype only one genetic locus at a time. New strategies are needed that can capture the spectrum of genetic effects, from Mendelian to multifactorial epistasis. Random Forests (RF and Relief-F are two powerful machine-learning methods that have been studied as filters for genetic case-control data due to their ability to account for the context of alleles at multiple genes when scoring the relevance of individual genetic variants to the phenotype. However, when variants interact strongly, the independence assumption of RF in the tree node-splitting criterion leads to diminished importance scores for relevant variants. Relief-F, on the other hand, was designed to detect strong interactions but is sensitive to large backgrounds of variants that are irrelevant to classification of the phenotype, which is an acute problem in genome-wide association studies. To overcome the weaknesses of these data mining approaches, we develop Evaporative Cooling (EC feature selection, a flexible machine learning method that can integrate multiple importance scores while removing irrelevant genetic variants. To characterize detailed interactions, we construct a genetic-association interaction network (GAIN, whose edges quantify the synergy between variants with respect to the phenotype. We use simulation analysis to show that EC is able to identify a wide range of interaction effects in genetic association data. We apply the EC filter to a smallpox vaccine cohort study of single nucleotide polymorphisms (SNPs and infer a GAIN for a collection of SNPs associated with adverse events. Our results suggest an important

The Genetic and Environmental Contributions to Internet Use and Associations With Psychopathology: A Twin Study.

Science.gov (United States)

Long, Elizabeth C; Verhulst, Brad; Neale, Michael C; Lind, Penelope A; Hickie, Ian B; Martin, Nicholas G; Gillespie, Nathan A

2016-02-01

Excessive internet use has been linked to psychopathology. Therefore, understanding the genetic and environmental risks underpinning internet use and their relation to psychopathology is important. This study aims to explore the genetic and environmental etiology of internet use measures and their associations with internalizing disorders and substance use disorders. The sample included 2,059 monozygotic (MZ) and dizygotic (DZ) young adult twins from the Brisbane Longitudinal Twin Study (BLTS). Younger participants reported more frequent internet use, while women were more likely to use the internet for interpersonal communication. Familial aggregation in 'frequency of internet use' was entirely explained by additive genetic factors accounting for 41% of the variance. Familial aggregation in 'frequency of use after 11 pm', 'using the internet to contact peers', and 'using the internet primarily to access social networking sites' was attributable to varying combinations of additive genetic and shared environmental factors. In terms of psychopathology, there were no significant associations between internet use measures and major depression (MD), but there were positive significant associations between 'frequency of internet use' and 'frequency of use after 11 pm' with social phobia (SP). 'Using the internet to contact peers' was positively associated with alcohol abuse, whereas 'using the internet to contact peers' and 'using the internet primarily to access social networking sites' were negatively associated with cannabis use disorders and nicotine symptoms. Individual differences in internet use can be attributable to varying degrees of genetic and environmental risks. Despite some significant associations of small effect, variation in internet use appears mostly unrelated to psychopathology.

A fast multilocus test with adaptive SNP selection for large-scale genetic-association studies

KAUST Repository

Zhang, Han

2013-09-11

As increasing evidence suggests that multiple correlated genetic variants could jointly influence the outcome, a multilocus test that aggregates association evidence across multiple genetic markers in a considered gene or a genomic region may be more powerful than a single-marker test for detecting susceptibility loci. We propose a multilocus test, AdaJoint, which adopts a variable selection procedure to identify a subset of genetic markers that jointly show the strongest association signal, and defines the test statistic based on the selected genetic markers. The P-value from the AdaJoint test is evaluated by a computationally efficient algorithm that effectively adjusts for multiple-comparison, and is hundreds of times faster than the standard permutation method. Simulation studies demonstrate that AdaJoint has the most robust performance among several commonly used multilocus tests. We perform multilocus analysis of over 26,000 genes/regions on two genome-wide association studies of pancreatic cancer. Compared with its competitors, AdaJoint identifies a much stronger association between the gene CLPTM1L and pancreatic cancer risk (6.0 × 10(-8)), with the signal optimally captured by two correlated single-nucleotide polymorphisms (SNPs). Finally, we show AdaJoint as a powerful tool for mapping cis-regulating methylation quantitative trait loci on normal breast tissues, and find many CpG sites whose methylation levels are jointly regulated by multiple SNPs nearby.

Genetically Distinct Subsets within ANCA-Associated Vasculitis

Science.gov (United States)

Lyons, Paul A.; Rayner, Tim F.; Trivedi, Sapna; Holle, Julia U.; Watts, Richard A.; Jayne, David R.W.; Baslund, Bo; Brenchley, Paul; Bruchfeld, Annette; Chaudhry, Afzal N.; Tervaert, Jan Willem Cohen; Deloukas, Panos; Feighery, Conleth; Gross, Wolfgang L.; Guillevin, Loic; Gunnarsson, Iva; P, Lorraine Harper M.R.C; Hrušková, Zdenka; Little, Mark A.; Martorana, Davide; Neumann, Thomas; Ohlsson, Sophie; Padmanabhan, Sandosh; Pusey, Charles D.; Salama, Alan D.; Sanders, Jan-Stephan F.; Savage, Caroline O.; Segelmark, Mårten; Stegeman, Coen A.; Tesař, Vladimir; Vaglio, Augusto; Wieczorek, Stefan; Wilde, Benjamin; Zwerina, Jochen; Rees, Andrew J.; Clayton, David G.; Smith, Kenneth G.C.

2013-01-01

BACKGROUND Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis. METHODS A genomewide association study was performed in a discovery cohort of 1233 U.K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria. RESULTS We found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti–proteinase 3 ANCA was associated with HLA-DP and the genes encoding α1-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P = 6.2×10−89, P = 5.6×10−12, and P = 2.6×10−7, respectively). Anti–myeloperoxidase ANCA was associated with HLA-DQ (P = 2.1×10−8). CONCLUSIONS This study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA–associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA–associated vasculitis and myeloperoxidase ANCA–associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.) PMID

Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake

NARCIS (Netherlands)

T. Tanaka (Toshiko); J.S. Ngwa; F.J.A. van Rooij (Frank); M.C. Zillikens (Carola); M.K. Wojczynski (Mary ); A.C. Frazier-Wood (Alexis); D.K. Houston (Denise); S. Kanoni (Stavroula); R.N. Lemaitre (Rozenn ); J. Luan; V. Mikkilä (Vera); F. Renström (Frida); E. Sonestedt (Emily); J.H. Zhao (Jing Hua); A.Y. Chu (Audrey); L. Qi (Lu); D.I. Chasman (Daniel); M.C. De Oliveira Otto (Marcia); E.J. Dhurandhar (Emily); M.F. Feitosa (Mary Furlan); I. Johansson (Ingegerd); K-T. Khaw (Kay-Tee); K. Lohman (Kurt); A. Manichaikul (Ani); N.M. McKeown (Nicola ); D. Mozaffarian (Dariush); A.B. Singleton (Andrew); K. Stirrups (Kathy); J. Viikari (Jorma); Z. Ye (Zheng); S. Bandinelli (Stefania); I.E. Barroso (Inês); P. Deloukas (Panagiotis); N.G. Forouhi (Nita); A. Hofman (Albert); Y. Liu (YongMei); L.-P. Lyytikäinen (Leo-Pekka); K.E. North (Kari); M. Dimitriou (Maria); G. Hallmans (Göran); M. Kähönen (Mika); C. Langenberg (Claudia); J.M. Ordovas (Jose); A.G. Uitterlinden (André); F.B. Hu (Frank); I.-P. Kalafati (Ioanna-Panagiota); O. Raitakari (Olli); O.H. Franco (Oscar); A. Johnson (Anthony); V. Emilsson (Valur); J.A. Schrack (Jennifer); R.D. Semba; D.S. Siscovick (David); D.K. Arnett (Donna); I.B. Borecki (Ingrid); P.W. Franks (Paul); S.B. Kritchevsky (Stephen); R.J.F. Loos (Ruth); M. Orho-Melander (Marju); J.I. Rotter (Jerome); N.J. Wareham (Nick); J.C.M. Witteman (Jacqueline); L. Ferrucci (Luigi); G.V. Dedoussis (George); L.A. Cupples (Adrienne); J.A. Nettleton (Jennifer )

2013-01-01

textabstractBackground: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants. Objective: The objective of the study was to identify common genetic variants that are associated with macronutrient intake.

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

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

Simple Algorithms to Calculate Asymptotic Null Distributions of Robust Tests in Case-Control Genetic Association Studies in R

Directory of Open Access Journals (Sweden)

Wing Kam Fung

2010-02-01

Full Text Available The case-control study is an important design for testing association between genetic markers and a disease. The Cochran-Armitage trend test (CATT is one of the most commonly used statistics for the analysis of case-control genetic association studies. The asymptotically optimal CATT can be used when the underlying genetic model (mode of inheritance is known. However, for most complex diseases, the underlying genetic models are unknown. Thus, tests robust to genetic model misspecification are preferable to the model-dependant CATT. Two robust tests, MAX3 and the genetic model selection (GMS, were recently proposed. Their asymptotic null distributions are often obtained by Monte-Carlo simulations, because they either have not been fully studied or involve multiple integrations. In this article, we study how components of each robust statistic are correlated, and find a linear dependence among the components. Using this new finding, we propose simple algorithms to calculate asymptotic null distributions for MAX3 and GMS, which greatly reduce the computing intensity. Furthermore, we have developed the R package Rassoc implementing the proposed algorithms to calculate the empirical and asymptotic p values for MAX3 and GMS as well as other commonly used tests in case-control association studies. For illustration, Rassoc is applied to the analysis of case-control data of 17 most significant SNPs reported in four genome-wide association studies.

An information-gain approach to detecting three-way epistatic interactions in genetic association studies

DEFF Research Database (Denmark)

Hu, Ting; Chen, Yuanzhu; Kiralis, Jeff W

2013-01-01

Background Epistasis has been historically used to describe the phenomenon that the effect of a given gene on a phenotype can be dependent on one or more other genes, and is an essential element for understanding the association between genetic and phenotypic variations. Quantifying epistasis......-way epistasis. Methods Such a measure is based on information gain, and is able to separate all lower order effects from pure three-way epistasis. Results Our method was verified on synthetic data and applied to real data from a candidate-gene study of tuberculosis in a West African population....... In the tuberculosis data, we found a statistically significant pure three-way epistatic interaction effect that was stronger than any lower-order associations. Conclusion Our study provides a methodological basis for detecting and characterizing high-order gene-gene interactions in genetic association studies....

Covariance Association Test (CVAT) Identifies Genetic Markers Associated with Schizophrenia in Functionally Associated Biological Processes.

Science.gov (United States)

Rohde, Palle Duun; Demontis, Ditte; Cuyabano, Beatriz Castro Dias; Børglum, Anders D; Sørensen, Peter

2016-08-01

Schizophrenia is a psychiatric disorder with large personal and social costs, and understanding the genetic etiology is important. Such knowledge can be obtained by testing the association between a disease phenotype and individual genetic markers; however, such single-marker methods have limited power to detect genetic markers with small effects. Instead, aggregating genetic markers based on biological information might increase the power to identify sets of genetic markers of etiological significance. Several set test methods have been proposed: Here we propose a new set test derived from genomic best linear unbiased prediction (GBLUP), the covariance association test (CVAT). We compared the performance of CVAT to other commonly used set tests. The comparison was conducted using a simulated study population having the same genetic parameters as for schizophrenia. We found that CVAT was among the top performers. When extending CVAT to utilize a mixture of SNP effects, we found an increase in power to detect the causal sets. Applying the methods to a Danish schizophrenia case-control data set, we found genomic evidence for association of schizophrenia with vitamin A metabolism and immunological responses, which previously have been implicated with schizophrenia based on experimental and observational studies. Copyright © 2016 by the Genetics Society of America.

Genetic variants associated with lung function

DEFF Research Database (Denmark)

Thyagarajan, Bharat; Wojczynski, Mary; Minster, Ryan L

2014-01-01

with exceptional longevity have not been identified. METHOD: We conducted a genome wide association study (GWAS) to identify novel genetic variants associated with lung function in the Long Life Family Study (LLFS) (n = 3,899). Replication was performed using data from the CHARGE/SpiroMeta consortia...

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.

A genetic association study of the IGF-1 gene and radiological osteoarthritis in a population-based cohort study (the Rotterdam study)

NARCIS (Netherlands)

Meulenbelt, I.; Bijkerk, C.; Miedema, H.S.; Breedveld, F.C.; Hofman, A.; Valkenburg, H.A.; Pols, H.A.P.; Slagboom, P.E.; Duijn, C.M. van

1998-01-01

Objective - A genetic association study was performed to investigate whether radiographical osteoarthritis (ROA) was associated with specific genotypes of the insulin-like growth factor I (IGF-1) gene. Methods - Subjects aged 55-65 years were selected from a population-based study of which ROA at

Study on the Method of Association Rules Mining Based on Genetic Algorithm and Application in Analysis of Seawater Samples

Directory of Open Access Journals (Sweden)

Qiuhong Sun

2014-04-01

Full Text Available Based on the data mining research, the data mining based on genetic algorithm method, the genetic algorithm is briefly introduced, while the genetic algorithm based on two important theories and theoretical templates principle implicit parallelism is also discussed. Focuses on the application of genetic algorithms for association rule mining method based on association rule mining, this paper proposes a genetic algorithm fitness function structure, data encoding, such as the title of the improvement program, in particular through the early issues study, proposed the improved adaptive Pc, Pm algorithm is applied to the genetic algorithm, thereby improving efficiency of the algorithm. Finally, a genetic algorithm based association rule mining algorithm, and be applied in sea water samples database in data mining and prove its effective.

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

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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

Phenotype variations affect genetic association studies of degenerative disc disease: conclusions of analysis of genetic association of 58 single nucleotide polymorphisms with highly specific phenotypes for disc degeneration in 332 subjects.

Science.gov (United States)

Rajasekaran, S; Kanna, Rishi Mugesh; Senthil, Natesan; Raveendran, Muthuraja; Cheung, Kenneth M C; Chan, Danny; Subramaniam, Sakthikanal; Shetty, Ajoy Prasad

2013-10-01

Although the influence of genetics on the process of disc degeneration is well recognized, in recently published studies, there is a wide variation in the race and selection criteria for such study populations. More importantly, the radiographic features of disc degeneration that are selected to represent the disc degeneration phenotype are variable in these studies. The study presented here evaluates the association between single nucleotide polymorphisms (SNPs) of candidate genes and three distinct radiographic features that can be defined as the degenerative disc disease (DDD) phenotype. The study objectives were to examine the allelic diversity of 58 SNPs related to 35 candidate genes related to lumbar DDD, to evaluate the association in a hitherto unevaluated ethnic Indian population that represents more than one-sixth of the world population, and to analyze how genetic associations can vary in the same study subjects with the choice of phenotype. A cross-sectional, case-control study of an ethnic Indian population was carried out. Fifty-eight SNPs in 35 potential candidate genes were evaluated in 342 subjects and the associations were analyzed against three highly specific markers for DDD, namely disc degeneration by Pfirrmann grading, end-plate damage evaluated by total end-plate damage score, and annular tears evaluated by disc herniations and hyperintense zones. Genotyping of cases and controls was performed on a genome-wide SNP array to identify potential associated disease loci. The results from the genome-wide SNP array were then used to facilitate SNP selection and genotype validation was conducted using Sequenom-based genotyping. Eleven of the 58 SNPs provided evidence of association with one of the phenotypes. For annular tears, rs1042631 SNP of AGC1 and rs467691 SNP of ADAMTS5 were highly significantly associated (p<.01) and SNPs in NGFB, IL1B, IL18RAP, and MMP10 were also significantly associated (p<.05). The rs4076018 SNP of NGFB was highly

Celiac disease : moving from genetic associations to causal variants

NARCIS (Netherlands)

Hrdlickova, B.; Westra, H-J; Franke, L.; Wijmenga, C.

Genome-wide association studies are providing insight into the genetic basis of common complex diseases: more than 1150 genetic loci [2165 unique single nucleotide polymorphisms (SNPs)] have recently been associated to 159 complex diseases. The hunt for genes contributing to immune-related diseases

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...

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.

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

OpenAIRE

Hensman Moss, Davina J; Pardinas, Antonio; Langbehn, Douglas; Lo, Kitty; Leavitt, Blair R; Roos, Raymund; Durr, Alexandra; Mead, Simon; Holmans, Peter; Jones, Lesley; Tabrizi, Sarah J; Coleman, A; Santos, R Dar; Decolongon, J; Sturrock, A

2017-01-01

Background\\ud \\ud Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure.\\ud \\ud Methods\\ud \\ud We generated a progression score on the basis of principal ...

A general framework for the evaluation of genetic association studies using multiple marginal models

DEFF Research Database (Denmark)

Kitsche, Andreas; Ritz, Christian; Hothorn, Ludwig A.

2016-01-01

OBJECTIVE: In this study, we present a simultaneous inference procedure as a unified analysis framework for genetic association studies. METHODS: The method is based on the formulation of multiple marginal models that reflect different modes of inheritance. The basic advantage of this methodology...

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.

Genetic Variations and their Association with Diseases among ...

African Journals Online (AJOL)

genetics plays in disease, death and infections. The mode of study involved a combination of a retrospective study and the analysis of genetic variation among Kenyan ethnic populations using ABO blood group system. The results showed that there was association between allele frequencies of ABO system and disease ...

Does cortisol moderate the environmental association between peer victimization and depression symptoms? A genetically informed twin study.

Science.gov (United States)

Brendgen, Mara; Ouellet-Morin, Isabelle; Lupien, Sonia; Vitaro, Frank; Dionne, Ginette; Boivin, Michel

2017-10-01

Many youths who are victimized by peers suffer from depression symptoms. However, not all bullying victims show depression symptoms and individuals' biological sensitivity may play an important moderating role in this regard. In line with this notion, peer victimization has been associated with increased depressive symptoms in youth with higher basal cortisol secretion. It is unclear, however, whether this moderating effect of cortisol really concerns the environmental effect of peer victimization on depression. Indeed, genetic factors can also influence individuals' environmental experiences, including peer victimization, and part of these genetic factors may be those associated with depression. Using a genetically informed design based on 159 monozygotic and 120 dizygotic twin pairs (52% girls) assessed at age 14 years, this study examined whether cortisol secretion moderates the environmental or the genetic association between peer victimization and depression symptoms. Salivary cortisol at awakening was obtained with buccal swabs during four school week days. Peer victimization and depression were assessed via self-reports. Cholesky modeling revealed that peer victimization was associated with depression symptoms via both genetic and environmental pathways. Moreover, the environmental association between peer victimization and depression symptoms steadily increased with increasing levels of morning cortisol. The genetic association between peer victimization and depression symptoms also varied, albeit less, as a function of individuals' cortisol secretion. These findings support the hypothesis that peer victimization increases internalizing psychopathology mainly in youth with heightened biological reactivity to environmental conditions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Novel genetic loci associated with hippocampal volume.

Science.gov (United States)

Hibar, Derrek P; Adams, Hieab H H; Jahanshad, Neda; Chauhan, Ganesh; Stein, Jason L; Hofer, Edith; Renteria, Miguel E; Bis, Joshua C; Arias-Vasquez, Alejandro; Ikram, M Kamran; Desrivières, Sylvane; Vernooij, Meike W; Abramovic, Lucija; Alhusaini, Saud; Amin, Najaf; Andersson, Micael; Arfanakis, Konstantinos; Aribisala, Benjamin S; Armstrong, Nicola J; Athanasiu, Lavinia; Axelsson, Tomas; Beecham, Ashley H; Beiser, Alexa; Bernard, Manon; Blanton, Susan H; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brickman, Adam M; Carmichael, Owen; Chakravarty, M Mallar; Chen, Qiang; Ching, Christopher R K; Chouraki, Vincent; Cuellar-Partida, Gabriel; Crivello, Fabrice; Den Braber, Anouk; Doan, Nhat Trung; Ehrlich, Stefan; Giddaluru, Sudheer; Goldman, Aaron L; Gottesman, Rebecca F; Grimm, Oliver; Griswold, Michael E; Guadalupe, Tulio; Gutman, Boris A; Hass, Johanna; Haukvik, Unn K; Hoehn, David; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Jørgensen, Kjetil N; Karbalai, Nazanin; Kasperaviciute, Dalia; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Liewald, David C M; Lopez, Lorna M; Luciano, Michelle; Macare, Christine; Marquand, Andre F; Matarin, Mar; Mather, Karen A; Mattheisen, Manuel; McKay, David R; Milaneschi, Yuri; Muñoz Maniega, Susana; Nho, Kwangsik; Nugent, Allison C; Nyquist, Paul; Loohuis, Loes M Olde; Oosterlaan, Jaap; Papmeyer, Martina; Pirpamer, Lukas; Pütz, Benno; Ramasamy, Adaikalavan; Richards, Jennifer S; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rommelse, Nanda; Ropele, Stefan; Rose, Emma J; Royle, Natalie A; Rundek, Tatjana; Sämann, Philipp G; Saremi, Arvin; Satizabal, Claudia L; Schmaal, Lianne; Schork, Andrew J; Shen, Li; Shin, Jean; Shumskaya, Elena; Smith, Albert V; Sprooten, Emma; Strike, Lachlan T; Teumer, Alexander; Tordesillas-Gutierrez, Diana; Toro, Roberto; Trabzuni, Daniah; Trompet, Stella; Vaidya, Dhananjay; Van der Grond, Jeroen; Van der Lee, Sven J; 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; Wittfeld, Katharina; Woldehawariat, Girma; Wolf, Christiane; Wolfers, Thomas; Yanek, Lisa R; Yang, Jingyun; Zijdenbos, Alex; Zwiers, Marcel P; Agartz, Ingrid; 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; 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 Craen, Anton J M; De Geus, Eco J C; De Jager, Philip L; De Zubicaray, Greig I; Deary, Ian J; Debette, Stéphanie; DeCarli, Charles; Delanty, Norman; Depondt, Chantal; DeStefano, Anita; Dillman, Allissa; Djurovic, Srdjan; Donohoe, Gary; Drevets, Wayne C; Duggirala, Ravi; Dyer, Thomas D; Enzinger, Christian; Erk, Susanne; Espeseth, Thomas; Fedko, Iryna O; Fernández, Guillén; Ferrucci, Luigi; Fisher, Simon E; Fleischman, Debra A; Ford, Ian; Fornage, Myriam; Foroud, Tatiana M; Fox, Peter T; Francks, Clyde; Fukunaga, Masaki; Gibbs, J Raphael; Glahn, David C; Gollub, Randy L; Göring, Harald H H; Green, Robert C; Gruber, Oliver; Gudnason, Vilmundur; Guelfi, Sebastian; Håberg, Asta K; 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; Huentelman, Matthew; Hulshoff Pol, Hilleke E; Ikeda, Masashi; 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; Lopez, Oscar L; Lovestone, Simon; Martinez, Oliver; Martinot, Jean-Luc; Mattay, Venkata S; McDonald, Colm; McIntosh, Andrew M; McMahon, Francis J; McMahon, Katie L; 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; Schmidt, Helena; Schofield, Peter R; Sigursson, Sigurdur; Simmons, Andrew; Singleton, Andrew; Sisodiya, Sanjay M; Smith, Colin; Smoller, Jordan W; Soininen, Hilkka; Steen, Vidar M; Stott, David J; Sussmann, Jessika E; Thalamuthu, Anbupalam; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Tsolaki, Magda; Tzourio, Christophe; Uitterlinden, Andre G; Hernández, Maria C Valdés; Van der Brug, Marcel; van der Lugt, Aad; van der Wee, Nic J A; Van Haren, Neeltje E M; van 't Ent, Dennis; Van Tol, Marie-Jose; Vardarajan, Badri N; Vellas, Bruno; Veltman, Dick J; 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, Ronald H; Zonderman, Alan B; Martin, Nicholas G; Van Duijn, Cornelia M; Wright, Margaret J; Longstreth, W T; Schumann, Gunter; Grabe, Hans J; Franke, Barbara; Launer, Lenore J; Medland, Sarah E; Seshadri, Sudha; Thompson, Paul M; Ikram, M Arfan

2017-01-18

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r g =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

Phenome Wide Association Studies demonstrating pleiotropy of genetic variants within FTO with and without adjustment for body mass index

Directory of Open Access Journals (Sweden)

Robert Michael Cronin

2014-08-01

Full Text Available Phenome-wide association studies (PheWAS have demonstrated utility in validating genetic associations derived from traditional genetic studies as well as identifying novel genetic associations. Here we used an electronic health record (EHR-based PheWAS to explore pleiotropy of genetic variants in the fat mass and obesity associated gene (FTO, some of which have been previously associated with obesity and type 2 diabetes (T2D. We used a population of 10,487 individuals of European ancestry with genome-wide genotyping from the Electronic Medical Records and Genomics (eMERGE Network and another population of 13,711 individuals of European ancestry from the BioVU DNA biobank at Vanderbilt genotyped using Illumina HumanExome BeadChip. A meta-analysis of the two study populations replicated the well-described associations between FTO variants and obesity (odds ratio [OR]=1.25, 95% Confidence Interval=1.11-1.24, p=2.10 x 10 9 and FTO variants and T2D (OR=1.14, 95% CI=1.08-1.21, p=2.34 x 10 6. The meta-analysis also demonstrated that FTO variant rs8050136 was significantly associated with sleep apnea (OR=1.14, 95% CI=1.07-1.22, p=3.33 x 10 5; however, the association was attenuated after adjustment for body mass index (BMI. Novel phenotype associations with obesity-associated FTO variants included fibrocystic breast disease (rs9941349, OR=0.81, 95% CI=0.74-0.91, p=5.41x10 5 and trends toward associations with nonalcoholic liver disease and gram-positive bacterial infections. FTO variants not associated with obesity demonstrated other potential disease associations including noninflammatory disorders of the cervix and chronic periodontitis. These results suggest that genetic variants in FTO may have pleiotropic associations, some of which are not mediated by obesity.

Genetic association studies of suicidal behaviour: A review of the past 10 years, progress, limitations and future directions.

Directory of Open Access Journals (Sweden)

BOJAN MIRKOVIC

2016-09-01

Full Text Available Suicidal behaviours, which range from suicidal ideation to suicide attempts and completed suicide, represent a fatal dimension of mental ill-health. The involvement of genetic risk factors in suicidal behaviour is supported by family, twin, and adoption studies. The aim of this paper is to review recent genetic association studies in suicidal behaviours including (i case-control studies, (ii family-based association studies and (iii genome-wide association studies (GWAS. Various studies on genetic associations have tended to suggest that a number of genes (e.g., tryptophan hydroxylase, serotonin receptors and transporters or brain-derived neurotrophic factors are linked to suicidal behaviours, but these findings are not consistently supported by the results obtained. Although the candidate-gene approach is useful, it is hampered by the present state of knowledge concerning the pathophysiology of diseases. Interpretations of GWAS results are mostly hindered by a lack of annotation describing the functions of most variation throughout the genome.Association studies have addressed a wide range of SNPs in numerous genes. We have included 104 such studies, of which 10 are family-based association studies and 11 are GWAS studies. Numerous meta-analyses of case-control studies have shown significant associations of suicidal behaviour with variants in the serotonin transporter gene (5-HTT or SLC6A4 and the tryptophane hydroxylase1 gene (TPH1, but others report contradictory results. The gene encoding brain-derived neurotrophic factor (BDNF and its receptor (NTRK2 are also promising candidates. Only two of the GWAS studies showed any significant associations. Several pathways are mentioned in an attempt to understand the lack of reproducibility and the disappointing results. Consequently, we review and discuss here the following aspects: (i sample characteristics and confounding factors; (ii statistical limits; (iii gene-gene interactions; (iv gene

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

Science.gov (United States)

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.

A Follow-up Association Study of Genetic Variants for Bone Mineral Density in a Korean Population

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Seokjin Ham

2014-09-01

Full Text Available Bone mineral density (BMD is one of the quantitative traits that are genetically inherited and affected by various factors. Over the past years, genome-wide association studies (GWASs have searched for many genetic loci that influence BMD. A recent meta-analysis of 17 GWASs for BMD of the femoral neck and lumbar spine is the largest GWAS for BMD to date and offers 64 single-nucleotide polymorphisms (SNPs in 56 associated loci. We investigated these BMD loci in a Korean population called Korea Association REsource (KARE to identify their validity in an independent study. The KARE population contains genotypes from 8,842 individuals, and their BMD levels were measured at the distal radius (BMD-RT and midshaft tibia (BMD-TT. Thirteen genomic loci among 56 loci were significantly associated with BMD variations, and 3 loci were involved in known biological pathways related to BMD. In order to find putative functional variants, nearby SNPs in relation to linkage equilibrium were annotated, and their possible functional effects were predicted. These findings reveal that tens of variants, not a single factor, may contribute to the genetic architecture of BMD; have an important role regardless of ethnic group; and may highlight the importance of a replication study in GWASs to validate genuine loci for BMD variation.

Covariance Association Test (CVAT) Identifies Genetic Markers Associated with Schizophrenia in Functionally Associated Biological Processes

DEFF Research Database (Denmark)

Rohde, Palle Duun; Demontis, Ditte; Castro Dias Cuyabano, Beatriz

2016-01-01

was among the top performers. When extending CVAT to utilize a mixture of SNP effects, we found an increase in power to detect the causal sets. Applying the methods to a Danish schizophrenia case–control data set, we found genomic evidence for association of schizophrenia with vitamin A metabolism......Schizophrenia is a psychiatric disorder with large personal and social costs, and understanding the genetic etiology is important. Such knowledge can be obtained by testing the association between a disease phenotype and individual genetic markers; however, such single-marker methods have limited...... genomic best linear unbiased prediction (GBLUP), the covariance association test (CVAT). We compared the performance of CVAT to other commonly used set tests. The comparison was conducted using a simulated study population having the same genetic parameters as for schizophrenia. We found that CVAT...

Association of functional MMP-2 gene variant with intracranial aneurysms: case-control genetic association study and meta-analysis.

Science.gov (United States)

Alg, Varinder S; Ke, Xiayi; Grieve, Joan; Bonner, Stephen; Walsh, Daniel C; Bulters, Diederik; Kitchen, Neil; Houlden, Henry; Werring, David J

2018-01-15

Abnormalities in Matrix Metalloproteinase (MMP) genes, which are important in extracellular matrix (ECM) maintenance and therefore arterial wall integrity are a plausible underlying mechanism of intracranial aneurysm (IA) formation, growth and subsequent rupture. We investigated whether the rs243865 C > T SNP (single nucleotide polymorphism) within the MMP-2 gene (which influences gene transcription) is associated with IA compared to matched controls. We conducted a case-control genetic association study, adjusted for known IA risk factors (smoking and hypertension), in a UK Caucasian population of 1409 patients with intracranial aneurysms (IA), and 1290 matched controls, to determine the association of the rs243865 C > T functional MMP-2 gene SNP with IA (overall, and classified as ruptured and unruptured). We also undertook a meta-analysis of two previous studies examining this SNP. The rs243865 T allele was associated with IA presence in univariate (OR 1.18 [95% CI 1.04-1.33], p = .01) and in multi-variable analyses adjusted for smoking and hypertension status (OR 1.16 [95% CI 1.01-1.35], p = .042). Subgroup analysis demonstrated an association of the rs243865 SNP with ruptured IA (OR 1.18 [95% CI 1.03-1.34] p = .017), but, not unruptured IA (OR 1.17 [95% CI 0.97-1.42], p = .11). Our study demonstrated an association between the functional MMP-2 rs243865 variant and IAs. Our findings suggest a genetic role for altered extracellular matrix integrity in the pathogenesis of IA development and rupture.

Moving into a new era of periodontal genetic studies: relevance of large case-control samples using severe phenotypes for genome-wide association studies.

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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.

Smoking and caffeine consumption: a genetic analysis of their association.

Science.gov (United States)

Treur, Jorien L; Taylor, Amy E; Ware, Jennifer J; Nivard, Michel G; Neale, Michael C; McMahon, George; Hottenga, Jouke-Jan; Baselmans, Bart M L; Boomsma, Dorret I; Munafò, Marcus R; Vink, Jacqueline M

2017-07-01

Smoking and caffeine consumption show a strong positive correlation, but the mechanism underlying this association is unclear. Explanations include shared genetic/environmental factors or causal effects. This study employed three methods to investigate the association between smoking and caffeine. First, bivariate genetic models were applied to data of 10 368 twins from the Netherlands Twin Register in order to estimate genetic and environmental correlations between smoking and caffeine use. Second, from the summary statistics of meta-analyses of genome-wide association studies on smoking and caffeine, the genetic correlation was calculated by LD-score regression. Third, causal effects were tested using Mendelian randomization analysis in 6605 Netherlands Twin Register participants and 5714 women from the Avon Longitudinal Study of Parents and Children. Through twin modelling, a genetic correlation of r0.47 and an environmental correlation of r0.30 were estimated between current smoking (yes/no) and coffee use (high/low). Between current smoking and total caffeine use, this was r0.44 and r0.00, respectively. LD-score regression also indicated sizeable genetic correlations between smoking and coffee use (r0.44 between smoking heaviness and cups of coffee per day, r0.28 between smoking initiation and coffee use and r0.25 between smoking persistence and coffee use). Consistent with the relatively high genetic correlations and lower environmental correlations, Mendelian randomization provided no evidence for causal effects of smoking on caffeine or vice versa. Genetic factors thus explain most of the association between smoking and caffeine consumption. These findings suggest that quitting smoking may be more difficult for heavy caffeine consumers, given their genetic susceptibility. © 2016 The Authors.Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.

SecureMA: protecting participant privacy in genetic association meta-analysis.

Science.gov (United States)

Xie, Wei; Kantarcioglu, Murat; Bush, William S; Crawford, Dana; Denny, Joshua C; Heatherly, Raymond; Malin, Bradley A

2014-12-01

Sharing genomic data is crucial to support scientific investigation such as genome-wide association studies. However, recent investigations suggest the privacy of the individual participants in these studies can be compromised, leading to serious concerns and consequences, such as overly restricted access to data. We introduce a novel cryptographic strategy to securely perform meta-analysis for genetic association studies in large consortia. Our methodology is useful for supporting joint studies among disparate data sites, where privacy or confidentiality is of concern. We validate our method using three multisite association studies. Our research shows that genetic associations can be analyzed efficiently and accurately across substudy sites, without leaking information on individual participants and site-level association summaries. Our software for secure meta-analysis of genetic association studies, SecureMA, is publicly available at http://github.com/XieConnect/SecureMA. Our customized secure computation framework is also publicly available at http://github.com/XieConnect/CircuitService. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

A possible genetic association with chronic fatigue in primary Sjögren's syndrome: a candidate gene study.

Science.gov (United States)

Norheim, Katrine Brække; Le Hellard, Stephanie; Nordmark, Gunnel; Harboe, Erna; Gøransson, Lasse; Brun, Johan G; Wahren-Herlenius, Marie; Jonsson, Roland; Omdal, Roald

2014-02-01

Fatigue is prevalent and disabling in primary Sjögren's syndrome (pSS). Results from studies in chronic fatigue syndrome (CFS) indicate that genetic variation may influence fatigue. The aim of this study was to investigate single nucleotide polymorphism (SNP) variations in pSS patients with high and low fatigue. A panel of 85 SNPs in 12 genes was selected based on previous studies in CFS. A total of 207 pSS patients and 376 healthy controls were genotyped. One-hundred and ninety-three patients and 70 SNPs in 11 genes were available for analysis after quality control. Patients were dichotomized based on fatigue visual analogue scale (VAS) scores, with VAS fatigue" (n = 53) and VAS ≥50 denominated "high fatigue" (n = 140). We detected signals of association with pSS for one SNP in SLC25A40 (unadjusted p = 0.007) and two SNPs in PKN1 (both p = 0.03) in our pSS case versus control analysis. The association with SLC25A40 was stronger when only pSS high fatigue patients were analysed versus controls (p = 0.002). One SNP in PKN1 displayed an association in the case-only analysis of pSS high fatigue versus pSS low fatigue (p = 0.005). This candidate gene study in pSS did reveal a trend for associations between genetic variation in candidate genes and fatigue. The results will need to be replicated. More research on genetic associations with fatigue is warranted, and future trials should include larger cohorts and multicentre collaborations with sharing of genetic material to increase the statistical power.

Genetic diversity, population structure and marker trait associations ...

Indian Academy of Sciences (India)

Supplementary data: Genetic diversity, population structure and marker trait associations for seed quality traits in cotton (Gossypium hirsutum). Ashok Badigannavar and Gerald O. Myers. J. Genet. 94, 87–94. Table 1. List of cotton germplasm lines used in this study. Germplasm no. Cultivar. Region. Germplasm no. Cultivar.

The Impact of Diagnostic Code Misclassification on Optimizing the Experimental Design of Genetic Association Studies

Directory of Open Access Journals (Sweden)

Steven J. Schrodi

2017-01-01

Full Text Available Diagnostic codes within electronic health record systems can vary widely in accuracy. It has been noted that the number of instances of a particular diagnostic code monotonically increases with the accuracy of disease phenotype classification. As a growing number of health system databases become linked with genomic data, it is critically important to understand the effect of this misclassification on the power of genetic association studies. Here, I investigate the impact of this diagnostic code misclassification on the power of genetic association studies with the aim to better inform experimental designs using health informatics data. The trade-off between (i reduced misclassification rates from utilizing additional instances of a diagnostic code per individual and (ii the resulting smaller sample size is explored, and general rules are presented to improve experimental designs.

Incorporating Functional Genomic Information in Genetic Association Studies Using an Empirical Bayes Approach.

Science.gov (United States)

Spencer, Amy V; Cox, Angela; Lin, Wei-Yu; Easton, Douglas F; Michailidou, Kyriaki; Walters, Kevin

2016-04-01

There is a large amount of functional genetic data available, which can be used to inform fine-mapping association studies (in diseases with well-characterised disease pathways). Single nucleotide polymorphism (SNP) prioritization via Bayes factors is attractive because prior information can inform the effect size or the prior probability of causal association. This approach requires the specification of the effect size. If the information needed to estimate a priori the probability density for the effect sizes for causal SNPs in a genomic region isn't consistent or isn't available, then specifying a prior variance for the effect sizes is challenging. We propose both an empirical method to estimate this prior variance, and a coherent approach to using SNP-level functional data, to inform the prior probability of causal association. Through simulation we show that when ranking SNPs by our empirical Bayes factor in a fine-mapping study, the causal SNP rank is generally as high or higher than the rank using Bayes factors with other plausible values of the prior variance. Importantly, we also show that assigning SNP-specific prior probabilities of association based on expert prior functional knowledge of the disease mechanism can lead to improved causal SNPs ranks compared to ranking with identical prior probabilities of association. We demonstrate the use of our methods by applying the methods to the fine mapping of the CASP8 region of chromosome 2 using genotype data from the Collaborative Oncological Gene-Environment Study (COGS) Consortium. The data we analysed included approximately 46,000 breast cancer case and 43,000 healthy control samples. © 2016 The Authors. *Genetic Epidemiology published by Wiley Periodicals, Inc.

Genetic pleiotropy explains associations between musical auditory discrimination and intelligence.

Science.gov (United States)

Mosing, Miriam A; Pedersen, Nancy L; Madison, Guy; Ullén, Fredrik

2014-01-01

Musical aptitude is commonly measured using tasks that involve discrimination of different types of musical auditory stimuli. Performance on such different discrimination tasks correlates positively with each other and with intelligence. However, no study to date has explored these associations using a genetically informative sample to estimate underlying genetic and environmental influences. In the present study, a large sample of Swedish twins (N = 10,500) was used to investigate the genetic architecture of the associations between intelligence and performance on three musical auditory discrimination tasks (rhythm, melody and pitch). Phenotypic correlations between the tasks ranged between 0.23 and 0.42 (Pearson r values). Genetic modelling showed that the covariation between the variables could be explained by shared genetic influences. Neither shared, nor non-shared environment had a significant effect on the associations. Good fit was obtained with a two-factor model where one underlying shared genetic factor explained all the covariation between the musical discrimination tasks and IQ, and a second genetic factor explained variance exclusively shared among the discrimination tasks. The results suggest that positive correlations among musical aptitudes result from both genes with broad effects on cognition, and genes with potentially more specific influences on auditory functions.

Epigenome-wide association study of DNA methylation in narcolepsy: an integrated genetic and epigenetic approach.

Science.gov (United States)

Shimada, Mihoko; Miyagawa, Taku; Toyoda, Hiromi; Tokunaga, Katsushi; Honda, Makoto

2018-04-01

Narcolepsy with cataplexy, which is a hypersomnia characterized by excessive daytime sleepiness and cataplexy, is a multifactorial disease caused by both genetic and environmental factors. Several genetic factors including HLA-DQB1*06:02 have been identified; however, the disease etiology is still unclear. Epigenetic modifications, such as DNA methylation, have been suggested to play an important role in the pathogenesis of complex diseases. Here, we examined DNA methylation profiles of blood samples from narcolepsy and healthy control individuals and performed an epigenome-wide association study (EWAS) to investigate methylation loci associated with narcolepsy. Moreover, data from the EWAS and a previously performed narcolepsy genome-wide association study were integrated to search for methylation loci with causal links to the disease. We found that (1) genes annotated to the top-ranked differentially methylated positions (DMPs) in narcolepsy were associated with pathways of hormone secretion and monocarboxylic acid metabolism. (2) Top-ranked narcolepsy-associated DMPs were significantly more abundant in non-CpG island regions and more than 95 per cent of such sites were hypomethylated in narcolepsy patients. (3) The integrative analysis identified the CCR3 region where both a single methylation site and multiple single-nucleotide polymorphisms were found to be associated with the disease as a candidate region responsible for narcolepsy. The findings of this study suggest the importance of future replication studies, using methylation technologies with wider genome coverage and/or larger number of samples, to confirm and expand on these results.

Signature of genetic associations in oral cancer.

Science.gov (United States)

Sharma, Vishwas; Nandan, Amrita; Sharma, Amitesh Kumar; Singh, Harpreet; Bharadwaj, Mausumi; Sinha, Dhirendra Narain; Mehrotra, Ravi

2017-10-01

Oral cancer etiology is complex and controlled by multi-factorial events including genetic events. Candidate gene studies, genome-wide association studies, and next-generation sequencing identified various chromosomal loci to be associated with oral cancer. There is no available review that could give us the comprehensive picture of genetic loci identified to be associated with oral cancer by candidate gene studies-based, genome-wide association studies-based, and next-generation sequencing-based approaches. A systematic literature search was performed in the PubMed database to identify the loci associated with oral cancer by exclusive candidate gene studies-based, genome-wide association studies-based, and next-generation sequencing-based study approaches. The information of loci associated with oral cancer is made online through the resource "ORNATE." Next, screening of the loci validated by candidate gene studies and next-generation sequencing approach or by two independent studies within candidate gene studies or next-generation sequencing approaches were performed. A total of 264 loci were identified to be associated with oral cancer by candidate gene studies, genome-wide association studies, and next-generation sequencing approaches. In total, 28 loci, that is, 14q32.33 (AKT1), 5q22.2 (APC), 11q22.3 (ATM), 2q33.1 (CASP8), 11q13.3 (CCND1), 16q22.1 (CDH1), 9p21.3 (CDKN2A), 1q31.1 (COX-2), 7p11.2 (EGFR), 22q13.2 (EP300), 4q35.2 (FAT1), 4q31.3 (FBXW7), 4p16.3 (FGFR3), 1p13.3 (GSTM1-GSTT1), 11q13.2 (GSTP1), 11p15.5 (H-RAS), 3p25.3 (hOGG1), 1q32.1 (IL-10), 4q13.3 (IL-8), 12p12.1 (KRAS), 12q15 (MDM2), 12q13.12 (MLL2), 9q34.3 (NOTCH1), 17p13.1 (p53), 3q26.32 (PIK3CA), 10q23.31 (PTEN), 13q14.2 (RB1), and 5q14.2 (XRCC4), were validated to be associated with oral cancer. "ORNATE" gives a snapshot of genetic loci associated with oral cancer. All 28 loci were validated to be linked to oral cancer for which further fine-mapping followed by gene-by-gene and gene

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

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)

Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes.

Science.gov (United States)

Miller, F W; Chen, W; O'Hanlon, T P; Cooper, R G; Vencovsky, J; Rider, L G; Danko, K; Wedderburn, L R; Lundberg, I E; Pachman, L M; Reed, A M; Ytterberg, S R; Padyukov, L; Selva-O'Callaghan, A; Radstake, T R; Isenberg, D A; Chinoy, H; Ollier, W E R; Scheet, P; Peng, B; Lee, A; Byun, J; Lamb, J A; Gregersen, P K; Amos, C I

2015-10-01

Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (Pmyositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.

Association between Genetic Variants and Diabetes Mellitus in Iranian Populations: A Systematic Review of Observational Studies

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Khodaeian, Mehrnoosh; Enayati, Samaneh; Tabatabaei-Malazy, Ozra; Amoli, Mahsa M.

2015-01-01

Introduction. Diabetes mellitus as the most prevalent metabolic disease is a multifactorial disease which is influenced by environmental and genetic factors. In this systematic review, we assessed the association between genetic variants and diabetes/its complications in studies with Iranian populations. Methods. Google Scholar, PubMed, Scopus, and Persian web databases were systematically searched up to January 2014. The search terms were “gene,” “polymorphism,” “diabetes,” and “diabetic complications”; nephropathy, retinopathy, neuropathy, foot ulcer, and CAD (coronary artery diseases); and Persian equivalents. Animal studies, letters to editor, and in vitro studies were excluded. Results. Out of overall 3029 eligible articles, 88 articles were included. We found significant association between CTLA-4, IL-18, VDR, TAP2, IL-12, and CD4 genes and T1DM, HNFα and MODY, haptoglobin, paraoxonase, leptin, TCF7L2, calreticulin, ERα, PPAR-γ2, CXCL5, calpain-10, IRS-1 and 2, GSTM1, KCNJ11, eNOS, VDR, INSR, ACE, apoA-I, apo E, adiponectin, PTPN1, CETP, AT1R, resistin, MMP-3, BChE K, AT2R, SUMO4, IL-10, VEGF, MTHFR, and GSTM1 with T2DM or its complications. Discussion. We found some controversial results due to heterogeneity in ethnicity and genetic background. We thought genome wide association studies on large number of samples will be helpful in identifying diabetes susceptible genes as an alternative to studying individual candidate genes in Iranian populations. PMID:26587547

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

Childhood constipation; an overview of genetic studies and associated syndromes

NARCIS (Netherlands)

Peeters, B.; Benninga, M. A.; Hennekam, R. C.

2011-01-01

Constipation is a common problem in children but little is known about its exact pathophysiology. Environmental, behavioural but also genetic factors are thought to play a role in the aetiology of childhood constipation. We provide an overview of genetic studies performed in constipation. Until now,

Evolving temporal association rules with genetic algorithms

OpenAIRE

Matthews, Stephen G.; Gongora, Mario A.; Hopgood, Adrian A.

2010-01-01

A novel framework for mining temporal association rules by discovering itemsets with a genetic algorithm is introduced. Metaheuristics have been applied to association rule mining, we show the efficacy of extending this to another variant - temporal association rule mining. Our framework is an enhancement to existing temporal association rule mining methods as it employs a genetic algorithm to simultaneously search the rule space and temporal space. A methodology for validating the ability of...

Association between Genetic Variants and Diabetes Mellitus in Iranian Populations: A Systematic Review of Observational Studies

Directory of Open Access Journals (Sweden)

Mehrnoosh Khodaeian

2015-01-01

Full Text Available Introduction. Diabetes mellitus as the most prevalent metabolic disease is a multifactorial disease which is influenced by environmental and genetic factors. In this systematic review, we assessed the association between genetic variants and diabetes/its complications in studies with Iranian populations. Methods. Google Scholar, PubMed, Scopus, and Persian web databases were systematically searched up to January 2014. The search terms were “gene,” “polymorphism,” “diabetes,” and “diabetic complications”; nephropathy, retinopathy, neuropathy, foot ulcer, and CAD (coronary artery diseases; and Persian equivalents. Animal studies, letters to editor, and in vitro studies were excluded. Results. Out of overall 3029 eligible articles, 88 articles were included. We found significant association between CTLA-4, IL-18, VDR, TAP2, IL-12, and CD4 genes and T1DM, HNFα and MODY, haptoglobin, paraoxonase, leptin, TCF7L2, calreticulin, ERα, PPAR-γ2, CXCL5, calpain-10, IRS-1 and 2, GSTM1, KCNJ11, eNOS, VDR, INSR, ACE, apoA-I, apo E, adiponectin, PTPN1, CETP, AT1R, resistin, MMP-3, BChE K, AT2R, SUMO4, IL-10, VEGF, MTHFR, and GSTM1 with T2DM or its complications. Discussion. We found some controversial results due to heterogeneity in ethnicity and genetic background. We thought genome wide association studies on large number of samples will be helpful in identifying diabetes susceptible genes as an alternative to studying individual candidate genes in Iranian populations.

Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy.

Directory of Open Access Journals (Sweden)

Klaus Stark

2010-10-01

Full Text Available Dilated cardiomyopathy (DCM is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39% and idiopathic DCM (p = 1.06 × 10⁻⁶, OR  = 0.67 [95% CI 0.57-0.79] for the minor allele T. Three more SNPs showed p < 2.21 × 10⁻⁵. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n =564, n = 981 controls, p = 2.07 × 10⁻³, OR = 0.79 [95% CI 0.67-0.92], France 1 (n = 433 cases, n = 395 controls, p =3.73 × 10⁻³, OR  = 0.74 [95% CI 0.60-0.91], and France 2 (n = 249 cases, n = 380 controls, p = 2.26 × 10⁻⁴, OR  = 0.63 [95% CI 0.50-0.81]. The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28 × 10⁻¹³, OR= 0.72 [95% CI 0.65-0.78]. None of the other three SNPs showed significant results in the replication stage.This finding of the HSPB7 gene from a genetic search for idiopathic DCM using

Genetic and Non-genetic Factors Associated WithConstipation in Cancer Patients Receiving Opioids

OpenAIRE

Laugsand, Eivor Alette; Skorpen, Frank; Kaasa, Stein; Sabatowski, Rainer; Strasser, Florian; Fayers, Peter; Klepstad, Pål

2015-01-01

Objectives: To examine whether the inter-individual variation in constipation among patients receiving opioids for cancer pain is associated with genetic or non-genetic factors. Methods: Cancer patients receiving opioids were included from 17 centers in 11 European countries. Intensity of constipation was reported by 1,568 patients on a four-point categorical scale. Non-genetic factors were included as covariates in stratified regression analyses on the association between constipation a...

Genetic association studies of glutamate, GABA and related genes in schizophrenia and bipolar disorder: a decade of advance.

Science.gov (United States)

Cherlyn, Suat Ying Tan; Woon, Puay San; Liu, Jian Jun; Ong, Wei Yi; Tsai, Guo Chuan; Sim, Kang

2010-05-01

Schizophrenia (SZ) and bipolar disorder (BD) are debilitating neurobehavioural disorders likely influenced by genetic and non-genetic factors and which can be seen as complex disorders of synaptic neurotransmission. The glutamatergic and GABAergic neurotransmission systems have been implicated in both diseases and we have reviewed extensive literature over a decade for evidence to support the association of glutamate and GABA genes in SZ and BD. Candidate-gene based population and family association studies have implicated some ionotrophic glutamate receptor genes (GRIN1, GRIN2A, GRIN2B and GRIK3), metabotropic glutamate receptor genes (such as GRM3), the G72/G30 locus and GABAergic genes (e.g. GAD1 and GABRB2) in both illnesses to varying degrees, but further replication studies are needed to validate these results. There is at present no consensus on specific single nucleotide polymorphisms or haplotypes associated with the particular candidate gene loci in these illnesses. The genetic architecture of glutamate systems in bipolar disorder need to be better studied in view of recent data suggesting an overlap in the genetic aetiology of SZ and BD. There is a pressing need to integrate research platforms in genomics, epistatic models, proteomics, metabolomics, neuroimaging technology and translational studies in order to allow a more integrated understanding of glutamate and GABAergic signalling processes and aberrations in SZ and BD as well as their relationships with clinical presentations and treatment progress over time. (c) 2010 Elsevier Ltd. All rights reserved.

Preliminary genetic imaging study of the association between estrogen receptor-α gene polymorphisms and harsh human maternal parenting.

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Lahey, Benjamin B; Michalska, Kalina J; Liu, Chunyu; Chen, Qi; Hipwell, Alison E; Chronis-Tuscano, Andrea; Waldman, Irwin D; Decety, Jean

2012-09-06

A failure of neural changes initiated by the estrogen surge in late pregnancy to reverse the valence of infant stimuli from aversive to rewarding is associated with dysfunctional maternal behavior in nonhuman mammals. Estrogen receptor-α plays the crucial role in mediating these neural effects of estrogen priming. This preliminary study examines associations between estrogen receptor-α gene polymorphisms and human maternal behavior. Two polymorphisms were associated with human negative maternal parenting. Furthermore, hemodynamic responses in functional magnetic resonance imaging to child stimuli in neural regions associated with social cognition fully mediated the association between genetic variation and negative parenting. This suggests testable hypotheses regarding a biological pathway between genetic variants and dysfunctional human maternal parenting. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

A generalized Kruskal-Wallis test incorporating group uncertainty with application to genetic association studies.

Science.gov (United States)

Acar, Elif F; Sun, Lei

2013-06-01

Motivated by genetic association studies of SNPs with genotype uncertainty, we propose a generalization of the Kruskal-Wallis test that incorporates group uncertainty when comparing k samples. The extended test statistic is based on probability-weighted rank-sums and follows an asymptotic chi-square distribution with k - 1 degrees of freedom under the null hypothesis. Simulation studies confirm the validity and robustness of the proposed test in finite samples. Application to a genome-wide association study of type 1 diabetic complications further demonstrates the utilities of this generalized Kruskal-Wallis test for studies with group uncertainty. The method has been implemented as an open-resource R program, GKW. © 2013, The International Biometric Society.

Associations of Fitness, Physical Activity, Strength, and Genetic Risk With Cardiovascular Disease: Longitudinal Analyses in the UK Biobank Study.

Science.gov (United States)

Tikkanen, Emmi; Gustafsson, Stefan; Ingelsson, Erik

2018-04-09

Background -Observational studies have shown inverse associations among fitness, physical activity, and cardiovascular disease. However, little is known about these associations in individuals with elevated genetic susceptibility for these diseases. Methods -We estimated associations of grip strength, objective and subjective physical activity, and cardiorespiratory fitness with cardiovascular events and all-cause death in a large cohort of 502635 individuals from the UK Biobank (median follow-up, 6.1 years; interquartile range, 5.4-6.8 years). Then we further examined these associations in individuals with different genetic burden by stratifying individuals based on their genetic risk scores for coronary heart disease and atrial fibrillation. We compared disease risk among individuals in different tertiles of fitness, physical activity, and genetic risk using lowest tertiles as reference. Results -Grip strength, physical activity, and cardiorespiratory fitness showed inverse associations with incident cardiovascular events (coronary heart disease: hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.77- 0.81; HR, 0.95; 95% CI, 0.93-0.97; and HR, 0.68; 95% CI, 0.63-0.74, per SD change, respectively; atrial fibrillation: HR, 0.75; 95% CI, 0.73- 0.76; HR, 0.93; 95% CI, 0.91-0.95; and HR, 0.60; 95% CI, 0.56-0.65, per SD change, respectively). Higher grip strength and cardiorespiratory fitness were associated with lower risk of incident coronary heart disease and atrial fibrillation in each genetic risk score group ( P trend fitness were associated with 49% lower risk for coronary heart disease (HR, 0.51; 95% CI, 0.38-0.69) and 60% lower risk for atrial fibrillation (HR, 0.40; 95%, CI 0.30-0.55) among individuals at high genetic risk for these diseases. Conclusions - Fitness and physical activity demonstrated inverse associations with incident cardiovascular disease in the general population, as well as in individuals with elevated genetic risk for these diseases.

Association Study of Common Genetic Variants and HIV-1 Acquisition in 6,300 Infected Cases and 7,200 Controls

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Ripke, Stephan; van den Berg, Leonard; Buchbinder, Susan; Carrington, Mary; Cossarizza, Andrea; Dalmau, Judith; Deeks, Steven G.; Delaneau, Olivier; De Luca, Andrea; Goedert, James J.; Haas, David; Herbeck, Joshua T.; Kathiresan, Sekar; Kirk, Gregory D.; Lambotte, Olivier; Luo, Ma; Mallal, Simon; van Manen, Daniëlle; Martinez-Picado, Javier; Meyer, Laurence; Miro, José M.; Mullins, James I.; Obel, Niels; O'Brien, Stephen J.; Pereyra, Florencia; Plummer, Francis A.; Poli, Guido; Qi, Ying; Rucart, Pierre; Sandhu, Manj S.; Shea, Patrick R.; Schuitemaker, Hanneke; Theodorou, Ioannis; Vannberg, Fredrik; Veldink, Jan; Walker, Bruce D.; Weintrob, Amy; Winkler, Cheryl A.; Wolinsky, Steven; Telenti, Amalio; Goldstein, David B.; de Bakker, Paul I. W.; Zagury, Jean-François; Fellay, Jacques

2013-01-01

Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6×10−11). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size. PMID:23935489

Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls.

Directory of Open Access Journals (Sweden)

Paul J McLaren

Full Text Available Multiple genome-wide association studies (GWAS have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1. After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6 × 10⁻¹¹. However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity. Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.

Genetics of Infectious and Inflammatory Diseases: Overlapping Discoveries from Association and Exome-Sequencing Studies.

Science.gov (United States)

Langlais, David; Fodil, Nassima; Gros, Philippe

2017-04-26

Genome technologies have defined a complex genetic architecture in major infectious, inflammatory, and autoimmune disorders. High density marker arrays and Immunochips have powered genome-wide association studies (GWAS) that have mapped nearly 450 genetic risk loci in 22 major inflammatory diseases, including a core of common genes that play a central role in pathological inflammation. Whole-exome and whole-genome sequencing have identified more than 265 genes in which mutations cause primary immunodeficiencies and rare forms of severe inflammatory bowel disease. Combined analysis of inflammatory disease GWAS and primary immunodeficiencies point to shared proteins and pathways that are required for immune cell development and protection against infections and are also associated with pathological inflammation. Finally, sequencing of chromatin immunoprecipitates containing specific transcription factors, with parallel RNA sequencing, has charted epigenetic regulation of gene expression by proinflammatory transcription factors in immune cells, providing complementary information to characterize morbid genes at infectious and inflammatory disease loci.

Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.

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Christian Gieger

2008-11-01

Full Text Available The rapidly evolving field of metabolomics aims at a comprehensive measurement of ideally all endogenous metabolites in a cell or body fluid. It thereby provides a functional readout of the physiological state of the human body. Genetic variants that associate with changes in the homeostasis of key lipids, carbohydrates, or amino acids are not only expected to display much larger effect sizes due to their direct involvement in metabolite conversion modification, but should also provide access to the biochemical context of such variations, in particular when enzyme coding genes are concerned. To test this hypothesis, we conducted what is, to the best of our knowledge, the first GWA study with metabolomics based on the quantitative measurement of 363 metabolites in serum of 284 male participants of the KORA study. We found associations of frequent single nucleotide polymorphisms (SNPs with considerable differences in the metabolic homeostasis of the human body, explaining up to 12% of the observed variance. Using ratios of certain metabolite concentrations as a proxy for enzymatic activity, up to 28% of the variance can be explained (p-values 10(-16 to 10(-21. We identified four genetic variants in genes coding for enzymes (FADS1, LIPC, SCAD, MCAD where the corresponding metabolic phenotype (metabotype clearly matches the biochemical pathways in which these enzymes are active. Our results suggest that common genetic polymorphisms induce major differentiations in the metabolic make-up of the human population. This may lead to a novel approach to personalized health care based on a combination of genotyping and metabolic characterization. These genetically determined metabotypes may subscribe the risk for a certain medical phenotype, the response to a given drug treatment, or the reaction to a nutritional intervention or environmental challenge.

[Enlightenment from genome-wide association study to genetics of psoriasis].

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ZHANG, Xue-jun

2009-07-01

Psoriasis is a common autoimmune and hyper proliferative skin disease, characterized by thick, silvery scale patches. Numerous family studies have provided compelling evidence of a genetic predisposition to psoriasis, although the inheritance pattern is unclear. However, few of these studies have achieved consistent results, except for the MHC locus, a problem frequently encountered in the investigation of complex disease. Using high-throughput techniques to genotype hundreds of thousands of single nucleotide polymorphisms explore their relationship with phenotypes, genome-wide association studies (GWAS) are now proven to be a powerful approach for screening the susceptibility genes (loci) of complex disease. Recently, three GWAS on psoriasis published in Nature Genetics have provided us with many novel clues concerning disease pathogenesis, in both immune and non-immune pathways. The MHC locus (HLA-Cw6 and other MHC variance), the major locus involved in the immune reactions of human immune disease, has consistently been shown to be associated with psoriasis, both in previous linkage and present GWAS. IL-12B and IL23R, which are the two non-MHC genes with highly associated evidence with psoriasis in multiple studies performed so far and potent cytokines with complex biological activities, should be of great importance in the pathogenesis of psoriasis. Recent clinical trials, in which anti-IL-12p40 antibodies were used for the treatment of psoriasis, have provided further evidence of the role of IL-12/23 in the pathophysiology of psoriasis,and highlighted a new road of treatment for psoriasis. In 2008,we performed the first large GWAS in the Chinese population and identified a novel susceptibility locus within the late cornified envelope (LCE) gene cluster: LCE3A and LCE3D on chromosome 1q21, with conclusive evidence (rs4085613, p(combined)=6.69*10(-30); odds ratio=0.76). Meanwhile, another group also identified a deletion comprising and LCE gene cluster of LCE3B

Use of modern tomato breeding germplasm for deciphering the genetic control of agronomical traits by Genome Wide Association study.

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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.

Genetic moderation of the association between regulatory focus and reward responsiveness: a proof-of-concept study.

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Goetz, Elena L; Hariri, Ahmad R; Pizzagalli, Diego A; Strauman, Timothy J

2013-02-01

Recent studies implicate individual differences in regulatory focus as contributing to self-regulatory dysfunction, particularly not responding to positive outcomes. How such individual differences emerge, however, is unclear. We conducted a proof-of-concept study to examine the moderating effects of genetically driven variation in dopamine signaling, a key modulator of neural reward circuits, on the association between regulatory focus and reward cue responsiveness. Healthy Caucasians (N=59) completed a measure of chronic regulatory focus and a probabilistic reward task. A common functional genetic polymorphism impacting prefrontal dopamine signaling (COMT rs4680) was evaluated. Response bias, the participants' propensity to modulate behavior as a function of reward, was predicted by an interaction of regulatory focus and COMT genotype. Specifically, self-perceived success at achieving promotion goals predicted total response bias, but only for individuals with the COMT genotype (Val/Val) associated with relatively increased phasic dopamine signaling and cognitive flexibility. The combination of success in promotion goal pursuit and Val/Val genotype appears to facilitate responding to reward opportunities in the environment. This study is among the first to integrate an assessment of self-regulatory style with an examination of genetic variability that underlies responsiveness to positive outcomes in goal pursuit.

A Generalized Kruskal-Wallis Test Incorporating Group Uncertainty with Application to Genetic Association Studies

OpenAIRE

Acar, Elif F.; Sun, Lei

2012-01-01

Motivated by genetic association studies of SNPs with genotype uncertainty, we propose a generalization of the Kruskal-Wallis test that incorporates group uncertainty when comparing k samples. The extended test statistic is based on probability-weighted rank-sums and follows an asymptotic chi-square distribution with k-1 degrees of freedom under the null hypothesis. Simulation studies confirm the validity and robustness of the proposed test in finite samples. Application to a genome-wide asso...

Novel genetic loci associated with hippocampal volume

OpenAIRE

Hibar, Derrek P.; Adams, Hieab H. H.; Jahanshad, Neda; Chauhan, Ganesh; Stein, Jason L.; Hofer, Edith; Renteria, Miguel E.; Bis, Joshua C.; Arias-Vasquez, Alejandro; Ikram, M. Kamran; Desrivieres, Sylvane; Vernooij, Meike W.; Abramovic, Lucija; Alhusaini, Saud; Amin, Najaf

2017-01-01

International audience; The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal ...

Reader Reaction On the generalized Kruskal-Wallis test for genetic association studies incorporating group uncertainty

OpenAIRE

Wu, Baolin; Guan, Weihua

2014-01-01

Acar and Sun (2013, Biometrics, 69, 427-435) presented a generalized Kruskal-Wallis (GKW) test for genetic association studies that incorporated the genotype uncertainty and showed its robust and competitive performance compared to existing methods. We present another interesting way to derive the GKW test via a rank linear model.

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

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

2018-01-01

Abstract Genome-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 determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother–child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10−8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights. PMID:29309628

Sequence imputation of HPV16 genomes for genetic association studies.

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Benjamin Smith

Full Text Available Human Papillomavirus type 16 (HPV16 causes over half of all cervical cancer and some HPV16 variants are more oncogenic than others. The genetic basis for the extraordinary oncogenic properties of HPV16 compared to other HPVs is unknown. In addition, we neither know which nucleotides vary across and within HPV types and lineages, nor which of the single nucleotide polymorphisms (SNPs determine oncogenicity.A reference set of 62 HPV16 complete genome sequences was established and used to examine patterns of evolutionary relatedness amongst variants using a pairwise identity heatmap and HPV16 phylogeny. A BLAST-based algorithm was developed to impute complete genome data from partial sequence information using the reference database. To interrogate the oncogenic risk of determined and imputed HPV16 SNPs, odds-ratios for each SNP were calculated in a case-control viral genome-wide association study (VWAS using biopsy confirmed high-grade cervix neoplasia and self-limited HPV16 infections from Guanacaste, Costa Rica.HPV16 variants display evolutionarily stable lineages that contain conserved diagnostic SNPs. The imputation algorithm indicated that an average of 97.5±1.03% of SNPs could be accurately imputed. The VWAS revealed specific HPV16 viral SNPs associated with variant lineages and elevated odds ratios; however, individual causal SNPs could not be distinguished with certainty due to the nature of HPV evolution.Conserved and lineage-specific SNPs can be imputed with a high degree of accuracy from limited viral polymorphic data due to the lack of recombination and the stochastic mechanism of variation accumulation in the HPV genome. However, to determine the role of novel variants or non-lineage-specific SNPs by VWAS will require direct sequence analysis. The investigation of patterns of genetic variation and the identification of diagnostic SNPs for lineages of HPV16 variants provides a valuable resource for future studies of HPV16

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

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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.

Are Associations between Parental Divorce and Children's Adjustment Genetically Mediated? An Adoption Study.

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O'Connor, Thomas G.; Caspi, Avshalom; DeFries, John C.; Plomin, Robert

2000-01-01

Data from Colorado Adoption Project were used to examine hypothesis that association between parental divorce and children's adjustment is mediated by genetic factors. Findings for psychopathology were consistent with an environmentally mediated explanation for the association. Findings for achievement and social adjustment were consistent with a…

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....

Multiple Genetic Associations with Irish Wolfhound Dilated Cardiomyopathy.

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Simpson, Siobhan; Dunning, Mark D; Brownlie, Serena; Patel, Janika; Godden, Megan; Cobb, Malcolm; Mongan, Nigel P; Rutland, Catrin S

2016-01-01

Cardiac disease is a leading cause of morbidity and mortality in dogs and humans, with dilated cardiomyopathy being a large contributor to this. The Irish Wolfhound (IWH) is one of the most commonly affected breeds and one of the few breeds with genetic loci associated with the disease. Mutations in more than 50 genes are associated with human dilated cardiomyopathy (DCM), yet very few are also associated with canine DCM. Furthermore, none of the identified canine loci explain many cases of the disease and previous work has indicated that genotypes at multiple loci may act together to influence disease development. In this study, loci previously associated with DCM in IWH were tested for associations in a new cohort both individually and in combination. We have identified loci significantly associated with the disease individually, but no genotypes individually or in pairs conferred a significantly greater risk of developing DCM than the population risk. However combining three loci together did result in the identification of a genotype which conferred a greater risk of disease than the overall population risk. This study suggests multiple rather than individual genetic factors, cooperating to influence DCM risk in IWH.

Multiple Genetic Associations with Irish Wolfhound Dilated Cardiomyopathy

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Siobhan Simpson

2016-01-01

Full Text Available Cardiac disease is a leading cause of morbidity and mortality in dogs and humans, with dilated cardiomyopathy being a large contributor to this. The Irish Wolfhound (IWH is one of the most commonly affected breeds and one of the few breeds with genetic loci associated with the disease. Mutations in more than 50 genes are associated with human dilated cardiomyopathy (DCM, yet very few are also associated with canine DCM. Furthermore, none of the identified canine loci explain many cases of the disease and previous work has indicated that genotypes at multiple loci may act together to influence disease development. In this study, loci previously associated with DCM in IWH were tested for associations in a new cohort both individually and in combination. We have identified loci significantly associated with the disease individually, but no genotypes individually or in pairs conferred a significantly greater risk of developing DCM than the population risk. However combining three loci together did result in the identification of a genotype which conferred a greater risk of disease than the overall population risk. This study suggests multiple rather than individual genetic factors, cooperating to influence DCM risk in IWH.

Genetic Variants Associated with Circulating Parathyroid Hormone.

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Robinson-Cohen, Cassianne; Lutsey, Pamela L; Kleber, Marcus E; Nielson, Carrie M; Mitchell, Braxton D; Bis, Joshua C; Eny, Karen M; Portas, Laura; Eriksson, Joel; Lorentzon, Mattias; Koller, Daniel L; Milaneschi, Yuri; Teumer, Alexander; Pilz, Stefan; Nethander, Maria; Selvin, Elizabeth; Tang, Weihong; Weng, Lu-Chen; Wong, Hoi Suen; Lai, Dongbing; Peacock, Munro; Hannemann, Anke; Völker, Uwe; Homuth, Georg; Nauk, Matthias; Murgia, Federico; Pattee, Jack W; Orwoll, Eric; Zmuda, Joseph M; Riancho, Jose Antonio; Wolf, Myles; Williams, Frances; Penninx, Brenda; Econs, Michael J; Ryan, Kathleen A; Ohlsson, Claes; Paterson, Andrew D; Psaty, Bruce M; Siscovick, David S; Rotter, Jerome I; Pirastu, Mario; Streeten, Elizabeth; März, Winfried; Fox, Caroline; Coresh, Josef; Wallaschofski, Henri; Pankow, James S; de Boer, Ian H; Kestenbaum, Bryan

2017-05-01

Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies ( n =22,653 and n =6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 ( P =4.2 × 10 -53 ), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 ( P =6.6 × 10 -17 ), rs219779 adjacent to CLDN14 ( P =3.5 × 10 -16 ), rs4443100 near RTDR1 ( P =8.7 × 10 -9 ), and rs73186030 near CASR ( P =4.8 × 10 -8 ). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued. Copyright © 2017 by the American Society of Nephrology.

Education influences the association between genetic variants and refractive error: a meta-analysis of five Singapore studies

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Fan, Qiao; Wojciechowski, Robert; Kamran Ikram, M.; Cheng, Ching-Yu; Chen, Peng; Zhou, Xin; Pan, Chen-Wei; Khor, Chiea-Chuen; Tai, E-Shyong; Aung, Tin; Wong, Tien-Yin; Teo, Yik-Ying; Saw, Seang-Mei

2014-01-01

Refractive error is a complex ocular trait governed by both genetic and environmental factors and possibly their interplay. Thus far, data on the interaction between genetic variants and environmental risk factors for refractive errors are largely lacking. By using findings from recent genome-wide association studies, we investigated whether the main environmental factor, education, modifies the effect of 40 single nucleotide polymorphisms on refractive error among 8461 adults from five studies including ethnic Chinese, Malay and Indian residents of Singapore. Three genetic loci SHISA6-DNAH9, GJD2 and ZMAT4-SFRP1 exhibited a strong association with myopic refractive error in individuals with higher secondary or university education (SHISA6-DNAH9: rs2969180 A allele, β = −0.33 D, P = 3.6 × 10–6; GJD2: rs524952 A allele, β = −0.31 D, P = 1.68 × 10−5; ZMAT4-SFRP1: rs2137277 A allele, β = −0.47 D, P = 1.68 × 10−4), whereas the association at these loci was non-significant or of borderline significance in those with lower secondary education or below (P for interaction: 3.82 × 10−3–4.78 × 10−4). The evidence for interaction was strengthened when combining the genetic effects of these three loci (P for interaction = 4.40 × 10−8), and significant interactions with education were also observed for axial length and myopia. Our study shows that low level of education may attenuate the effect of risk alleles on myopia. These findings further underline the role of gene–environment interactions in the pathophysiology of myopia. PMID:24014484

Replication of genetic associations as pseudoreplication due to shared genealogy.

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Rosenberg, Noah A; Vanliere, Jenna M

2009-09-01

The genotypes of individuals in replicate genetic association studies have some level of correlation due to shared descent in the complete pedigree of all living humans. As a result of this genealogical sharing, replicate studies that search for genotype-phenotype associations using linkage disequilibrium between marker loci and disease-susceptibility loci can be considered as "pseudoreplicates" rather than true replicates. We examine the size of the pseudoreplication effect in association studies simulated from evolutionary models of the history of a population, evaluating the excess probability that both of a pair of studies detect a disease association compared to the probability expected under the assumption that the two studies are independent. Each of nine combinations of a demographic model and a penetrance model leads to a detectable pseudoreplication effect, suggesting that the degree of support that can be attributed to a replicated genetic association result is less than that which can be attributed to a replicated result in a context of true independence.

Role of genetics in infection-associated arthritis.

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Benham, Helen; Robinson, Philip C; Baillet, Athan C; Rehaume, Linda M; Thomas, Ranjeny

2015-04-01

Genetic discoveries in arthritis and their associated biological pathways spanning the innate and adaptive immune system demonstrate the strong association between susceptibility to arthritis and control of exogenous organisms. The canonical theory of the aetiology of immune-mediated arthritis and other immune-mediated diseases is that the introduction of exogenous antigenic stimuli to a genetically susceptible host sets up the environment for an abnormal immune response manifesting as disease. A disruption in host-microbe homeostasis driven by disease-associated genetic variants could ultimately provide the source of exogenous antigen triggering disease development. We discuss genetic variants impacting the innate and adaptive arms of the immune system and their relationship to microbial control and arthritic disease. We go on to consider the evidence for a relationship between HLA-B27, infection and arthritis, and then emerging evidence for an interaction between microbiota and rheumatoid arthritis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Testing for direct genetic effects using a screening step in family-based association studies

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Sharon M Lutz

2013-11-01

Full Text Available In genome wide association studies (GWAS, families based studies tend to have less power to detect genetic associations than population based studies, such as case-control studies. This can be an issue when testing if genes in a family based GWAS have a direct effect on the phenotype of interest or if the genes act indirectly through a secondary phenotype. When multiple SNPs are tested for a direct effect in the family based study, a screening step can be used to minimize the burden of multiple comparisons in the causal analysis. We propose a 2-stage screening step that can be incorporated into the family based association test (FBAT approach similar to the conditional mean model approach in the VanSteen-algorithm [1]. Simulations demonstrate that the type 1 error is preserved and this method is advantageous when multiple markers are tested. This method is illustrated by an application to the Framingham Heart Study.

Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls

DEFF Research Database (Denmark)

McLaren, Paul J; Coulonges, Cédric; Ripke, Stephan

2013-01-01

Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although...... of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6 × 10(-11)). However, restricting analysis to individuals with a known date of seroconversion suggested...... no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size....

Phenotypic and genetic associations between reading and attention-deficit/hyperactivity disorder dimensions in adolescence.

Science.gov (United States)

Plourde, Vickie; Boivin, Michel; Brendgen, Mara; Vitaro, Frank; Dionne, Ginette

2017-10-01

Multiple studies have shown that reading abilities and attention-deficit/hyperactivity disorder symptoms, mainly inattention symptoms, are phenotypically and genetically associated during childhood. However, few studies have looked at these associations during adolescence to investigate possible developmental changes. The aim of the study is to examine the genetic and environmental etiology of the associations between inattention and hyperactivity reported by parents, and reading accuracy, reading speed, and word reading in a population-based twin sample (Quebec Newborn Twin Study). Participants were between 14 and 15 years of age at the time of testing (N = 668-837). Phenotypic results showed that when nonverbal and verbal abilities were controlled, inattention, but not hyperactivity/impulsivity, was a modest and significant predictor of reading accuracy, reading speed, and word reading. The associations between inattention and all reading abilities were partly explained by genetic and unique environmental factors. However, the genetic correlations were no longer significant after controlling for verbal abilities. In midadolescence, inattention is the attention-deficit/hyperactivity disorder dimension associated with reading abilities, but they could also share genetic factors with general verbal skills.

Distinguishing Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia-Associated Mutations From Background Genetic Noise

NARCIS (Netherlands)

Kapplinger, Jamie D.; Landstrom, Andrew P.; Salisbury, Benjamin A.; Callis, Thomas E.; Pollevick, Guido D.; Tester, David J.; Cox, Moniek G. P. J.; Bhuiyan, Zahir; Bikker, Hennie; Wiesfeld, Ans C. P.; Hauer, Richard N. W.; van Tintelen, J. Peter; Jongbloed, Jan D. H.; Calkins, Hugh; Judge, Daniel P.; Wilde, Arthur A. M.; Ackerman, Michael J.

2011-01-01

Objectives The aims of this study were to determine the spectrum and prevalence of "background genetic noise" in the arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC) genetic test and to determine genetic associations that can guide the interpretation of a positive test result.

Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study.

Science.gov (United States)

Allen, Richard J; Porte, Joanne; Braybrooke, Rebecca; Flores, Carlos; Fingerlin, Tasha E; Oldham, Justin M; Guillen-Guio, Beatriz; Ma, Shwu-Fan; Okamoto, Tsukasa; John, Alison E; Obeidat, Ma'en; Yang, Ivana V; Henry, Amanda; Hubbard, Richard B; Navaratnam, Vidya; Saini, Gauri; Thompson, Norma; Booth, Helen L; Hart, Simon P; Hill, Mike R; Hirani, Nik; Maher, Toby M; McAnulty, Robin J; Millar, Ann B; Molyneaux, Philip L; Parfrey, Helen; Rassl, Doris M; Whyte, Moira K B; Fahy, William A; Marshall, Richard P; Oballa, Eunice; Bossé, Yohan; Nickle, David C; Sin, Don D; Timens, Wim; Shrine, Nick; Sayers, Ian; Hall, Ian P; Noth, Imre; Schwartz, David A; Tobin, Martin D; Wain, Louise V; Jenkins, R Gisli

2017-11-01

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high mortality, uncertain cause, and few treatment options. Studies have identified a significant genetic risk associated with the development of IPF; however, mechanisms by which genetic risk factors promote IPF remain unclear. We aimed to identify genetic variants associated with IPF susceptibility and provide mechanistic insight using gene and protein expression analyses. We used a two-stage approach: a genome-wide association study in patients with IPF of European ancestry recruited from nine different centres in the UK and controls selected from UK Biobank (stage 1) matched for age, sex, and smoking status; and a follow-up of associated genetic variants in independent datasets of patients with IPF and controls from two independent US samples from the Chicago consortium and the Colorado consortium (stage 2). We investigated the effect of novel signals on gene expression in large transcriptomic and genomic data resources, and examined expression using lung tissue samples from patients with IPF and controls. 602 patients with IPF and 3366 controls were selected for stage 1. For stage 2, 2158 patients with IPF and 5195 controls were selected. We identified a novel genome-wide significant signal of association with IPF susceptibility near A-kinase anchoring protein 13 (AKAP13; rs62025270, odds ratio [OR] 1·27 [95% CI 1·18-1·37], p=1·32 × 10 -9 ) and confirmed previously reported signals, including in mucin 5B (MUC5B; rs35705950, OR 2·89 [2·56-3·26], p=1·12 × 10 -66 ) and desmoplakin (DSP; rs2076295, OR 1·44 [1·35-1·54], p=7·81 × 10 -28 ). For rs62025270, the allele A associated with increased susceptibility to IPF was also associated with increased expression of AKAP13 mRNA in lung tissue from patients who had lung resection procedures (n=1111). We showed that AKAP13 is expressed in the alveolar epithelium and lymphoid follicles from patients with IPF, and AKAP

Reader reaction on the generalized Kruskal-Wallis test for genetic association studies incorporating group uncertainty.

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Wu, Baolin; Guan, Weihua

2015-06-01

Acar and Sun (2013, Biometrics 69, 427-435) presented a generalized Kruskal-Wallis (GKW) test for genetic association studies that incorporated the genotype uncertainty and showed its robust and competitive performance compared to existing methods. We present another interesting way to derive the GKW test via a rank linear model. © 2014, The International Biometric Society.

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

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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.

Association study of functional genetic variants of innate immunity related genes in celiac disease

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Martín J

2005-08-01

Full Text Available Abstract Background Recent evidence suggest that the innate immune system is implicated in the early events of celiac disease (CD pathogenesis. In this work for the first time we have assessed the relevance of different proinflammatory mediators typically related to innate immunity in CD predisposition. Methods We performed a familial study in which 105 celiac families characterized by the presence of an affected child with CD were genotyped for functional polymorphisms located at regulatory regions of IL-1α, IL-1β, IL-1RN, IL-18, RANTES and MCP-1 genes. Familial data was analysed with a transmission disequilibrium test (TDT that revealed no statistically significant differences in the transmission pattern of the different genetic markers considered. Results The TDT analysis for IL-1α, IL-1β, IL-1RN, IL-18, and MCP-1 genes genetic variants did not reveal biased transmission to the affected offspring. Only a borderline association of RANTES promoter genetic variants with CD predisposition was observed. Conclusion Our results suggest that the analysed polymorphisms of IL-1α, IL-1β, IL-1RN, IL-18, RANTES and MCP-1 genes do not seem to play a major role in CD genetic predisposition in our population.

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

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

An association study of 13 SNPs from seven candidate genes with pediatric asthma and a preliminary study for genetic testing by multiple variants in Taiwanese population.

Science.gov (United States)

Wang, Jiu-Yao; Liou, Ya-Huei; Wu, Ying-Jye; Hsiao, Ya-Hsin; Wu, Lawrence Shih-Hsin

2009-03-01

Asthma is one of the most common chronic diseases in children. It is caused by complex interactions between various genetic factors and exposures to environmental allergens and irritants. Because of the heterogeneity of the disease and the genetic and cultural differences among different populations, a proper association study and genetic testing for asthma and susceptibility genes is difficult to perform. We assessed 13 single-nucleotide polymorphisms (SNPs) in seven well-known asthma susceptibility genes and looked for association with pediatric asthma using 449 asthmatic subjects and 512 non-asthma subjects in Taiwanese population. CD14-159 C/T and MS4A2 Glu237Gly were identified to have difference in genotype/allele frequencies between the control group and asthma patients. Moreover, the genotype synergistic analysis showed that the co-contribution of two functional SNPs was riskier or more protective from asthma attack. Our study provided a genotype synergistic method for studying gene-gene interaction on polymorphism basis and genetic testing using multiple polymorphisms.

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.

Genetic and Environmental Associations Between Procrastination and Internalizing/Externalizing Psychopathology.

Science.gov (United States)

Gustavson, Daniel E; du Pont, Alta; Hatoum, Alexander S; Hyun Rhee, Soo; Kremen, William S; Hewitt, John K; Friedman, Naomi P

2017-09-01

Recent work on procrastination has begun to unravel the genetic and environmental correlates of this problematic behavior. However, little is known about how strongly procrastination is associated with internalizing and externalizing psychopathology, and the extent to which shared genetic/environmental factors or relevant personality constructs (e.g., fear of failure, impulsivity, and neuroticism) can inform the structure of these associations. The current study examined data from 764 young adult twins who completed questionnaires assessing procrastination and personality and structured interviews regarding psychopathology symptoms. Results indicated that procrastination was positively correlated with both internalizing and externalizing latent variables, and that these correlations were driven by shared genetic influences. Moreover, the association between procrastination and internalizing was accounted for by fear of failure and neuroticism, whereas the association between procrastination and externalizing was primarily explained by impulsivity. The role of procrastination in psychopathology is discussed using a framework that highlights common and broadband-specific variance.

Genetic mutations associated with status epilepticus.

Science.gov (United States)

Bhatnagar, M; Shorvon, S

2015-08-01

This paper reports the results of a preliminary search of the literature aimed at identifying the genetic mutations reported to be strongly associated with status epilepticus. Genetic mutations were selected for inclusion if status epilepticus was specifically mentioned as a consequence of the mutation in standard genetic databases or in a case report or review article. Mutations in 122 genes were identified. The genetic mutations identified were found in only rare conditions (sometimes vanishingly rare) and mostly in infants and young children with multiple other handicaps. Most of the genetic mutations can be subdivided into those associated with cortical dysplasias, inborn errors of metabolism, mitochondrial disease, or epileptic encephalopathies and childhood syndromes. There are no identified 'pure status epilepticus genes'. The range of genes underpinning status epilepticus differs in many ways from the range of genes underpinning epilepsy, which suggests that the processes underpinning status epilepticus differ from those underpinning epilepsy. It has been frequently postulated that status epilepticus is the result of a failure of 'seizure termination mechanisms', but the wide variety of genes affecting very diverse biochemical pathways identified in this survey makes any unitary cause unlikely. The genetic influences in status epilepticus are likely to involve a wide range of mechanisms, some related to development, some to cerebral energy production, some to diverse altered biochemical pathways, some to transmitter and membrane function, and some to defects in networks or systems. The fact that many of the identified genes are involved with cerebral development suggests that status epilepticus might often be a system or network phenomenon. To date, there are very few genes identified which are associated with adult-onset status epilepticus (except in those with preexisting neurological damage), and this is disappointing as the cause of many adult

Genetic association between the phospholipase A2 gene and unipolar affective disorder: a multicentre case-control study.

Science.gov (United States)

Papadimitriou, George N; Dikeos, Dimitris G; Souery, Daniel; Del-Favero, Jurgen; Massat, Isabelle; Avramopoulos, Dimitrios; Blairy, Sylvie; Cichon, Sven; Ivezic, Sladjana; Kaneva, Radka; Karadima, Georgia; Lilli, Roberta; Milanova, Vihra; Nöthen, Markus; Oruc, Lilijana; Rietschel, Marcella; Serretti, Alessandro; Van Broeckhoven, Christine; Stefanis, Costas N; Mendlewicz, Julien

2003-12-01

The co-segregation in one pedigree of bipolar affective disorder with Darier's disease whose gene is on chromosome 12q23-q24.1, and findings from linkage and association studies with the neighbouring gene of phospholipase A2 (PLA2) indicate that PLA2 may be considered as a candidate gene for affective disorders. All relevant genetic association studies, however, were conducted on bipolar patients. In the present study, the possible association between the PLA2 gene and unipolar affective disorder was examined on 321 unipolar patients and 604 controls (all personally interviewed), recruited from six countries (Belgium, Bulgaria, Croatia, Germany, Greece, and Italy) participating in the European Collaborative Project on Affective Disorders. After controlling for population group and gender, one of the eight alleles of the investigated marker (allele 7) was found to be more frequent among unipolar patients with more than three major depressive episodes than among controls (P<0.01); genotypic association was also observed, under the dominant model of genetic transmission (P<0.02). In addition, presence of allele 7 was correlated with a higher frequency of depressive episodes (P<0.02). These findings suggest that structural variations at the PLA2 gene or the chromosomal region around it may confer susceptibility for unipolar affective disorder.

Smoking and caffeine consumption: a genetic analysis of their association

NARCIS (Netherlands)

Treur, J.L.; Taylor, A.E.; Ware, J.J.; Nivard, M.G.; Neale, M.C.; McMahon, G.; Hottenga, J.J.; Baselmans, B.M.L.; Boomsma, D.I.; Munafò, M.; Vink, J.M.

2017-01-01

Smoking and caffeine consumption show a strong positive correlation, but the mechanism underlying this association is unclear. Explanations include shared genetic/environmental factors or causal effects. This study employed three methods to investigate the association between smoking and caffeine.

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

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

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

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

Multiple genetic variants associated with primary biliary cirrhosis in a Han Chinese population.

Science.gov (United States)

Dong, Ming; Li, Jinxin; Tang, Ruqi; Zhu, Ping; Qiu, Fang; Wang, Chan; Qiu, Jie; Wang, Lan; Dai, Yaping; Xu, Ping; Gao, Yueqiu; Han, Chongxu; Wang, Yongzhong; Wu, Jian; Wu, Xudong; Zhang, Kui; Dai, Na; Sun, Weihao; Zhou, Jianpo; Hu, Zhigang; Liu, Lei; Jiang, Yuzhang; Nie, Jinshan; Zhao, Yi; Gong, Yuhua; Tian, Ye; Ji, Hualiang; Jiao, Zhijun; Jiang, Po; Shi, Xingjuan; Jawed, Rohil; Zhang, Yu; Huang, Qinghai; Li, Enling; Wei, Yiran; Xie, Wei; Zhao, Weifeng; Liu, Xiang; Zhu, Xiang; Qiu, Hong; He, Gengsheng; Chen, Weichang; Seldin, Michael F; Gershwin, M Eric; Liu, Xiangdong; Ma, Xiong

2015-06-01

Multiple genome-wide association studies of primary biliary cirrhosis (PBC) in both European and Japanese ancestries have shown significant associations of many genetic loci contributing to the susceptibility to PBC. Major differences in susceptibility loci between these two population groups were observed. In this study, we examined whether the most significant loci observed in either European and/or Japanese cohorts are associated with PBC in a Han Chinese population. In 1070 PBC patients and 1198 controls, we observed highly significant associations at CD80 (rs2293370, P = 2.67 × 10(-8)) and TNFSF15 (rs4979462, P = 3.86 × 10(-8)) and significant associations at 17q12-21 (rs9303277), PDGFB (rs715505), NF-κB1 (rs7665090), IL12RB2 (rs11209050), and STAT4 (rs7574865; all corrected P values rs7574865) was strongly associated after additional control samples were analyzed. Our study is the first large-scale genetic analysis in a Han Chinese PBC cohort. These results do not only reflect that Han Chinese PBC patients share common genetic susceptibility genes with both their Japanese and European counterparts but also suggest a distinctly different genetic susceptibility profile.

Molecular evaluation of genetic diversity and association studies in ...

Indian Academy of Sciences (India)

In the present study, we tested rice genotypes that included un(der)exploited landraces of Tamil Nadu along with indica and japonica test cultivars to ascertain their genetic diversity structure. Highly polymorphic microsatellite markers were used for generating marker segregation data. A novel measure, allele discrimination ...

Contribution of Large Region Joint Associations to Complex Traits Genetics

Science.gov (United States)

Paré, Guillaume; Asma, Senay; Deng, Wei Q.

2015-01-01

A polygenic model of inheritance, whereby hundreds or thousands of weakly associated variants contribute to a trait’s heritability, has been proposed to underlie the genetic architecture of complex traits. However, relatively few genetic variants have been positively identified so far and they collectively explain only a small fraction of the predicted heritability. We hypothesized that joint association of multiple weakly associated variants over large chromosomal regions contributes to complex traits variance. Confirmation of such regional associations can help identify new loci and lead to a better understanding of known ones. To test this hypothesis, we first characterized the ability of commonly used genetic association models to identify large region joint associations. Through theoretical derivation and simulation, we showed that multivariate linear models where multiple SNPs are included as independent predictors have the most favorable association profile. Based on these results, we tested for large region association with height in 3,740 European participants from the Health and Retirement Study (HRS) study. Adjusting for SNPs with known association with height, we demonstrated clustering of weak associations (p = 2x10-4) in regions extending up to 433.0 Kb from known height loci. The contribution of regional associations to phenotypic variance was estimated at 0.172 (95% CI 0.063-0.279; p < 0.001), which compared favorably to 0.129 explained by known height variants. Conversely, we showed that suggestively associated regions are enriched for known height loci. To extend our findings to other traits, we also tested BMI, HDLc and CRP for large region associations, with consistent results for CRP. Our results demonstrate the presence of large region joint associations and suggest these can be used to pinpoint weakly associated SNPs. PMID:25856144

Coronary artery disease-associated genetic variants and biomarkers of inflammation

DEFF Research Database (Denmark)

Christiansen, Morten Krogh; Larsen, Sanne Bøjet; Nyegaard, Mette

2017-01-01

score was calculated to assess the combined risk associated with all the genetic variants. A multiple linear regression model was used to assess associations between the genetic risk score, single SNPs, and the five inflammatory biomarkers. RESULTS:The minor allele (G) (CAD risk allele) of rs2075650......INTRODUCTION:Genetic constitution and inflammation both contribute to development of coronary artery disease (CAD). Several CAD-associated single-nucleotide polymorphisms (SNPs) have recently been identified, but their functions are largely unknown. We investigated the associations between CAD...

CRY2 genetic variants associate with dysthymia.

Directory of Open Access Journals (Sweden)

Leena Kovanen

Full Text Available People with mood disorders often have disruptions in their circadian rhythms. Recent molecular genetics has linked circadian clock genes to mood disorders. Our objective was to study two core circadian clock genes, CRY1 and CRY2 as well as TTC1 that interacts with CRY2, in relation to depressive and anxiety disorders. Of these three genes, 48 single-nucleotide polymorphisms (SNPs whose selection was based on the linkage disequilibrium and potential functionality were genotyped in 5910 individuals from a nationwide population-based sample. The diagnoses of major depressive disorder, dysthymia and anxiety disorders were assessed with a structured interview (M-CIDI. In addition, the participants filled in self-report questionnaires on depressive and anxiety symptoms. Logistic and linear regression models were used to analyze the associations of the SNPs with the phenotypes. Four CRY2 genetic variants (rs10838524, rs7121611, rs7945565, rs1401419 associated significantly with dysthymia (false discovery rate q<0.05. This finding together with earlier CRY2 associations with winter depression and with bipolar type 1 disorder supports the view that CRY2 gene has a role in mood disorders.

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...

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

Genetic association of marbling score with intragenic nucleotide variants at selection signals of the bovine genome.

Science.gov (United States)

Ryu, J; Lee, C

2016-04-01

Selection signals of Korean cattle might be attributed largely to artificial selection for meat quality. Rapidly increased intragenic markers of newly annotated genes in the bovine genome would help overcome limited findings of genetic markers associated with meat quality at the selection signals in a previous study. The present study examined genetic associations of marbling score (MS) with intragenic nucleotide variants at selection signals of Korean cattle. A total of 39 092 nucleotide variants of 407 Korean cattle were utilized in the association analysis. A total of 129 variants were selected within newly annotated genes in the bovine genome. Their genetic associations were analyzed using the mixed model with random polygenic effects based on identical-by-state genetic relationships among animals in order to control for spurious associations produced by population structure. Genetic associations of MS were found (Pdirectional selection for greater MS and remain selection signals in the bovine genome. Further studies of fine mapping would be useful to incorporate favorable alleles in marker-assisted selection for MS of Korean cattle.

SNP in TXNRD2 Associated With Radiation-Induced Fibrosis: A Study of Genetic Variation in Reactive Oxygen Species Metabolism and Signaling

International Nuclear Information System (INIS)

Edvardsen, Hege; Landmark-Høyvik, Hege; Reinertsen, Kristin V.; Zhao, Xi; Grenaker-Alnæs, Grethe Irene; Nebdal, Daniel; Syvänen, Ann-Christine; Rødningen, Olaug; Alsner, Jan; Overgaard, Jens; Borresen-Dale, Anne-Lise; Fosså, Sophie D.; Kristensen, Vessela N.

2013-01-01

Purpose: The aim of the study was to identify noninvasive markers of treatment-induced side effects. Reactive oxygen species (ROS) are generated after irradiation, and genetic variation in genes related to ROS metabolism might influence the level of radiation-induced adverse effects (AEs). Methods and Materials: 92 breast cancer (BC) survivors previously treated with hypofractionated radiation therapy were assessed for the AEs subcutaneous atrophy and fibrosis, costal fractures, lung fibrosis, pleural thickening, and telangiectasias (median follow-up time 17.1 years). Single-nucleotide polymorphisms (SNPs) in 203 genes were analyzed for association to AE grade. SNPs associated with subcutaneous fibrosis were validated in an independent BC survivor material (n=283). The influence of the studied genetic variation on messenger ribonucleic acid (mRNA) expression level of 18 genes previously associated with fibrosis was assessed in fibroblast cell lines from BC patients. Results: Subcutaneous fibrosis and atrophy had the highest correlation (r=0.76) of all assessed AEs. The nonsynonymous SNP rs1139793 in TXNRD2 was associated with grade of subcutaneous fibrosis, the reference T-allele being more prevalent in the group experiencing severe levels of fibrosis. This was confirmed in another sample cohort of 283 BC survivors, and rs1139793 was found significantly associated with mRNA expression level of TXNRD2 in blood. Genetic variation in 24 ROS-related genes, including EGFR, CENPE, APEX1, and GSTP1, was associated with mRNA expression of 14 genes previously linked to fibrosis (P≤.005). Conclusion: Development of subcutaneous fibrosis can be associated with genetic variation in the mitochondrial enzyme TXNRD2, critically involved in removal of ROS, and maintenance of the intracellular redox balance

Study books on ADHD genetics: balanced or biased?

Science.gov (United States)

Te Meerman, Sanne; Batstra, Laura; Hoekstra, Rink; Grietens, Hans

2017-06-01

Academic study books are essential assets for disseminating knowledge about ADHD to future healthcare professionals. This study examined if they are balanced with regard to genetics. We selected and analyzed study books (N=43) used in (pre) master's programmes at 10 universities in the Netherlands. Because the mere behaviourally informed quantitative genetics give a much higher effect size of the genetic involvement in ADHD, it is important that study books contrast these findings with molecular genetics' outcomes. The latter studies use real genetic data, and their low effect sizes expose the potential weaknesses of quantitative genetics, like underestimating the involvement of the environment. Only a quarter of books mention both effect sizes and contrast these findings, while another quarter does not discuss any effect size. Most importantly, however, roughly half of the books in our sample mention only the effect sizes from quantitative genetic studies without addressing the low explained variance of molecular genetic studies. This may confuse readers by suggesting that the weakly associated genes support the quite spectacular, but potentially flawed estimates of twin, family and adoption studies, while they actually contradict them.

Genetic association of telomere length with hepatocellular carcinoma risk: A Mendelian randomization analysis.

Science.gov (United States)

Cheng, Yue; Yu, Chengxiao; Huang, Mingtao; Du, Fangzhi; Song, Ci; Ma, Zijian; Zhai, Xiangjun; Yang, Yuan; Liu, Jibin; Bei, Jin-Xin; Jia, Weihua; Jin, Guangfu; Li, Shengping; Zhou, Weiping; Liu, Jianjun; Dai, Juncheng; Hu, Zhibin

2017-10-01

Observational studies show an association between telomere length and Hepatocellular carcinoma (HCC) risk, but the relationship is controversial. Particularly, it remains unclear whether the association is due to confounding or biases inherent in conventional epidemiological studies. Here, we applied Mendelian randomization approach to evaluate whether telomere length is causally associated with HCC risk. Individual-level data were from HBV-related HCC Genome-wide association studies (1,538 HBV positive HCC patients and 1,465 HBV positive controls). Genetic risk score, as proxy for actual measured telomere length, derived from nine telomere length-associated genetic variants was used to evaluate the effect of telomere length on HCC risk. We observed a significant risk signal between genetically increased telomere length and HBV-related HCC risk (OR=2.09, 95% CI 1.32-3.31, P=0.002). Furthermore, a U-shaped curve was fitted by the restricted cubic spline curve, which indicated that either short or long telomere length would increase HCC risk (P=0.0022 for non-linearity test). Subgroup analysis did not reveal significant heterogeneity between different age, gender, smoking status and drinking status groups. Our results indicated that a genetic background that favors longer or shorter telomere length may increase HBV-related HCC risk-a U-shaped association. Copyright © 2017 Elsevier Ltd. All rights reserved.

Genetics of immune-mediated disorders : from genome-wide association to molecular mechanism

NARCIS (Netherlands)

Kumar, Vinod; Wijmenga, Cisca; Xavier, Ramnik J.

2014-01-01

Genetic association studies have identified not only hundreds of susceptibility loci to immune-mediated diseases but also pinpointed causal amino-acid variants of HLA genes that contribute to many autoimmune reactions. Majority of non-HLA genetic variants are located within non-coding regulatory

The value of some Corsican sub-populations for genetic association studies

Directory of Open Access Journals (Sweden)

Vona Giuseppe

2008-07-01

Full Text Available Abstract Background Genetic isolates with a history of a small founder population, long-lasting isolation and population bottlenecks represent exceptional resources in the identification of disease genes. In these populations the disease allele reveals Linkage Disequilibrium (LD with markers over significant genetic intervals, therefore facilitating disease locus identification. In a previous study we examined the LD extension on the Xq13 region in three Corsican sub-populations from the inner mountainous region of the island. On the basis of those previous results we have proposed a multistep procedure to carry out studies aimed at the identification of genes involved in complex diseases in Corsica. A prerequisite to carry out the proposed multi-step procedure was the presence of different degrees of LD on the island and a common genetic derivation of the different Corsican sub-populations. In order to evaluate the existence of these conditions in the present paper we extended the analysis to the Corsican coastal populations. Methods Samples were analyzed using seven dinucleotide microsatellite markers on chromosome Xq13-21: DXS983, DXS986, DXS8092, DXS8082, DXS1225, DXS8037 and DXS995 spanning approximately 4.0 cM (13.3 Mb. We have also investigated the distribution of the DXS1225-DXS8082 haplotype which has been recently proposed as a good marker of population genetic history due to its low recombination rate. Results the results obtained indicate a decrease of LD on the island from the central mountainous toward the coastal sub-populations. In addition the analysis of the DXS1225-DXS8082 haplotype revealed: 1 the presence of a particular haplotype with high frequency; 2 the derivation from a common genetic pool of the sub-populations examined in the present study. Conclusion These results indicate the Corsican sub-populations useful for the fine mapping of genes contributing to complex diseases.

Novel mutations associated with nephrogenic diabetes insipidus. A clinical-genetic study.

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García Castaño, Alejandro; Pérez de Nanclares, Gustavo; Madariaga, Leire; Aguirre, Mireia; Chocron, Sara; Madrid, Alvaro; Lafita Tejedor, Francisco Javier; Gil Campos, Mercedes; Sánchez Del Pozo, Jaime; Ruiz Cano, Rafael; Espino, Mar; Gomez Vida, Jose Maria; Santos, Fernando; García Nieto, Victor Manuel; Loza, Reyner; Rodríguez, Luis Miguel; Hidalgo Barquero, Emilia; Printza, Nikoleta; Camacho, Juan Antonio; Castaño, Luis; Ariceta, Gema

2015-10-01

Molecular diagnosis is a useful diagnostic tool in primary nephrogenic diabetes insipidus (NDI), an inherited disease characterized by renal inability to concentrate urine. The AVPR2 and AQP2 genes were screened for mutations in a cohort of 25 patients with clinical diagnosis of NDI. Patients presented with dehydration, polyuria-polydipsia, failure to thrive (mean ± SD; Z-height -1.9 ± 2.1 and Z-weight -2.4 ± 1.7), severe hypernatremia (mean ± SD; Na 150 ± 10 mEq/L), increased plasma osmolality (mean ± SD; 311 ± 18 mOsm/Kg), but normal glomerular filtration rate. Genetic diagnosis revealed that 24 male patients were hemizygous for 17 different putative disease-causing mutations in the AVPR2 gene (each one in a different family). Of those, nine had not been previously reported, and eight were recurrent. Moreover, we found those same AVPR2 changes in 12 relatives who were heterozygous carriers. Further, in one female patient, AVPR2 gene study turned out to be negative and she was found to be homozygous for the novel AQP2 p.Ala86Val alteration. Genetic analysis presumably confirmed the diagnosis of nephrogenic diabetes insipidus in every patient of the studied cohort. We emphasize that we detected a high presence (50 %) of heterozygous females with clinical NDI symptoms. • In most cases (90 %), inherited nephrogenic diabetes insipidus (NDI) is an X-linked disease, caused by mutations in the AVPR2 gene. • In rare occasions (10 %), it is caused by mutations in the AQP2 gene. What is new: • In this study, we report 10 novel mutations associated with NDI. • We have detected a high presence (50 %) of heterozygous carriers with clinical NDI symptoms.

Association between intake of dairy products and short-term memory with and without adjustment for genetic and family environmental factors: A twin study.

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Ogata, Soshiro; Tanaka, Haruka; Omura, Kayoko; Honda, Chika; Hayakawa, Kazuo

2016-04-01

Previous studies have indicated associations between intake of dairy products and better cognitive function and reduced risk of dementia. However, these studies did not adjust for genetic and family environmental factors that may influence food intake, cognitive function, and metabolism of dairy product nutrients. In the present study, we investigated the association between intake of dairy products and short-term memory with and without adjustment for almost all genetic and family environmental factors using a genetically informative sample of twin pairs. A cross-sectional study was conducted among twin pairs aged between 20 and 74. Short-term memory was assessed as primary outcome variable, intake of dairy products was analyzed as the predictive variable, and sex, age, education level, marital status, current smoking status, body mass index, dietary alcohol intake, and medical history of hypertension or diabetes were included as possible covariates. Generalized estimating equations (GEE) were performed by treating twins as individuals and regression analyses were used to identify within-pair differences of a twin pair to adjust for genetic and family environmental factors. Data are reported as standardized coefficients and 95% confidence intervals (CI). Analyses were performed on data from 78 men and 278 women. Among men, high intake of dairy products was significantly associated with better short-term memory after adjustment for the possible covariates (standardized coefficients = 0.22; 95% CI, 0.06-0.38) and almost all genetic and family environmental factors (standardized coefficients = 0.38; 95% CI, 0.07-0.69). Among women, no significant associations were found between intake of dairy products and short-term memory. Subsequent sensitivity analyses were adjusted for small samples and showed similar results. Intake of dairy product may prevent cognitive declines regardless of genetic and family environmental factors in men. Copyright © 2015 Elsevier Ltd

Associations between the parent-child relationship and adolescent self-worth: a genetically informed study of twin parents and their adolescent children.

Science.gov (United States)

McAdams, Tom A; Rijsdijk, Fruhling V; Narusyte, Jurgita; Ganiban, Jody M; Reiss, David; Spotts, Erica; Neiderhiser, Jenae M; Lichtenstein, Paul; Eley, Thalia C

2017-01-01

Low self-worth during adolescence predicts a range of emotional and behavioural problems. As such, identifying potential sources of influence on self-worth is important. Aspects of the parent-child relationship are often associated with adolescent self-worth but to date it is unclear whether such associations may be attributable to familial confounding (e.g. genetic relatedness). We set out to clarify the nature of relationships between parental expressed affection and adolescent self-worth, and parent-child closeness and adolescent self-worth. We used data from the Twin and Offspring Study in Sweden, a children-of-twins sample comprising 909 adult twin pairs with adolescent children. Using these data we were able to apply structural equation models with which we could examine whether associations remained after accounting for genetic transmission. Results demonstrated that parent-child closeness and parental-expressed affection were both phenotypically associated with adolescent self-worth. Associations could not be attributed to genetic relatedness between parent and child. Parent-child closeness and parental affection are associated with adolescent self-worth above and beyond effects attributable to genetic relatedness. Data were cross-sectional, so the direction of effects cannot be confirmed but findings support the notion that positive parent-child relationships increase adolescent self-worth. © 2016 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.

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

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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

Genetics of Beckwith-Wiedemann syndrome-associated tumors: common genetic pathways

NARCIS (Netherlands)

Steenman, M.; Westerveld, A.; Mannens, M.

2000-01-01

A specific subset of solid childhood tumors-Wilms' tumor, adrenocortical carcinoma, rhabdomyosarcoma, and hepatoblastoma-is characterized by its association with Beckwith-Wiedemann syndrome. Genetic abnormalities found in these tumors affect the same chromosome region (11p15), which has been

A genome-wide association study identifies rs2000999 as a strong genetic determinant of circulating haptoglobin levels.

Directory of Open Access Journals (Sweden)

Philippe Froguel

Full Text Available Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far.We used a genome-wide association study initially conducted in 631 French children followed by a replication in three additional European sample sets and we identified a common single nucleotide polymorphism (SNP, rs2000999 located in the Haptoglobin gene (HP as a strong genetic predictor of circulating Haptoglobin levels (P(overall = 8.1 × 10(-59, explaining 45.4% of its genetic variability (11.8% of Hp global variance. The functional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels (β = 0.23 ± 0.08, P = 0.007. Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789 European children (P(total cholesterol = 0.002 and P(LDL = 0.0008.Given the central position of haptoglobin in many inflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobin concentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact.

Chromosome 15q25.1 genetic markers associated with level of response to alcohol in humans.

Science.gov (United States)

Joslyn, Geoff; Brush, Gerry; Robertson, Margaret; Smith, Tom L; Kalmijn, Jelger; Schuckit, Marc; White, Raymond L

2008-12-23

As with other genetically complex common psychiatric and medical conditions, multiple genetic and environmental components contribute to alcohol use disorders (AUDs), which can confound attempts to identify genetic components. Intermediate phenotypes are often more closely correlated with underlying biology and have often proven invaluable in genetic studies. Level of response (LR) to alcohol is an intermediate phenotype for AUDs, and individuals with a low LR are at increased risk. A high rate of concurrent alcohol and nicotine use and dependence suggests that these conditions may share biochemical and genetic mechanisms. Genetic association studies indicate that a genetic locus, which includes the CHRNA5-CHRNA3-CHRNB4 gene cluster, plays a role in nicotine consumption and dependence. Genetic association with alcohol dependence was also recently shown. We show here that two of the markers from the nicotine studies also show an association (multiple testing corrected P a sample of 367 siblings. Additional markers in the region were analyzed and shown to be located in a 250-kb expanse of high linkage disequilibrium containing three additional genes. These findings indicate that LR intermediate phenotypes have utility in genetic approaches to AUDs and will prove valuable in the identification of other genetic loci conferring susceptibility to AUDs.

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

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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

Genetic and Non-genetic Factors Associated With Constipation in Cancer Patients Receiving Opioids.

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Laugsand, Eivor A; Skorpen, Frank; Kaasa, Stein; Sabatowski, Rainer; Strasser, Florian; Fayers, Peter; Klepstad, Pål

2015-06-18

To examine whether the inter-individual variation in constipation among patients receiving opioids for cancer pain is associated with genetic or non-genetic factors. Cancer patients receiving opioids were included from 17 centers in 11 European countries. Intensity of constipation was reported by 1,568 patients on a four-point categorical scale. Non-genetic factors were included as covariates in stratified regression analyses on the association between constipation and 75 single-nucleotide polymorphisms (SNPs) within 15 candidate genes related to opioid- or constipation-signaling pathways (HTR3E, HTR4, HTR2A, TPH1, ADRA2A, CHRM3, TACR1, CCKAR, KIT, ARRB2, GHRL, ABCB1, COMT, OPRM1, and OPRD1). The non-genetic factors significantly associated with constipation were type of laxative, mobility and place of care among patients receiving laxatives (N=806), in addition to Karnofsky performance status and presence of metastases among patients not receiving laxatives (N=762) (Pconstipation. Five SNPs, rs1800532 in TPH1, rs1799971 in OPRM1, rs4437575 in ABCB1, rs10802789 in CHRM3, and rs2020917 in COMT were associated with constipation (Phospitalization, Karnofsky performance status, presence of metastases, and five SNPs within TPH1, OPRM1, ABCB1, CHRM3, and COMT may contribute to the variability in constipation among cancer patients treated with opioids. Knowledge of these factors may help to develop new therapies and to identify patients needing a more individualized approach to treatment.

Genetic diversity of the Acropora-associated hydrozoans: new insight from the Red Sea

KAUST Repository

Maggioni, Davide

2017-01-21

To date, four nominal species and several other unidentified species of Zanclea hydrozoans are known to live symbiotically with scleractinians, and recent surveys reported this association also in the Red Sea. Previous molecular studies showed that each coral genus involved in this association hosts only one species or molecular clade of Zanclea, with the only exception being the genus Acropora, which hosts at least two Zanclea species. Moreover, some of the detected genetic lineages were morphologically undistinguishable in the polyp stage, suggesting the presence of cryptic species. In this study, we investigated the morphology and genetic diversity of Acropora-associated Zanclea specimens collected in previous studies in Egypt and Israel, as well as new samples collected in Saudi Arabia. Based on the current data, all the analysed samples were morphologically identical to Zanclea gallii, a species associated with Acropora corals from the Maldives. However, molecular analyses separated the samples collected in the Red Sea from all other coral-associated hydroids. Therefore, phylogenetic reconstructions, haplotype networks, genetic distance analyses and distribution data allowed us to identify a previously unknown cryptic species of Acropora-associated hydroid, here named Zanclea gallii IIa, following a recently proposed molecular nomenclature.

An Efficient Stepwise Statistical Test to Identify Multiple Linked Human Genetic Variants Associated with Specific Phenotypic Traits.

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Iksoo Huh

Full Text Available Recent advances in genotyping methodologies have allowed genome-wide association studies (GWAS to accurately identify genetic variants that associate with common or pathological complex traits. Although most GWAS have focused on associations with single genetic variants, joint identification of multiple genetic variants, and how they interact, is essential for understanding the genetic architecture of complex phenotypic traits. Here, we propose an efficient stepwise method based on the Cochran-Mantel-Haenszel test (for stratified categorical data to identify causal joint multiple genetic variants in GWAS. This method combines the CMH statistic with a stepwise procedure to detect multiple genetic variants associated with specific categorical traits, using a series of associated I × J contingency tables and a null hypothesis of no phenotype association. Through a new stratification scheme based on the sum of minor allele count criteria, we make the method more feasible for GWAS data having sample sizes of several thousands. We also examine the properties of the proposed stepwise method via simulation studies, and show that the stepwise CMH test performs better than other existing methods (e.g., logistic regression and detection of associations by Markov blanket for identifying multiple genetic variants. Finally, we apply the proposed approach to two genomic sequencing datasets to detect linked genetic variants associated with bipolar disorder and obesity, respectively.

Comprehensive genetic study of fatty acids helps explain the role of noncoding inflammatory bowel disease associated SNPs and fatty acid metabolism in disease pathogenesis.

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Jezernik, Gregor; Potočnik, Uroš

2018-03-01

Fatty acids and their derivatives play an important role in inflammation. Diet and genetics influence fatty acid profiles. Abnormalities of fatty acid profiles have been observed in inflammatory bowel diseases (IBD), a group of complex diseases defined by chronic gastrointestinal inflammation. IBD associated fatty acid profile abnormalities were observed independently of nutritional status or disease activity, suggesting a common genetic background. However, no study so far has attempted to look for overlap between IBD loci and fatty acid associated loci or investigate the genetics of fatty acid profiles in IBD. To this end, we conducted a comprehensive genetic study of fatty acid profiles in IBD using iCHIP, a custom microarray platform designed for deep sequencing of immune-mediated disease associated loci. This study identifies 10 loci associated with fatty acid profiles in IBD. The most significant associations were a locus near CBS (p = 7.62 × 10 -8 ) and a locus in LRRK2 (p = 1.4 × 10 -7 ). Of note, this study replicates the FADS gene cluster locus, previously associated with both fatty acid profiles and IBD pathogenesis. Furthermore, we identify 18 carbon chain trans-fatty acids (p = 1.12 × 10 -3 ), total trans-fatty acids (p = 4.49 × 10 -3 ), palmitic acid (p = 5.85 × 10 -3 ) and arachidonic acid (p = 8.58 × 10 -3 ) as significantly associated with IBD pathogenesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

Genetic Ancestry Is not Associated with Breast Cancer Recurrence or Survival in U.S. Latina Women Enrolled in the Kaiser Permanente Pathways Study.

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Engmann, Natalie J; Ergas, Isaac J; Yao, Song; Kwan, Marilyn L; Roh, Janise M; Ambrosone, Christine B; Kushi, Lawrence H; Fejerman, Laura

2017-09-01

Background: The U.S. Hispanic/Latino population is heterogeneous both socioculturally and by the proportion of European, Indigenous American, and African ancestry of the regions from which individuals originate. A previous study reported that genetic ancestry was associated with breast cancer survival among Latinas, independent of sociodemographic and tumor characteristics, suggesting that a genetic factor associated with ancestry may affect breast cancer survival. Methods: We evaluated the association of genetic ancestry with breast cancer outcomes among 506 Latina women with invasive breast cancer in the Pathways Study, a cohort study within Kaiser Permanente, an integrated health care delivery system. Proportional hazards models were used to assess the effect of ancestry on breast cancer recurrence (53 events), breast cancer-specific mortality (31 events) and all-cause mortality (54 events), with a mean follow-up time of 6 years. Results: Indigenous American ancestry was not associated with breast cancer recurrence [HR = 1.00 per 10% increase; 95% confidence interval (CI), 0.86-1.16], breast cancer mortality (HR = 0.95; 95% CI, 0.77-1.17), or all-cause mortality (HR = 0.93; 95% CI, 0.80-1.08). Adjustment for sociodemographic variables, tumor characteristics, and treatment did not alter the associations. Conclusions: Our results suggest that previously reported differences in breast cancer survival by genetic ancestry may be overcome by improving health care access and/or quality. Impact: Improving health care access and quality may reduce breast cancer disparities among U.S. Latinas. Cancer Epidemiol Biomarkers Prev; 26(9); 1466-9. ©2017 AACR . ©2017 American Association for Cancer Research.

A weighted U statistic for association analyses considering genetic heterogeneity.

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Wei, Changshuai; Elston, Robert C; Lu, Qing

2016-07-20

Converging evidence suggests that common complex diseases with the same or similar clinical manifestations could have different underlying genetic etiologies. While current research interests have shifted toward uncovering rare variants and structural variations predisposing to human diseases, the impact of heterogeneity in genetic studies of complex diseases has been largely overlooked. Most of the existing statistical methods assume the disease under investigation has a homogeneous genetic effect and could, therefore, have low power if the disease undergoes heterogeneous pathophysiological and etiological processes. In this paper, we propose a heterogeneity-weighted U (HWU) method for association analyses considering genetic heterogeneity. HWU can be applied to various types of phenotypes (e.g., binary and continuous) and is computationally efficient for high-dimensional genetic data. Through simulations, we showed the advantage of HWU when the underlying genetic etiology of a disease was heterogeneous, as well as the robustness of HWU against different model assumptions (e.g., phenotype distributions). Using HWU, we conducted a genome-wide analysis of nicotine dependence from the Study of Addiction: Genetics and Environments dataset. The genome-wide analysis of nearly one million genetic markers took 7h, identifying heterogeneous effects of two new genes (i.e., CYP3A5 and IKBKB) on nicotine dependence. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

A genetic association study between growth differentiation factor 5 (GDF 5 polymorphism and knee osteoarthritis in Thai population

Directory of Open Access Journals (Sweden)

Sura Thanyachai

2011-09-01

Full Text Available Abstract Objective Osteoarthritis (OA is a multi-factorial disease and genetic factor is one of the important etiologic risk factors. Various genetic polymorphisms have been elucidated that they might be associated with OA. Recently, several studies have shown an association between Growth Differentiation Factor 5(GDF5 polymorphism and knee OA. However, the role of genetic predisposing factor in each ethnic group cannot be replicated to all, with conflicting data in the literatures. Therefore, the aim of this study was to investigate the association between GDF5 polymorphism and knee OA in Thai population. Materials and Methods One hundred and ninety three patients aged 54-88 years who attended Ramathibodi Hospital were enrolled. Ninety cases with knee OA according to American College of Rheumatology criteria and one hundred and three cases in control group gave informed consent. Blood sample (5 ml were collected for identification of GDF5 (rs143383 single nucleotide polymorphism by PCR/RFLP according to a standard protocol. This study protocol was approved by the Ethics Committee on human experimentation of Ramathibodi Hospital Faculty of Medicine, Mahidol University. Odds ratios (OR and 95% confidence intervals were calculated for the risk of knee OA by genotype (TT, TC and CC and allele (T/C analyses. Results The baseline characteristics between two groups including job, smoking and activity were not different, except age and BMI. The entire cases and controls were in Hardy-Weinberg equilibrium (p > 0.05. The OA knee group (n = 90 had genotypic figure which has shown by TT 42.2% (n = 38, TC 45.6% (n = 41 and CC 12% (n = 11, whereas the control group (n = 103 revealed TT 32% (n = 33, TC 45.6% (n = 47, and CC 22.3% (n = 23, respectively. Genotypic TT increased risk of knee OA as compared to CC [OR = 2.41 (P = 0.04, 95%CI = 1.02-5.67]. In the allele analysis, the T allele was found to be significantly associated with knee OA [OR = 1.53 (P = 0

Conserved genetic pathways associated with microphthalmia, anophthalmia, and coloboma.

Science.gov (United States)

Reis, Linda M; Semina, Elena V

2015-06-01

The human eye is a complex organ whose development requires extraordinary coordination of developmental processes. The conservation of ocular developmental steps in vertebrates suggests possible common genetic mechanisms. Genetic diseases involving the eye represent a leading cause of blindness in children and adults. During the last decades, there has been an exponential increase in genetic studies of ocular disorders. In this review, we summarize current success in identification of genes responsible for microphthalmia, anophthalmia, and coloboma (MAC) phenotypes, which are associated with early defects in embryonic eye development. Studies in animal models for the orthologous genes identified overlapping phenotypes for most factors, confirming the conservation of their function in vertebrate development. These animal models allow for further investigation of the mechanisms of MAC, integration of various identified genes into common developmental pathways and finally, provide an avenue for the development and testing of therapeutic interventions. © 2015 Wiley Periodicals, Inc.

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

Review: fetal programming of polycystic ovary syndrome by androgen excess: evidence from experimental, clinical, and genetic association studies.

Science.gov (United States)

Xita, Nectaria; Tsatsoulis, Agathocles

2006-05-01

Polycystic ovary syndrome (PCOS) is a common endocrine disorder of premenopausal women, characterized by hyperandrogenism, polycystic ovaries, and chronic anovulation along with insulin resistance and abdominal obesity as frequent metabolic traits. Although PCOS manifests clinically during adolescence, emerging data suggest that the natural history of PCOS may originate in intrauterine life. Evidence from experimental, clinical, and genetic research supporting the hypothesis for the fetal origins of PCOS has been analyzed. Female primates, exposed in utero to androgen excess, exhibit the phenotypic features of PCOS during adult life. Clinical observations also support a potential fetal origin of PCOS. Women with fetal androgen excess disorders, including congenital 21-hydroxylase deficiency and congenital adrenal virilizing tumors, develop features characteristic of PCOS during adulthood despite the normalization of androgen excess after birth. The potential mechanisms of fetal androgen excess leading to a PCOS phenotype in humans are not clearly understood. However, maternal and/or fetal hyperandrogenism can provide a plausible mechanism for fetal programing of PCOS, and this, in part, may be genetically determined. Thus, genetic association studies have indicated that common polymorphic variants of genes determining androgen activity or genes that influence the availability of androgens to target tissues are associated with PCOS and increased androgen levels. These genomic variants may provide the genetic link to prenatal androgenization in human PCOS. Prenatal androgenization of the female fetus induced by genetic and environmental factors, or the interaction of both, may program differentiating target tissues toward the development of PCOS phenotype in adult life.

Using the longest significance run to estimate region-specific p-values in genetic association mapping studies

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Yang Hsin-Chou

2008-05-01

Full Text Available Abstract Background Association testing is a powerful tool for identifying disease susceptibility genes underlying complex diseases. Technological advances have yielded a dramatic increase in the density of available genetic markers, necessitating an increase in the number of association tests required for the analysis of disease susceptibility genes. As such, multiple-tests corrections have become a critical issue. However the conventional statistical corrections on locus-specific multiple tests usually result in lower power as the number of markers increases. Alternatively, we propose here the application of the longest significant run (LSR method to estimate a region-specific p-value to provide an index for the most likely candidate region. Results An advantage of the LSR method relative to procedures based on genotypic data is that only p-value data are needed and hence can be applied extensively to different study designs. In this study the proposed LSR method was compared with commonly used methods such as Bonferroni's method and FDR controlling method. We found that while all methods provide good control over false positive rate, LSR has much better power and false discovery rate. In the authentic analysis on psoriasis and asthma disease data, the LSR method successfully identified important candidate regions and replicated the results of previous association studies. Conclusion The proposed LSR method provides an efficient exploratory tool for the analysis of sequences of dense genetic markers. Our results show that the LSR method has better power and lower false discovery rate comparing with the locus-specific multiple tests.

Temperament and character associated with depressive symptoms in women: analysis of two genetically informative samples.

Science.gov (United States)

Yuh, Jongil; Neiderhiser, Jenae M; Lichtenstein, Paul; Hansson, Kjell; Cederblad, Marianne; Elthammer, Olle; Reiss, David

2009-09-01

Although previous research has explored associations between personality and depressive symptoms, a limited number of studies have assessed the extent to which genetic and environmental influences explain the association. This study investigated how temperament and character were associated with depressive symptoms in 131 pairs of twin and sibling women in early adulthood, as well as 326 pairs of twin women in middle adulthood. Results indicated that genetic influences accounted for a moderate to substantial percentage of the association between these personality features and depressive symptoms, emphasizing the role of genetic influences. Nonshared environmental influences made important contributions to the association between character and depressive symptoms, particularly in the sample of middle-aged twin women. These findings suggest that unique social experiences and relationships with a partner in adulthood may play an important role in these associations between character and depressive symptoms.

GENIE: a software package for gene-gene interaction analysis in genetic association studies using multiple GPU or CPU cores

Directory of Open Access Journals (Sweden)

Wang Kai

2011-05-01

Full Text Available Abstract Background Gene-gene interaction in genetic association studies is computationally intensive when a large number of SNPs are involved. Most of the latest Central Processing Units (CPUs have multiple cores, whereas Graphics Processing Units (GPUs also have hundreds of cores and have been recently used to implement faster scientific software. However, currently there are no genetic analysis software packages that allow users to fully utilize the computing power of these multi-core devices for genetic interaction analysis for binary traits. Findings Here we present a novel software package GENIE, which utilizes the power of multiple GPU or CPU processor cores to parallelize the interaction analysis. GENIE reads an entire genetic association study dataset into memory and partitions the dataset into fragments with non-overlapping sets of SNPs. For each fragment, GENIE analyzes: 1 the interaction of SNPs within it in parallel, and 2 the interaction between the SNPs of the current fragment and other fragments in parallel. We tested GENIE on a large-scale candidate gene study on high-density lipoprotein cholesterol. Using an NVIDIA Tesla C1060 graphics card, the GPU mode of GENIE achieves a speedup of 27 times over its single-core CPU mode run. Conclusions GENIE is open-source, economical, user-friendly, and scalable. Since the computing power and memory capacity of graphics cards are increasing rapidly while their cost is going down, we anticipate that GENIE will achieve greater speedups with faster GPU cards. Documentation, source code, and precompiled binaries can be downloaded from http://www.cceb.upenn.edu/~mli/software/GENIE/.

Combinations of genetic variants associated with bipolar disorder

DEFF Research Database (Denmark)

Mellerup, Erling; Andreassen, Ole A; Bennike, Bente

2017-01-01

The main objective of the study was to find genetic variants that in combination are significantly associated with bipolar disorder. In previous studies of bipolar disorder, combinations of three and four single nucleotide polymorphisms (SNP) genotypes taken from 803 SNPs were analyzed, and five...... clusters of combinations were found to be significantly associated with bipolar disorder. In the present study, combinations of ten SNP genotypes taken from the same 803 SNPs were analyzed, and one cluster of combinations was found to be significantly associated with bipolar disorder. Combinations from......, heterozygote or variant homozygote. In the combinations containing 10 SNP genotypes almost all the genotypes were the normal homozygote. Such a finding may indicate that accumulation in the genome of combinations containing few SNP genotypes may be a risk factor for bipolar disorder when those combinations...

Cox proportional hazards models have more statistical power than logistic regression models in cross-sectional genetic association studies

NARCIS (Netherlands)

van der Net, Jeroen B.; Janssens, A. Cecile J. W.; Eijkemans, Marinus J. C.; Kastelein, John J. P.; Sijbrands, Eric J. G.; Steyerberg, Ewout W.

2008-01-01

Cross-sectional genetic association studies can be analyzed using Cox proportional hazards models with age as time scale, if age at onset of disease is known for the cases and age at data collection is known for the controls. We assessed to what degree and under what conditions Cox proportional

Inflammatory and apoptotic signalling pathways and concussion severity: a genetic association study.

Science.gov (United States)

Mc Fie, Sarah; Abrahams, Shameemah; Patricios, Jon; Suter, Jason; Posthumus, Michael; September, Alison V

2018-03-06

The objective was to investigate the relationship between IL-1B rs16944, IL-6 rs1800795, and CASP8 rs3834129 genetic polymorphisms and concussion severity. Rugby players from high school, senior amateur, and professional teams completed a concussion severity questionnaire and donated a DNA sample. Participants (n = 163) were split into symptom severity groups around the median number and duration of symptoms. The frequency of participants with high symptom counts (more than five symptoms) increased across the IL-1B (C/C: 35%; C/T: 51%; T/T: 56%; P = 0.047) and the IL-6 (C/C: 31%; C/G: 44%; G/G: 58%; P = 0.027) genotypes. The C-C inferred interleukin allele construct frequency, created from combining the IL-1B and IL-6 genotype data, was lower in participants reporting a high symptom count (18%), compared to those with a low symptom count (fewer than six symptoms, 36%, P = 0.002). Similarly, the C-C inferred interleukin allele construct frequency was lower in those reporting prolonged symptom duration (more than one week, 16%), as opposed to short symptom duration (less than one week, 34%, P = 0.015). This study provides evidence of novel inflammatory pathway genetic associations with concussion severity, which supports the hypothesis implicating neuroinflammation in the development of concussion symptoms.

Genetic Variations Associated with Vitamin A Status and Vitamin A Bioavailability

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Patrick Borel

2017-03-01

Full Text Available Blood concentration of vitamin A (VA, which is present as different molecules, i.e., mainly retinol and provitamin A carotenoids, plus retinyl esters in the postprandial period after a VA-containing meal, is affected by numerous factors: dietary VA intake, VA absorption efficiency, efficiency of provitamin A carotenoid conversion to VA, VA tissue uptake, etc. Most of these factors are in turn modulated by genetic variations in genes encoding proteins involved in VA metabolism. Genome-wide association studies (GWAS and candidate gene association studies have identified single nucleotide polymorphisms (SNPs associated with blood concentrations of retinol and β-carotene, as well as with β-carotene bioavailability. These genetic variations likely explain, at least in part, interindividual variability in VA status and in VA bioavailability. However, much work remains to be done to identify all of the SNPs involved in VA status and bioavailability and to assess the possible involvement of other kinds of genetic variations, e.g., copy number variants and insertions/deletions, in these phenotypes. Yet, the potential usefulness of this area of research is exciting regarding the proposition of more personalized dietary recommendations in VA, particularly in populations at risk of VA deficiency.

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...

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

Genetic variation associated with differential educational attainment in adults has anticipated associations with school performance in children

NARCIS (Netherlands)

Ward, M.E.; McMahon, G.; St. Pourcain, B.; Evans, D.M.; Rietveld, C.A.; Benjamin, D.J.; Koellinger, P.D.; Cesarini, D.; Davey Smith, G.; Timpson, N.J.

2014-01-01

Genome-wide association study results have yielded evidence for the association of common genetic variants with crude measures of completed educational attainment in adults. Whilst informative, these results do not inform as to the mechanism of these effects or their presence at earlier ages and

Power and sample size calculations in the presence of phenotype errors for case/control genetic association studies

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Finch Stephen J

2005-04-01

Full Text Available Abstract Background Phenotype error causes reduction in power to detect genetic association. We present a quantification of phenotype error, also known as diagnostic error, on power and sample size calculations for case-control genetic association studies between a marker locus and a disease phenotype. We consider the classic Pearson chi-square test for independence as our test of genetic association. To determine asymptotic power analytically, we compute the distribution's non-centrality parameter, which is a function of the case and control sample sizes, genotype frequencies, disease prevalence, and phenotype misclassification probabilities. We derive the non-centrality parameter in the presence of phenotype errors and equivalent formulas for misclassification cost (the percentage increase in minimum sample size needed to maintain constant asymptotic power at a fixed significance level for each percentage increase in a given misclassification parameter. We use a linear Taylor Series approximation for the cost of phenotype misclassification to determine lower bounds for the relative costs of misclassifying a true affected (respectively, unaffected as a control (respectively, case. Power is verified by computer simulation. Results Our major findings are that: (i the median absolute difference between analytic power with our method and simulation power was 0.001 and the absolute difference was no larger than 0.011; (ii as the disease prevalence approaches 0, the cost of misclassifying a unaffected as a case becomes infinitely large while the cost of misclassifying an affected as a control approaches 0. Conclusion Our work enables researchers to specifically quantify power loss and minimum sample size requirements in the presence of phenotype errors, thereby allowing for more realistic study design. For most diseases of current interest, verifying that cases are correctly classified is of paramount importance.

An Adaptive Genetic Association Test Using Double Kernel Machines.

Science.gov (United States)

Zhan, Xiang; Epstein, Michael P; Ghosh, Debashis

2015-10-01

Recently, gene set-based approaches have become very popular in gene expression profiling studies for assessing how genetic variants are related to disease outcomes. Since most genes are not differentially expressed, existing pathway tests considering all genes within a pathway suffer from considerable noise and power loss. Moreover, for a differentially expressed pathway, it is of interest to select important genes that drive the effect of the pathway. In this article, we propose an adaptive association test using double kernel machines (DKM), which can both select important genes within the pathway as well as test for the overall genetic pathway effect. This DKM procedure first uses the garrote kernel machines (GKM) test for the purposes of subset selection and then the least squares kernel machine (LSKM) test for testing the effect of the subset of genes. An appealing feature of the kernel machine framework is that it can provide a flexible and unified method for multi-dimensional modeling of the genetic pathway effect allowing for both parametric and nonparametric components. This DKM approach is illustrated with application to simulated data as well as to data from a neuroimaging genetics study.

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...

Functional relevance for associations between genetic variants and systemic lupus erythematosus.

Directory of Open Access Journals (Sweden)

Fei-Yan Deng

Full Text Available Systemic lupus erythematosus (SLE is a serious prototype autoimmune disease characterized by chronic inflammation, auto-antibody production and multi-organ damage. Recent association studies have identified a long list of loci that were associated with SLE with relatively high statistical power. However, most of them only established the statistical associations of genetic markers and SLE at the DNA level without supporting evidence of functional relevance. Here, using publically available datasets, we performed integrative analyses (gene relationship across implicated loci analysis, differential gene expression analysis and functional annotation clustering analysis and combined with expression quantitative trait loci (eQTLs results to dissect functional mechanisms underlying the associations for SLE. We found that 14 SNPs, which were significantly associated with SLE in previous studies, have cis-regulation effects on four eQTL genes (HLA-DQA1, HLA-DQB1, HLA-DQB2, and IRF5 that were also differentially expressed in SLE-related cell groups. The functional evidence, taken together, suggested the functional mechanisms underlying the associations of 14 SNPs and SLE. The study may serve as an example of mining publically available datasets and results in validation of significant disease-association results. Utilization of public data resources for integrative analyses may provide novel insights into the molecular genetic mechanisms underlying human diseases.

A Genetically Informed Study of the Association Between Harsh Punishment and Offspring Behavioral Problems

Science.gov (United States)

Lynch, Stacy K.; Turkheimer, Eric; D’Onofrio, Brian M.; Mendle, Jane; Emery, Robert E.; Slutske, Wendy S.; Martin, Nicholas G.

2010-01-01

Conclusions about the effects of harsh parenting on children have been limited by research designs that cannot control for genetic or shared environmental confounds. The present study used a sample of children of twins and a hierarchical linear modeling statistical approach to analyze the consequences of varying levels of punishment while controlling for many confounding influences. The sample of 887 twin pairs and 2,554 children came from the Australian Twin Registry. Although corporal punishment per se did not have significant associations with negative childhood outcomes, harsher forms of physical punishment did appear to have specific and significant effects. The observed association between harsh physical punishment and negative outcomes in children survived a relatively rigorous test of its causal status, thereby increasing the authors’ conviction that harsh physical punishment is a serious risk factor for children. PMID:16756394

Homologous Recombination between Genetically Divergent Campylobacter fetus Lineages Supports Host-Associated Speciation

Science.gov (United States)

Duim, Birgitta; van der Graaf-van Bloois, Linda; Wagenaar, Jaap A; Zomer, Aldert L

2018-01-01

Abstract Homologous recombination is a major driver of bacterial speciation. Genetic divergence and host association are important factors influencing homologous recombination. Here, we study these factors for Campylobacter fetus, which shows a distinct intraspecific host dichotomy. Campylobacter fetus subspecies fetus (Cff) and venerealis are associated with mammals, whereas C. fetus subsp. testudinum (Cft) is associated with reptiles. Recombination between these genetically divergent C. fetus lineages is extremely rare. Previously it was impossible to show whether this barrier to recombination was determined by the differential host preferences, by the genetic divergence between both lineages or by other factors influencing recombination, such as restriction-modification, CRISPR/Cas, and transformation systems. Fortuitously, a distinct C. fetus lineage (ST69) was found, which was highly related to mammal-associated C. fetus, yet isolated from a chelonian. The whole genome sequences of two C. fetus ST69 isolates were compared with those of mammal- and reptile-associated C. fetus strains for phylogenetic and recombination analysis. In total, 5.1–5.5% of the core genome of both ST69 isolates showed signs of recombination. Of the predicted recombination regions, 80.4% were most closely related to Cft, 14.3% to Cff, and 5.6% to C. iguaniorum. Recombination from C. fetus ST69 to Cft was also detected, but to a lesser extent and only in chelonian-associated Cft strains. This study shows that despite substantial genetic divergence no absolute barrier to homologous recombination exists between two distinct C. fetus lineages when occurring in the same host type, which provides valuable insights in bacterial speciation and evolution. PMID:29608720

Genetic variation in PCAF, a key mediator in epigenetics, is associated with reduced vascular morbidity and mortality: evidence for a new concept from three independent prospective studies

NARCIS (Netherlands)

Pons, D.; Trompet, S.; Craen, A.J.M.; Thijssen, P.E.; Quax, P.H.A.; de Vries, M.R.; Wierda, R.J.; van den Elsen, P.J.; Monraats, P.S.; Ewing, M.M.; Heijmans, B.T.; Slagboom, P.E.; Zwinderman, A.H.; Doevendans, P.A.F.M.; Tio, R.A.; de Winter, R.J.; de Maat, M.P.M.; Lakoubova, O.A.; Sattar, N.; Sheperd, J.; Westendorp, R.G.J.; Jukema, J.W.

2011-01-01

Aims: This study was designed to investigate the counterbalancing influence of genetic variation in the promoter of the gene encoding P300/CBP associated factor (PCAF), a lysine acetyltransferase (KAT), on coronary heart disease (CHD) and mortality. Methods and results: The association of genetic

Influence of Factor V Leiden on susceptibility to and outcome from critical illness: a genetic association study

DEFF Research Database (Denmark)

Benfield, Thomas; Ejrnæs, Karen; Juul, Klaus

2010-01-01

ABSTRACT: INTRODUCTION: Disturbance of the pro-coagulatant and anti-coagulant balance is associated with a poor outcome from critical illness. The objective of this study is to determine whether the Factor V Leiden (FVL) mutation is associated with susceptibility to or death from critical illness....... METHODS: A genetic association study involving four case cohorts comprising two Gram negative sepsis, one invasive pneumococcal disease and one intensive care unit cohort with a total of 1,249 patients. Controls were derived from a population-based cohort study (N = 8,147). DNA from patients and controls...... not appear to increase the risk of admission due to severe invasive infections. Nevertheless, in the subgroup of patients admitted to intensive care an increased risk and a poorer long-term outcome for individuals with critical illness were observed for FVL mutation carriers....

A practical introduction to Random Forest for genetic association studies in ecology and evolution.

Science.gov (United States)

Brieuc, Marine S O; Waters, Charles D; Drinan, Daniel P; Naish, Kerry A

2018-03-05

Large genomic studies are becoming increasingly common with advances in sequencing technology, and our ability to understand how genomic variation influences phenotypic variation between individuals has never been greater. The exploration of such relationships first requires the identification of associations between molecular markers and phenotypes. Here, we explore the use of Random Forest (RF), a powerful machine-learning algorithm, in genomic studies to discern loci underlying both discrete and quantitative traits, particularly when studying wild or nonmodel organisms. RF is becoming increasingly used in ecological and population genetics because, unlike traditional methods, it can efficiently analyse thousands of loci simultaneously and account for nonadditive interactions. However, understanding both the power and limitations of Random Forest is important for its proper implementation and the interpretation of results. We therefore provide a practical introduction to the algorithm and its use for identifying associations between molecular markers and phenotypes, discussing such topics as data limitations, algorithm initiation and optimization, as well as interpretation. We also provide short R tutorials as examples, with the aim of providing a guide to the implementation of the algorithm. Topics discussed here are intended to serve as an entry point for molecular ecologists interested in employing Random Forest to identify trait associations in genomic data sets. © 2018 John Wiley & Sons Ltd.

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

Clinical and genetic factors associated with suicide in mood disorder patients.

Science.gov (United States)

Antypa, Niki; Souery, Daniel; Tomasini, Mario; Albani, Diego; Fusco, Federica; Mendlewicz, Julien; Serretti, Alessandro

2016-03-01

Suicidality is a continuum ranging from ideation to attempted and completed suicide, with a complex etiology involving both genetic heritability and environmental factors. The majority of suicide events occur in the context of psychiatric conditions, preeminently major depression and bipolar disorder. The present study investigates clinical factors associated with suicide in a sample of 553 mood disorder patients, recruited within the 'Psy Pluriel' center, Centre Européen de Psychologie Médicale, and the Department of Psychiatry of Erasme Hospital (Brussels). Furthermore, genetic association analyses examining polymorphisms within COMT, BDNF, MAPK1 and CREB1 genes were performed in a subsample of 259 bipolar patients. The presence or absence of a previous suicide attempt and of current suicide risk were assessed. A positive association with suicide attempt was reported for younger patients, females, lower educated, smokers, those with higher scores on depressive symptoms and higher functional disability and those with anxiety comorbidity and familial history of suicidality in first- and second-degree relatives. Anxiety disorder comorbidity was the stronger predictor of current suicide risk. No associations were found with polymorphisms within COMT and BDNF genes, whereas significant associations were found with variations in rs13515 (MAPK1) and rs6740584 (CREB1) polymorphisms. From a clinical perspective, our study proposes several clinical characteristics, such as increased depressive symptomatology, anxiety comorbidity, functional disability and family history of suicidality, as correlates associated with suicide. Genetic risk variants in MAPK1 and CREB1 genes might be involved in a dysregulation of inflammatory and neuroplasticity pathways and are worthy of future investigation.

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...

Overview of Epidemiology, Genetics, Birth Defects, and Chromosome Abnormalities Associated With CDH

Science.gov (United States)

Pober, Barbara R.

2010-01-01

Congenital diaphragmatic hernia (CDH) is a common and well-studied birth defect. The etiology of most cases remains unknown but increasing evidence points to genetic causation. The data supporting genetic etiologies which are detailed below include the association of CDH with recurring chromosome abnormalities, the existence of CDH-multiplex families, and the co-occurrence of CDH with additional congenital malformations. PMID:17436298

Insight into the genetic components of community genetics: QTL mapping of insect association in a fast-growing forest tree.

Directory of Open Access Journals (Sweden)

Jennifer DeWoody

Full Text Available Identifying genetic sequences underlying insect associations on forest trees will improve the understanding of community genetics on a broad scale. We tested for genomic regions associated with insects in hybrid poplar using quantitative trait loci (QTL analyses conducted on data from a common garden experiment. The F2 offspring of a hybrid poplar (Populus trichocarpa x P. deltoides cross were assessed for seven categories of insect leaf damage at two time points, June and August. Positive and negative correlations were detected among damage categories and between sampling times. For example, sap suckers on leaves in June were positively correlated with sap suckers on leaves (P<0.001 but negatively correlated with skeletonizer damage (P<0.01 in August. The seven forms of leaf damage were used as a proxy for seven functional groups of insect species. Significant variation in insect association occurred among the hybrid offspring, including transgressive segregation of susceptibility to damage. NMDS analyses revealed significant variation and modest broad-sense heritability in insect community structure among genets. QTL analyses identified 14 genomic regions across 9 linkage groups that correlated with insect association. We used three genomics tools to test for putative mechanisms underlying the QTL. First, shikimate-phenylpropanoid pathway genes co-located to 9 of the 13 QTL tested, consistent with the role of phenolic glycosides as defensive compounds. Second, two insect association QTL corresponded to genomic hotspots for leaf trait QTL as identified in previous studies, indicating that, in addition to biochemical attributes, leaf morphology may influence insect preference. Third, network analyses identified categories of gene models over-represented in QTL for certain damage types, providing direction for future functional studies. These results provide insight into the genetic components involved in insect community structure in a fast

Association Study of MiR-34b/c Genetic Variation and Ulcerative Colitis in Guilan Province

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Zeynab Hosseinpour

2017-04-01

Full Text Available Abstract Background: Ulcerative colitis (UC is a chronic disease that specifically affects the mucosa of the rectum and colon. The pathogenesis of UC is not well defined, but it is proposed that genetic and environmental factors result in an aberrant immune response to a subset of commensal enteric bacteria.The aim of this study was to investigate whether miR-34b/c rs4938723 T/C polymorphism is associated with UC risk. Materials and Methods: Blood samples were collected from 50 patients diagnosed with UC and 100 healthy control subjects. Genomic DNA was extracted from peripheral blood. Genetic variation of miR34b/c was determined by tetra-primers ARMS-PCR (amplification refractory mutation system-polymerase chain reaction. All statistical analyses were conducted using the MedCalc version 12.1. Results: There was a significant difference in genotype and allele distributions between cases and controls. It was observed that the CT heterozygotes had a 2.29-fold increase in risk of UC (OR=2.29, 95%CI=1.08-4.82, p=0.02. Conclusion: It is suggested that the miR34b/c (rs4938723 T>C polymorphism may be associated with the risk of UC. However, larger studies with more patients and controls are needed to confirm this result.

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...

Genetic and Non-genetic Factors Associated With Constipation in Cancer Patients Receiving Opioids

Science.gov (United States)

Laugsand, Eivor A; Skorpen, Frank; Kaasa, Stein; Sabatowski, Rainer; Strasser, Florian; Fayers, Peter; Klepstad, Pål

2015-01-01

Objectives: To examine whether the inter-individual variation in constipation among patients receiving opioids for cancer pain is associated with genetic or non-genetic factors. Methods: Cancer patients receiving opioids were included from 17 centers in 11 European countries. Intensity of constipation was reported by 1,568 patients on a four-point categorical scale. Non-genetic factors were included as covariates in stratified regression analyses on the association between constipation and 75 single-nucleotide polymorphisms (SNPs) within 15 candidate genes related to opioid- or constipation-signaling pathways (HTR3E, HTR4, HTR2A, TPH1, ADRA2A, CHRM3, TACR1, CCKAR, KIT, ARRB2, GHRL, ABCB1, COMT, OPRM1, and OPRD1). Results: The non-genetic factors significantly associated with constipation were type of laxative, mobility and place of care among patients receiving laxatives (N=806), in addition to Karnofsky performance status and presence of metastases among patients not receiving laxatives (N=762) (P<0.01). Age, gender, body mass index, cancer diagnosis, time on opioids, opioid dose, and type of opioid did not contribute to the inter-individual differences in constipation. Five SNPs, rs1800532 in TPH1, rs1799971 in OPRM1, rs4437575 in ABCB1, rs10802789 in CHRM3, and rs2020917 in COMT were associated with constipation (P<0.01). Only rs2020917 in COMT passed the Benjamini–Hochberg criterion for a 10% false discovery rate. Conclusions: Type of laxative, mobility, hospitalization, Karnofsky performance status, presence of metastases, and five SNPs within TPH1, OPRM1, ABCB1, CHRM3, and COMT may contribute to the variability in constipation among cancer patients treated with opioids. Knowledge of these factors may help to develop new therapies and to identify patients needing a more individualized approach to treatment. PMID:26087058

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

Genetics of dietary habits and obesity - a twin study

DEFF Research Database (Denmark)

Hasselbalch, Ann Louise

2010-01-01

residual genetic influence existed. Based on information about habitual diet from the FFQ the genetic influence on total energy intake, macronutrient intake, as well as intake of energy from 20 food groups, was estimated. The proportion of variation in dietary intake explained by variation in genes...... exposures as well as genetic differences between individuals, resulting in differentiated susceptibility to environmental exposures. The evidence for genetic influence on anthropometry has previously been established and has been estimated to be 60-70% based on twin studies. These inter...... mass, but only limited evidence for associations between habitual dietary intake and anthropometry exists. Differences in habitual dietary intake are also partly determined by differences in genes influencing smell and taste preferences. But, so far, only few studies have investigated genetic...

Accounting for genetic and environmental confounds in associations between parent and child characteristics: a systematic review of children-of-twins studies.

Science.gov (United States)

McAdams, Tom A; Neiderhiser, Jenae M; Rijsdijk, Fruhling V; Narusyte, Jurgita; Lichtenstein, Paul; Eley, Thalia C

2014-07-01

Parental psychopathology, parenting style, and the quality of intrafamilial relationships are all associated with child mental health outcomes. However, most research can say little about the causal pathways underlying these associations. This is because most studies are not genetically informative and are therefore not able to account for the possibility that associations are confounded by gene-environment correlation. That is, biological parents not only provide a rearing environment for their child, but also contribute 50% of their genes. Any associations between parental phenotype and child phenotype are therefore potentially confounded. One technique for disentangling genetic from environmental effects is the children-of-twins (COT) method. This involves using data sets comprising twin parents and their children to distinguish genetic from environmental associations between parent and child phenotypes. The COT technique has grown in popularity in the last decade, and we predict that this surge in popularity will continue. In the present article we explain the COT method for those unfamiliar with its use. We present the logic underlying this approach, discuss strengths and weaknesses, and highlight important methodological considerations for researchers interested in the COT method. We also cover variations on basic COT approaches, including the extended-COT method, capable of distinguishing forms of gene-environment correlation. We then present a systematic review of all the behavioral COT studies published to date. These studies cover such diverse phenotypes as psychosis, substance abuse, internalizing, externalizing, parenting, and marital difficulties. In reviewing this literature, we highlight past applications, identify emergent patterns, and suggest avenues for future research. PsycINFO Database Record (c) 2014 APA, all rights reserved.

A large-scale rheumatoid arthritis genetic study identifies association at chromosome 9q33.2.

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Monica Chang

2008-06-01

Full Text Available Rheumatoid arthritis (RA is a chronic, systemic autoimmune disease affecting both joints and extra-articular tissues. Although some genetic risk factors for RA are well-established, most notably HLA-DRB1 and PTPN22, these markers do not fully account for the observed heritability. To identify additional susceptibility loci, we carried out a multi-tiered, case-control association study, genotyping 25,966 putative functional SNPs in 475 white North American RA patients and 475 matched controls. Significant markers were genotyped in two additional, independent, white case-control sample sets (661 cases/1322 controls from North America and 596 cases/705 controls from The Netherlands identifying a SNP, rs1953126, on chromosome 9q33.2 that was significantly associated with RA (OR(common = 1.28, trend P(comb = 1.45E-06. Through a comprehensive fine-scale-mapping SNP-selection procedure, 137 additional SNPs in a 668 kb region from MEGF9 to STOM on 9q33.2 were chosen for follow-up genotyping in a staged-approach. Significant single marker results (P(comb 5.41E-09. The observed association patterns for these SNPs had heightened statistical significance and a higher degree of consistency across sample sets. In addition, the allele frequencies for these SNPs displayed reduced variability between control groups when compared to other SNPs. Lastly, in combination with the other two known genetic risk factors, HLA-DRB1 and PTPN22, the variants reported here generate more than a 45-fold RA-risk differential.

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.

Associations between Salivary Testosterone Levels, Androgen‐Related Genetic Polymorphisms, and Self‐Estimated Ejaculation Latency Time

Directory of Open Access Journals (Sweden)

Patrick Jern, PhD

2014-08-01

Conclusions: We were unable to find support for the hypothesis suggesting an association between T levels and ELT, possibly because of the low number of phenotypically extreme cases (the sample used in the present study was population based. Our results concerning genetic associations should be interpreted with caution until replication studies have been conducted. Jern P, Westberg L, Ankarberg‐Lindgren C, Johansson A, Gunst A, Sandnabba NK, and Santtila P. Associations between salivary testosterone levels, androgen‐related genetic polymorphisms, and self‐estimated ejaculation latency time. Sex Med 2014;2:107–114.

Preimplantation genetic diagnosis associated to Duchenne muscular dystrophy.

Science.gov (United States)

Bianco, Bianca; Christofolini, Denise Maria; Conceição, Gabriel Seixas; Barbosa, Caio Parente

2017-01-01

Duchenne muscular dystrophy is the most common muscle disease found in male children. Currently, there is no effective therapy available for Duchenne muscular dystrophy patients. Therefore, it is essential to make a prenatal diagnosis and provide genetic counseling to reduce the birth of such boys. We report a case of preimplantation genetic diagnosis associated with Duchenne muscular dystrophy. The couple E.P.R., 38-year-old, symptomatic patient heterozygous for a 2 to 47 exon deletion mutation in DMD gene and G.T.S., 39-year-old, sought genetic counseling about preimplantation genetic diagnosis process. They have had a 6-year-old son who died due to Duchenne muscular dystrophy complications. The couple underwent four cycles of intracytoplasmic sperm injection (ICSI) and eight embryos biopsies were analyzed by polymerase chain reaction (PCR) for specific mutation analysis, followed by microarray-based comparative genomic hybridisation (array CGH) for aneuploidy analysis. Preimplantation genetic diagnosis revealed that two embryos had inherited the maternal DMD gene mutation, one embryo had a chromosomal alteration and five embryos were normal. One blastocyst was transferred and resulted in successful pregnancy. The other embryos remain vitrified. We concluded that embryo analysis using associated techniques of PCR and array CGH seems to be safe for embryo selection in cases of X-linked disorders, such as Duchenne muscular dystrophy.

Genetic association with overall survival of taxane-treated lung cancer patients - a genome-wide association study in human lymphoblastoid cell lines followed by a clinical association study

International Nuclear Information System (INIS)

Niu, Nifang; Cunningham, Julie M; Li, Liang; Sun, Zhifu; Yang, Ping; Wang, Liewei; Schaid, Daniel J; Abo, Ryan P; Kalari, Krishna; Fridley, Brooke L; Feng, Qiping; Jenkins, Gregory; Batzler, Anthony; Brisbin, Abra G

2012-01-01

Taxane is one of the first line treatments of lung cancer. In order to identify novel single nucleotide polymorphisms (SNPs) that might contribute to taxane response, we performed a genome-wide association study (GWAS) for two taxanes, paclitaxel and docetaxel, using 276 lymphoblastoid cell lines (LCLs), followed by genotyping of top candidate SNPs in 874 lung cancer patient samples treated with paclitaxel. GWAS was performed using 1.3 million SNPs and taxane cytotoxicity IC50 values for 276 LCLs. The association of selected SNPs with overall survival in 76 small or 798 non-small cell lung cancer (SCLC, NSCLC) patients were analyzed by Cox regression model, followed by integrated SNP-microRNA-expression association analysis in LCLs and siRNA screening of candidate genes in SCLC (H196) and NSCLC (A549) cell lines. 147 and 180 SNPs were associated with paclitaxel or docetaxel IC50s with p-values <10 -4 in the LCLs, respectively. Genotyping of 153 candidate SNPs in 874 lung cancer patient samples identified 8 SNPs (p-value < 0.05) associated with either SCLC or NSCLC patient overall survival. Knockdown of PIP4K2A, CCT5, CMBL, EXO1, KMO and OPN3, genes within 200 kb up-/downstream of the 3 SNPs that were associated with SCLC overall survival (rs1778335, rs2662411 and rs7519667), significantly desensitized H196 to paclitaxel. SNPs rs2662411 and rs1778335 were associated with mRNA expression of CMBL or PIP4K2A through microRNA (miRNA) hsa-miR-584 or hsa-miR-1468. GWAS in an LCL model system, joined with clinical translational and functional studies, might help us identify genetic variations associated with overall survival of lung cancer patients treated paclitaxel

Shared genetics underlying epidemiological association between endometriosis and ovarian cancer

DEFF Research Database (Denmark)

Lu, Yi; Cuellar-Partida, Gabriel; Painter, Jodie N

2015-01-01

Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address...... this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested...... that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We...

[Hypothetical link between endometriosis and xenobiotics-associated genetically modified food].

Science.gov (United States)

Aris, A; Paris, K

2010-12-01

Endometriosis is an oestrogen-dependent inflammatory disease affecting 10 % of reproductive-aged women. Often accompanied by chronic pelvic pain and infertility, endometriosis rigorously interferes with women's quality of life. Although the pathophysiology of endometriosis remains unclear, a growing body of evidence points to the implication of environmental toxicants. Over the last decade, an increase in the incidence of endometriosis has been reported and coincides with the introduction of genetically modified foods in our diet. Even though assessments of genetically modified food risk have not indicated any hazard on human health, xenobiotics-associated genetically modified food, such as pesticides residues and xenoproteins, could be harmful in the long-term. The "low-dose hypothesis", accumulation and biotransformation of pesticides-associated genetically modified food and the multiplied toxicity of pesticides-formulation adjuvants support this hypothesis. This review summarizes toxic effects (in vitro and on animal models) of some xenobiotics-associated genetically modified food, such as glyphosate and Cry1Ab protein, and extrapolates on their potential role in the pathophysiology of endometriosis. Their roles as immune toxicants, pro-oxidants, endocrine disruptors and epigenetic modulators are discussed. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Application of computational methods in genetic study of inflammatory bowel disease.

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Li, Jin; Wei, Zhi; Hakonarson, Hakon

2016-01-21

Genetic factors play an important role in the etiology of inflammatory bowel disease (IBD). The launch of genome-wide association study (GWAS) represents a landmark in the genetic study of human complex disease. Concurrently, computational methods have undergone rapid development during the past a few years, which led to the identification of numerous disease susceptibility loci. IBD is one of the successful examples of GWAS and related analyses. A total of 163 genetic loci and multiple signaling pathways have been identified to be associated with IBD. Pleiotropic effects were found for many of these loci; and risk prediction models were built based on a broad spectrum of genetic variants. Important gene-gene, gene-environment interactions and key contributions of gut microbiome are being discovered. Here we will review the different types of analyses that have been applied to IBD genetic study, discuss the computational methods for each type of analysis, and summarize the discoveries made in IBD research with the application of these methods.

Association of genetic ancestry with breast cancer in ethnically diverse women from Chicago.

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Umaima Al-Alem

Full Text Available Non-Hispanic (nH Black and Hispanic women are disproportionately affected by early onset disease, later stage, and with more aggressive, higher grade and ER/PR negative breast cancers. The purpose of this analysis was to examine whether genetic ancestry could account for these variation in breast cancer characteristics, once data were stratified by self-reported race/ethnicity and adjusted for potential confounding by social and behavioral factors.We used a panel of 100 ancestry informative markers (AIMs to estimate individual genetic ancestry in 656 women from the "Breast Cancer Care in Chicago" study, a multi-ethnic cohort of breast cancer patients to examine the association between individual genetic ancestry and breast cancer characteristics. In addition we examined the association of individual AIMs and breast cancer to identify genes/regions that may potentially play a role in breast cancer disease disparities.As expected, nH Black and Hispanic patients were more likely than nH White patients to be diagnosed at later stages, with higher grade, and with ER/PR negative tumors. Higher European genetic ancestry was protective against later stage at diagnosis (OR 0.7 95%CI: 0.54-0.92 among Hispanic patients, and higher grade (OR 0.73, 95%CI: 0.56-0.95 among nH Black patients. After adjustment for multiple social and behavioral risk factors, the association with later stage remained, while the association with grade was not significant. We also found that the AIM SNP rs10954631 on chromosome 7 was associated with later stage (p = 0.02 and higher grade (p = 0.012 in nH Whites and later stage (p = 0.03 in nH Blacks.Non-European genetic ancestry was associated with later stage at diagnosis in ethnic minorities. The relation between genetic ancestry and stage at diagnosis may be due to genetic factors and/or unmeasured environmental factors that are overrepresented within certain racial/ethnic groups.

Accounting for genetic and environmental confounds in associations between parent and child characteristics : a systematic review of children-of-twins studies

OpenAIRE

McAdams, Tom A; Neiderhiser, Jenae M; Rijsdijk, Fruhling V; Narusyte, Jurgita; Lichtenstein, Paul; Eley, Thalia C

2014-01-01

Parental psychopathology, parenting style, and the quality of intrafamilial relationships are all associated with child mental health outcomes. However, most research can say little about the causal pathways underlying these associations. This is because most studies are not genetically informative and are therefore not able to account for the possibility that associations are confounded by gene-environment correlation. That is, biological parents not only provide a rearing environment for th...

No increase in autism-associated genetic events in children conceived by assisted reproduction.

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Ackerman, Sean; Wenegrat, Julia; Rettew, David; Althoff, Robert; Bernier, Raphael

2014-08-01

To understand the rate of genetic events in patients with autism spectrum disorder (ASD) who were exposed to assisted reproduction. Case control study using genetics data. Twelve collaborating data collection sites across North America as part of the Simons Simplex Collection. 2,760 children with ASD, for whom 1,994 had published copy number variation data and 424 had published gene mutation status available. None. Rates of autism-associated genetic events in children with ASD conceived with assisted reproduction versus those conceived naturally. No statistically significant differences in copy number variations or autism-associated gene-disrupting events were found when comparing ASD patients exposed to assisted reproduction with those not exposed to assisted reproduction. This is the first large genetic association to concurrently examine the genotype of individuals with ASD in relation to their exposure to ART versus natural conception, and it adds reassuring evidence to the argument that ART does not increase the risk of ASD. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

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...

Hierarchical linear modeling of longitudinal pedigree data for genetic association analysis

DEFF Research Database (Denmark)

Tan, Qihua; B Hjelmborg, Jacob V; Thomassen, Mads

2014-01-01

-effect models to explicitly model the genetic relationship. These have proved to be an efficient way of dealing with sample clustering in pedigree data. Although current algorithms implemented in popular statistical packages are useful for adjusting relatedness in the mixed modeling of genetic effects...... associated with blood pressure with estimated inflation factors of 0.99, suggesting that our modeling of random effects efficiently handles the genetic relatedness in pedigrees. Application to simulated data captures important variants specified in the simulation. Our results show that the method is useful......Genetic association analysis on complex phenotypes under a longitudinal design involving pedigrees encounters the problem of correlation within pedigrees, which could affect statistical assessment of the genetic effects. Approaches have been proposed to integrate kinship correlation into the mixed...

Investigation of Genetic Variants Associated with Alzheimer Disease in Parkinson Disease Cognition.

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Barrett, Matthew J; Koeppel, Alexander F; Flanigan, Joseph L; Turner, Stephen D; Worrall, Bradford B

2016-01-01

Meta-analysis of genome-wide association studies have implicated multiple single nucleotide polymorphisms (SNPs) and associated genes with Alzheimer disease. The role of these SNPs in cognitive impairment in Parkinson disease (PD) remains incompletely evaluated. The objective of this study was to test alleles associated with risk of Alzheimer disease for association with cognitive impairment in Parkinson disease (PD). Two datasets with PD subjects accessed through the NIH database of Genotypes and Phenotypes contained both single nucleotide polymorphism (SNP) arrays and mini-mental state exam (MMSE) scores. Genetic data underwent rigorous quality control and we selected SNPs for genes associated with AD other than APOE. We constructed logistic regression and ordinal regression models, adjusted for sex, age at MMSE, and duration of PD, to assess the association between selected SNPs and MMSE score. In one dataset, PICALM rs3851179 was associated with cognitive impairment (MMSE  70 years old (OR = 2.3; adjusted p-value = 0.017; n = 250) but not in PD subjects ≤ 70 years old. Our finding suggests that PICALM rs3851179 could contribute to cognitive impairment in older patients with PD. It is important that future studies consider the interaction of age and genetic risk factors in the development of cognitive impairment in PD.

Genetic architecture for susceptibility to gout in the KARE cohort study.

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Shin, Jimin; Kim, Younyoung; Kong, Minyoung; Lee, Chaeyoung

2012-06-01

This study aimed to identify functional associations of cis-regulatory regions with gout susceptibility using data resulted from a genome-wide association study (GWAS), and to show a genetic architecture for gout with interaction effects among genes within each of the identified functions. The GWAS was conducted with 8314 control subjects and 520 patients with gout in the Korea Association REsource cohort. However, genetic associations with any individual nucleotide variants were not discovered by Bonferroni multiple testing in the GWAS (P>1.42 × 10(-7)). Genomic regions enrichment analysis was employed to identify functional associations of cis-regulatory regions. This analysis revealed several biological processes associated with gout susceptibility, and they were quite different from those with serum uric acid level. Epistasis for susceptibility to gout was estimated using entropy decomposition with selected genes within each biological process identified by the genomic regions enrichment analysis. Some epistases among nucleotide sequence variants for gout susceptibility were found to be larger than their individual effects. This study provided the first evidence that genetic factors for gout susceptibility greatly differed from those for serum uric acid level, which may suggest that research endeavors for identifying genetic factors for gout susceptibility should not be heavily dependent on pathogenesis of uric acid. Interaction effects between genes should be examined to explain a large portion of phenotypic variability for gout susceptibility.

What Ideas Do Students Associate with "Biotechnology" and "Genetic Engineering"?

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Hill, Ruaraidh; Stanisstreet, Martin; Boyes, Edward

2000-01-01

Explores the ideas that students aged 16-19 associate with the terms 'biotechnology' and 'genetic engineering'. Indicates that some students see biotechnology as risky whereas genetic engineering was described as ethically wrong. (Author/ASK)

Genetic association with overall survival of taxane-treated lung cancer patients - a genome-wide association study in human lymphoblastoid cell lines followed by a clinical association study

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Niu Nifang

2012-09-01

Full Text Available Abstract Background Taxane is one of the first line treatments of lung cancer. In order to identify novel single nucleotide polymorphisms (SNPs that might contribute to taxane response, we performed a genome-wide association study (GWAS for two taxanes, paclitaxel and docetaxel, using 276 lymphoblastoid cell lines (LCLs, followed by genotyping of top candidate SNPs in 874 lung cancer patient samples treated with paclitaxel. Methods GWAS was performed using 1.3 million SNPs and taxane cytotoxicity IC50 values for 276 LCLs. The association of selected SNPs with overall survival in 76 small or 798 non-small cell lung cancer (SCLC, NSCLC patients were analyzed by Cox regression model, followed by integrated SNP-microRNA-expression association analysis in LCLs and siRNA screening of candidate genes in SCLC (H196 and NSCLC (A549 cell lines. Results 147 and 180 SNPs were associated with paclitaxel or docetaxel IC50s with p-values -4 in the LCLs, respectively. Genotyping of 153 candidate SNPs in 874 lung cancer patient samples identified 8 SNPs (p-value PIP4K2A, CCT5, CMBL, EXO1, KMO and OPN3, genes within 200 kb up-/downstream of the 3 SNPs that were associated with SCLC overall survival (rs1778335, rs2662411 and rs7519667, significantly desensitized H196 to paclitaxel. SNPs rs2662411 and rs1778335 were associated with mRNA expression of CMBL or PIP4K2A through microRNA (miRNA hsa-miR-584 or hsa-miR-1468. Conclusions GWAS in an LCL model system, joined with clinical translational and functional studies, might help us identify genetic variations associated with overall survival of lung cancer patients treated paclitaxel.

Children's History of Speech-Language Difficulties: Genetic Influences and Associations with Reading-Related Measures

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DeThorne, Laura Segebart; Hart, Sara A.; Petrill, Stephen A.; Deater-Deckard, Kirby; Thompson, Lee Anne; Schatschneider, Chris; Davison, Megan Dunn

2006-01-01

Purpose: This study examined (a) the extent of genetic and environmental influences on children's articulation and language difficulties and (b) the phenotypic associations between such difficulties and direct assessments of reading-related skills during early school-age years. Method: Behavioral genetic analyses focused on parent-report data…

Using imputed genotype data in the joint score tests for genetic association and gene-environment interactions in case-control studies.

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Song, Minsun; Wheeler, William; Caporaso, Neil E; Landi, Maria Teresa; Chatterjee, Nilanjan

2018-03-01

Genome-wide association studies (GWAS) are now routinely imputed for untyped single nucleotide polymorphisms (SNPs) based on various powerful statistical algorithms for imputation trained on reference datasets. The use of predicted allele counts for imputed SNPs as the dosage variable is known to produce valid score test for genetic association. In this paper, we investigate how to best handle imputed SNPs in various modern complex tests for genetic associations incorporating gene-environment interactions. We focus on case-control association studies where inference for an underlying logistic regression model can be performed using alternative methods that rely on varying degree on an assumption of gene-environment independence in the underlying population. As increasingly large-scale GWAS are being performed through consortia effort where it is preferable to share only summary-level information across studies, we also describe simple mechanisms for implementing score tests based on standard meta-analysis of "one-step" maximum-likelihood estimates across studies. Applications of the methods in simulation studies and a dataset from GWAS of lung cancer illustrate ability of the proposed methods to maintain type-I error rates for the underlying testing procedures. For analysis of imputed SNPs, similar to typed SNPs, the retrospective methods can lead to considerable efficiency gain for modeling of gene-environment interactions under the assumption of gene-environment independence. Methods are made available for public use through CGEN R software package. © 2017 WILEY PERIODICALS, INC.

Genetic Variants Involved in Mitochondrial Oxidative Metabolism are associated with Type 2 Diabetes Mellitus in studies of 9,132 Danes

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Snogdal, Lena Sønder

Genetic Variants Involved in Mitochondrial Oxidative Metabolism are associated with Type 2 Diabetes Mellitus in studies of 9,132 Danes Lena Soender Snogdal, Mette Wod, Marie Vestmar, Thomas Sparsø, Daniel R Witte, Torben Jørgensen, Torsten Lauritzen, Anneli Sandbæk, Niels Grarup, Henning Beck......; Research Centre for Prevention and Health, Glostrup University Hospital, Denmark; Faculty of Health Sciences, University of Aarhus, Denmark; Faculty of Health Sciences, University of Aarhus, Denmark Type 2 Diabetes (T2D) is characterized by insulin resistance and failure of the pancreatic beta cells......, the rs9915302 variant in COX10 showed strong association with T2D (OR=1.14, p=7.7x10-6). Our data suggest that genetic variants in or near genes encoding subunits in complex IV (COX5B, COX6B1, COX10) contribute to the pathogenesis of T2D. The observed association of variants in COX5B, COX10 and NDUFV3...

Insight into the Genetic Components of Community Genetics: QTL Mapping of Insect Association in a Fast-Growing Forest Tree

NARCIS (Netherlands)

DeWoody, J.; Viger, M.; Lakatos, F.; Tuba, K.; Taylor, G.; Smulders, M.J.M.

2013-01-01

Identifying genetic sequences underlying insect associations on forest trees will improve the understanding of community genetics on a broad scale. We tested for genomic regions associated with insects in hybrid poplar using quantitative trait loci (QTL) analyses conducted on data from a common

Childhood Abuse Experiences and the COMT and MTHFR Genetic Variants Associated With Male Sexual Orientation in the Han Chinese Populations: A Case-Control Study.

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Qin, Jia-Bi; Zhao, Guang-Lu; Wang, Feng; Cai, Yu-Mao; Lan, Li-Na; Yang, Lin; Feng, Tie-Jian

2018-01-01

Although it is widely acknowledged that genetic and environmental factors are involved in the development of male homosexuality, the causes are not fully understood. To explore the association and interaction of childhood abuse experiences and genetic variants of the catechol-O-methyltransferase (COMT) and methylenetetrahydrofolate reductase (MTHFR) genes with the development of male homosexuality. A case-control study of 537 exclusively homosexual men and 583 exclusively heterosexual men was conducted, with data collected from March 2013 to August 2015. Data were analyzed using χ 2 tests and logistic regression models. Sociodemographic characteristics, childhood abuse experiences, and polymorphisms of COMT at rs4680, rs4818, and rs6267 and MTHFR at rs1801133. More frequent occurrence of physical (adjusted odds ratio [aOR] = 1.78), emotional (aOR = 2.07), and sexual (aOR = 2.53) abuse during childhood was significantly associated with the development of male homosexuality. The polymorphisms of MTHFR at rs1801133 and COMT at rs4818 also were significantly associated with the development of male homosexuality in the homozygote comparisons (T/T vs C/C at rs1801133, aOR = 1.68; G/G vs C/C at rs4818, aOR = 1.75). In addition, significant interaction effects between childhood abuse experiences and the COMT and MTHFR genetic variants on the development of male homosexuality were found. This is the first time that an association of childhood abuse, COMT and MTHFR genetic variants, and their interactions with development of male homosexuality was exhaustively explored, which could help provide new insight into the etiology of male homosexuality. Because homosexual men are a relatively obscure population, it was impossible to select the study participants by random sampling, which could lead to selection bias. In addition, because this was a case-control study, recall bias was inevitable, and we could not verify causality. Childhood abuse and the COMT and MTHFR genetic

Bayesian meta-analysis of genetic association studies with different sets of markers

NARCIS (Netherlands)

Verzilli, Claudio; Shah, Tina; Casas, Juan P.; Chapman, Juliet; Sandhu, Manjinder; Debenham, Sally L.; Boekholdt, Matthijs S.; Khaw, Kay Tee; Wareham, Nicholas J.; Judson, Richard; Benjamin, Emelia J.; Kathiresan, Sekar; Larson, Martin G.; Rong, Jian; Sofat, Reecha; Humphries, Steve E.; Smeeth, Liam; Cavalleri, Gianpiero; Whittaker, John C.; Hingorani, Aroon D.

2008-01-01

Robust assessment of genetic effects on quantitative traits or complex-disease risk requires synthesis of evidence from multiple studies. Frequently, studies have genotyped partially overlapping sets of SNPs within a gene or region of interest, hampering attempts to combine all the available data.

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

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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

A weighted U-statistic for genetic association analyses of sequencing data.

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Wei, Changshuai; Li, Ming; He, Zihuai; Vsevolozhskaya, Olga; Schaid, Daniel J; Lu, Qing

2014-12-01

With advancements in next-generation sequencing technology, a massive amount of sequencing data is generated, which offers a great opportunity to comprehensively investigate the role of rare variants in the genetic etiology of complex diseases. Nevertheless, the high-dimensional sequencing data poses a great challenge for statistical analysis. The association analyses based on traditional statistical methods suffer substantial power loss because of the low frequency of genetic variants and the extremely high dimensionality of the data. We developed a Weighted U Sequencing test, referred to as WU-SEQ, for the high-dimensional association analysis of sequencing data. Based on a nonparametric U-statistic, WU-SEQ makes no assumption of the underlying disease model and phenotype distribution, and can be applied to a variety of phenotypes. Through simulation studies and an empirical study, we showed that WU-SEQ outperformed a commonly used sequence kernel association test (SKAT) method when the underlying assumptions were violated (e.g., the phenotype followed a heavy-tailed distribution). Even when the assumptions were satisfied, WU-SEQ still attained comparable performance to SKAT. Finally, we applied WU-SEQ to sequencing data from the Dallas Heart Study (DHS), and detected an association between ANGPTL 4 and very low density lipoprotein cholesterol. © 2014 WILEY PERIODICALS, INC.

Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.

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Lubitz, Steven A; Lunetta, Kathryn L; Lin, Honghuang; Arking, Dan E; Trompet, Stella; Li, Guo; Krijthe, Bouwe P; Chasman, Daniel I; Barnard, John; Kleber, Marcus E; Dörr, Marcus; Ozaki, Kouichi; Smith, Albert V; Müller-Nurasyid, Martina; Walter, Stefan; Agarwal, Sunil K; Bis, Joshua C; Brody, Jennifer A; Chen, Lin Y; Everett, Brendan M; Ford, Ian; Franco, Oscar H; Harris, Tamara B; Hofman, Albert; Kääb, Stefan; Mahida, Saagar; Kathiresan, Sekar; Kubo, Michiaki; Launer, Lenore J; MacFarlane, Peter W; Magnani, Jared W; McKnight, Barbara; McManus, David D; Peters, Annette; Psaty, Bruce M; Rose, Lynda M; Rotter, Jerome I; Silbernagel, Guenther; Smith, Jonathan D; Sotoodehnia, Nona; Stott, David J; Taylor, Kent D; Tomaschitz, Andreas; Tsunoda, Tatsuhiko; Uitterlinden, Andre G; Van Wagoner, David R; Völker, Uwe; Völzke, Henry; Murabito, Joanne M; Sinner, Moritz F; Gudnason, Vilmundur; Felix, Stephan B; März, Winfried; Chung, Mina; Albert, Christine M; Stricker, Bruno H; Tanaka, Toshihiro; Heckbert, Susan R; Jukema, J Wouter; Alonso, Alvaro; Benjamin, Emelia J; Ellinor, Patrick T

2014-04-01

This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk. AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored. We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases). We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements. The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Associations between branched chain amino acid intake and biomarkers of adiposity and cardiometabolic health independent of genetic factors: A twin study.

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Jennings, Amy; MacGregor, Alex; Pallister, Tess; Spector, Tim; Cassidy, Aedín

2016-11-15

Conflicting data exist on the impact of dietary and circulating levels of branched chain amino acids (BCAA) on cardiometabolic health and it is unclear to what extent these relations are mediated by genetics. In a cross-sectional study of 1997 female twins we examined associations between BCAA intake, measured using food frequency-questionnaires, and a range of markers of cardiometabolic health, including DXA-measured body fat, blood pressure, HOMA-IR, high-sensitivity C-reactive protein (hs-CRP) and lipids. We also measured plasma concentrations of BCAA and known metabolites of amino acid metabolism using untargeted mass spectrometry. Using a within-twin design, multivariable analyses were used to compare the associations between BCAA intake and endpoints of cardiometabolic health, independently of genetic confounding. Higher BCAA intake was significantly associated with lower HOMA-IR (-0.1, P-trend 0.02), insulin (-0.5μU/mL, P-trend 0.03), hs-CRP -0.3mg/L, P-trend 0.01), systolic blood pressure (-2.3mmHg, P-trend 0.01) and waist-to-height ratio (-0.01, P-trend 0.04), comparing extreme quintiles of intake. These associations persisted in within-pair analysis for monozygotic twins for insulin resistance (PBCAA intake and plasma concentrations, although two metabolites previously associated with obesity were inversely associated with BCAA intake (alpha-hydroxyisovalerate and trans-4-hydroxyproline). Higher intakes of BCAA were associated, independently of genetics, with lower insulin resistance, inflammation, blood pressure and adiposity-related metabolites. The BCAA intake associated with our findings is easily achievable in the habitual diet. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Genetic polymorphisms and their association with the prevalence and severity of chronic postsurgical pain: a systematic review.

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Hoofwijk, D M N; van Reij, R R I; Rutten, B P; Kenis, G; Buhre, W F; Joosten, E A

2016-12-01

Although several patient characteristic, clinical, and psychological risk factors for chronic postsurgical pain (CPSP) have been identified, genetic variants including single nucleotide polymorphisms have also become of interest as potential risk factors for the development of CPSP. The aim of this review is to summarize the current evidence on genetic polymorphisms associated with the prevalence and severity of CPSP in adult patients. A systematic review of the literature was performed, and additional literature was obtained by reference tracking. The primary outcome was CPSP, defined as pain at least 2 months after the surgery. Studies performed exclusively in animals were excluded. Out of the 1001 identified studies, 14 studies were selected for inclusion. These studies described 5269 participants in 17 cohorts. A meta-analysis was not possible because of heterogeneity of data and data analysis. Associations with the prevalence or severity of CPSP were reported for genetic variants in the COMT gene, OPRM1, potassium channel genes, GCH1, CACNG, CHRNA6, P2X7R, cytokine-associated genes, human leucocyte antigens, DRD2, and ATXN1 CONCLUSIONS: Research on the topic of genetic variants associated with CPSP is still in its initial phase. Hypothesis-free, genome-wide association studies on large cohorts are needed in this field. In addition, future studies may also integrate genetic risk factors and patient characteristic, clinical, and psychological predictors for CPSP. © The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Systems Genetics Analysis to Identify the Genetic Modulation of a Glaucoma-Associated Gene.

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Chintalapudi, Sumana R; Jablonski, Monica M

2017-01-01

Loss of retinal ganglion cells (RGCs) is one of the hallmarks of retinal neurodegenerative diseases, glaucoma being one of the most common. Recently, γ-synuclein (SNCG) was shown to be highly expressed in the somas and axons of RGCs. In various mouse models of glaucoma, downregulation of Sncg gene expression correlates with RGC loss. To investigate the regulation of Sncg in RGCs, we used a systems genetics approach to identify a gene that modulates the expression of Sncg, followed by confirmatory studies in both healthy and diseased retinas. We found that chromosome 1 harbors an eQTL that modulates the expression of Sncg in the mouse retina and identified Pfdn2 as the candidate upstream modulator of Sncg expression. Downregulation of Pfdn2 in enriched RGCs causes a concomitant reduction in Sncg. In this chapter, we describe our strategy and methods for identifying and confirming a genetic modulation of a glaucoma-associated gene. A similar method can be applied to other genes expressed in other tissues.

Admixture mapping in the Hispanic Community Health Study/Study of Latinos reveals regions of genetic associations with blood pressure traits.

Directory of Open Access Journals (Sweden)

Tamar Sofer

Full Text Available Admixture mapping can be used to detect genetic association regions in admixed populations, such as Hispanics/Latinos, by estimating associations between local ancestry allele counts and the trait of interest. We performed admixture mapping of the blood pressure traits systolic and diastolic blood pressure (SBP, DBP, mean arterial pressure (MAP, and pulse pressure (PP, in a dataset of 12,116 participants from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL. Hispanics/Latinos have three predominant ancestral populations (European, African, and Amerindian, for each of which we separately tested local ancestry intervals across the genome. We identified four regions that were significantly associated with a blood pressure trait at the genome-wide admixture mapping level. A 6p21.31 Amerindian ancestry association region has multiple known associations, but none explained the admixture mapping signal. We identified variants that completely explained this signal. One of these variants had p-values of 0.02 (MAP and 0.04 (SBP in replication testing in Pima Indians. A 11q13.4 Amerindian ancestry association region spans a variant that was previously reported (p-value = 0.001 in a targeted association study of Blood Pressure (BP traits and variants in the vitamin D pathway. There was no replication evidence supporting an association in the identified 17q25.3 Amerindian ancestry association region. For a region on 6p12.3, associated with African ancestry, we did not identify any candidate variants driving the association. It may be driven by rare variants. Whole genome sequence data may be necessary to fine map these association signals, which may contribute to disparities in BP traits between diverse populations.

Genetic diversity of disease-associated loci in Turkish population.

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Karaca, Sefayet; Cesuroglu, Tomris; Karaca, Mehmet; Erge, Sema; Polimanti, Renato

2015-04-01

Many consortia and international projects have investigated the human genetic variation of a large number of ethno-geographic groups. However, populations with peculiar genetic features, such as the Turkish population, are still absent in publically available datasets. To explore the genetic predisposition to health-related traits of the Turkish population, we analyzed 34 genes associated with different health-related traits (for example, lipid metabolism, cardio-vascular diseases, hormone metabolism, cellular detoxification, aging and energy metabolism). We observed relevant differences between the Turkish population and populations with non-European ancestries (that is, Africa and East Asia) in some of the investigated genes (that is, AGT, APOE, CYP1B1, GNB3, IL10, IL6, LIPC and PON1). As most complex traits are highly polygenic, we developed polygenic scores associated with different health-related traits to explore the genetic diversity of the Turkish population with respect to other human groups. This approach showed significant differences between the Turkish population and populations with non-European ancestries, as well as between Turkish and Northern European individuals. This last finding is in agreement with the genetic structure of European and Middle East populations, and may also agree with epidemiological evidences about the health disparities of Turkish communities in Northern European countries.

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.

Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases

Directory of Open Access Journals (Sweden)

Liang He

2016-10-01

Full Text Available Age-related diseases may result from shared biological mechanisms in intrinsic processes of aging. Genetic effects on age-related diseases are often modulated by environmental factors due to their little contribution to fitness or are mediated through certain endophenotypes. Identification of genetic variants with pleiotropic effects on both common complex diseases and endophenotypes may reveal potential conflicting evolutionary pressures and deliver new insights into shared genetic contribution to healthspan and lifespan. Here, we performed pleiotropic meta-analyses of genetic variants using five NIH-funded datasets by integrating univariate summary statistics for age-related diseases and endophenotypes. We investigated three groups of traits: (1 endophenotypes such as blood glucose, blood pressure, lipids, hematocrit, and body mass index, (2 time-to-event outcomes such as the age-at-onset of diabetes mellitus (DM, cancer, cardiovascular diseases (CVDs and neurodegenerative diseases (NDs, and (3 both combined. In addition to replicating previous findings, we identify seven novel genome-wide significant loci (< 5e-08, out of which five are low-frequency variants. Specifically, from Group 2, we find rs7632505 on 3q21.1 in SEMA5B, rs460976 on 21q22.3 (1 kb from TMPRSS2 and rs12420422 on 11q24.1 predominantly associated with a variety of CVDs, rs4905014 in ITPK1 associated with stroke and heart failure, rs7081476 on 10p12.1 in ANKRD26 associated with multiple diseases including DM, CVDs, and NDs. From Group 3, we find rs8082812 on 18p11.22 and rs1869717 on 4q31.3 associated with both endophenotypes and CVDs. Our follow-up analyses show that rs7632505, rs4905014, and rs8082812 have age-dependent effects on coronary heart disease or stroke. Functional annotation suggests that most of these SNPs are within regulatory regions or DNase clusters and in linkage disequilibrium with expression quantitative trait loci, implying their potential regulatory

Solar Radiation-Associated Adaptive SNP Genetic Differentiation in Wild Emmer Wheat, Triticum dicoccoides.

Science.gov (United States)

Ren, Jing; Chen, Liang; Jin, Xiaoli; Zhang, Miaomiao; You, Frank M; Wang, Jirui; Frenkel, Vladimir; Yin, Xuegui; Nevo, Eviatar; Sun, Dongfa; Luo, Ming-Cheng; Peng, Junhua

2017-01-01

Whole-genome scans with large number of genetic markers provide the opportunity to investigate local adaptation in natural populations and identify candidate genes under positive selection. In the present study, adaptation genetic differentiation associated with solar radiation was investigated using 695 polymorphic SNP markers in wild emmer wheat originated in a micro-site at Yehudiyya, Israel. The test involved two solar radiation niches: (1) sun, in-between trees; and (2) shade, under tree canopy, separated apart by a distance of 2-4 m. Analysis of molecular variance showed a small (0.53%) but significant portion of overall variation between the sun and shade micro-niches, indicating a non-ignorable genetic differentiation between sun and shade habitats. Fifty SNP markers showed a medium (0.05 ≤ F ST ≤ 0.15) or high genetic differentiation ( F ST > 0.15). A total of 21 outlier loci under positive selection were identified by using four different F ST -outlier testing algorithms. The markers and genome locations under positive selection are consistent with the known patterns of selection. These results suggested that genetic differentiation between sun and shade habitats is substantial, radiation-associated, and therefore ecologically determined. Hence, the results of this study reflected effects of natural selection through solar radiation on EST-related SNP genetic diversity, resulting presumably in different adaptive complexes at a micro-scale divergence. The present work highlights the evolutionary theory and application significance of solar radiation-driven natural selection in wheat improvement.

Common genetic variants and modification of penetrance of BRCA2-associated breast cancer

DEFF Research Database (Denmark)

Gaudet, Mia M; Kirchhoff, Tomas; Green, Todd

2010-01-01

The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carri...

Common genetic variants and modification of penetrance of BRCA2-associated breast cancer

DEFF Research Database (Denmark)

Gaudet, Mia M; Kirchhoff, Tomas; Green, Todd

2010-01-01

The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation...

Common genetic variants associated with cognitive performance identified using the proxy-phenotype method

NARCIS (Netherlands)

C.A. Rietveld (Niels); T. Esko (Tõnu); G. Davies (Gail); T.H. Pers (Tune); P. Turley (Patrick); B. Benyamin (Beben); C.F. Chabris (Christopher F.); V. Emilsson (Valur); A.D. Johnson (Andrew); J.J. Lee (James J.); C. de Leeuw (Christiaan); R.E. Marioni (Riccardo); S.E. Medland (Sarah Elizabeth); M. Miller (Mike); O. Rostapshova (Olga); S.J. van der Lee (Sven); A.A.E. Vinkhuyzen (Anna A.); N. Amin (Najaf); D. Conley (Dalton); J. Derringer; C.M. van Duijn (Cornelia); R.S.N. Fehrmann (Rudolf); L. Franke (Lude); E.L. Glaeser (Edward L.); N.K. Hansell (Narelle); C. Hayward (Caroline); W.G. Iacono (William); C.A. Ibrahim-Verbaas (Carla); V.W.V. Jaddoe (Vincent); J. Karjalainen (Juha); D. Laibson (David); P. Lichtenstein (Paul); D.C. Liewald (David C.); P.K. Magnusson (Patrik); N.G. Martin (Nicholas); M. McGue (Matt); G. Mcmahon (George); N.L. Pedersen (Nancy); S. Pinker (Steven); D.J. Porteous (David J.); D. Posthuma (Danielle); F. Rivadeneira Ramirez (Fernando); B.H. Smithk (Blair H.); J.M. Starr (John); H.W. Tiemeier (Henning); N.J. Timpsonm (Nicholas J.); M. Trzaskowskin (Maciej); A.G. Uitterlinden (André); F.C. Verhulst (Frank); M.E. Ward (Mary); M.J. Wright (Margaret); G.D. Smith; I.J. Deary (Ian J.); M. Johannesson (Magnus); R. Plomin (Robert); P.M. Visscher (Peter); D.J. Benjamin (Daniel J.); D. Cesarini (David); Ph.D. Koellinger (Philipp)

2014-01-01

textabstractWe identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxyphenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69

Assessing the Probability that a Finding Is Genuine for Large-Scale Genetic Association Studies.

Science.gov (United States)

Kuo, Chia-Ling; Vsevolozhskaya, Olga A; Zaykin, Dmitri V

2015-01-01

Genetic association studies routinely involve massive numbers of statistical tests accompanied by P-values. Whole genome sequencing technologies increased the potential number of tested variants to tens of millions. The more tests are performed, the smaller P-value is required to be deemed significant. However, a small P-value is not equivalent to small chances of a spurious finding and significance thresholds may fail to serve as efficient filters against false results. While the Bayesian approach can provide a direct assessment of the probability that a finding is spurious, its adoption in association studies has been slow, due in part to the ubiquity of P-values and the automated way they are, as a rule, produced by software packages. Attempts to design simple ways to convert an association P-value into the probability that a finding is spurious have been met with difficulties. The False Positive Report Probability (FPRP) method has gained increasing popularity. However, FPRP is not designed to estimate the probability for a particular finding, because it is defined for an entire region of hypothetical findings with P-values at least as small as the one observed for that finding. Here we propose a method that lets researchers extract probability that a finding is spurious directly from a P-value. Considering the counterpart of that probability, we term this method POFIG: the Probability that a Finding is Genuine. Our approach shares FPRP's simplicity, but gives a valid probability that a finding is spurious given a P-value. In addition to straightforward interpretation, POFIG has desirable statistical properties. The POFIG average across a set of tentative associations provides an estimated proportion of false discoveries in that set. POFIGs are easily combined across studies and are immune to multiple testing and selection bias. We illustrate an application of POFIG method via analysis of GWAS associations with Crohn's disease.

Exploring genetic variants predisposing to diabetes mellitus and their association with indicators of socioeconomic status.

Science.gov (United States)

Schmidt, Börge; Dragano, Nico; Scherag, André; Pechlivanis, Sonali; Hoffmann, Per; Nöthen, Markus M; Erbel, Raimund; Jöckel, Karl-Heinz; Moebus, Susanne

2014-06-16

The relevance of disease-related genetic variants for the explanation of social inequalities in complex diseases is unclear and empirical analyses are largely missing. The aim of our study was to examine whether genetic variants predisposing to diabetes mellitus are associated with socioeconomic status in a population-based cohort. We genotyped 11 selected diabetes-related single nucleotide polymorphisms in 4655 participants (age 45-75 years) of the Heinz Nixdorf Recall study. Diabetes status was self-reported or defined by blood glucose levels. Education, income and paternal occupation were assessed as indicators of socioeconomic status. Multiple regression analyses were used to examine the association of socioeconomic status and diabetes by estimating sex-specific and age-adjusted prevalence ratios and their corresponding 95%-confidence intervals. To explore the relationship between individual single nucleotide polymorphisms and socioeconomic status sex- and age-adjusted odds ratios were computed. We adjusted the alpha-level for multiple testing of 11 single nucleotide polymorphisms using Bonferroni's method (α(BF) ~ 0.005). In addition, we explored the association of a genetic risk score with socioeconomic status. Social inequalities in diabetes were observed for all indicators of socioeconomic status. However, there were no significant associations between individual diabetes-related risk alleles and socioeconomic status with odds ratios ranging from 0.87 to 1.23. Similarly, the genetic risk score analysis revealed no evidence for an association. Our data provide no evidence for an association between 11 diabetes-related risk alleles and different indicators of socioeconomic status in a population-based cohort, suggesting that the explored genetic variants do not contribute to health inequalities in diabetes.

Eleven loci with new reproducible genetic associations with allergic disease risk

NARCIS (Netherlands)

Ferreira, Manuel A.R.; Vonk, Judith M; Baurecht, Hansjörg; Marenholz, Ingo; Tian, Chao; Hoffman, Joshua D; Helmer, Quinta; Tillander, Annika; Ullemar, Vilhelmina; Lu, Yi; Rüschendorf, Franz; Hinds, David A; Hübner, Norbert; Weidinger, Stephan; Magnusson, Patrik Ke; Jorgenson, Eric; Lee, Young-Ae; Boomsma, Dorret I; Karlsson, Robert; Almqvist, Catarina; Koppelman, Gerard H; Paternoster, Lavinia

2018-01-01

BACKGROUND: A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever and eczema. Many more risk loci shared between these common allergic diseases remain to be discovered, which could point to new therapeutic opportunities.

Association study of genetic variants in estrogen metabolic pathway genes and colorectal cancer risk and survival.

Science.gov (United States)

Li, Shuwei; Xie, Lisheng; Du, Mulong; Xu, Kaili; Zhu, Lingjun; Chu, Haiyan; Chen, Jinfei; Wang, Meilin; Zhang, Zhengdong; Gu, Dongying

2018-05-16

Although studies have investigated the association of genetic variants and the abnormal expression of estrogen-related genes with colorectal cancer risk, the evidence remains inconsistent. We clarified the relationship of genetic variants in estrogen metabolic pathway genes with colorectal cancer risk and survival. A case-control study was performed to assess the association of single-nucleotide polymorphisms (SNPs) in ten candidate genes with colorectal cancer risk in a Chinese population. A logistic regression model and Cox regression model were used to calculate SNP effects on colorectal cancer susceptibility and survival, respectively. Expression quantitative trait loci (eQTL) analysis was conducted using the Genotype-Tissue Expression (GTEx) project dataset. The sequence kernel association test (SKAT) was used to perform gene-set analysis. Colorectal cancer risk and rs3760806 in SULT2B1 were significantly associated in both genders [male: OR = 1.38 (1.15-1.66); female: OR = 1.38 (1.13-1.68)]. Two SNPs in SULT1E1 were related to progression-free survival (PFS) [rs1238574: HR = 1.24 (1.02-1.50), P = 2.79 × 10 -2 ; rs3822172: HR = 1.30 (1.07-1.57), P = 8.44 × 10 -3 ] and overall survival (OS) [rs1238574: HR = 1.51 (1.16-1.97), P = 2.30 × 10 -3 ; rs3822172: HR = 1.53 (1.67-2.00), P = 2.03 × 10 -3 ]. Moreover, rs3760806 was an eQTL for SULT2B1 in colon samples (transverse: P = 3.6 × 10 -3 ; sigmoid: P = 1.0 × 10 -3 ). SULT2B1 expression was significantly higher in colorectal tumor tissues than in normal tissues in the Cancer Genome Atlas (TCGA) database (P colorectal cancer susceptibility and survival.

Genetic Alterations in Gastric Cancer Associated with Helicobacter pylori Infection

Directory of Open Access Journals (Sweden)

Gonzalo Castillo-Rojas

2017-05-01

Full Text Available Gastric cancer is a world health problem and depicts the fourth leading mortality cause from malignancy in Mexico. Causation of gastric cancer is not only due to the combined effects of environmental factors and genetic variants. Recent molecular studies have transgressed a number of genes involved in gastric carcinogenesis. The aim of this review is to understand the recent basics of gene expression in the development of the process of gastric carcinogenesis. Genetic variants, polymorphisms, desoxyribonucleic acid methylation, and genes involved in mediating inflammation have been associated with the development of gastric carcinogenesis. Recently, these genes (interleukin 10, Il-17, mucin 1, β-catenin, CDX1, SMAD4, SERPINE1, hypoxia-inducible factor 1 subunit alpha, GSK3β, CDH17, matrix metalloproteinase 7, RUNX3, RASSF1A, TFF1, HAI-2, and COX-2 have been studied in association with oncogenic activation or inactivation of tumor suppressor genes. All these mechanisms have been investigated to elucidate the process of gastric carcinogenesis, as well as their potential use as biomarkers and/or molecular targets to treatment of disease.

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

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

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

Genome-wide association study identifies variants in HORMAD2 associated with tonsillectomy

DEFF Research Database (Denmark)

Feenstra, Bjarke; Bager, Peter; Liu, Xueping

2017-01-01

BACKGROUND: Inflammation of the tonsils is a normal response to infection, but some individuals experience recurrent, severe tonsillitis and massive hypertrophy of the tonsils in which case surgical removal of the tonsils may be considered. OBJECTIVE: To identify common genetic variants associate...... the molecular mechanisms underlying the genetic association involve general lymphoid hyper-reaction throughout the mucosa-associated lymphoid tissue system.......BACKGROUND: Inflammation of the tonsils is a normal response to infection, but some individuals experience recurrent, severe tonsillitis and massive hypertrophy of the tonsils in which case surgical removal of the tonsils may be considered. OBJECTIVE: To identify common genetic variants associated...... with tonsillectomy. METHODS: We used tonsillectomy information from Danish health registers and carried out a genome-wide association study comprising 1464 patients and 12 019 controls of Northwestern European ancestry, with replication in an independent sample set of 1575 patients and 1367 controls. RESULTS...

Genetic origin of the relationship between parental negativity and behavior problems from early childhood to adolescence: A longitudinal genetically sensitive study

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Alemany, Silvia; Rijsdijk, Frühling V.; Haworth, Claire Margaret Alison; Fañanás, Lourdes; Plomin, Robert

2013-01-01

Little is known about how genetic and environmental factors contribute to the association between parental negativity and behavior problems from early childhood to adolescence. The current study fitted a cross-lagged model in a sample consisting of 4,075 twin pairs to explore (a) the role of genetic and environmental factors in the relationship between parental negativity and behavior problems from age 4 to age 12, (b) whether parent-driven and child-driven processes independently explain the association, and (c) whether there are sex differences in this relationship. Both phenotypes showed substantial genetic influence at both ages. The concurrent overlap between them was mainly accounted for by genetic factors. Causal pathways representing stability of the phenotypes and parent-driven and child-driven effects significantly and independently account for the association. Significant but slight differences were found between males and females for parent-driven effects. These results were highly similar when general cognitive ability was added asa covariate. In summary, the longitudinal association between parental negativity and behavior problems seems to be bidirectional and mainly accounted for by genetic factors. Furthermore, child-driven effects were mainly genetically mediated, and parent-driven effects were a function of both genetic and shared-environmental factors. PMID:23627958

Dietary ascorbic acid and subsequent change in body weight and waist circumference: associations may depend on genetic predisposition to obesity - a prospective study of three independent cohorts

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2014-01-01

Background Cross-sectional data suggests that a low level of plasma ascorbic acid positively associates with both Body Mass Index (BMI) and Waist Circumference (WC). This leads to questions about a possible relationship between dietary intake of ascorbic acid and subsequent changes in anthropometry, and whether such associations may depend on genetic predisposition to obesity. Hence, we examined whether dietary ascorbic acid, possibly in interaction with the genetic predisposition to a high BMI, WC or waist-hip ratio adjusted for BMI (WHR), associates with subsequent annual changes in weight (∆BW) and waist circumference (∆WC). Methods A total of 7,569 participants’ from MONICA, the Diet Cancer and Health study and the INTER99 study were included in the study. We combined 50 obesity associated single nucleotide polymorphisms (SNPs) in four genetic scores: a score of all SNPs and a score for each of the traits (BMI, WC and WHR) with which the SNPs associate. Linear regression was used to examine the association between ascorbic acid intake and ΔBW or ΔWC. SNP-score × ascorbic acid interactions were examined by adding product terms to the models. Results We found no significant associations between dietary ascorbic acid and ∆BW or ∆WC. Regarding SNP-score × ascorbic acid interactions, each additional risk allele of the 14 WHR associated SNPs associated with a ∆WC of 0.039 cm/year (P = 0.02, 95% CI: 0.005 to 0.073) per 100 mg/day higher ascorbic acid intake. However, the association to ∆WC only remained borderline significant after adjustment for ∆BW. Conclusion In general, our study does not support an association between dietary ascorbic acid and ∆BW or ∆WC, but a diet with a high content of ascorbic acid may be weakly associated to higher WC gain among people who are genetically predisposed to a high WHR. However, given the quite limited association any public health relevance is questionable. PMID:24886192

T-cell receptor variable genes and genetic susceptibility to celiac disease: an association and linkage study.

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Roschmann, E; Wienker, T F; Gerok, W; Volk, B A

1993-12-01

Genetic susceptibility of celiac disease is primarily associated with a particular combination of and HLA-DQA1/DQB1 gene; however, this does not fully account for the genetic predisposition. Therefore, the aim of this study was to examine whether T-cell receptor (TCR) genes may be susceptibility genes in celiac disease. HLA class II typing was performed by polymerase chain reaction amplification in combination with sequence-specific oligonucleotide hybridization. TCR alpha (TCRA), TCR gamma (TCRG), and TCR beta (TCRB) loci were investigated by restriction fragment length polymorphism analysis. Allelic frequencies of TCRA, TCRG, and TCRB variable genes were compared between patients with celiac disease (n = 53) and control patients (n = 67), and relative risk (RR) estimates were calculated. The RR was 1.67 for allele C1 at TCRA1, 3.35 for allele D2 at TCRA2, 1.66 for allele B2 at TCRG, and 1.35 for allele B at TCRB, showing no significant association. Additionally, linkage analysis was performed in 23 families. The logarithm of odd scores for celiac disease vs. the TCR variable genes at TCRA, TCRG, and TCRB showed no significant linkage. These data suggest that the analyzed TCR variable gene segments V alpha 1.2, V gamma 11, and V beta 8 do not play a major role in susceptibility to celiac disease.

Genetic Variants in Transcription Factors Are Associated With the Pharmacokinetics and Pharmacodynamics of Metformin

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Goswami, S; Yee, SW; Stocker, S; Mosley, JD; Kubo, M; Castro, R; Mefford, JA; Wen, C; Liang, X; Witte, J; Brett, C; Maeda, S; Simpson, MD; Hedderson, MM; Davis, RL; Roden, DM; Giacomini, KM; Savic, RM

2014-01-01

One-third of type 2 diabetes patients do not respond to metformin. Genetic variants in metformin transporters have been extensively studied as a likely contributor to this high failure rate. Here, we investigate, for the first time, the effect of genetic variants in transcription factors on metformin pharmacokinetics (PK) and response. Overall, 546 patients and healthy volunteers contributed their genome-wide, pharmacokinetic (235 subjects), and HbA1c data (440 patients) for this analysis. Five variants in specificity protein 1 (SP1), a transcription factor that modulates the expression of metformin transporters, were associated with changes in treatment HbA1c (P < 0.01) and metformin secretory clearance (P < 0.05). Population pharmacokinetic modeling further confirmed a 24% reduction in apparent clearance in homozygous carriers of one such variant, rs784888. Genetic variants in other transcription factors, peroxisome proliferator–activated receptor-α and hepatocyte nuclear factor 4-α, were significantly associated with HbA1c change only. Overall, our study highlights the importance of genetic variants in transcription factors as modulators of metformin PK and response. PMID:24853734

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

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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

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.

Genetic determinants of cardiometabolic risk: a proposed model for phenotype association and interaction.

Science.gov (United States)

Blackett, Piers R; Sanghera, Dharambir K

2013-01-01

This review provides a translational and unifying summary of metabolic syndrome genetics and highlights evidence that genetic studies are starting to unravel and untangle origins of the complex and challenging cluster of disease phenotypes. The associated genes effectively express in the brain, liver, kidney, arterial endothelium, adipocytes, myocytes, and β cells. Progression of syndrome traits has been associated with ectopic lipid accumulation in the arterial wall, visceral adipocytes, myocytes, and liver. Thus, it follows that the genetics of dyslipidemia, obesity, and nonalcoholic fatty liver disease are central in triggering progression of the syndrome to overt expression of disease traits and have become a key focus of interest for early detection and for designing prevention and treatments. To support the "birds' eye view" approach, we provide a road-map depicting commonality and interrelationships between the traits and their genetic and environmental determinants based on known risk factors, metabolic pathways, pharmacologic targets, treatment responses, gene networks, pleiotropy, and association with circadian rhythm. Although only a small portion of the known heritability is accounted for and there is insufficient support for clinical application of gene-based prediction models, there is direction and encouraging progress in a rapidly moving field that is beginning to show clinical relevance. Copyright © 2013 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Pitfalls in setting up genetic studies on preeclampsia.

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Laivuori, Hannele

2013-04-01

This presentation will consider approaches to discover susceptibility genes for a complex genetic disorder such as preeclampsia. The clinical disease presumably results from the additive effects of multiple sequence variants from the mother and the foetus together with environmental factors. Disease heterogeneity and underpowered study designs are likely to be behind non-reproducible results in candidate gene association studies. To avoid spurious findings, sample size and characteristics of the study populations as well as replication studies in an independent study population should be an essential part of a study design. In family-based linkage studies relationship with genotype and phenotype may be modified by a variety of factors. The large number of families needed in discovering genetic variants with modest effect sizes is difficult to attain. Moreover, the identification of underlying mutations has proven difficult. When pooling data or performing meta-analyses from different populations, disease and locus heterogeneity may become a major issue. First genome-wide association studies (GWAS) have identified risk loci for preeclampsia. Adequately powered replication studies are critical in order to replicate the initial GWAS findings. This approach requires rigorous multiple testing correction. The expected effect sizes of individual sequence variants on preeclampsia are small, but this approach is likely to decipher new clues to the pathogenesis. The rare variants, gene-gene and gene-environmental interactions as well as noncoding genetic variations and epigenetics are expected to explain the missing heritability. Next-generation sequencing technologies will make large amount of data on genomes and transcriptomes available. Complexity of the data poses a challenge. Different depths of coverage might be chosen depending on the design of the study, and validation of the results by different methods is mandatory. In order to minimize disease heterogeneity in

Common genetic variation and novel loci associated with volumetric mammographic density.

Science.gov (United States)

Brand, Judith S; Humphreys, Keith; Li, Jingmei; Karlsson, Robert; Hall, Per; Czene, Kamila

2018-04-17

Mammographic density (MD) is a strong and heritable intermediate phenotype of breast cancer, but much of its genetic variation remains unexplained. We conducted a genetic association study of volumetric MD in a Swedish mammography screening cohort (n = 9498) to identify novel MD loci. Associations with volumetric MD phenotypes (percent dense volume, absolute dense volume, and absolute nondense volume) were estimated using linear regression adjusting for age, body mass index, menopausal status, and six principal components. We also estimated the proportion of MD variance explained by additive contributions from single-nucleotide polymorphisms (SNP-based heritability [h 2 SNP ]) in 4948 participants of the cohort. In total, three novel MD loci were identified (at P associated with breast cancer in available meta-analysis data including 122,977 breast cancer cases and 105,974 control subjects (P < 0.05). h 2 SNP (SE) estimates for percent dense, absolute dense, and nondense volume were 0.29 (0.07), 0.31 (0.07), and 0.25 (0.07), respectively. Corresponding ratios of h 2 SNP to previously observed narrow-sense h 2 estimates in the same cohort were 0.46, 0.72, and 0.41, respectively. These findings provide new insights into the genetic basis of MD and biological mechanisms linking MD to breast cancer risk. Apart from identifying three novel loci, we demonstrate that at least 25% of the MD variance is explained by common genetic variation with h 2 SNP /h 2 ratios varying between dense and nondense MD components.

A new lead from genetic studies in depressed siblings: assessing studies of chromosome 3.

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Hamilton, Steven P

2011-08-01

Studies by Breen et al. and Pergadia et al. find evidence for genetic linkage between major depressive disorder and the same region on chromosome 3. The linked region contains the gene GRM7, which encodes a protein for the metabotropic glutamate receptor 7 (mGluR7). Both studies used affected sibling pairs, and neither was able to replicate its finding using association studies in individuals from larger population-based studies. Other family-based studies have also failed to find a signal in this region. Furthermore, there are some differences in how the phenotype was classified, with Breen et al. finding evidence only in the most severely affected patients. Nonetheless, the finding is not without other substantive support. A meta-analysis of 3,957 case subjects with major depressive disorder and 3,428 control subjects from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D), Genetics of Recurrent Early-onset Depression (GenRED), and the Genetic Association Information Network-MDD (GAIN-MDD) data sets demonstrated a region of association for major depressive disorder within GRM7. Thus, the significance of this finding remains uncertain, although it points to a gene that might hold significant promise for further developments in studying the pathophysiology and treatment of major depressive disorder.

Psoriasis and cardiometabolic traits: modest association but distinct genetic architectures

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Koch, Manja; Baurecht, Hansjörg; Ried, Janina S.; Rodriguez, Elke; Schlesinger, Sabrina; Volks, Natalie; Gieger, Christian; Rückert, Ina-Maria; Heinrich, Luise; Willenborg, Christina; Smith, Catherine; Peters, Annette; Thorand, Barbara; Koenig, Wolfgang; Lamina, Claudia; Jansen, Henning; Kronenberg, Florian; Seissler, Jochen; Thiery, Joachim; Rathmann, Wolfgang; Schunkert, Heribert; Erdmann, Jeanette; Barker, Jonathan; Nair, Rajan P; Tsoi, Lam C; Elder, James T; Mrowietz, Ulrich; Weichenthal, Michael; Mucha, Sören; Schreiber, Stefan; Franke, Andre; Schmitt, Jochen; Lieb, Wolfgang; Weidinger, Stephan

2015-01-01

Psoriasis has been linked to cardiometabolic diseases, but epidemiological findings are inconsistent. We investigated the association between psoriasis and cardiometabolic outcomes in a German cross-sectional study (n=4.185) and a prospective cohort of German Health Insurance beneficiaries (n=1.811.098). A potential genetic overlap was explored using genome-wide data from >22.000 coronary artery disease (CAD) and >4.000 psoriasis cases, and with a dense genotyping study of cardiometabolic risk loci on 927 psoriasis cases and 3.717 controls. Controlling for major confounders, in the cross-sectional analysis psoriasis was significantly associated with type 2 diabetes (T2D, adjusted odd’s ratio OR=2.36; 95% confidence interval CI=1.26–4.41) and myocardial infarction (MI, OR=2.26, 95% CI=1.03–4.96). In the longitudinal study, psoriasis slightly increased the risk for incident T2D (adjusted relative risk RR=1.11; 95%CI=1.08–1.14) and MI (RR=1.14; 95%CI=1.06–1.22), with highest risk increments in systemically treated psoriasis, which accounted for 11 and 17 excess cases of T2D and MI per 10,000 person-years. Except for weak signals from within the MHC, there was no evidence for genetic risk loci shared between psoriasis and cardiometabolic traits. Our findings suggest that psoriasis, in particular severe psoriasis, increases risk for T2D and MI, and that the genetic architecture of psoriasis and cardiometabolic traits is largely distinct. PMID:25599394

Genetic diversity and population structure of Pisum sativum accessions for marker-trait association of lipid content

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Sajjad Ahmad

2015-06-01

Full Text Available Field pea (Pisum sativum L. is an important protein-rich pulse crop produced globally. Increasing the lipid content of Pisum seeds through conventional and contemporary molecular breeding tools may bring added value to the crop. However, knowledge about genetic diversity and lipid content in field pea is limited. An understanding of genetic diversity and population structure in diverse germplasm is important and a prerequisite for genetic dissection of complex characteristics and marker-trait associations. Fifty polymorphic microsatellite markers detecting a total of 207 alleles were used to obtain information on genetic diversity, population structure and marker-trait associations. Cluster analysis was performed using UPGMA to construct a dendrogram from a pairwise similarity matrix. Pea genotypes were divided into five major clusters. A model-based population structure analysis divided the pea accessions into four groups. Percentage lipid content in 35 diverse pea accessions was used to find potential associations with the SSR markers. Markers AD73, D21, and AA5 were significantly associated with lipid content using a mixed linear model (MLM taking population structure (Q and relative kinship (K into account. The results of this preliminary study suggested that the population could be used for marker-trait association mapping studies.

A Population Based Study of the Genetic Association between Catecholamine Gene Variants and Spontaneous Low-Frequency Fluctuations in Reaction Time.

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Jojanneke A Bastiaansen

Full Text Available The catecholamines dopamine and noradrenaline have been implicated in spontaneous low-frequency fluctuations in reaction time, which are associated with attention deficit hyperactivity disorder (ADHD and subclinical attentional problems. The molecular genetic substrates of these behavioral phenotypes, which reflect frequency ranges of intrinsic neuronal oscillations (Slow-4: 0.027-0.073 Hz; Slow-5: 0.010-0.027 Hz, have not yet been investigated. In this study, we performed regression analyses with an additive model to examine associations between low-frequency fluctuations in reaction time during a sustained attention task and genetic markers across 23 autosomal catecholamine genes in a large young adult population cohort (n = 964, which yielded greater than 80% power to detect a small effect size (f(2 = 0.02 and 100% power to detect a small/medium effect size (f(2 = 0.15. At significance levels corrected for multiple comparisons, none of the gene variants were associated with the magnitude of low-frequency fluctuations. Given the study's strong statistical power and dense coverage of the catecholamine genes, this either indicates that associations between low-frequency fluctuation measures and catecholamine gene variants are absent or that they are of very small effect size. Nominally significant associations were observed between variations in the alpha-2A adrenergic receptor gene (ADRA2A and the Slow-5 band. This is in line with previous reports of an association between ADRA2A gene variants and general reaction time variability during response selection tasks, but the specific association of these gene variants and low-frequency fluctuations requires further confirmation. Pharmacological challenge studies could in the future provide convergent evidence for the noradrenergic modulation of both general and time sensitive measures of intra-individual variability in reaction time.

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

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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.

The association of XRCC3 Thr241Met genetic variant with risk of ...

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genetic variant could be potentially associated with the risk of prostate cancer. However ... Results: Overall, significant associations were detected in the heterozygote comparison genetic model. (CT versus (vs.) ..... Quantifying hetero- geneity in ...

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

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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.

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.

Significance of genetic variants in DLC1 and their association with hepatocellular carcinoma

Science.gov (United States)

XIE, CHENG-RONG; SUN, HONG-GUANG; SUN, YU; ZHAO, WEN-XIU; ZHANG, SHENG; WANG, XIAO-MIN; YIN, ZHEN-YU

2015-01-01

DLC1 has been shown to be downregulated or absent in hepatocellular carcinoma (HCC) and is associated with tumorigenesis and development. However, only a small number of studies have focused on genetic variations of DLC1. The present study performed exon sequencing for the DLC1 gene in HCC tissue samples from 105 patients to identify functional genetic variation of DLC1 and its association with HCC susceptibility, clinicopathological features and prognosis. A novel missense mutation and four non-synonymous single nucleotide polymorphisms (SNPs; rs3816748, rs11203495, rs3816747 and rs532841) were identified. A significant correlation of rs3816747 polymorphisms with HCC susceptibility was identified. Compared to individuals with the GG genotype of rs3816747, those with the GA (odds ratio (OR)=0.486; P=0.037) or GA+AA genotype (OR=0.51; P=0.039) were associated with a significantly decreased HCC risk. Furthermore, patients with the GC+CC genotype of rs3816748, the TC+CC genotype of rs11203495 or the GA+AA genotype of rs3816747 had small-sized tumors compared with those carrying the wild-type genotype. No significant association of DLC1 SNPs with the patients' prognosis was found. These results indicated that genetic variations in the DLC1 gene may confer a risk for HCC. PMID:26095787

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.

The Association between Infants' Attention Control and Social Inhibition Is Moderated by Genetic and Environmental Risk for Anxiety

Science.gov (United States)

Brooker, Rebecca J.; Neiderhiser, Jenae M.; Kiel, Elizabeth J.; Leve, Leslie D.; Shaw, Daniel S.; Reiss, David

2011-01-01

Infant social inhibition is associated with increased risk for anxiety later in life. Although both genetic and environmental factors are associated with anxiety, little empirical work has addressed how developing regulatory abilities work with genetic and environmental risk to exacerbate or mitigate problem behaviors. The current study was aimed…

A genetic analysis of epistaxis as associated with EIPH in the ...

African Journals Online (AJOL)

Pedigree and race run data from Thoroughbreds racing in Southern Africa, covering the period 1986-2002 (63 146 horses in pedigree data-set and 778 532 race runs), were analysed in order to study genetic and environmental factors affecting the incidence of epistaxis as associated with \\"exercise-induced pulmonary ...

Genetic relatedness and spatial associations of dusky-footed woodrats (Neotoma fuscipes)

Science.gov (United States)

Robin J. Innes; Mary Brooke McEachern; Dirk H. Van Vuren; John M. Eadie; Douglas A. Kelt; Michael L. Johnson

2012-01-01

We studied the association between space sharing and kinship in a solitary rodent, the dusky-footed woodrat (Neotoma fuscipes). Genetic relatedness was inversely correlated with geographic distance for female woodrats but not for males, a pattern consistent with female philopatry and male dispersal. However, some female neighbors were unrelated, suggesting the...

Effect of Two Lipoprotein (a-Associated Genetic Variants on Plasminogen Levels and Fibrinolysis

Directory of Open Access Journals (Sweden)

Hong Wang

2016-11-01

Full Text Available Two genetic variants (rs3798220 and rs10455872 in the apolipoprotein (a gene (LPA have been implicated in cardiovascular disease (CVD, presumably through their association with lipoprotein (a [Lp(a] levels. While Lp(a is recognized as a lipoprotein with atherogenic and thrombogenic characteristics, it is unclear whether or not the two Lp(a-associated genetic variants are also associated with markers of thrombosis (i.e., plasminogen levels and fibrinolysis. In the present study, we genotyped the two genetic variants in 2919 subjects of the Old Order Amish (OOA and recruited 146 subjects according to the carrier and noncarrier status for rs3798220 and rs10455872, and also matched for gender and age. We measured plasma Lp(a and plasminogen levels in these subjects, and found that the concentrations of plasma Lp(a were 2.62- and 1.73-fold higher in minor allele carriers of rs3798220 and rs10455872, respectively, compared with noncarriers (P = 2.04 × 10−17 and P = 1.64 × 10−6, respectively. By contrast, there was no difference in plasminogen concentrations between carriers and noncarriers of rs3798220 and rs10455872. Furthermore, we observed no association between carrier status of rs3798220 or rs10455872 with clot lysis time. Finally, plasminogen mRNA expression in liver samples derived from 76 Caucasian subjects was not significantly different between carriers and noncarriers of these two genetic variants. Our results provide further insight into the mechanism of action behind two genetic variants previously implicated in CVD risk and show that these polymorphisms are not major modulating factors for plasma plasminogen levels and fibrinolysis.

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....

Bias due to two-stage residual-outcome regression analysis in genetic association studies.

Science.gov (United States)

Demissie, Serkalem; Cupples, L Adrienne

2011-11-01

Association studies of risk factors and complex diseases require careful assessment of potential confounding factors. Two-stage regression analysis, sometimes referred to as residual- or adjusted-outcome analysis, has been increasingly used in association studies of single nucleotide polymorphisms (SNPs) and quantitative traits. In this analysis, first, a residual-outcome is calculated from a regression of the outcome variable on covariates and then the relationship between the adjusted-outcome and the SNP is evaluated by a simple linear regression of the adjusted-outcome on the SNP. In this article, we examine the performance of this two-stage analysis as compared with multiple linear regression (MLR) analysis. Our findings show that when a SNP and a covariate are correlated, the two-stage approach results in biased genotypic effect and loss of power. Bias is always toward the null and increases with the squared-correlation between the SNP and the covariate (). For example, for , 0.1, and 0.5, two-stage analysis results in, respectively, 0, 10, and 50% attenuation in the SNP effect. As expected, MLR was always unbiased. Since individual SNPs often show little or no correlation with covariates, a two-stage analysis is expected to perform as well as MLR in many genetic studies; however, it produces considerably different results from MLR and may lead to incorrect conclusions when independent variables are highly correlated. While a useful alternative to MLR under , the two -stage approach has serious limitations. Its use as a simple substitute for MLR should be avoided. © 2011 Wiley Periodicals, Inc.

Differential Genetic Associations for Systemic Lupus Erythematosus Based on Anti–dsDNA Autoantibody Production

Science.gov (United States)

Chung, Sharon A.; Taylor, Kimberly E.; Graham, Robert R.; Nititham, Joanne; Lee, Annette T.; Ortmann, Ward A.; Jacob, Chaim O.; Alarcón-Riquelme, Marta E.; Tsao, Betty P.; Harley, John B.; Gaffney, Patrick M.; Moser, Kathy L.; Petri, Michelle; Demirci, F. Yesim; Kamboh, M. Ilyas; Manzi, Susan; Gregersen, Peter K.; Langefeld, Carl D.; Behrens, Timothy W.; Criswell, Lindsey A.

2011-01-01

Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti–dsDNA autoantibody production, a SLE–related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti–dsDNA autoantibody positive (anti–dsDNA +, n = 811) and anti–dsDNA autoantibody negative (anti–dsDNA –, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti–dsDNA + SLE. Far fewer and weaker associations were observed for anti–dsDNA – SLE. For example, rs7574865 in STAT4 had an OR for anti–dsDNA + SLE of 1.77 (95% CI 1.57–1.99, p = 2.0E-20) compared to an OR for anti–dsDNA – SLE of 1.26 (95% CI 1.12–1.41, p = 2.4E-04), with pheterogeneity<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti–dsDNA + SLE and were not associated with anti–dsDNA – SLE. In conclusion, we identified differential genetic associations with SLE based on anti–dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti–dsDNA – SLE. PMID

Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production.

Directory of Open Access Journals (Sweden)

Sharon A Chung

2011-03-01

Full Text Available Systemic lupus erythematosus (SLE is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti-dsDNA autoantibody production, a SLE-related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti-dsDNA autoantibody positive (anti-dsDNA +, n = 811 and anti-dsDNA autoantibody negative (anti-dsDNA -, n = 906 SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti-dsDNA + SLE. Far fewer and weaker associations were observed for anti-dsDNA - SLE. For example, rs7574865 in STAT4 had an OR for anti-dsDNA + SLE of 1.77 (95% CI 1.57-1.99, p = 2.0E-20 compared to an OR for anti-dsDNA - SLE of 1.26 (95% CI 1.12-1.41, p = 2.4E-04, with p(heterogeneity<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti-dsDNA + SLE and were not associated with anti-dsDNA - SLE. In conclusion, we identified differential genetic associations with SLE based on anti-dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti-dsDNA - SLE.

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

In search of shared and non-shared influences on infant attachment: A behavior-genetic study of the association between sensitivity and attachment

NARCIS (Netherlands)

Fearon, R.M.; van IJzendoorn, M.H.; Fonagy, P.; Bakermans-Kranenburg, M.J.; Schuengel, C.; Bokhorst, C.L.

2006-01-01

The current article presents results from a twin study of genetic and environmental components of maternal sensitivity and infant attachment and their association. The sample consisted of 136 twin pairs from 2 sites: Leiden, the Netherlands, and London, UK. Maternal sensitivity was assessed in the

Association studies in common endocrine diseases (review article

Directory of Open Access Journals (Sweden)

Akrami SM

2007-05-01

Full Text Available Our understanding of the pathogenesis of endocrine disorders increase rapidly by genetic studies at the molecular level. Common endocrine disorders such as diabetes mellitus, obesity, osteoporosis, dyslipidemia and cancer follow the multifactorial model in the genetic aspect. This review tries to clarify the approach in molecular studies of such diseases for clinicians in different specialties. How to evaluate a possible association between a single nucleotide polymorphism and an endocrinopathy or its complication is the main concern of this review. Two approaches for gene mapping will be discussed as well as main challenges regarding each approach. All such genetic studies ideally include some test of the association between genome sequence variation and the phenotype of interest such as the trait itself, the presence of a given complication, or measures of some endocrinopathy-related intermediate trait. Despite different advances in this analysis, there are major concerns regarding the overall performance and robustness of genetic association studies. By using powerful new high-throughput methods, further insights to molecular basis of such endocrine disorders can be expected. Close correlation between geneticists and clinicians can effectively bridge between basic sciences and clinical investigations.

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

SimHap GUI: an intuitive graphical user interface for genetic association analysis.

Science.gov (United States)

Carter, Kim W; McCaskie, Pamela A; Palmer, Lyle J

2008-12-25

Researchers wishing to conduct genetic association analysis involving single nucleotide polymorphisms (SNPs) or haplotypes are often confronted with the lack of user-friendly graphical analysis tools, requiring sophisticated statistical and informatics expertise to perform relatively straightforward tasks. Tools, such as the SimHap package for the R statistics language, provide the necessary statistical operations to conduct sophisticated genetic analysis, but lacks a graphical user interface that allows anyone but a professional statistician to effectively utilise the tool. We have developed SimHap GUI, a cross-platform integrated graphical analysis tool for conducting epidemiological, single SNP and haplotype-based association analysis. SimHap GUI features a novel workflow interface that guides the user through each logical step of the analysis process, making it accessible to both novice and advanced users. This tool provides a seamless interface to the SimHap R package, while providing enhanced functionality such as sophisticated data checking, automated data conversion, and real-time estimations of haplotype simulation progress. SimHap GUI provides a novel, easy-to-use, cross-platform solution for conducting a range of genetic and non-genetic association analyses. This provides a free alternative to commercial statistics packages that is specifically designed for genetic association analysis.

Consanguinity and major genetic disorders in Saudi children: Acommunity-based cross-sectional study

International Nuclear Information System (INIS)

El-Mouzan, Mohammad I.; Al-Salloum, Abdullah A.; Al-Herbish, Abdullah S.; Qurachi, Mansour M.; Al-Omar, Ahmad A.

2008-01-01

There is a high rate of consanguinity in Saudi Arabia; however,information on its relationship with genetic disorders is limited. Theobjective of this cross-sectional study was to explore the role ofconsanguinity in genetic disorders. The study sample was determined by amultistage probability random sampling procedure. Primary care physiciansperformed a history and physical examination of all children and adolescentsyounger than 19 years and all cases of genetic diseases were recorded. Thechi-square test was used to compare proportions. During the two-year studyperiod (2004-2005), 11554 of 11874 (97%) mothers answered the question onconsanguinity and 6470 of 11554 (56%) were consanguineous. There was nosignificant association between first-cousin consanguinity and Down syndrome(P=0.55). Similarly, there was no significant association with either sicklecell disease (P=0.97) or glucose-6-phosphate dehydrogenase deficiency(P=0.67) for-cousin in consanguinity. A borderline statistical significancewas found for major congenital malformations (P=0.05). However, the mostsignificant association with first-cousin consanguinity was congenital heartdisease (CHD) (P=0.01). Finally, no significant association was found fortype 1 diabetes mellitus (P=0.92). For all types of consanguinity, similartrends of association were found, with a definite statistically significantassociation only with CHD (P=0.003). The data suggest a significant role ofparental consanguinity in CHD. However, a relationship between consanguinityand other genetic diseases could not be established. The effect ofconsanguinity on genetic diseases is not uniform and this should be takeninto consideration in genetic counseling. (author)

In situ genetic association for serotiny, a fire-related trait, in Mediterranean maritime pine (Pinus pinaster).

Science.gov (United States)

Budde, Katharina B; Heuertz, Myriam; Hernández-Serrano, Ana; Pausas, Juli G; Vendramin, Giovanni G; Verdú, Miguel; González-Martínez, Santiago C

2014-01-01

Wildfire is a major ecological driver of plant evolution. Understanding the genetic basis of plant adaptation to wildfire is crucial, because impending climate change will involve fire regime changes worldwide. We studied the molecular genetic basis of serotiny, a fire-related trait, in Mediterranean maritime pine using association genetics. A single nucleotide polymorphism (SNP) set was used to identify genotype : phenotype associations in situ in an unstructured natural population of maritime pine (eastern Iberian Peninsula) under a mixed-effects model framework. RR-BLUP was used to build predictive models for serotiny in this region. Model prediction power outside the focal region was tested using independent range-wide serotiny data. Seventeen SNPs were potentially associated with serotiny, explaining approximately 29% of the trait phenotypic variation in the eastern Iberian Peninsula. Similar prediction power was found for nearby geographical regions from the same maternal lineage, but not for other genetic lineages. Association genetics for ecologically relevant traits evaluated in situ is an attractive approach for forest trees provided that traits are under strong genetic control and populations are unstructured, with large phenotypic variability. This will help to extend the research focus to ecological keystone non-model species in their natural environments, where polymorphisms acquired their adaptive value. © 2013 The Authors. New Phytologist © 2013 New Phytologist Trust.

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

Lifestyle modifies obesity-associated risk of cardiovascular disease in a genetically homogeneous population

DEFF Research Database (Denmark)

Jørgensen, Marit E; Borch-Johnsen, Knut; Bjerregaard, Peter

2006-01-01

BACKGROUND: The association between obesity and cardiovascular disease risk differs across populations. Whether such differences in obesity-related risk factors exist within population groups of the same genetic origin but with differences in lifestyle remains to be determined. OBJECTIVE: The aim...... was to analyze whether obesity was associated with the same degree of metabolic disturbances in 2 groups of genetically homogeneous Inuit who were exposed to considerable differences in lifestyle. DESIGN: We studied obesity and cardiovascular disease risk factors in a cross-sectional population survey of 2311...... Inuit living in Denmark (n = 995) or Greenland (n = 1316). The participants received an oral-glucose-tolerance test. Blood tests were supplemented by structured interviews and anthropometric and blood pressure measurements. RESULTS: The trend in the association between obesity and metabolic effects...

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

Seasonality shows evidence for polygenic architecture and genetic correlation with schizophrenia and bipolar disorder – a meta-analysis of genetic studies

Science.gov (United States)

Byrne, Enda M; Raheja, Uttam; Stephens, Sarah H.; Heath, Andrew C; Madden, Pamela AF; Vaswani, Dipika; Nijjar, Gagan V.; Ryan, Kathleen A.; Youssufi, Hassaan; Gehrman, Philip R; Shuldiner, Alan R; Martin, Nicholas G; Montgomery, Grant W; Wray, Naomi R; Nelson, Elliot C; Mitchell, Braxton D; Postolache, Teodor T

2015-01-01

Objective To test common genetic variants for association with seasonality (seasonal changes in mood and behavior) and to investigate whether there are shared genetic risk factors between psychiatric disorders and seasonality. Methods A meta-analysis of genome-wide association studies (GWAS) conducted in Australian and Amish populations in whom the Seasonal Pattern Assessment Questionnaire (SPAQ) had been administered. The total sample size was 4,156 individuals. Genetic risk scores based on results from prior large GWAS studies of bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ) were calculated to test for overlap in risk between psychiatric disorders and seasonality. Results The most significant association was with rs11825064 (p = 1.7 × 10−6, β = 0.64, S.E = 0.13), an intergenic SNP found on chromosome 11. The evidence for overlap in risk factors was strongest for SCZ and seasonality, with the SCZ genetic profile scores explaining 3% of the variance in log-transformed GSS. BD genetic profile scores were also significantly associated with seasonality, although at much weaker levels, and no evidence for overlap in risk was detected between MDD and seasonality. Conclusions Common SNPs of very large effect likely do not exist for seasonality in the populations examined. As expected, there was overlapping genetic risk factors for BD (but not MDD) with seasonality. Unexpectedly, the risk for SCZ and seasonality had the largest overlap, an unprecedented finding that requires replication in other populations, and has potential clinical implications considering overlapping cognitive deficits in seasonal affective disorders and SCZ PMID:25562672

Molecular evaluation of genetic diversity and association studies in ...

Indian Academy of Sciences (India)

2012-04-05

Apr 5, 2012 ... Phenotypic data were collected for yield and component traits. Pattern of ...... ical isolation, evolutionary time gaps, mutation, selection and genetic drift ..... along chromosome 1 of maize (Zea mays ssp. mays L.). Proc. Natl.

Two-level mixed modeling of longitudinal pedigree data for genetic association analysis

DEFF Research Database (Denmark)

Tan, Q.

2013-01-01

of follow-up. Approaches have been proposed to integrate kinship correlation into the mixed effect models to explicitly model the genetic relationship which have been proven as an efficient way for dealing with sample clustering in pedigree data. Although useful for adjusting relatedness in the mixed...... assess the genetic associations with the mean level and the rate of change in a phenotype both with kinship correlation integrated in the mixed effect models. We apply our method to longitudinal pedigree data to estimate the genetic effects on systolic blood pressure measured over time in large pedigrees......Genetic association analysis on complex phenotypes under a longitudinal design involving pedigrees encounters the problem of correlation within pedigrees which could affect statistical assessment of the genetic effects on both the mean level of the phenotype and its rate of change over the time...

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

Genetic Variants Associated with Hyperandrogenemia in PCOS Pathophysiology

Science.gov (United States)

2018-01-01

Polycystic ovary syndrome is a multifactorial endocrine disorder whose pathophysiology baffles many researchers till today. This syndrome is typically characterized by anovulatory cycles and infertility, altered gonadotropin levels, obesity, and bulky multifollicular ovaries on ultrasound. Hyperandrogenism and insulin resistance are hallmark features of its complex pathophysiology. Hyperandrogenemia is a salient feature of PCOS and a major contributor to cosmetic anomalies including hirsutism, acne, and male pattern alopecia in affected women. Increased androgen levels may be intrinsic or aggravated by preexisting insulin resistance in women with PCOS. Studies have reported augmented ovarian steroidogenesis patterns attributed mainly to theca cell hypertrophy and altered expression of key enzymes in the steroidogenic pathway. Candidate gene studies have been performed in order to delineate the association of polymorphisms in genes, which encode enzymes in the intricate cascade of steroidogenesis or modulate the levels and action of circulating androgens, with risk of PCOS development and its related traits. However, inconsistent findings have impacted the emergence of a unanimously accepted genetic marker for PCOS susceptibility. In the current review, we have summarized the influence of polymorphisms in important androgen related genes in governing genetic predisposition to PCOS and its related metabolic and reproductive traits. PMID:29670770

Genetic and environmental influences on the association between performance-based self-esteem and exhaustion: A study of the self-worth notion of burnout.

Science.gov (United States)

Svedberg, Pia; Hallsten, Lennart; Narusyte, Jurgita; Bodin, Lennart; Blom, Victoria

2016-10-01

In the self-worth model, burnout is considered to be a syndrome of performance-based self-esteem (PBSE) and experiences of exhaustion. Studies have shown that PBSE and burnout indices such as Pines' Burnout Measure (BM) are associated. Whether these variables have overlapping etiologies has however not been studied before. Genetic and environmental components of covariation between PBSE and exhaustion measured with Pines' BM were examined in a bivariate Cholesky model using data from 14,875 monozygotic and dizygotic Swedish twins. Fifty-two per cent of the phenotypic correlation (r = 0.41) between PBSE and Pines' BM was explained by genetics and 48% by environmental factors. The findings of the present study strengthen the assumption that PBSE should be considered in the burnout process as proposed by the self-worth conception of burnout. The present results extend our understanding of the link between this contingent self-esteem construct and exhaustion and provide additional information about the underlying mechanisms in terms of genetics and environment. This finding corroborates the assumed syndrome view on burnout, while it also suggests an altered view of how the syndrome emerges and how it can be alleviated. © 2016 Scandinavian Psychological Associations and John Wiley & Sons Ltd.

Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

Science.gov (United States)

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, Tõnu; Go, Min Jin; Harris, Sarah E; Hartiala, Jaana; Kasela, Silva; Kasturiratne, Anuradhani; Khor, Chiea-Chuen; Kleber, Marcus E; Li, Huaixing; Yu Mok, Zuan; 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; Da Silva Couto Alves, Alexessander; Das, Shikta; Dorajoo, Rajkumar; Hopewell, Jemma C; Kim, Yun Kyoung; Koivula, Robert W; Luan, Jian’an; Lyytikäinen, 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, Inês; 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; Katsuya, 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; Müller-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; Ann Rozario, Michelle; Ruggiero, Daniela; Sala, Cinzia F; Sarju, Ralhan; Shimokawa, Kazuro; Snieder, Harold; Sparsø, 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, Väinö; Ueshima, Hirotsugu; Uitterlinden, André 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; Jørgensen, Torben; Jukema, J Wouter; kähönen, Mika; Kajio, Hiroshi; Kivimaki, Mika; Lee, Jong-Young; Lehtimäki, Terho; Linneberg, Allan; Miki, Tetsuro; Pedersen, Oluf; Samani, Nilesh J; Sørensen, 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; März, 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

2016-01-01

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 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation. PMID:26390057

Genetically distinct subsets within ANCA-associated vasculitis.

LENUS (Irish Health Repository)

Lyons, Paul A

2012-07-19

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener\\'s granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis.

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....

SIRT1 genetic variants associate with the metabolic response of Caucasians to a controlled lifestyle intervention – the TULIP Study

Directory of Open Access Journals (Sweden)

Stefan Norbert

2008-11-01

Full Text Available Abstract Background Sirtuin1 (SIRT1 regulates gene expression in distinct metabolic pathways and mediates beneficial effects of caloric restriction in animal models. In humans, SIRT1 genetic variants associate with fasting energy expenditure. To investigate the relevance of SIRT1 for human metabolism and caloric restriction, we analyzed SIRT1 genetic variants in respect to the outcome of a controlled lifestyle intervention in Caucasians at risk for type 2 diabetes. Methods A total of 1013 non-diabetic Caucasians from the Tuebingen Family Study (TUEF were genotyped for four tagging SIRT1 SNPs (rs730821, rs12413112, rs7069102, rs2273773 for cross-sectional association analyses with prediabetic traits. SNPs that associated with basal energy expenditure in the TUEF cohort were additionally analyzed in 196 individuals who underwent a controlled lifestyle intervention (Tuebingen Lifestyle Intervention Program; TULIP. Multivariate regressions analyses with adjustment for relevant covariates were performed to detect associations of SIRT1 variants with the changes in anthropometrics, weight, body fat or metabolic characteristics (blood glucose, insulin sensitivity, insulin secretion and liver fat, measured by magnetic resonance techniques after the 9-month follow-up test in the TULIP study. Results Minor allele (X/A carriers of rs12413112 (G/A had a significantly lower basal energy expenditure (p = 0.04 and an increased respiratory quotient (p = 0.02. This group (rs12413112: X/A was resistant against lifestyle-induced improvement of fasting plasma glucose (GG: -2.01%, X/A: 0.53%; p = 0.04, had less increase in insulin sensitivity (GG: 17.3%, X/A: 9.6%; p = 0.05 and an attenuated decline in liver fat (GG: -38.4%, X/A: -7.5%; p = 0.01. Conclusion SIRT1 plays a role for the individual lifestyle intervention response, possibly owing to decreased basal energy expenditure and a lower lipid-oxidation rate in rs12413112 X/A allele carriers. SIRT1 genetic

Genetic Association of CD247 (CD3ζ) with SLE in a Large-Scale Multiethnic Study

OpenAIRE

Martins, Madalena; Williams, Adrienne H.; Comeau, Mary; Marion, Miranda; Ziegler, Julie T.; Freedman, Barry I.; Merrill, Joan T.; Glenn, Stuart B.; Kelly, Jennifer A.; Sivils, Kathy M.; James, Judith A.; Guthridge, Joel M.; Alarcón-Riquelme, Marta E.; Bae, Sang-Cheol; Kim, Jae-Hoon

2015-01-01

A classic T-cell phenotype in systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters T-cell receptor signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multiethnic population. We typed 44 contiguous CD247 single-nucleotide polymorphisms (SNPs) i...

Genetic association of HCRTR2, ADH4 and CLOCK genes with cluster headache: a Chinese population-based case-control study.

Science.gov (United States)

Fan, Zhiliang; Hou, Lei; Wan, Dongjun; Ao, Ran; Zhao, Dengfa; Yu, Shengyuan

2018-01-09

Cluster headache (CH), a rare primary headache disorder, is currently thought to be a genetic susceptibility which play a role in CH susceptibility. A large numbers of genetic association studies have confirmed that the HCRTR2 (Hypocretin Receptor 2) SNP rs2653349, and the ADH4 (Alcohol Dehydrogenase 4) SNP rs1126671 and rs1800759 polymorphisms are linked to CH. In addition, the CLOCK (Circadian Locomotor Output Cycles Kaput) gene is becoming a research hotspot for CH due to encoding a transcription factor that serves as a basic driving force for circadian rhythm in humans. The purpose of this study was to evaluate the association between CH and the HCRTR2, ADH4 and CLOCK genes in a Chinese CH case-control sample. We genotyped polymorphisms of nine single nucleotide polymorphisms (SNPs) in the HCRTR2, ADH4 and CLOCK genes to perform an association study on a Chinese Han CH case-control sample (112 patients and 192 controls),using Sequenom MALDI-TOF mass spectrometry iPLEX platform. The frequencies and distributions of genotypes and haplotypes were statistically compared between the case and control groups to identify associations with CH. The effects of SNPs on CH were further investigated by multiple logistic regression. The frequency of the HCRTR2 SNP rs3800539 GA genotype was significantly higher in cases than in controls (48.2% vs.37.0%). The GA genotypes was associated with a higher CH risk (OR = 1.483, 95% CI: 0.564-3.387, p = 0.038), however, after Bonferroni correction, the association lost statistical significance. Haplotype analysis of the HCRTR2 SNPs showed that among eight haplotypes, only H1-GTGGGG was linked to a reduced CH risk (44.7% vs. 53.1%, OR = 0.689, 95% CI =0.491~0.966, p = 0.030). No significant association of ADH4, CLOCK SNPs with CH was statistically detected in the present study. Association between HCRTR2, ADH4,CLOCK gene polymorphisms and CH was not significant in the present study, however, haplotype analysis indicated

Does degree of gyrification underlie the phenotypic and genetic associations between cortical surface area and cognitive ability?

Science.gov (United States)

Docherty, Anna R; Hagler, Donald J; Panizzon, Matthew S; Neale, Michael C; Eyler, Lisa T; Fennema-Notestine, Christine; Franz, Carol E; Jak, Amy; Lyons, Michael J; Rinker, Daniel A; Thompson, Wesley K; Tsuang, Ming T; Dale, Anders M; Kremen, William S

2015-02-01

The phenotypic and genetic relationship between global cortical size and general cognitive ability (GCA) appears to be driven by surface area (SA) and not cortical thickness (CT). Gyrification (cortical folding) is an important property of the cortex that helps to increase SA within a finite space, and may also improve connectivity by reducing distance between regions. Hence, gyrification may be what underlies the SA-GCA relationship. In previous phenotypic studies, a 3-dimensional gyrification index (3DGI) has been positively associated with cognitive ability and negatively associated with mild cognitive impairment, Alzheimer's disease, and psychiatric disorders affecting cognition. However, the differential genetic associations of 3DGI and SA with GCA are still unclear. We examined the heritability of 3DGI, and the phenotypic, genetic, and environmental associations of 3DGI with SA and GCA in a large sample of adult male twins (N = 512). Nearly 85% of the variance in 3DGI was due to genes, and 3DGI had a strong phenotypic and genetic association with SA. Both 3DGI and total SA had positive phenotypic correlations with GCA. However, the SA-GCA correlation remained significant after controlling for 3DGI, but not the other way around. There was also significant genetic covariance between SA and GCA, but not between 3DGI and GCA. Thus, despite the phenotypic and genetic associations between 3DGI and SA, our results do not support the hypothesis that gyrification underlies the association between SA and GCA. Copyright © 2014 Elsevier Inc. All rights reserved.

Music genetics research: Association with musicality of a polymorphism in the AVPR1A gene.

Science.gov (United States)

Mariath, Luiza Monteavaro; Silva, Alexandre Mauat da; Kowalski, Thayne Woycinck; Gattino, Gustavo Schulz; Araujo, Gustavo Andrade de; Figueiredo, Felipe Grahl; Tagliani-Ribeiro, Alice; Roman, Tatiana; Vianna, Fernanda Sales Luiz; Schuler-Faccini, Lavínia; Schuch, Jaqueline Bohrer

2017-01-01

Musicality is defined as a natural tendency, sensibility, knowledge, or talent to create, perceive, and play music. Musical abilities involve a great range of social and cognitive behaviors, which are influenced by both environmental and genetic factors. Although a number of studies have yielded insights into music genetics research, genes and biological pathways related to these traits are not fully understood. Our hypothesis in the current study is that genes associated with different behaviors could also influence the musical phenotype. Our aim was to investigate whether polymorphisms in six genes (AVPR1A, SLC6A4, ITGB3, COMT, DRD2 and DRD4) related to social and cognitive traits are associated with musicality in a sample of children. Musicality was assessed through an individualized music therapy assessment profile (IMTAP) which has been validated in Brazil to measure musical ability. We show here that the RS1 microsatellite of the AVPR1A gene is nominally associated with musicality, corroborating previous results linking AVPR1A with musical activity. This study is one of the first to investigate musicality in a comprehensive way, and it contributes to better understand the genetic basis underlying musical ability.

Acquisition of Genetic Aberrations by Activation-Induced Cytidine Deaminase (AID) during Inflammation-Associated Carcinogenesis

International Nuclear Information System (INIS)

Takai, Atsushi; Marusawa, Hiroyuki; Chiba, Tsutomu

2011-01-01

Genetic abnormalities such as nucleotide alterations and chromosomal disorders that accumulate in various tumor-related genes have an important role in cancer development. The precise mechanism of the acquisition of genetic aberrations, however, remains unclear. Activation-induced cytidine deaminase (AID), a nucleotide editing enzyme, is essential for the diversification of antibody production. AID is expressed only in activated B lymphocytes under physiologic conditions and induces somatic hypermutation and class switch recombination in immunoglobulin genes. Inflammation leads to aberrant AID expression in various gastrointestinal organs and increased AID expression contributes to cancer development by inducing genetic alterations in epithelial cells. Studies of how AID induces genetic disorders are expected to elucidate the mechanism of inflammation-associated carcinogenesis

Characterization of clinical and genetic risk factors associated with dyslipidemia after kidney transplantation.

Science.gov (United States)

Numakura, Kazuyuki; Kagaya, Hideaki; Yamamoto, Ryohei; Komine, Naoki; Saito, Mitsuru; Hiroshi, Tsuruta; Akihama, Susumu; Inoue, Takamitsu; Narita, Shintaro; Tsuchiya, Norihiko; Habuchi, Tomonori; Niioka, Takenori; Miura, Masatomo; Satoh, Shigeru

2015-01-01

We determined the prevalence of dyslipidemia in a Japanese cohort of renal allograft recipients and investigated clinical and genetic characteristics associated with having the disease. In total, 126 patients that received renal allograft transplants between February 2002 and August 2011 were studied, of which 44 recipients (34.9%) were diagnosed with dyslipidemia at 1 year after transplantation. Three clinical factors were associated with a risk of having dyslipidemia: a higher prevalence of disease observed among female than male patients (P = 0.021) and treatment with high mycophenolate mofetil (P = 0.012) and prednisolone (P = 0.023) doses per body weight at 28 days after transplantation. The genetic association between dyslipidemia and 60 previously described genetic polymorphisms in 38 putative disease-associated genes was analyzed. The frequency of dyslipidemia was significantly higher in patients with the glucocorticoid receptor (NR3C1) Bcl1 G allele than in those with the CC genotype (P = 0.001). A multivariate analysis revealed that the NR3C1 Bcl1 G allele was a significant risk factor for the prevalence of dyslipidemia (odds ratio = 4.6; 95% confidence interval = 1.8-12.2). These findings may aid in predicting a patient's risk of developing dyslipidemia.

Characterization of Clinical and Genetic Risk Factors Associated with Dyslipidemia after Kidney Transplantation

Science.gov (United States)

Numakura, Kazuyuki; Kagaya, Hideaki; Yamamoto, Ryohei; Komine, Naoki; Saito, Mitsuru; Hiroshi, Tsuruta; Akihama, Susumu; Narita, Shintaro; Tsuchiya, Norihiko; Habuchi, Tomonori; Niioka, Takenori; Miura, Masatomo; Satoh, Shigeru

2015-01-01

We determined the prevalence of dyslipidemia in a Japanese cohort of renal allograft recipients and investigated clinical and genetic characteristics associated with having the disease. In total, 126 patients that received renal allograft transplants between February 2002 and August 2011 were studied, of which 44 recipients (34.9%) were diagnosed with dyslipidemia at 1 year after transplantation. Three clinical factors were associated with a risk of having dyslipidemia: a higher prevalence of disease observed among female than male patients (P = 0.021) and treatment with high mycophenolate mofetil (P = 0.012) and prednisolone (P = 0.023) doses per body weight at 28 days after transplantation. The genetic association between dyslipidemia and 60 previously described genetic polymorphisms in 38 putative disease-associated genes was analyzed. The frequency of dyslipidemia was significantly higher in patients with the glucocorticoid receptor (NR3C1) Bcl1 G allele than in those with the CC genotype (P = 0.001). A multivariate analysis revealed that the NR3C1 Bcl1 G allele was a significant risk factor for the prevalence of dyslipidemia (odds ratio = 4.6; 95% confidence interval = 1.8–12.2). These findings may aid in predicting a patient's risk of developing dyslipidemia. PMID:25944971

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...

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

Candidate genetic pathways for attention-deficit/hyperactivity disorder (ADHD) show association to hyperactive/impulsive symptoms in children with ADHD.

Science.gov (United States)

Bralten, Janita; Franke, Barbara; Waldman, Irwin; Rommelse, Nanda; Hartman, Catharina; Asherson, Philip; Banaschewski, Tobias; Ebstein, Richard P; Gill, Michael; Miranda, Ana; Oades, Robert D; Roeyers, Herbert; Rothenberger, Aribert; Sergeant, Joseph A; Oosterlaan, Jaap; Sonuga-Barke, Edmund; Steinhausen, Hans-Christoph; Faraone, Stephen V; Buitelaar, Jan K; Arias-Vásquez, Alejandro

2013-11-01

Because multiple genes with small effect sizes are assumed to play a role in attention-deficit/hyperactivity disorder (ADHD) etiology, considering multiple variants within the same analysis likely increases the total explained phenotypic variance, thereby boosting the power of genetic studies. This study investigated whether pathway-based analysis could bring scientists closer to unraveling the biology of ADHD. The pathway was described as a predefined gene selection based on a well-established database or literature data. Common genetic variants in pathways involved in dopamine/norepinephrine and serotonin neurotransmission and genes involved in neuritic outgrowth were investigated in cases from the International Multicentre ADHD Genetics (IMAGE) study. Multivariable analysis was performed to combine the effects of single genetic variants within the pathway genes. Phenotypes were DSM-IV symptom counts for inattention and hyperactivity/impulsivity (n = 871) and symptom severity measured with the Conners Parent (n = 930) and Teacher (n = 916) Rating Scales. Summing genetic effects of common genetic variants within the pathways showed a significant association with hyperactive/impulsive symptoms ((p)empirical = .007) but not with inattentive symptoms ((p)empirical = .73). Analysis of parent-rated Conners hyperactive/impulsive symptom scores validated this result ((p)empirical = .0018). Teacher-rated Conners scores were not associated. Post hoc analyses showed a significant contribution of all pathways to the hyperactive/impulsive symptom domain (dopamine/norepinephrine, (p)empirical = .0004; serotonin, (p)empirical = .0149; neuritic outgrowth, (p)empirical = .0452). The present analysis shows an association between common variants in 3 genetic pathways and the hyperactive/impulsive component of ADHD. This study demonstrates that pathway-based association analyses, using quantitative measurements of ADHD symptom domains, can increase the power of genetic analyses to

Cannabis Controversies: How genetics can inform the study of comorbidity

Science.gov (United States)

Agrawal, Arpana; Lynskey, Michael T.

2014-01-01

Aims To review three key and controversial comorbidities of cannabis use – other illicit drug use, psychosis and depression as well as suicide, from a genetically informed perspective. Design Selective review. Results Genetic factors play a critical role in the association between cannabis use, particularly early-onset use and use of other illicit drugs, psychosis and depression as well as suicide, albeit via differing mechanisms. For other illicit drugs, while there is strong evidence for shared genetic influences, residual association that is attributable to causal or person-specific environmental factors cannot be ruled out. For depression, common genetic influences are solely responsible for the association with cannabis use but for suicidal attempt, evidence for person-specific factors persists. Finally, even though rates of cannabis use are inordinately high in those with psychotic disorders, there is no evidence of shared genetic etiologies underlying this comorbidity. Instead, there is limited evidence that adolescent cannabis use might moderate the extent to which diathesis influences psychosis. Conclusions Overlapping genetic influences underlie the association between early-onset cannabis use and other illicit drug use as well as depression and suicide. For psychosis, mechanisms other than shared genetic influences might be at play. PMID:24438181

HGV&TB: a comprehensive online resource on human genes and genetic variants associated with tuberculosis

OpenAIRE

Sahajpal, Ruchika; Kandoi, Gaurav; Dhiman, Heena; Raj, Sweety; Scaria, Vinod; Bhartiya, Deeksha; Hasija, Yasha

2014-01-01

Abstract Tuberculosis (TB) is an infectious disease caused by fastidious pathogen Mycobacterium tuberculosis. TB has emerged as one of the major causes of mortality in the developing world. Role of host genetic factors that modulate disease susceptibility have not been studied widely. Recent studies have reported few genetic loci that provide impetus to this area of research. The availability of tools has enabled genome-wide scans for disease susceptibility loci associated with infectious dis...

Genetic association between leg conformation in young pigs and sow reproduction

DEFF Research Database (Denmark)

Le, Thu Hong; Nilsson, Katja; Norberg, Elise

2015-01-01

Lameness is an issue of concern in pig production due both to animal welfare and to economical aspects. Lame sows are believed to suffer from pain and stress which is reported to have a negative influence on reproduction. Leg conformation and locomotion traits in young animals are associated...... with the risk of lameness at higher age. The purpose of this study was to estimate the genetic parameters of leg conformation traits recorded at performance testing (around 5 months of age) and their genetic correlations with reproduction traits. Information on leg conformation traits from 123,307 pigs scored...... and on reproduction traits from 22,204 litters in the first and second parity from Swedish Yorkshire nucleus herds were available for genetic analysis. Eight conformation and locomotion traits, coming from the old or the new scoring system in Sweden, included old movement, old overall leg score, new movement, new...

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.

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.

Evolutionary Meta-Analysis of Association Studies Reveals Ancient Constraints Affecting Disease Marker Discovery

Science.gov (United States)

Dudley, Joel T.; Chen, Rong; Sanderford, Maxwell; Butte, Atul J.; Kumar, Sudhir

2012-01-01

Genome-wide disease association studies contrast genetic variation between disease cohorts and healthy populations to discover single nucleotide polymorphisms (SNPs) and other genetic markers revealing underlying genetic architectures of human diseases. Despite scores of efforts over the past decade, many reproducible genetic variants that explain substantial proportions of the heritable risk of common human diseases remain undiscovered. We have conducted a multispecies genomic analysis of 5,831 putative human risk variants for more than 230 disease phenotypes reported in 2,021 studies. We find that the current approaches show a propensity for discovering disease-associated SNPs (dSNPs) at conserved genomic positions because the effect size (odds ratio) and allelic P value of genetic association of an SNP relates strongly to the evolutionary conservation of their genomic position. We propose a new measure for ranking SNPs that integrates evolutionary conservation scores and the P value (E-rank). Using published data from a large case-control study, we demonstrate that E-rank method prioritizes SNPs with a greater likelihood of bona fide and reproducible genetic disease associations, many of which may explain greater proportions of genetic variance. Therefore, long-term evolutionary histories of genomic positions offer key practical utility in reassessing data from existing disease association studies, and in the design and analysis of future studies aimed at revealing the genetic basis of common human diseases. PMID:22389448

The association of XRCC3 Thr241Met genetic variant with risk of ...

African Journals Online (AJOL)

Background: Previous studies suggest that the X-ray repair cross-complementing group 3 gene (XRCC3) Thr241Met genetic variant could be potentially associated with the risk of prostate cancer. However, results from these published studies were conflicting rather than conclusive. Objectives:This meta-analysis aimed to ...

Genetic Determinants of Cardio-Metabolic Risk: A Proposed Model for Phenotype Association and Interaction

Science.gov (United States)

Blackett, Piers R; Sanghera, Dharambir K

2012-01-01

This review provides a translational and unifying summary of metabolic syndrome genetics and highlights evidence that genetic studies are starting to unravel and untangle origins of the complex and challenging cluster of disease phenotypes. The associated genes effectively express in the brain, liver, kidney, arterial endothelium, adipocytes, myocytes and β cells. Progression of syndrome traits has been associated with ectopic lipid accumulation in the arterial wall, visceral adipocytes, myocytes, and liver. Thus it follows that the genetics of dyslipidemia, obesity, and non-alcoholic fatty liver (NAFLD) disease are central in triggering progression of the syndrome to overt expression of disease traits, and have become a key focus of interest for early detection and for designing prevention and treatments. To support the “birds’ eye view” approach we provide a road-map depicting commonality and interrelationships between the traits and their genetic and environmental determinants based on known risk factors, metabolic pathways, pharmacological targets, treatment responses, gene networks, pleiotropy, and association with circadian rhythm. Although only a small portion of the known heritability is accounted for and there is insufficient support for clinical application of gene-based prediction models, there is direction and encouraging progress in a rapidly moving field that is beginning to show clinical relevance. PMID:23351585

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

Examination of association to autism of common genetic variationin genes related to dopamine.

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Anderson, B M; Schnetz-Boutaud, N; Bartlett, J; Wright, H H; Abramson, R K; Cuccaro, M L; Gilbert, J R; Pericak-Vance, M A; Haines, J L

2008-12-01

Autism is a severe neurodevelopmental disorder characterized by a triad of complications. Autistic individuals display significant disturbances in language and reciprocal social interactions, combined with repetitive and stereotypic behaviors. Prevalence studies suggest that autism is more common than originally believed, with recent estimates citing a rate of one in 150. Although multiple genetic linkage and association studies have yielded multiple suggestive genes or chromosomal regions, a specific risk locus has yet to be identified and widely confirmed. Because many etiologies have been suggested for this complex syndrome, we hypothesize that one of the difficulties in identifying autism genes is that multiple genetic variants may be required to significantly increase the risk of developing autism. Thus, we took the alternative approach of examining 14 prominent dopamine pathway candidate genes for detailed study by genotyping 28 single nucleotide polymorphisms. Although we did observe a nominally significant association for rs2239535 (P=0.008) on chromosome 20, single-locus analysis did not reveal any results as significant after correction for multiple comparisons. No significant interaction was identified when Multifactor Dimensionality Reduction was employed to test specifically for multilocus effects. Although genome-wide linkage scans in autism have provided support for linkage to various loci along the dopamine pathway, our study does not provide strong evidence of linkage or association to any specific gene or combination of genes within the pathway. These results demonstrate that common genetic variation within the tested genes located within this pathway at most play a minor to moderate role in overall autism pathogenesis.

Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes

DEFF Research Database (Denmark)

Bonàs-Guarch, Sílvia; Guindo-Martínez, Marta; Miguel-Escalada, Irene

2018-01-01

The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel...... available data using novel genetic resources and analytical approaches....... associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly...

Genetic polymorphisms associated with psoriasis and development of psoriatic arthritis in patients with psoriasis.

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Loft, Nikolai Dyrberg; Skov, Lone; Rasmussen, Mads Kirchheiner; Gniadecki, Robert; Dam, Tomas Norman; Brandslund, Ivan; Hoffmann, Hans Jürgen; Andersen, Malene Rohr; Dessau, Ram Benny; Bergmann, Ann Christina; Andersen, Niels Møller; Abildtoft, Mikkel Kramme; Andersen, Paal Skytt; Hetland, Merete Lund; Glintborg, Bente; Bank, Steffen; Vogel, Ulla; Andersen, Vibeke

2018-01-01

Psoriasis (PsO) is a chronic inflammatory disease with predominantly cutaneous manifestations. Approximately one third of patients with PsO develop psoriatic arthritis (PsA), whereas the remaining proportion of patients has isolated cutaneous psoriasis (PsC). These two phenotypes share common immunology, but with different heredity that might in part be explained by genetic variables. Using a candidate gene approach, we studied 53 single nucleotide polymorphisms (SNPs) in 37 genes that regulate inflammation. In total, we assessed 480 patients with PsO from DERMBIO, of whom 151 had PsC for 10 years or more (PsC10), 459 patients with PsA from DANBIO, and 795 healthy controls. Using logistic regression analysis, crude and adjusted for age and gender, we assessed associations between genetic variants and PsO, PsC10, and PsA, as well as associations between genetic variants and development of PsA in PsO. Eleven polymorphisms in 10 genes were nominally associated with PsO and/or PsC and/or PsA (P psoriasis, two SNPs in the IL12B and TNF genes were associated with susceptibility of psoriasis. None of the SNPs were specifically associated with isolated cutaneous psoriasis or psoriatic arthritis.

The association between a genetic risk score for allergy and the risk of developing allergies in childhood-Results of the WHISTLER cohort

NARCIS (Netherlands)

Arabkhazaeli, Ali; Ahmadizar, Fariba; Leusink, Maarten; Arets, Hubertus G. M.; Raaijmakers, Jan A. M.; Uiterwaal, Cuno S. P. M.; van der Ent, Cornelis K.; Maitland-van der Zee, Anke-Hilse; Vijverberg, Susanne J. H.

2018-01-01

Background: Several genetic variants have been associated with the susceptibility to allergic disease in adults, but it remains unclear whether these genetic variants are also associated with the onset of allergic disease early in life. The aim of this study was to develop a genetic risk score (GRS)

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....

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...

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

Unexpected high genetic diversity in small populations suggests maintenance by associative overdominance

DEFF Research Database (Denmark)

Schou, Mads F.; Loeschcke, Volker; Bechsgaard, Jesper

2017-01-01

fragmented populations. More genetic diversity was retained in areas of low recombination, suggesting that associative overdominance, driven by disfavoured homozygosity of recessive deleterious alleles, is responsible for the maintenance of genetic diversity in smaller populations. Consistent...

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...

Genetic, Psychological, and Personal Network Factors Associated With Changes in Binge Drinking Over 2 Years Among Mexican Heritage Adolescents in the USA.

Science.gov (United States)

Song, Sunmi; Marcum, Christopher Steven; Wilkinson, Anna V; Shete, Sanjay; Koehly, Laura M

2018-04-24

Despite prevalent binge drinking and alcohol-dependent symptoms among Hispanics, few studies have examined how multidimensional factors influence Hispanic adolescents' binge drinking. Purpose This study examines the effects of genetic, psychological, and social network factors on binge drinking over time among Mexican heritage adolescents in the USA and whether there are correlations among genetic variants that are associated with binge drinking and psychological and network characteristics. Mexican heritage adolescents (n = 731) participated in a longitudinal study, which included genetic testing at baseline, alcohol use assessments at first and second follow-ups, and questionnaires on sensation seeking, impulsivity, and peer and family network characteristics at second follow-up. Logistic regression and Spearman correlation analyses were performed. After adjusting for demographic characteristics, underlying genetic clustering, and binge drinking at first follow-up, two genetic variants on tryptophan hydroxylase 2 (TPH2; rs17110451, rs7963717), sensation seeking and impulsivity, and having a greater fraction of peers who drink or encourage drinking alcohol were associated with greater risk whereas another genetic variant on TPH2 (rs11178999) and having a greater fraction of close family relationships were associated with reduced risk for binge drinking at second follow-up. Genetic variants in TPH1 (rs591556) were associated with sensation seeking and impulsivity, while genetic variants in TPH2 (rs17110451) were associated with the fraction of drinkers in family. Results reveal that genetic variants in the serotonin pathway, behavioral disinhibition traits, and social networks exert joint influences on binge drinking in Mexican heritage adolescents in the USA.

PedGenie: meta genetic association testing in mixed family and case-control designs

Directory of Open Access Journals (Sweden)

Allen-Brady Kristina

2007-11-01

Full Text Available Abstract Background- PedGenie software, introduced in 2006, includes genetic association testing of cases and controls that may be independent or related (nuclear families or extended pedigrees or mixtures thereof using Monte Carlo significance testing. Our aim is to demonstrate that PedGenie, a unique and flexible analysis tool freely available in Genie 2.4 software, is significantly enhanced by incorporating meta statistics for detecting genetic association with disease using data across multiple study groups. Methods- Meta statistics (chi-squared tests, odds ratios, and confidence intervals were calculated using formal Cochran-Mantel-Haenszel techniques. Simulated data from unrelated individuals and individuals in families were used to illustrate meta tests and their empirically-derived p-values and confidence intervals are accurate, precise, and for independent designs match those provided by standard statistical software. Results- PedGenie yields accurate Monte Carlo p-values for meta analysis of data across multiple studies, based on validation testing using pedigree, nuclear family, and case-control data simulated under both the null and alternative hypotheses of a genotype-phenotype association. Conclusion- PedGenie allows valid combined analysis of data from mixtures of pedigree-based and case-control resources. Added meta capabilities provide new avenues for association analysis, including pedigree resources from large consortia and multi-center studies.

The bipolar puzzle, adding new pieces. Factors associated with bipolar disorder, Genetic and environmental influences

NARCIS (Netherlands)

van der Schot, A.C.

2009-01-01

The focus of this thesis is twofold. The first part will discuss the structural brain abnormalities and schoolperformance associated with bipolar disorder and the influence of genetic and/or environmental factors to this association. It is part of a large twin study investigating several potential

Genetic Variants Associated with Hyperandrogenemia in PCOS Pathophysiology

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Roshan Dadachanji

2018-01-01

Full Text Available Polycystic ovary syndrome is a multifactorial endocrine disorder whose pathophysiology baffles many researchers till today. This syndrome is typically characterized by anovulatory cycles and infertility, altered gonadotropin levels, obesity, and bulky multifollicular ovaries on ultrasound. Hyperandrogenism and insulin resistance are hallmark features of its complex pathophysiology. Hyperandrogenemia is a salient feature of PCOS and a major contributor to cosmetic anomalies including hirsutism, acne, and male pattern alopecia in affected women. Increased androgen levels may be intrinsic or aggravated by preexisting insulin resistance in women with PCOS. Studies have reported augmented ovarian steroidogenesis patterns attributed mainly to theca cell hypertrophy and altered expression of key enzymes in the steroidogenic pathway. Candidate gene studies have been performed in order to delineate the association of polymorphisms in genes, which encode enzymes in the intricate cascade of steroidogenesis or modulate the levels and action of circulating androgens, with risk of PCOS development and its related traits. However, inconsistent findings have impacted the emergence of a unanimously accepted genetic marker for PCOS susceptibility. In the current review, we have summarized the influence of polymorphisms in important androgen related genes in governing genetic predisposition to PCOS and its related metabolic and reproductive traits.

Genetic Thinking in the Study of Social Relationships: Five Points of Entry.

Science.gov (United States)

Reiss, David

2010-09-01

For nearly a generation, researchers studying human behavioral development have combined genetically informed research designs with careful measures of social relationships such as parenting, sibling relationships, peer relationships, marital processes, social class stratifications, and patterns of social engagement in the elderly. In what way have these genetically informed studies altered the construction and testing of social theories of human development? We consider five points of entry where genetic thinking is taking hold. First, genetic findings suggest an alternative scenario for explaining social data. Associations between measures of the social environment and human development may be due to genes that influence both. Second, genetic studies add to other prompts to study the early developmental origins of current social phenomena in midlife and beyond. Third, genetic analyses promise to shed light on understudied social systems, such as sibling relationships, that have an impact on human development independent of genotype. Fourth, genetic analyses anchor in neurobiology individual differences in resilience and sensitivity to both adverse and favorable social environments. Finally, genetic analyses increase the utility of laboratory simulations of human social processes and of animal models. © The Author(s) 2010.

Epigenome-wide association study of fasting measures of glucose, insulin, and HOMA-IR in the Genetics of Lipid Lowering Drugs and Diet Network study.

Science.gov (United States)

Hidalgo, Bertha; Irvin, M Ryan; Sha, Jin; Zhi, Degui; Aslibekyan, Stella; Absher, Devin; Tiwari, Hemant K; Kabagambe, Edmond K; Ordovas, Jose M; Arnett, Donna K

2014-02-01

Known genetic susceptibility loci for type 2 diabetes (T2D) explain only a small proportion of heritable T2D risk. We hypothesize that DNA methylation patterns may contribute to variation in diabetes-related risk factors, and this epigenetic variation across the genome can contribute to the missing heritability in T2D and related metabolic traits. We conducted an epigenome-wide association study for fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) among 837 nondiabetic participants in the Genetics of Lipid Lowering Drugs and Diet Network study, divided into discovery (N = 544) and replication (N = 293) stages. Cytosine guanine dinucleotide (CpG) methylation at ∼470,000 CpG sites was assayed in CD4(+) T cells using the Illumina Infinium HumanMethylation 450 Beadchip. We fit a mixed model with the methylation status of each CpG as the dependent variable, adjusting for age, sex, study site, and T-cell purity as fixed-effects and family structure as a random-effect. A Bonferroni corrected P value of 1.1 × 10(-7) was considered significant in the discovery stage. Significant associations were tested in the replication stage using identical models. Methylation of a CpG site in ABCG1 on chromosome 21 was significantly associated with insulin (P = 1.83 × 10(-7)) and HOMA-IR (P = 1.60 × 10(-9)). Another site in the same gene was significant for HOMA-IR and of borderline significance for insulin (P = 1.29 × 10(-7) and P = 3.36 × 10(-6), respectively). Associations with the top two signals replicated for insulin and HOMA-IR (P = 5.75 × 10(-3) and P = 3.35 × 10(-2), respectively). Our findings suggest that methylation of a CpG site within ABCG1 is associated with fasting insulin and merits further evaluation as a novel disease risk marker.

Music genetics research: Association with musicality of a polymorphism in the AVPR1A gene

Directory of Open Access Journals (Sweden)

Luiza Monteavaro Mariath

2017-05-01

Full Text Available Abstract Musicality is defined as a natural tendency, sensibility, knowledge, or talent to create, perceive, and play music. Musical abilities involve a great range of social and cognitive behaviors, which are influenced by both environmental and genetic factors. Although a number of studies have yielded insights into music genetics research, genes and biological pathways related to these traits are not fully understood. Our hypothesis in the current study is that genes associated with different behaviors could also influence the musical phenotype. Our aim was to investigate whether polymorphisms in six genes (AVPR1A, SLC6A4, ITGB3, COMT, DRD2 and DRD4 related to social and cognitive traits are associated with musicality in a sample of children. Musicality was assessed through an individualized music therapy assessment profile (IMTAP which has been validated in Brazil to measure musical ability. We show here that the RS1 microsatellite of the AVPR1A gene is nominally associated with musicality, corroborating previous results linking AVPR1A with musical activity. This study is one of the first to investigate musicality in a comprehensive way, and it contributes to better understand the genetic basis underlying musical ability.

Genetic aspects of pathological gambling: a complex disorder with shared genetic vulnerabilities.

Science.gov (United States)

Lobo, Daniela S S; Kennedy, James L

2009-09-01

To summarize and discuss findings from genetic studies conducted on pathological gambling (PG). Searches were conducted on PubMed and PsychInfo databases using the keywords: 'gambling and genes', 'gambling and family' and 'gambling and genetics', yielding 18 original research articles investigating the genetics of PG. Twin studies using the Vietnam Era Twin Registry have found that: (i) the heritability of PG is estimated to be 50-60%; (ii) PG and subclinical PG are a continuum of the same disorder; (iii) PG shares genetic vulnerability factors with antisocial behaviours, alcohol dependence and major depressive disorder; (iv) genetic factors underlie the association between exposure to traumatic life-events and PG. Molecular genetic investigations on PG are at an early stage and published studies have reported associations with genes involved in the brain's reward and impulse control systems. Despite the paucity of studies in this area, published studies have provided considerable evidence of the influence of genetic factors on PG and its complex interaction with other psychiatric disorders and environmental factors. The next step would be to investigate the association and interaction of these variables in larger molecular genetic studies with subphenotypes that underlie PG. Results from family and genetic investigations corroborate further the importance of understanding the biological underpinnings of PG in the development of more specific treatment and prevention strategies.

An association study of suicide and candidate genes in the serotonergic system

DEFF Research Database (Denmark)

Buttenschøn, Henriette N; Flint, Tracey J; Foldager, Leslie

2013-01-01

Introduction: Strong evidence demonstrates a genetic susceptibility to suicidal behaviour and a relationship between suicide and mental disorders. The aim of this study was to test for association between suicide and five selected genetic variants, which had shown association with suicide in other...... populations. Method: We performed a nationwide case-control study on all suicide cases sent for autopsy in Denmark between the years 2000 and 2007. The study comprised 572 cases and 1049 controls and is one of the largest genetic studies in completed suicide to date. The analysed markers were located within...... the Serotonin Transporter (SLC6A4), Monoamine Oxidase-A (MAOA) and the Ttyptophan Hydroxylase I and II (TPH1 and TPH2) genes. Results: None of the genetic markers within SLC6A4, MAOA, TPH1 and TPH2 were significantly associated with completed suicide or suicide method in the basic association tests. Exploratory...

Association of Genetic Variants Related to Serum Calcium Levels With Coronary Artery Disease and Myocardial Infarction.

Science.gov (United States)

Larsson, Susanna C; Burgess, Stephen; Michaëlsson, Karl

2017-07-25

Serum calcium has been associated with cardiovascular disease in observational studies and evidence from randomized clinical trials indicates that calcium supplementation, which raises serum calcium levels, may increase the risk of cardiovascular events, particularly myocardial infarction. To evaluate the potential causal association between genetic variants related to elevated serum calcium levels and risk of coronary artery disease (CAD) and myocardial infarction using mendelian randomization. The analyses were performed using summary statistics obtained for single-nucleotide polymorphisms (SNPs) identified from a genome-wide association meta-analysis of serum calcium levels (N = up to 61 079 individuals) and from the Coronary Artery Disease Genome-wide Replication and Meta-analysis Plus the Coronary Artery Disease Genetics (CardiogramplusC4D) consortium's 1000 genomes-based genome-wide association meta-analysis (N = up to 184 305 individuals) that included cases (individuals with CAD and myocardial infarction) and noncases, with baseline data collected from 1948 and populations derived from across the globe. The association of each SNP with CAD and myocardial infarction was weighted by its association with serum calcium, and estimates were combined using an inverse-variance weighted meta-analysis. Genetic risk score based on genetic variants related to elevated serum calcium levels. Co-primary outcomes were the odds of CAD and myocardial infarction. Among the mendelian randomized analytic sample of 184 305 individuals (60 801 CAD cases [approximately 70% with myocardial infarction] and 123 504 noncases), the 6 SNPs related to serum calcium levels and without pleiotropic associations with potential confounders were estimated to explain about 0.8% of the variation in serum calcium levels. In the inverse-variance weighted meta-analysis (combining the estimates of the 6 SNPs), the odds ratios per 0.5-mg/dL increase (about 1 SD) in genetically

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

Association Between Genetic Polymorphisms and Pain Sensitivity in Patients with Hip Osteoarthritis

DEFF Research Database (Denmark)

Olesen, Anne E; Nielsen, Lecia M; Feddersen, Søren

2018-01-01

, kappa, and delta opioid receptor genes (OPRM1, OPRK1, and OPRD1) and the catechol-O-methyltransferase gene (COMT) influenced the pain phenotype in patients with osteoarthritis. METHODS: The frequencies of 17 polymorphisms were examined. Pain sensitivity was assessed preoperatively by (1) hip rotation......BACKGROUND: Factors such as age, gender, and genetic polymorphisms may explain individual differences in pain phenotype. Genetic associations with pain sensitivity have previously been investigated in osteoarthritis patients, with a focus on the P2X7, TRPV1, and TACR1 genes. However, other genes...... may play a role as well. Osteoarthritis is a common joint disease, and many patients suffering from this disease are thought to have increased sensitivity to noxious stimuli resulting from sensitization in the nociceptive system. The aim of this study was to investigate if genetic variants of mu...

Association of education & lifestyle factors with the perception of genetic knowledge on the development of lung cancer

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Liang Wang

2016-01-01

Full Text Available Background & objectives: The perception of genetic knowledge is useful for improving the heath behaviour change against developing cancers. However, no studies have investigated the perception of genetic knowledge on the development of lung cancer. The aim of this study was to examine demographic and lifestyle factors of the perception of genetic knowledge on the development of lung cancer. Methods: Data on 2,295 US adults (739 had the perception of genetic knowledge were taken from the 2003 Health Information National Trends Survey. Multiple logistic regression models were used to evaluate potential factors of the perception of genetic knowledge of lung cancer. Results: Participants aged ≥65 yr were more likely to have the perception of genetic knowledge than those aged 18-44 yr (OR=1.77, 95% CI=1.27-2.46. Higher education was associated with a greater perception of genetic knowledge (OR=1.47, 95% CI=1.16-1.87. Subjects with correct smoking attitude were more than three times more likely to have the perception of genetic knowledge (OR=3.15, 95% CI=2.10-4.72. Subjects with exercise were at an increased likelihood of having the perception of genetic knowledge than those without exercise (OR=1.63, 95% CI=1.24-2.13. Interpretation & conclusions: Positive associations were observed between education and lifestyle factors and the perception of genetic knowledge on the development of lung cancer among US adults. Strategies developed to improve the perception of genetic knowledge of lung cancer may target on individuals who are young, less educated, and lack correct smoking attitude or exercise.

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

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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.

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease : a molecular and genetic association study

NARCIS (Netherlands)

Zewinger, Stephen; Kleber, Marcus E.; Tragante Do O, V; McCubrey, Raymond O.; Schmidt, Amand F.; Direk, Kenan; Laufs, Ulrich; Werner, Christian; Koenig, Wolfgang; Rothenbacher, Dietrich; Mons, Ute; Breitling, Lutz P; Brenner, Herrmann; Jennings, Richard T.; Petrakis, Ioannis; Triem, Sarah; Klug, Mira; Filips, Alexandra; Blankenberg, Stefan; Waldeyer, Christoph; Sinning, Christoph; Schnabel, Renate B.; Lackner, Karl J.; Vlachopoulou, Efthymia; Nygård, Ottar; Svingen, Gard Frodahl Tveitevåg; Pedersen, Eva Ringdal; Tell, Grethe S.; Sinisalo, Juha; Nieminen, Markku S.; Laaksonen, Reijo; Trompet, Stella; Smit, Roelof A.J.; Sattar, Naveed; Jukema, J. Wouter; Groesdonk, Heinrich V.; Delgado, Graciela; Stojakovic, Tatjana; Pilbrow, Anna P.; Cameron, Vicky A.; Richards, A. Mark; Doughty, Robert N.; Gong, Yan; Cooper-Dehoff, Rhonda M; Johnson, Julie A; Scholz, Markus; Beutner, Frank; Thiery, Joachim; Smith, J. Gustav; Vilmundarson, Ragnar O.; McPherson, Ruth; Stewart, Alexandre F. R.; Cresci, Sharon; Lenzini, Petra A.; Spertus, John A.; Olivieri, Oliviero; Girelli, Domenico; Martinelli, Nicola I.; Leiherer, Andreas; Saely, Christoph H.; Drexel, Heinz; Mündlein, Axel; Braund, Peter S; Nelson, Christopher P.; Samani, Nilesh J.; Kofink, Daniel; Hoefer, Imo E.; Pasterkamp, Gerard; Quyyumi, Arshed A.; Ko, Yi-An; Hartiala, Jaana A.; Allayee, Hooman; Tang, W. H. Wilson; Hazen, Stanley L.; Eriksson, Niclas; Held, Claes; Hagström, Emil; Wallentin, Lars; Åkerblom, Axel; Siegbahn, Agneta; Karp, Igor; Labos, Christopher; Pilote, Louise; Engert, James C.; Brophy, James M.; Thanassoulis, George; Bogaty, Peter; Szczeklik, Wojciech; Kaczor, Marcin; Sanak, Marek; Virani, Salim S.; Ballantyne, Christie M.; Lee, Vei Vei; Boerwinkle, Eric; Holmes, Michael V.; Horne, Benjamin D; Hingorani, Aroon D.; Asselbergs, Folkert W.; Patel, Riyaz S; Krämer, Bernhard K; Scharnagl, Hubert; Fliser, Danilo; März, Winfried; Speer, Thimoteus

Background Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. Methods We obtained

A genetic perspective on the association between exercise and mental health.

NARCIS (Netherlands)

de Geus, E.J.C.; de Moor, M.H.M.

2008-01-01

Regular exercise is associated with better mental health. This association is widely assumed to reflect causal effects of exercise. In this paper we propose that two additional mechanisms contribute to the association between exercise and mental health in the population-at-large: genetic pleiotropy

Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry.

Science.gov (United States)

Zhao, Zhiguo; Wen, Wanqing; Michailidou, Kyriaki; Bolla, Manjeet K; Wang, Qin; Zhang, Ben; Long, Jirong; Shu, Xiao-Ou; Schmidt, Marjanka K; Milne, Roger L; García-Closas, Montserrat; Chang-Claude, Jenny; Lindstrom, Sara; Bojesen, Stig E; Ahsan, Habibul; Aittomäki, Kristiina; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W; Beeghly-Fadiel, Alicia; Benitez, Javier; Blomqvist, Carl; Bogdanova, Natalia V; Børresen-Dale, Anne-Lise; Brand, Judith; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Cai, Qiuyin; Casey, Graham; Chenevix-Trench, Georgia; Couch, Fergus J; Cox, Angela; Cross, Simon S; Czene, Kamila; Dörk, Thilo; Dumont, Martine; Fasching, Peter A; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Fostira, Florentia; Gammon, Marilie; Giles, Graham G; Guénel, Pascal; Haiman, Christopher A; Hamann, Ute; Harrington, Patricia; Hartman, Mikael; Hooning, Maartje J; Hopper, John L; Jakubowska, Anna; Jasmine, Farzana; John, Esther M; Johnson, Nichola; Kabisch, Maria; Khan, Sofia; Kibriya, Muhammad; Knight, Julia A; Kosma, Veli-Matti; Kriege, Mieke; Kristensen, Vessela; Le Marchand, Loic; Lee, Eunjung; Li, Jingmei; Lindblom, Annika; Lophatananon, Artitaya; Luben, Robert; Lubinski, Jan; Malone, Kathleen E; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; McLean, Catriona; Meijers-Heijboer, Hanne; Meindl, Alfons; Miao, Hui; Muir, Kenneth; Neuhausen, Susan L; Nevanlinna, Heli; Neven, Patrick; Olson, Janet E; Perkins, Barbara; Peterlongo, Paolo; Phillips, Kelly-Anne; Pylkäs, Katri; Rudolph, Anja; Santella, Regina; Sawyer, Elinor J; Schmutzler, Rita K; Schoemaker, Minouk; Shah, Mitul; Shrubsole, Martha; Southey, Melissa C; Swerdlow, Anthony J; Toland, Amanda E; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Ursin, Giske; Van Der Luijt, Rob B; Verhoef, Senno; Wang-Gohrke, Shan; Whittemore, Alice S; Winqvist, Robert; Pilar Zamora, M; Zhao, Hui; Dunning, Alison M; Simard, Jacques; Hall, Per; Kraft, Peter; Pharoah, Paul; Hunter, David; Easton, Douglas F; Zheng, Wei

2016-05-01

Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors. We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies. The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.

Genetic studies of body mass index yield new insights for obesity biology

DEFF Research Database (Denmark)

Locke, Adam E.; Kahali, Bratati; Berndt, Sonja I.

2015-01-01

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in upto 339,224 individu......Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in upto 339......, insulin secretion/action, energy metabolism, lipid biology and adipogenesis....

Genetic divergence across habitats in the widespread coral Seriatopora hystrix and its associated Symbiodinium.

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Pim Bongaerts

2010-05-01

Full Text Available Coral reefs are hotspots of biodiversity, yet processes of diversification in these ecosystems are poorly understood. The environmental heterogeneity of coral reef environments could be an important contributor to diversification, however, evidence supporting ecological speciation in corals is sparse. Here, we present data from a widespread coral species that reveals a strong association of host and symbiont lineages with specific habitats, consistent with distinct, sympatric gene pools that are maintained through ecologically-based selection.Populations of a common brooding coral, Seriatopora hystrix, were sampled from three adjacent reef habitats (spanning a approximately 30 m depth range at three locations on the Great Barrier Reef (n = 336. The populations were assessed for genetic structure using a combination of mitochondrial (putative control region and nuclear (three microsatellites markers for the coral host, and the ITS2 region of the ribosomal DNA for the algal symbionts (Symbiodinium. Our results show concordant genetic partitioning of both the coral host and its symbionts across the different habitats, independent of sampling location.This study demonstrates that coral populations and their associated symbionts can be highly structured across habitats on a single reef. Coral populations from adjacent habitats were found to be genetically isolated from each other, whereas genetic similarity was maintained across similar habitat types at different locations. The most parsimonious explanation for the observed genetic partitioning across habitats is that adaptation to the local environment has caused ecological divergence of distinct genetic groups within S. hystrix.

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

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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

Association of Multiple Genetic Variants with the Extension and Severity of Coronary Artery Disease

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Simone Cristina Pinto Matheus Fischer

2018-02-01

Full Text Available Abstract Background: Metabolic syndrome (MS is a condition that, when associated with ischemic heart disease and cardiovascular events, can be influenced by genetic variants and determine more severe coronary atherosclerosis. Objectives: To examine the contribution of genetic polymorphisms to the extension and severity of coronary disease in subjects with MS and recent acute coronary syndrome (ACS. Methods: Patients (n = 116, 68% males aged 56 (9 years, with criteria for MS, were prospectively enrolled to the study during the hospitalization period after an ACS. Clinical and laboratory parameters, high-sensitivity C-reactive protein, thiobarbituric acid reactive substances, adiponectin, endothelial function, and the Gensini score were assessed. Polymorphisms of paraoxonase-1 (PON-1, methylenotetrahydrofolate reductase (MTHFR, endothelial nitric oxide synthase (ENOS, angiotensin-converting enzyme (ACE, angiotensin II type 1 receptor (AT1R, apolipoprotein C3 (APOC3, lipoprotein lipase (LPL were analysed by polymerase chain reaction (PCR technique, followed by the identification of restriction fragment length polymorphisms (RFLP, and a genetic score was calculated. Parametric and non-parametric tests were used, as appropriate. Significance was set at p < 0.05. Results: Polymorphisms of PON-1, MTHFR and ENOS were not in the Hardy-Weinberg equilibrium. The DD genotype of LPL was associated with higher severity and greater extension of coronary lesions. Genetic score tended to be higher in patients with Gensini score < P50 (13.7 ± 1.5 vs. 13.0 ± 1.6, p = 0.066, with an inverse correlation between genetic and Gensini scores (R = -0.194, p = 0.078. Conclusions: The LPL polymorphism contributed to the severity of coronary disease in patients with MS and recent ACS. Combined polymorphisms were associated with the extension of coronary disease, and the lower the genetic score the more severe the disease.

[Genetic variants in miRNAs and its association with breast cancer].

Science.gov (United States)

Méndez-Gómez, Susana; Ruiz Esparza-Garrido, Ruth; Velázquez-Flores, Miguel; Dolores-Vergara, Maria; Salamanca-Gómez, Fabio; Arenas-Aranda, Diego Julio

2014-01-01

In Mexico, breast cancer represents the first cause of cancer death in females. At the molecular level, non-coding RNAs and especially microRNAs have played an important role in the origin and development of this neoplasm In the Anglo-Saxon population, diverse genetic variants in microRNA genes and in their targets are associated with the development of this disease. In the Mexican population it is not known if these or other variants exist. Identification of these or new variants in our population is fundamental in order to have a better understanding of cancer development and to help establish a better diagnostic strategy. DNA was isolated from mammary tumors, adjacent tissue and peripheral blood of Mexican females with or without cancer. From DNA, five microRNA genes and three of their targets were amplified and sequenced. Genetic variants associated with breast cancer in an Anglo- Saxon population have been previously identified in these sequences. In the samples studied we identified seven single nucleotide polymorphisms (SNPs). Two had not been previously described and were identified only in women with cancer. The new variants may be genetic predisposition factors for the development of breast cancer in our population. Further experiments are needed to determine the involvement of these variants in the development, establishment and progression of breast cancer.

Genetic HLA Associations in Complex Regional Pain Syndrome With and Without Dystonia

NARCIS (Netherlands)

van Rooijen, D.E.; Roelen, D.L.; Verduijn, W.; Haasnoot, G.W.; Huygen, F.J.P.M.; Perez, R.S.G.M.; Claas, F.H.J.; Marinus, J.; van Hilten, J.J.; van den Maagdenberg, A.M.J.M.

2012-01-01

We previously showed evidence for a genetic association of the human leukocyte antigen (HLA) system and complex regional pain syndrome (CRPS) with dystonia. Involvement of the HLA system suggests that CRPS has a genetic component with perturbed regulation of inflammation and neuroplasticity as

Genetic and Association Mapping Study of Wheat Agronomic Traits Under Contrasting Water Regimes

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Dejan Dodig

2012-05-01

Full Text Available Genetic analyses and association mapping were performed on a winter wheat core collection of 96 accessions sampled from a variety of geographic origins. Twenty-four agronomic traits were evaluated over 3 years under fully irrigated, rainfed and drought treatments. Grain yield was the most sensitive trait to water deficit and was highly correlated with above-ground biomass per plant and number of kernels per m². The germplasm was structured into four subpopulations. The association of 46 SSR loci distributed throughout the wheat genome with yield and agronomic traits was analyzed using a general linear model, where subpopulation information was used to control false-positive or spurious marker-trait associations (MTAs. A total of 26, 21 and 29 significant (P < 0.001 MTAs were identified in irrigated, rainfed and drought treatments, respectively. The marker effects ranged from 14.0 to 50.8%. Combined across all treatments, 34 significant (P < 0.001 MTAs were identified with nine markers, and R² ranged from 14.5 to 50.2%. Marker psp3200 (6DS and particularly gwm484 (2DS were associated with many significant MTAs in each treatment and explained the greatest proportion of phenotypic variation. Although we were not able to recognize any marker related to grain yield under drought stress, a number of MTAs associated with developmental and agronomic traits highly correlated with grain yield under drought were identified.

Efficient multiple-trait association and estimation of genetic correlation using the matrix-variate linear mixed model.

Science.gov (United States)

Furlotte, Nicholas A; Eskin, Eleazar

2015-05-01

Multiple-trait association mapping, in which multiple traits are used simultaneously in the identification of genetic variants affecting those traits, has recently attracted interest. One class of approaches for this problem builds on classical variance component methodology, utilizing a multitrait version of a linear mixed model. These approaches both increase power and provide insights into the genetic architecture of multiple traits. In particular, it is possible to estimate the genetic correlation, which is a measure of the portion of the total correlation between traits that is due to additive genetic effects. Unfortunately, the practical utility of these methods is limited since they are computationally intractable for large sample sizes. In this article, we introduce a reformulation of the multiple-trait association mapping approach by defining the matrix-variate linear mixed model. Our approach reduces the computational time necessary to perform maximum-likelihood inference in a multiple-trait model by utilizing a data transformation. By utilizing a well-studied human cohort, we show that our approach provides more than a 10-fold speedup, making multiple-trait association feasible in a large population cohort on the genome-wide scale. We take advantage of the efficiency of our approach to analyze gene expression data. By decomposing gene coexpression into a genetic and environmental component, we show that our method provides fundamental insights into the nature of coexpressed genes. An implementation of this method is available at http://genetics.cs.ucla.edu/mvLMM. Copyright © 2015 by the Genetics Society of America.

Genetic Variation of Follicle-Stimulating Hormone Action Is Associated With Age at Testicular Growth in Boys

DEFF Research Database (Denmark)

Busch, Alexander S; Hagen, Casper P; Main, Katharina M

2017-01-01

Context: Although genetic factors play a pivotal role in male pubertal timing, genome-wide association studies have identified only a few loci. Genetic variation of follicle-stimulating hormone (FSH) action affects adult reproductive parameters and female pubertal timing. Objective: To investigate...... effective FSH action. Effects explained 1.7% (Denmark) and 1.5% (Chile) of the variance. In addition, BMI z score was negatively associated with pubertal timing (β = -0.35 years in both cohorts), explaining 17.2% (Denmark) and 7.2% (Chile) of the variance. Conclusion: In two ethnically distinct populations...

Genome-wide association study identified genetic variations and candidate genes for plant architecture component traits in Chinese upland cotton.

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Su, Junji; Li, Libei; Zhang, Chi; Wang, Caixiang; Gu, Lijiao; Wang, Hantao; Wei, Hengling; Liu, Qibao; Huang, Long; Yu, Shuxun

2018-06-01

Thirty significant associations between 22 SNPs and five plant architecture component traits in Chinese upland cotton were identified via GWAS. Four peak SNP loci located on chromosome D03 were simultaneously associated with more plant architecture component traits. A candidate gene, Gh_D03G0922, might be responsible for plant height in upland cotton. A compact plant architecture is increasingly required for mechanized harvesting processes in China. Therefore, cotton plant architecture is an important trait, and its components, such as plant height, fruit branch length and fruit branch angle, affect the suitability of a cultivar for mechanized harvesting. To determine the genetic basis of cotton plant architecture, a genome-wide association study (GWAS) was performed using a panel composed of 355 accessions and 93,250 single nucleotide polymorphisms (SNPs) identified using the specific-locus amplified fragment sequencing method. Thirty significant associations between 22 SNPs and five plant architecture component traits were identified via GWAS. Most importantly, four peak SNP loci located on chromosome D03 were simultaneously associated with more plant architecture component traits, and these SNPs were harbored in one linkage disequilibrium block. Furthermore, 21 candidate genes for plant architecture were predicted in a 0.95-Mb region including the four peak SNPs. One of these genes (Gh_D03G0922) was near the significant SNP D03_31584163 (8.40 kb), and its Arabidopsis homologs contain MADS-box domains that might be involved in plant growth and development. qRT-PCR showed that the expression of Gh_D03G0922 was upregulated in the apical buds and young leaves of the short and compact cotton varieties, and virus-induced gene silencing (VIGS) proved that the silenced plants exhibited increased PH. These results indicate that Gh_D03G0922 is likely the candidate gene for PH in cotton. The genetic variations and candidate genes identified in this study lay a foundation

Using trajectory analyses to refine phenotype for genetic association: conduct problems and the serotonin transporter (5HTTLPR).

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Sakai, Joseph T; Boardman, Jason D; Gelhorn, Heather L; Smolen, Andrew; Corley, Robin P; Huizinga, David; Menard, Scott; Hewitt, John K; Stallings, Michael C

2010-10-01

Conduct disorder is a serious, relatively common disorder of childhood and adolescence. Findings from genetic association studies searching for genetic determinants of the liability toward such behaviors have been inconsistent. One possible explanation for differential results is that most studies define phenotype from a single assessment; for many adolescents conduct problems decrease in severity over time, whereas for others such behaviors persist. Therefore, longitudinal datasets offer the opportunity to refine phenotype. We used Caucasians that were first assessed during adolescence from the National Youth Survey Family Study. Nine waves of data were used to create latent growth trajectories and test for associations between trajectory class and 5HTTLPR genotype. For the full sample, 5HTTLPR was not associated with conduct problem phenotypes. However, the short (s) allele was associated with chronic conduct problems in females; a nominally significant sex by 5HTTLPR genotype interaction was noted. Longitudinal studies provide unique opportunities for phenotypic refinement and such techniques, with large samples, may be useful for phenotypic definition with other study designs, such as whole genome association studies.

Unraveling the genetic etiology of adult antisocial behavior: A genome-wide association study

NARCIS (Netherlands)

Tielbeek, J.J.; Medland, S.E.; Benyamin, B.; Byrne, E.M.; Heath, A.C.; Madden, P.A.F.; Martin, N.G.; Wray, N.R.; Verweij, K.J.H.

2012-01-01

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

A genetic risk score is associated with polycystic ovary syndrome-related traits.

Science.gov (United States)

Lee, Hyejin; Oh, Jee-Young; Sung, Yeon-Ah; Chung, Hye Won

2016-01-01

Is a genetic risk score (GRS) associated with polycystic ovary syndrome (PCOS) and its related clinical features? The GRS calculated by genome-wide association studies (GWASs) was significantly associated with PCOS status and its related clinical features. PCOS is a heterogeneous disorder and is characterized by oligomenorrhea, hyperandrogenism and polycystic ovary morphology. Although recent GWASs have identified multiple genes associated with PCOS, a comprehensive genetic risk study of these loci with PCOS and related traits (e.g. free testosterone, menstruation number/year and ovarian morphology) has not been performed. This study was designed as a cross-sectional case-control study. We recruited 862 women with PCOS and 860 controls. Women with PCOS were divided into four subgroups: (1) oligomenorrhea + hyperandrogenism + polycystic ovary, (2) oligomenorrhea + hyperandrogenism, (3) oligomenorrhea + polycystic ovary and (4) hyperandrogenism + polycystic ovary. Genomic DNA was genotyped for the PCOS susceptibility loci using the HumanOmni1-Quad v1 array. Venous blood was drawn in the early follicular phase to measure baseline metabolic and hormonal parameters. A GRS was calculated by summing the number of risk alleles from 11 single-nucleotide polymorphisms (SNPs) that were identified in previous GWASs on PCOS. A weighted GRS (wGRS) was calculated by multiplying the number of risk alleles for each SNP by its estimated effect (beta) obtained from the association analysis. The GRS was higher in women with PCOS than in controls (8.8 versus 8.2, P treatment approaches, which could potentially improve health outcomes. None of the authors have any conflicts of interest to declare. No funding was obtained for the study. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Addictive behaviors and addiction-prone personality traits: associations with a dopamine multilocus genetic profile.

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Davis, Caroline; Loxton, Natalie J

2013-07-01

The purpose of this study was to examine reward-related genetic risk for addictive behaviors in a healthy community sample (n=217) of men and women. We tested a mediation model predicting that a quantitative multilocus genetic profile score - reflecting the additive effects of alleles known to confer relatively increased dopamine signaling in the ventral striatum - would relate positively to a composite measure of addictive behaviors, and that this association would be mediated by personality traits consistently associated with addiction disorders. Our model was strongly supported by the data, and accounted for 24% of the variance in addictive behaviors. These data suggest that brain reward processes tend to exert their influence on addiction risk by their role in the development of relatively stable personality traits associated with addictive behaviors. Copyright © 2013 Elsevier Ltd. All rights reserved.

Genetic modifiers of CHEK2*1100delC-associated breast cancer risk

DEFF Research Database (Denmark)

Muranen, Taru A; Greco, Dario; Blomqvist, Carl

2017-01-01

PURPOSE: CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion....... We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC). METHODS: Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77...

Childhood victimization and inflammation in young adulthood: A genetically sensitive cohort study.

Science.gov (United States)

Baldwin, Jessie R; Arseneault, Louise; Caspi, Avshalom; Fisher, Helen L; Moffitt, Terrie E; Odgers, Candice L; Pariante, Carmine; Ambler, Antony; Dove, Rosamund; Kepa, Agnieszka; Matthews, Timothy; Menard, Anne; Sugden, Karen; Williams, Benjamin; Danese, Andrea

2018-01-01

Childhood victimization is an important risk factor for later immune-related disorders. Previous evidence has demonstrated that childhood victimization is associated with elevated levels of inflammation biomarkers measured decades after exposure. However, it is unclear whether this association is (1) already detectable in young people, (2) different in males and females, and (3) confounded by genetic liability to inflammation. Here we sought to address these questions. Participants were 2232 children followed from birth to age 18years as part of the Environmental Risk (E-Risk) Longitudinal Twin Study. Childhood victimization was measured prospectively from birth to age 12years. Inflammation was measured through C-reactive protein (CRP) levels in dried blood spots at age 18years. Latent genetic liability for high inflammation levels was assessed through a twin-based method. Greater exposure to childhood victimization was associated with higher CRP levels at age 18 (serum-equivalent means were 0.65 in non-victimized Study members, 0.74 in those exposed to one victimization type, and 0.81 in those exposed to poly-victimization; p=0.018). However, this association was driven by a significant association in females (serum-equivalent means were 0.75 in non-victimized females, 0.87 in those exposed to one type of victimization, and 1.19 in those exposed to poly-victimization; p=0.010), while no significant association was observed in males (p=0.19). Victimized females showed elevated CRP levels independent of latent genetic influence, as well as childhood socioeconomic status, and waist-hip ratio and body temperature at the time of CRP assessment. Childhood victimization is associated with elevated CRP levels in young women, independent of latent genetic influences and other key risk factors. These results strengthen causal inference about the effects of childhood victimization on inflammation levels in females by accounting for potential genetic confounding. Copyright �

WONOEP appraisal: new genetic approaches to study epilepsy

Science.gov (United States)

Rossignol, Elsa; Kobow, Katja; Simonato, Michele; Loeb, Jeffrey A.; Grisar, Thierry; Gilby, Krista L.; Vinet, Jonathan; Kadam, Shilpa D.; Becker, Albert J.

2014-01-01

Objective New genetic investigation techniques, including next-generation sequencing, epigenetic profiling, cell lineage mapping, targeted genetic manipulation of specific neuronal cell types, stem cell reprogramming and optogenetic manipulations within epileptic networks are progressively unravelling the mysteries of epileptogenesis and ictogenesis. These techniques have opened new avenues to discover the molecular basis of epileptogenesis and to study the physiological impacts of mutations in epilepsy-associated genes on a multilayer level, from cells to circuits. Methods This manuscript reviews recently published applications of these new genetic technologies in the study of epilepsy, as well as work presented by the authors at the genetic session of the XII Workshop on the Neurobiology of Epilepsy in Quebec, Canada. Results Next-generation sequencing is providing investigators with an unbiased means to assess the molecular causes of sporadic forms of epilepsy and have revealed the complexity and genetic heterogeneity of sporadic epilepsy disorders. To assess the functional impact of mutations in these newly identified genes on specific neuronal cell-types during brain development, new modeling strategies in animals, including conditional genetics in mice and in utero knockdown approaches, are enabling functional validation with exquisite cell-type and temporal specificity. In addition, optogenetics, using cell-type specific Cre recombinase driver lines, is enabling investigators to dissect networks involved in epilepsy. Genetically-encoded cell-type labeling is also providing new means to assess the role of the non-neuronal components of epileptic networks such as glial cells. Furthermore, beyond its role in revealing coding variants involved in epileptogenesis, next-generation sequencing can be used to assess the epigenetic modifications that lead to sustained network hyperexcitability in epilepsy, including methylation changes in gene promoters and non

Global Distribution of Human-Associated Fecal Genetic Markers in Reference Samples from Six Continents.

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Mayer, René E; Reischer, Georg H; Ixenmaier, Simone K; Derx, Julia; Blaschke, Alfred Paul; Ebdon, James E; Linke, Rita; Egle, Lukas; Ahmed, Warish; Blanch, Anicet R; Byamukama, Denis; Savill, Marion; Mushi, Douglas; Cristóbal, Héctor A; Edge, Thomas A; Schade, Margit A; Aslan, Asli; Brooks, Yolanda M; Sommer, Regina; Masago, Yoshifumi; Sato, Maria I; Taylor, Huw D; Rose, Joan B; Wuertz, Stefan; Shanks, Orin C; Piringer, Harald; Mach, Robert L; Savio, Domenico; Zessner, Matthias; Farnleitner, Andreas H

2018-05-01

Numerous bacterial genetic markers are available for the molecular detection of human sources of fecal pollution in environmental waters. However, widespread application is hindered by a lack of knowledge regarding geographical stability, limiting implementation to a small number of well-characterized regions. This study investigates the geographic distribution of five human-associated genetic markers (HF183/BFDrev, HF183/BacR287, BacHum-UCD, BacH, and Lachno2) in municipal wastewaters (raw and treated) from 29 urban and rural wastewater treatment plants (750-4 400 000 population equivalents) from 13 countries spanning six continents. In addition, genetic markers were tested against 280 human and nonhuman fecal samples from domesticated, agricultural and wild animal sources. Findings revealed that all genetic markers are present in consistently high concentrations in raw (median log 10 7.2-8.0 marker equivalents (ME) 100 mL -1 ) and biologically treated wastewater samples (median log 10 4.6-6.0 ME 100 mL -1 ) regardless of location and population. The false positive rates of the various markers in nonhuman fecal samples ranged from 5% to 47%. Results suggest that several genetic markers have considerable potential for measuring human-associated contamination in polluted environmental waters. This will be helpful in water quality monitoring, pollution modeling and health risk assessment (as demonstrated by QMRAcatch) to guide target-oriented water safety management across the globe.

Morphological Characterization and Assessment of Genetic Variability, Character Association, and Divergence in Soybean Mutants

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M. A. Malek

2014-01-01

Full Text Available Genetic diversity is important for crop improvement. An experiment was conducted during 2011 to study genetic variability, character association, and genetic diversity among 27 soybean mutants and four mother genotypes. Analysis of variance revealed significant differences among the mutants and mothers for nine morphological traits. Eighteen mutants performed superiorly to their mothers in respect to seed yield and some morphological traits including yield attributes. Narrow differences between phenotypic and genotypic coefficients of variation (PCV and GCV for most of the characters revealed less environmental influence on their expression. High values of heritability and genetic advance with high GCV for branch number, plant height, pod number, and seed weight can be considered as favorable attributes for soybean improvement through phenotypic selection and high expected genetic gain can be achieved. Pod and seed number and maturity period appeared to be the first order traits for higher yield and priority should be given in selection due to their strong associations and high magnitudes of direct effects on yield. Cluster analysis grouped 31 genotypes into five groups at the coefficient value of 235. The mutants/genotypes from cluster I and cluster II could be used for hybridization program with the mutants of clusters IV and V in order to develop high yielding mutant-derived soybean varieties for further improvement.

Common genetic variations in cell cycle and DNA repair pathways associated with pediatric brain tumor susceptibility

DEFF Research Database (Denmark)

Fahmideh, Maral Adel; Lavebratt, Catharina; Schüz, Joachim

2016-01-01

Knowledge on the role of genetic polymorphisms in the etiology of pediatric brain tumors (PBTs) is limited. Therefore, we investigated the association between single nucleotide polymorphisms (SNPs), identified by candidate gene-association studies on adult brain tumors, and PBT risk. The study is...... cycle and DNA repair pathways variations associated with susceptibility to adult brain tumors also seem to be associated with PBT risk, suggesting pediatric and adult brain tumors might share similar etiological pathways....

Novel bayes factors that capture expert uncertainty in prior density specification in genetic association studies.

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Spencer, Amy V; Cox, Angela; Lin, Wei-Yu; Easton, Douglas F; Michailidou, Kyriaki; Walters, Kevin

2015-05-01

Bayes factors (BFs) are becoming increasingly important tools in genetic association studies, partly because they provide a natural framework for including prior information. The Wakefield BF (WBF) approximation is easy to calculate and assumes a normal prior on the log odds ratio (logOR) with a mean of zero. However, the prior variance (W) must be specified. Because of the potentially high sensitivity of the WBF to the choice of W, we propose several new BF approximations with logOR ∼N(0,W), but allow W to take a probability distribution rather than a fixed value. We provide several prior distributions for W which lead to BFs that can be calculated easily in freely available software packages. These priors allow a wide range of densities for W and provide considerable flexibility. We examine some properties of the priors and BFs and show how to determine the most appropriate prior based on elicited quantiles of the prior odds ratio (OR). We show by simulation that our novel BFs have superior true-positive rates at low false-positive rates compared to those from both P-value and WBF analyses across a range of sample sizes and ORs. We give an example of utilizing our BFs to fine-map the CASP8 region using genotype data on approximately 46,000 breast cancer case and 43,000 healthy control samples from the Collaborative Oncological Gene-environment Study (COGS) Consortium, and compare the single-nucleotide polymorphism ranks to those obtained using WBFs and P-values from univariate logistic regression. © 2015 The Authors. *Genetic Epidemiology published by Wiley Periodicals, Inc.

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.

A genetic study on attention problems and academic skills: results of a longitudinal study in twins

NARCIS (Netherlands)

Polderman, T.J.C.; Huizink, A.C.; Verhulst, F.C.; van Beijsterveldt, C.E.M.; Boomsma, D.I.; Bartels, M.

2011-01-01

Objective Several studies reported a negative association between ADHD symptoms and academic achievement. We investigated the etiology of the association between Attention Problems (AP, one of the core symptoms in ADHD) in early childhood and four academic skills across childhood in a genetically