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Sample records for genetic association analysis

  1. Genetic associations in diabetic nephropathy: a meta-analysis

    OpenAIRE

    Mooyaart, A. L.; Valk, E. J. J.; van Es, L A; Bruijn, J. A.; De Heer, E.; Freedman, B.I.; Dekkers, O.M.; Baelde, H. J.

    2010-01-01

    Aims/hypothesis This meta-analysis assessed the pooled effect of each genetic variant reproducibly associated with diabetic nephropathy. Methods PubMed, EMBASE and Web of Science were searched for articles assessing the association between genes and diabetic nephropathy. All genetic variants statistically associated with diabetic nephropathy in an initial study, then independently reproduced in at least one additional study, were selected. Subsequently, all studies assessing these variants we...

  2. Genetic Association Analysis of Drusen Progression

    NARCIS (Netherlands)

    Hoffman, J.D.; Grinsven, M.J.J.P. van; Li, C.; Brantley, M., Jr.; McGrath, J.; Agarwal, A.; Scott, W.K.; Schwartz, S.G.; Kovach, J.; Pericak-Vance, M.; Sanchez, C.I.; Haines, J.L.

    2016-01-01

    PURPOSE: Age-related macular degeneration is a common form of vision loss affecting older adults. The etiology of AMD is multifactorial and is influenced by environmental and genetic risk factors. In this study, we examine how 19 common risk variants contribute to drusen progression, a hallmark of

  3. Genetic associations in diabetic nephropathy: a meta-analysis.

    Science.gov (United States)

    Mooyaart, A L; Valk, E J J; van Es, L A; Bruijn, J A; de Heer, E; Freedman, B I; Dekkers, O M; Baelde, H J

    2011-03-01

    This meta-analysis assessed the pooled effect of each genetic variant reproducibly associated with diabetic nephropathy. PubMed, EMBASE and Web of Science were searched for articles assessing the association between genes and diabetic nephropathy. All genetic variants statistically associated with diabetic nephropathy in an initial study, then independently reproduced in at least one additional study, were selected. Subsequently, all studies assessing these variants were included. The association between these variants and diabetic nephropathy (defined as macroalbuminuria/proteinuria or end-stage renal disease [ESRD]) was calculated at the allele level and the main measure of effect was a pooled odds ratio. Pre-specified subgroup analyses were performed, stratifying for type 1/type 2 diabetes mellitus, proteinuria/ESRD and ethnic group. The literature search yielded 3,455 citations, of which 671 were genetic association studies investigating diabetic nephropathy. We identified 34 replicated genetic variants. Of these, 21 remained significantly associated with diabetic nephropathy in a random-effects meta-analysis. These variants were in or near the following genes: ACE, AKR1B1 (two variants), APOC1, APOE, EPO, NOS3 (two variants), HSPG2, VEGFA, FRMD3 (two variants), CARS (two variants), UNC13B, CPVL and CHN2, and GREM1, plus four variants not near genes. The odds ratios of associated genetic variants ranged from 0.48 to 1.70. Additional variants were detected in subgroup analyses: ELMO1 (Asians), CCR5 (Asians) and CNDP1 (type 2 diabetes). This meta-analysis found 24 genetic variants associated with diabetic nephropathy. The relative contribution and relevance of the identified genes in the pathogenesis of diabetic nephropathy should be the focus of future studies.

  4. 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.

  5. Repeated measurement sampling in genetic association analysis with genotyping errors.

    Science.gov (United States)

    Lai, Renzhen; Zhang, Hong; Yang, Yaning

    2007-02-01

    Genotype misclassification occurs frequently in human genetic association studies. When cases and controls are subject to the same misclassification model, Pearson's chi-square test has the correct type I error but may lose power. Most current methods adjusting for genotyping errors assume that the misclassification model is known a priori or can be assessed by a gold standard instrument. But in practical applications, the misclassification probabilities may not be completely known or the gold standard method can be too costly to be available. The repeated measurement design provides an alternative approach for identifying misclassification probabilities. With this design, a proportion of the subjects are measured repeatedly (five or more repeats) for the genotypes when the error model is completely unknown. We investigate the applications of the repeated measurement method in genetic association analysis. Cost-effectiveness study shows that if the phenotyping-to-genotyping cost ratio or the misclassification rates are relatively large, the repeat sampling can gain power over the regular case-control design. We also show that the power gain is not sensitive to the genetic model, genetic relative risk and the population high-risk allele frequency, all of which are typically important ingredients in association studies. An important implication of this result is that whatever the genetic factors are, the repeated measurement method can be applied if the genotyping errors must be accounted for or the phenotyping cost is high.

  6. A strategy analysis for genetic association studies with known inbreeding

    Directory of Open Access Journals (Sweden)

    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

  7. 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.R.; 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.

  8. A Generalized Genetic Random Field Method for the Genetic Association Analysis of Sequencing Data

    Science.gov (United States)

    Li, Ming; He, Zihuai; Zhang, Min; Zhan, Xiaowei; Wei, Changshuai; Elston, Robert C.; Lu, Qing

    2017-01-01

    With the advance of high-throughput sequencing technologies, it has become feasible to investigate the influence of the entire spectrum of sequencing variations on complex human diseases. Although association studies utilizing the new sequencing technologies hold great promise to unravel novel genetic variants, especially rare genetic variants that contribute to human diseases, the statistical analysis of high-dimensional sequencing data remains a challenge. Advanced analytical methods are in great need to facilitate high-dimensional sequencing data analyses. In this article, we propose a generalized genetic random field (GGRF) method for association analyses of sequencing data. Like other similarity-based methods (e.g., SIMreg and SKAT), the new method has the advantages of avoiding the need to specify thresholds for rare variants and allowing for testing multiple variants acting in different directions and magnitude of effects. The method is built on the generalized estimating equation framework and thus accommodates a variety of disease phenotypes (e.g., quantitative and binary phenotypes). Moreover, it has a nice asymptotic property, and can be applied to small-scale sequencing data without need for small-sample adjustment. Through simulations, we demonstrate that the proposed GGRF attains an improved or comparable power over a commonly used method, SKAT, under various disease scenarios, especially when rare variants play a significant role in disease etiology. We further illustrate GGRF with an application to a real dataset from the Dallas Heart Study. By using GGRF, we were able to detect the association of two candidate genes, ANGPTL3 and ANGPTL4, with serum triglyceride. PMID:24482034

  9. Hierarchical linear modeling of longitudinal pedigree data for genetic association analysis.

    Science.gov (United States)

    Tan, Qihua; B Hjelmborg, Jacob V; Thomassen, Mads; Jensen, Andreas Kryger; Christiansen, Lene; Christensen, Kaare; Zhao, Jing Hua; Kruse, Torben A

    2014-01-01

    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-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 on the mean level of a phenotype, they are not sufficiently straightforward to handle the kinship correlation on the time-dependent trajectories of a phenotype. We introduce a 2-level hierarchical linear model to separately assess the genetic associations with the mean level and the rate of change of a phenotype, integrating kinship correlation in the analysis. We apply our method to the Genetic Analysis Workshop 18 genome-wide association studies data on chromosome 3 to estimate the genetic effects on systolic blood pressure measured over time in large pedigrees. Our method identifies genetic variants 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 for genetic association studies in related samples using longitudinal design.

  10. Systematic analysis, comparison, and integration of disease based human genetic association data and mouse genetic phenotypic information

    Directory of Open Access Journals (Sweden)

    Wang S Alex

    2010-01-01

    Full Text Available Abstract Background The genetic contributions to human common disorders and mouse genetic models of disease are complex and often overlapping. In common human diseases, unlike classical Mendelian disorders, genetic factors generally have small effect sizes, are multifactorial, and are highly pleiotropic. Likewise, mouse genetic models of disease often have pleiotropic and overlapping phenotypes. Moreover, phenotypic descriptions in the literature in both human and mouse are often poorly characterized and difficult to compare directly. Methods In this report, human genetic association results from the literature are summarized with regard to replication, disease phenotype, and gene specific results; and organized in the context of a systematic disease ontology. Similarly summarized mouse genetic disease models are organized within the Mammalian Phenotype ontology. Human and mouse disease and phenotype based gene sets are identified. These disease gene sets are then compared individually and in large groups through dendrogram analysis and hierarchical clustering analysis. Results Human disease and mouse phenotype gene sets are shown to group into disease and phenotypically relevant groups at both a coarse and fine level based on gene sharing. Conclusion This analysis provides a systematic and global perspective on the genetics of common human disease as compared to itself and in the context of mouse genetic models of disease.

  11. GPFrontend and GPGraphics: graphical analysis tools for genetic association studies.

    Science.gov (United States)

    Uebe, Steffen; Pasutto, Francesca; Krumbiegel, Mandy; Schanze, Denny; Ekici, Arif B; Reis, André

    2010-09-21

    Most software packages for whole genome association studies are non-graphical, purely text based programs originally designed to run with UNIX-like operating systems. Graphical output is often not intended or supposed to be performed with other command line tools, e.g. gnuplot. Using the Microsoft .NET 2.0 platform and Visual Studio 2005, we have created a graphical software package to analyze data from microarray whole genome association studies, both for a DNA-pooling based approach as well as regular single sample data. Part of this package was made to integrate with GenePool 0.8.2, a previously existing software suite for GNU/Linux systems, which we have modified to run in a Microsoft Windows environment. Further modifications cause it to generate some additional data. This enables GenePool to interact with the .NET parts created by us. The programs we developed are GPFrontend, a graphical user interface and frontend to use GenePool and create metadata files for it, and GPGraphics, a program to further analyze and graphically evaluate output of different WGA analysis programs, among them also GenePool. Our programs enable regular MS Windows users without much experience in bioinformatics to easily visualize whole genome data from a variety of sources.

  12. GPFrontend and GPGraphics: graphical analysis tools for genetic association studies

    Directory of Open Access Journals (Sweden)

    Schanze Denny

    2010-09-01

    Full Text Available Abstract Background Most software packages for whole genome association studies are non-graphical, purely text based programs originally designed to run with UNIX-like operating systems. Graphical output is often not intended or supposed to be performed with other command line tools, e.g. gnuplot. Results Using the Microsoft .NET 2.0 platform and Visual Studio 2005, we have created a graphical software package to analyze data from microarray whole genome association studies, both for a DNA-pooling based approach as well as regular single sample data. Part of this package was made to integrate with GenePool 0.8.2, a previously existing software suite for GNU/Linux systems, which we have modified to run in a Microsoft Windows environment. Further modifications cause it to generate some additional data. This enables GenePool to interact with the .NET parts created by us. The programs we developed are GPFrontend, a graphical user interface and frontend to use GenePool and create metadata files for it, and GPGraphics, a program to further analyze and graphically evaluate output of different WGA analysis programs, among them also GenePool. Conclusions Our programs enable regular MS Windows users without much experience in bioinformatics to easily visualize whole genome data from a variety of sources.

  13. A Systematic Meta-Analysis of Genetic Association Studies for Diabetic Retinopathy

    OpenAIRE

    Abhary, Sotoodeh; Hewitt, Alex W.; Burdon, Kathryn P.; Craig, Jamie E.

    2009-01-01

    OBJECTIVE Diabetic retinopathy is a sight-threatening microvascular complication of diabetes with a complex multifactorial pathogenesis. A systematic meta-analysis was undertaken to collectively assess genetic studies and determine which previously investigated polymorphisms are associated with diabetic retinopathy. RESEARCH DESIGN AND METHODS All studies investigating the association of genetic variants with the development of diabetic retinopathy were identified in PubMed and ISI Web of Kno...

  14. Genetic variants associated with gestational diabetes mellitus: a meta-analysis and subgroup analysis

    Science.gov (United States)

    Wu, Ling; Cui, Long; Tam, Wing Hung; Ma, Ronald C. W.; Wang, Chi Chiu

    2016-01-01

    Previous studies have demonstrated that gestational diabetes mellitus (GDM) and Type 2 diabetes mellitus (T2D) share common genetic polymorphisms. We conducted meta-analysis and subgroup analysis of all available variants and determined the effects of confounding and experimental components on the genetic association of GDM. Any case-controlled or cohort studies with genotype distribution compared GDM cases with controls were included. In total, 28 articles including 8,204 cases and 15,221 controls for 6 polymorphisms were studied. rs10830963(MTNR1B), rs7903146(TCF7L2), and rs1801278(IRS1) were significantly associated with the increased GDM risk. The association of rs4402960(IGF2BP2) and rs1800629(TNF-α) was significant only when the studies with control allele frequency deviation and publication bias were excluded. Further subgroup analysis showed the risk alleles of rs7903146(TCF7L2) and rs1801282(PPARG) were significantly associated with the GDM risk only in Asian, but not in Caucasian population. The OGTT test using 100 g, but not 75 g; and genotype detection by other assays, but not Taqman method, were also significantly associated with increased GDM risk in rs1801278(IRS1) and rs7903146(TCF7L2). Overall GDM was associated with rs10830963(MTNR1B), rs7903146(TCF7L2), and rs1801278(IRS1), but only rs7903146(TCF7L2) and rs1801282(PPARG) were significant in Asian populations. While rs1801278(IRS1) and rs7903146(TCF7L2) were significantly affected by OGTT protocol and genotyping methods. PMID:27468700

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

    DEFF Research Database (Denmark)

    Tan, Q.

    2013-01-01

    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...... 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....... Our results show that the method efficiently handles relatedness in detecting genetic variations that affect the mean level or the rate of change for a phenotype of interest....

  16. Genetic association analysis of LARS2 with type 2 diabetes

    DEFF Research Database (Denmark)

    Reiling, E; Jafar-Mohammadi, B; van 't Riet, E;

    2010-01-01

    AIMS/HYPOTHESIS: LARS2 has been previously identified as a potential type 2 diabetes susceptibility gene through the low-frequency H324Q (rs71645922) variant (minor allele frequency [MAF] 3.0%). However, this association did not achieve genome-wide levels of significance. The aim of this study...... was to establish the true contribution of this variant and common variants in LARS2 (MAF > 5%) to type 2 diabetes risk. METHODS: We combined genome-wide association data (n = 10,128) from the DIAGRAM consortium with independent data derived from a tagging single nucleotide polymorphism (SNP) approach in Dutch...... individuals (n = 999) and took forward two SNPs of interest to replication in up to 11,163 Dutch participants (rs17637703 and rs952621). In addition, because inspection of genome-wide association study data identified a cluster of low-frequency variants with evidence of type 2 diabetes association, we...

  17. Genetic association analysis of LARS2 with type 2 diabetes

    NARCIS (Netherlands)

    E. Reiling (Erwin); B. Jafar-Mohammadi (Bahram); E. van 't Riet (Esther); M.N. Weedon (Michael); J.V. van Vliet-Ostaptchouk (Jana); T. Hansen (Torben); R. Saxena (Richa); T.W. van Haeften (Timon); P.P. Arp (Pascal); S. Das; M.G.A.A.M. Nijpels (Giel); M.J. Groenewoud (Marlous); E.C. van Hove (Els); A.G. Uitterlinden (André); J.W.A. Smit (Jan); A.D. Morris (Andrew); A.S.F. Doney (Alex); C.N.A. Palmer (Colin); C. Guiducci (Candace); A.T. Hattersley (Andrew); T.M. Frayling (Timothy); O. Pedersen (Oluf); P.E. Slagboom (Eline); D. Altshuler (David); L. Groop (Leif); J.A. Romijn; J.A. Maassen (Johannes); M.A. Hofker (Marten); J.M. Dekker (Jacqueline); M.I. McCarthy (Mark); L.M. 't Hart (Leen)

    2010-01-01

    textabstractAims/hypothesis: LARS2 has been previously identified as a potential type 2 diabetes susceptibility gene through the low-frequency H324Q (rs71645922) variant (minor allele frequency [MAF] 3.0%). However, this association did not achieve genome-wide levels of significance. The aim of this

  18. Genome-Wide Pathway Analysis Identifies Genetic Pathways Associated with Psoriasis.

    Science.gov (United States)

    Aterido, Adrià; Julià, Antonio; Ferrándiz, Carlos; Puig, Lluís; Fonseca, Eduardo; Fernández-López, Emilia; Dauden, Esteban; Sánchez-Carazo, José Luís; López-Estebaranz, José Luís; Moreno-Ramírez, David; Vanaclocha, Francisco; Herrera, Enrique; de la Cueva, Pablo; Dand, Nick; Palau, Núria; Alonso, Arnald; López-Lasanta, María; Tortosa, Raül; García-Montero, Andrés; Codó, Laia; Gelpí, Josep Lluís; Bertranpetit, Jaume; Absher, Devin; Capon, Francesca; Myers, Richard M; Barker, Jonathan N; Marsal, Sara

    2016-03-01

    Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To date, the psoriasis heritability is only partially explained. However, there is increasing evidence that the missing heritability in psoriasis could be explained by multiple genetic variants of low effect size from common genetic pathways. The objective of this study was to identify new genetic variation associated with psoriasis risk at the pathway level. We genotyped 598,258 single nucleotide polymorphisms in a discovery cohort of 2,281 case-control individuals from Spain. We performed a genome-wide pathway analysis using 1,053 reference biological pathways. A total of 14 genetic pathways (PFDR ≤ 2.55 × 10(-2)) were found to be significantly associated with psoriasis risk. Using an independent validation cohort of 7,353 individuals from the UK, a total of 6 genetic pathways were significantly replicated (PFDR ≤ 3.46 × 10(-2)). We found genetic pathways that had not been previously associated with psoriasis risk such as retinol metabolism (Pcombined = 1.84 × 10(-4)), the transport of inorganic ions and amino acids (Pcombined = 1.57 × 10(-7)), and post-translational protein modification (Pcombined = 1.57 × 10(-7)). In the latter pathway, MGAT5 showed a strong network centrality, and its association with psoriasis risk was further validated in an additional case-control cohort of 3,429 individuals (P psoriasis susceptibility.

  19. 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

  20. Cluster headache and the hypocretin receptor 2 reconsidered: a genetic association study and meta-analysis.

    Science.gov (United States)

    Weller, Claudia M; Wilbrink, Leopoldine A; Houwing-Duistermaat, Jeanine J; Koelewijn, Stephany C; Vijfhuizen, Lisanne S; Haan, Joost; Ferrari, Michel D; Terwindt, Gisela M; van den Maagdenberg, Arn M J M; de Vries, Boukje

    2015-08-01

    Cluster headache is a severe neurological disorder with a complex genetic background. A missense single nucleotide polymorphism (rs2653349; p.Ile308Val) in the HCRTR2 gene that encodes the hypocretin receptor 2 is the only genetic factor that is reported to be associated with cluster headache in different studies. However, as there are conflicting results between studies, we re-evaluated its role in cluster headache. We performed a genetic association analysis for rs2653349 in our large Leiden University Cluster headache Analysis (LUCA) program study population. Systematic selection of the literature yielded three additional studies comprising five study populations, which were included in our meta-analysis. Data were extracted according to predefined criteria. A total of 575 cluster headache patients from our LUCA study and 874 controls were genotyped for HCRTR2 SNP rs2653349 but no significant association with cluster headache was found (odds ratio 0.91 (95% confidence intervals 0.75-1.10), p = 0.319). In contrast, the meta-analysis that included in total 1167 cluster headache cases and 1618 controls from the six study populations, which were part of four different studies, showed association of the single nucleotide polymorphism with cluster headache (random effect odds ratio 0.69 (95% confidence intervals 0.53-0.90), p = 0.006). The association became weaker, as the odds ratio increased to 0.80, when the meta-analysis was repeated without the initial single South European study with the largest effect size. Although we did not find evidence for association of rs2653349 in our LUCA study, which is the largest investigated study population thus far, our meta-analysis provides genetic evidence for a role of HCRTR2 in cluster headache. Regardless, we feel that the association should be interpreted with caution as meta-analyses with individual populations that have limited power have diminished validity. © International Headache Society 2014.

  1. Moving towards system genetics through multiple trait analysis in genome-wide association studies

    Directory of Open Access Journals (Sweden)

    Daniel eShriner

    2012-01-01

    Full Text Available Association studies are a staple of genotype-phenotype mapping studies, whether they are based on single markers, haplotypes, candidate genes, genome-wide genotypes, or whole genome sequences. Although genetic epidemiological studies typically contain data collected on multiple traits which themselves are often correlated, most analyses have been performed on single traits. Here, I review several methods that have been developed to perform multiple trait analysis. These methods range from traditional multivariate models for systems of equations to recently developed graphical approaches based on network theory. The application of network theory to genetics is termed systems genetics and has the potential to address long-standing questions in genetics about complex processes such as coordinate regulation, homeostasis, and pleiotropy.

  2. Nine genetic polymorphisms associated with power athlete status - A Meta-Analysis.

    Science.gov (United States)

    Weyerstraß, Jan; Stewart, Kelly; Wesselius, Anke; Zeegers, Maurice

    2017-06-21

    In this study the association between genetic polymorphisms and power athlete status with possible interference by race and sex was investigated to identify genetic variants favourable for becoming a power athlete. This meta-analysis included both, case-control and Cohort studies. Databases of PubMed and Web of Science were searched for studies reporting on genetic polymorphisms associated with the status of being a power athlete. Thirty-five articles published between 2008 and 2016 were identified as eligible including a total number of 5834 power athletes and 14,018 controls. A series of meta-analyses were conducted for each of the identified genetic polymorphisms associated with power athlete status. Odds ratios (ORs) based on the allele and genotype frequency with corresponding 95% confidence intervals (95%CI) were calculated per genetic variant. Heterogeneity of the studies was addressed by Chi-square based Q-statistics at 5% significance level and a fixed or random effects model was used in absence or presence of heterogeneity respectively. Stratified analyses were conducted by race and sex to explore potential sources of heterogeneity. Significant associations were found for the genetic polymorphisms in the ACE (rs4363, rs1799752), ACTN3 (rs1815739), AGT (rs699), IL6-174 (rs1800795), MnSOD (rs1799725), NOS3 (rs1799983, rs2070744) and SOD2 (rs4880) genes. Nine genetic polymorphisms have been identified in the meta-analyses to have a significant association with the status of being a power athlete. Nevertheless, more research on the investigated genes needs to be done to draw comprehensive conclusions. Copyright © 2017 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

  3. Pathway analysis to identify genetic variants associated with efficacy of adalimumab in rheumatoid arthritis.

    Science.gov (United States)

    Eektimmerman, Frank; Swen, Jesse J; Böhringer, Stefan; Huizinga, Tom Wj; Kooloos, Wouter M; Allaart, Cornelia F; Guchelaar, Henk-Jan

    2017-07-01

    About 30% of rheumatoid arthritis patients have no clinical benefit from TNF inhibitors. Genome-wide association (GWA) and candidate gene studies tested several putative genetic variants for TNF inhibitor efficacy with inconclusive results. Therefore, this study applied a systematic pathway analysis. A total of 325 rheumatoid arthritis patients treated with adalimumab were genotyped for 223 SNPs. We tested the association between SNPs and European League Against Rheumatism response and remission at 14 weeks under the additive genetic model using logistic regression. A total of 3 SNPs located in CD40LG (rs1126535), TANK (rs1267067) and VEGFA (rs25648) showed association with both end points. TNFAIP3 (rs2230926) had the strongest effect related to European League Against Rheumatism response. This exploratory study suggests that TNFAIP3, CD40LG, TANK and VEGFA play a role in the response to adalimumab treatment.

  4. Analysis of the association between host genetics, smoking, and sputum microbiota in healthy humans.

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    Lim, Mi Young; Yoon, Hyo Shin; Rho, Mina; Sung, Joohon; Song, Yun-Mi; Lee, Kayoung; Ko, GwangPyo

    2016-03-31

    Recent studies showing clear differences in the airway microbiota between healthy and diseased individuals shed light on the importance of the airway microbiota in health. Here, we report the associations of host genetics and lifestyles such as smoking, alcohol consumption, and physical activity with the composition of the sputum microbiota using 16S rRNA gene sequence data generated from 257 sputum samples of Korean twin-family cohort. By estimating the heritability of each microbial taxon, we found that several taxa, including Providencia and Bacteroides, were significantly influenced by host genetic factors. Smoking had the strongest effect on the overall microbial community structure among the tested lifestyle factors. The abundances of Veillonella and Megasphaera were higher in current-smokers, and increased with the pack-year value and the Fagerstrom Test of Nicotine Dependence (FTND) score. In contrast, Haemophilus decreased with the pack-year of smoking and the FTND score. Co-occurrence network analysis showed that the taxa were clustered according to the direction of associations with smoking, and that the taxa influenced by host genetics were found together. These results demonstrate that the relationships among sputum microbial taxa are closely associated with not only smoking but also host genetics.

  5. Multivariate Meta-Analysis of Genetic Association Studies: A Simulation Study.

    Science.gov (United States)

    Neupane, Binod; Beyene, Joseph

    2015-01-01

    In a meta-analysis with multiple end points of interests that are correlated between or within studies, multivariate approach to meta-analysis has a potential to produce more precise estimates of effects by exploiting the correlation structure between end points. However, under random-effects assumption the multivariate estimation is more complex (as it involves estimation of more parameters simultaneously) than univariate estimation, and sometimes can produce unrealistic parameter estimates. Usefulness of multivariate approach to meta-analysis of the effects of a genetic variant on two or more correlated traits is not well understood in the area of genetic association studies. In such studies, genetic variants are expected to roughly maintain Hardy-Weinberg equilibrium within studies, and also their effects on complex traits are generally very small to modest and could be heterogeneous across studies for genuine reasons. We carried out extensive simulation to explore the comparative performance of multivariate approach with most commonly used univariate inverse-variance weighted approach under random-effects assumption in various realistic meta-analytic scenarios of genetic association studies of correlated end points. We evaluated the performance with respect to relative mean bias percentage, and root mean square error (RMSE) of the estimate and coverage probability of corresponding 95% confidence interval of the effect for each end point. Our simulation results suggest that multivariate approach performs similarly or better than univariate method when correlations between end points within or between studies are at least moderate and between-study variation is similar or larger than average within-study variation for meta-analyses of 10 or more genetic studies. Multivariate approach produces estimates with smaller bias and RMSE especially for the end point that has randomly or informatively missing summary data in some individual studies, when the missing data

  6. Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function

    NARCIS (Netherlands)

    Wild, Philipp S.; Felix, Janine F.; Schillert, Arne; Teumer, Alexander; Chen, Ming-Huei; Leening, Maarten J. G.; Voelker, Uwe; Grossmann, Vera; Brody, Jennifer A.; Irvin, Marguerite R.; Shah, Sanjiv J.; Pramana, Setia; Lieb, Wolfgang; Schmidt, Reinhold; Stanton, Alice V.; Malzahn, Doerthe; Smith, Albert Vernon; Sundstrom, Johan; Minelli, Cosetta; Ruggiero, Daniela; Lyytikainen, Leo-Pekka; Tiller, Daniel; Smith, J. Gustav; Monnereau, Claire; Di Tullio, Marco R.; Musani, Solomon K.; Morrison, Alanna C.; Pers, Tune H.; Morley, Michael; Kleber, Marcus E.; Aragam, Jayashri; Benjamin, Emelia J.; Bis, Joshua C.; Bisping, Egbert; Broeckel, Ulrich; Cheng, Susan; Deckers, Jaap W.; Del Greco, Fabiola; Edelmann, Frank; Fornage, Myriam; Franke, Lude; Friedrich, Nele; Harris, Tamara B.; Hofer, Edith; Hofman, Albert; Huang, Jie; Hughes, Alun D.; Kahonen, Mika; Kruppa, Jochen; Lackner, Karl J.; Lannfelt, Lars; Laskowski, Rafael; Launer, Lenore J.; Leosdottir, Margret; Lin, Honghuang; Lindgren, Cecilia M.; Loley, Christina; MacRae, Calum A.; Mascalzoni, Deborah; Mayet, Jamil; Medenwald, Daniel; Morris, Andrew P.; Mueller, Christian; Mueller-Nurasyid, Martina; Nappo, Stefania; Nilsson, Peter M.; Nuding, Sebastian; Nutile, Teresa; Peters, Annette; Pfeufer, Arne; Pietzner, Diana; Pramstaller, Peter P.; Raitakari, Olli T.; Rice, Kenneth M.; Rivadeneira, Fernando; Rotter, Jerome I.; Ruohonen, Saku T.; Sacco, Ralph L.; Samdarshi, Tandaw E.; Schmidt, Helena; Sharp, Andrew S. P.; Shields, Denis C.; Sorice, Rossella; Sotoodehnia, Nona; Stricker, Bruno H.; Surendran, Praveen; Thom, Simon; Toeglhofer, Anna M.; Uitterlinden, Andre G.; Wachter, Rolf; Voelzke, Henry; Ziegler, Andreas; Muenzel, Thomas; Maerz, Winfried; Cappola, Thomas P.; Hirschhorn, Joel N.; Mitchell, Gary F.; Smith, Nicholas L.; Fox, Ervin R.; Dueker, Nicole D.; Jaddoe, Vincent W. V.; Melander, Olle; Russ, Martin; Lehtimaki, Terho; Ciullo, Marina; Hicks, Andrew A.; Lind, Lars; Gudnason, Vilmundur; Pieske, Burkert; Barron, Anthony J.; Zweiker, Robert; Schunkert, Heribert; Ingelsson, Erik; Liu, Kiang; Arnett, Donna K.; Psaty, Bruce M.; Blankenberg, Stefan; Larson, Martin G.; Felix, Stephan B.; Franco, Oscar H.; Zeller, Tanja; Vasan, Ramachandran S.; Doerr, Marcus

    2017-01-01

    BACKGROUND. Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS. A GWAS

  7. On the validity of within-nuclear-family genetic association analysis in samples of extended families.

    Science.gov (United States)

    Bureau, Alexandre; Duchesne, Thierry

    2015-12-01

    Splitting extended families into their component nuclear families to apply a genetic association method designed for nuclear families is a widespread practice in familial genetic studies. Dependence among genotypes and phenotypes of nuclear families from the same extended family arises because of genetic linkage of the tested marker with a risk variant or because of familial specificity of genetic effects due to gene-environment interaction. This raises concerns about the validity of inference conducted under the assumption of independence of the nuclear families. We indeed prove theoretically that, in a conditional logistic regression analysis applicable to disease cases and their genotyped parents, the naive model-based estimator of the variance of the coefficient estimates underestimates the true variance. However, simulations with realistic effect sizes of risk variants and variation of this effect from family to family reveal that the underestimation is negligible. The simulations also show the greater efficiency of the model-based variance estimator compared to a robust empirical estimator. Our recommendation is therefore, to use the model-based estimator of variance for inference on effects of genetic variants.

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

    Directory of Open Access Journals (Sweden)

    Kim Nora

    2012-07-01

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

  9. A systematic meta-analysis of genetic association studies for diabetic retinopathy.

    Science.gov (United States)

    Abhary, Sotoodeh; Hewitt, Alex W; Burdon, Kathryn P; Craig, Jamie E

    2009-09-01

    Diabetic retinopathy is a sight-threatening microvascular complication of diabetes with a complex multifactorial pathogenesis. A systematic meta-analysis was undertaken to collectively assess genetic studies and determine which previously investigated polymorphisms are associated with diabetic retinopathy. All studies investigating the association of genetic variants with the development of diabetic retinopathy were identified in PubMed and ISI Web of Knowledge. Crude odds ratios (ORs) and 95% CIs were calculated for single nucleotide polymorphisms and microsatellite markers previously investigated in at least two published studies. Twenty genes and 34 variants have previously been studied in multiple cohorts. The aldose reductase (AKR1B1) gene was found to have the largest number of polymorphisms significantly associated with diabetic retinopathy. The z-2 microsatellite was found to confer risk (OR 2.33 [95% CI 1.49-3.64], P = 2 x 10(-4)) in type 1 and type 2 diabetes and z+2 to confer protection (0.58 [0.36-0.93], P = 0.02) against diabetic retinopathy in type 2 diabetes regardless of ethnicity. The T allele of the AKR1B1 promoter rs759853 variant is also significantly protective against diabetic retinopathy in type 1 diabetes (0.5 [0.35-0.71], P = 1.00 x 10(-4)), regardless of ethnicity. These associations were also found in the white population alone (P NOS3, VEGF, ITGA2, and ICAM1 are also associated with diabetic retinopathy after meta-analysis. Variations within the AKR1B1 gene are highly significantly associated with diabetic retinopathy development irrespective of ethnicity. Identification of genetic risk factors in diabetic retinopathy will assist in further understanding of this complex and debilitating diabetes complication.

  10. Methods for meta-analysis in genetic association studies: a review of their potential and pitfalls.

    Science.gov (United States)

    Kavvoura, Fotini K; Ioannidis, John P A

    2008-02-01

    Meta-analysis offers the opportunity to combine evidence from retrospectively accumulated or prospectively generated data. Meta-analyses may provide summary estimates and can help in detecting and addressing potential inconsistency between the combined datasets. Application of meta-analysis in genetic associations presents considerable potential and several pitfalls. In this review, we present basic principles of meta-analytic methods, adapted for human genome epidemiology. We describe issues that arise in the retrospective or the prospective collection of relevant data through various sources, common traps to consider in the appraisal of evidence and potential biases that may interfere. We describe the relative merits and caveats for common methods used to trace inconsistency across studies along with possible reasons for non-replication of proposed associations. Different statistical models may be employed to combine data and some common misconceptions may arise in the process. Several meta-analysis diagnostics are often applied or misapplied in the literature, and we comment on their use and limitations. An alternative to overcome limitations arising from retrospective combination of data from published studies is to create networks of research teams working in the same field and perform collaborative meta-analyses of individual participant data, ideally on a prospective basis. We discuss the advantages and the challenges inherent in such collaborative approaches. Meta-analysis can be a useful tool in dissecting the genetics of complex diseases and traits, provided its methods are properly applied and interpreted.

  11. Genetic Association Analysis under Complex Survey Sampling: The Hispanic Community Health Study/Study of Latinos

    Science.gov (United States)

    Lin, Dan-Yu; Tao, Ran; Kalsbeek, William D.; Zeng, Donglin; Gonzalez, Franklyn; Fernández-Rhodes, Lindsay; Graff, Mariaelisa; Koch, Gary G.; North, Kari E.; Heiss, Gerardo

    2014-01-01

    The cohort design allows investigators to explore the genetic basis of a variety of diseases and traits in a single study while avoiding major weaknesses of the case-control design. Most cohort studies employ multistage cluster sampling with unequal probabilities to conveniently select participants with desired characteristics, and participants from different clusters might be genetically related. Analysis that ignores the complex sampling design can yield biased estimation of the genetic association and inflation of the type I error. Herein, we develop weighted estimators that reflect unequal selection probabilities and differential nonresponse rates, and we derive variance estimators that properly account for the sampling design and the potential relatedness of participants in different sampling units. We compare, both analytically and numerically, the performance of the proposed weighted estimators with unweighted estimators that disregard the sampling design. We demonstrate the usefulness of the proposed methods through analysis of MetaboChip data in the Hispanic Community Health Study/Study of Latinos, which is the largest health study of the Hispanic/Latino population in the United States aimed at identifying risk factors for various diseases and determining the role of genes and environment in the occurrence of diseases. We provide guidelines on the use of weighted and unweighted estimators, as well as the relevant software. PMID:25480034

  12. [Replicative association analysis of genetic markers of cognitive traits with Alzheimer's disease in a Russian population].

    Science.gov (United States)

    Stepanov, V A; Bocharova, A V; Marusin, A V; Zhukova, N G; Alifirova, V M; Zhukova, I A

    2014-01-01

    Replicative association analysis of Alzheimer's disease (AD) with 15 genetic markers associated with cognitive traits in genome-wide association studies was performed. In a Russian populations associations of rs2616984 in CSMD1 gene with AD (OR = 1.50, 95% CI = 1.07-2.09, p-value = 0.018) and putative associations with the disease of rs3131296 in NOTCH4 gene (OR = 1.53, 95% CI = 0.98-2.39, p-value = 0.06) and rs2229741 of NRIP1 gene (OR = 1.35, CI = 0.99-1.85, p-value = 0.061) were revealed. Combinations of epistatic interacting genes (CSMD1 and NRIP1; NOTCH4, CSMD1 and NRIP1; TLR4, CSMD1 and NRIP1) were found, as well as their genotypes combinations significantly associated with AD and characterized by highest predictive values. Probable molecular mechanisms implicated in the relation of genes under study to AD pathogenesis are discussed. Bioinformatic analysis of biological processes, molecular functions and protein-protein interactions of BA genes demonstrated that genes under study may play modulating and modifying role by participation in various regulatory and signal pathways involved in a disease development.

  13. A Co-Association Network Analysis of the Genetic Determination of Pig Conformation, Growth and Fatness

    Science.gov (United States)

    Puig-Oliveras, Anna; Ballester, Maria; Corominas, Jordi; Revilla, Manuel; Estellé, Jordi; Fernández, Ana I.; Ramayo-Caldas, Yuliaxis; Folch, Josep M.

    2014-01-01

    Background Several QTLs have been identified for major economically relevant traits in livestock, such as growth and meat quality, revealing the complex genetic architecture of these traits. The use of network approaches considering the interactions of multiple molecules and traits provides useful insights into the molecular underpinnings of complex traits. Here, a network based methodology, named Association Weight Matrix, was applied to study gene interactions and pathways affecting pig conformation, growth and fatness traits. Results The co-association network analysis underpinned three transcription factors, PPARγ, ELF1, and PRDM16 involved in mesoderm tissue differentiation. Fifty-four genes in the network belonged to growth-related ontologies and 46 of them were common with a similar study for growth in cattle supporting our results. The functional analysis uncovered the lipid metabolism and the corticotrophin and gonadotrophin release hormone pathways among the most important pathways influencing these traits. Our results suggest that the genes and pathways here identified are important determining either the total body weight of the animal and the fat content. For instance, a switch in the mesoderm tissue differentiation may determinate the age-related preferred pathways being in the puberty stage those related with the miogenic and osteogenic lineages; on the contrary, in the maturity stage cells may be more prone to the adipocyte fate. Hence, our results demonstrate that an integrative genomic co-association analysis is a powerful approach for identifying new connections and interactions among genes. Conclusions This work provides insights about pathways and key regulators which may be important determining the animal growth, conformation and body proportions and fatness traits. Molecular information concerning genes and pathways here described may be crucial for the improvement of genetic breeding programs applied to pork meat production. PMID:25503799

  14. A co-association network analysis of the genetic determination of pig conformation, growth and fatness.

    Directory of Open Access Journals (Sweden)

    Anna Puig-Oliveras

    Full Text Available Several QTLs have been identified for major economically relevant traits in livestock, such as growth and meat quality, revealing the complex genetic architecture of these traits. The use of network approaches considering the interactions of multiple molecules and traits provides useful insights into the molecular underpinnings of complex traits. Here, a network based methodology, named Association Weight Matrix, was applied to study gene interactions and pathways affecting pig conformation, growth and fatness traits.The co-association network analysis underpinned three transcription factors, PPARγ, ELF1, and PRDM16 involved in mesoderm tissue differentiation. Fifty-four genes in the network belonged to growth-related ontologies and 46 of them were common with a similar study for growth in cattle supporting our results. The functional analysis uncovered the lipid metabolism and the corticotrophin and gonadotrophin release hormone pathways among the most important pathways influencing these traits. Our results suggest that the genes and pathways here identified are important determining either the total body weight of the animal and the fat content. For instance, a switch in the mesoderm tissue differentiation may determinate the age-related preferred pathways being in the puberty stage those related with the miogenic and osteogenic lineages; on the contrary, in the maturity stage cells may be more prone to the adipocyte fate. Hence, our results demonstrate that an integrative genomic co-association analysis is a powerful approach for identifying new connections and interactions among genes.This work provides insights about pathways and key regulators which may be important determining the animal growth, conformation and body proportions and fatness traits. Molecular information concerning genes and pathways here described may be crucial for the improvement of genetic breeding programs applied to pork meat production.

  15. Personality endophenotypes for bipolar affective disorder: a family-based genetic association analysis.

    Science.gov (United States)

    Savitz, J; van der Merwe, L; Ramesar, R

    2008-11-01

    Genetic analyses of complex conditions such as bipolar disorder (BD) may be facilitated by the use of intermediate phenotypes. Various personality traits are overrepresented in people with BD and their unaffected relatives, and may constitute genetically transmitted risk factors or endophenotypes of the illness. In this study, we administered a battery of seven different personality questionnaires comprising 19 subscales to 31 Caucasian BD families (n = 241). Ten of these personality traits showed significant evidence of heritability and were therefore selected as candidate endophenotypes. In addition, a principal components analysis produced two heritable components (negative affect and appetitive drive), which accounted for a considerable proportion of the variance (29% + 12%) and were also used in the analysis. A family-based quantitative association study was carried out using the orthogonal model from the quantitative transmission disequilibrium tests (QTDT) program. Monte Carlo permutations (M = 500), which allow for non-normal data and provide a global P value, corrected for multiple testing, were used to calculate empirical P values for the within-family component of association. The 3' untranslated region repeat polymorphism of the dopamine transporter gene (SLC6A3) was associated with self-directedness (P personality traits, 'Spirituality' (P = 0.040) and irritable temperament (P = 0.022). Furthermore, the met allele of the brain-derived neurotrophic factor val66met polymorphism was associated with higher hyperthymic temperament scores. We raise the possibility that the 10R allele of the SLC6A3 repeat polymorphism and the short allele of the SLC6A4 promoter variant constitute risk factors for irritable-aggressive and anxious-dysthymic subtypes of BD, respectively.

  16. Genetic Associations of Angiotensin-Converting Enzyme with Primary Intracerebral Hemorrhage: A Meta-analysis.

    Directory of Open Access Journals (Sweden)

    Yuhao Sun

    Full Text Available A number of studies have reported an association of angiotensin-converting enzyme (ACE gene polymorphism with primary intracerebral hemorrhage (PICH, however the reports have demonstrated inconclusive results. To clarify this conflict, we updated the previously performed meta-analysis by Peck et al., which revealed negative results, by investigating the ACE polymorphism and its correlation to PICH.PubMed and Embase databases (through Dec 2012 were searched for English articles on the relationship of the I/D polymorphism in ACE with PICH in humans. Summary odds ratios (ORs were estimated and potential sources of heterogeneity and bias were explored.A total of 805 PICH cases and 1641 control cases obtained from 8 case-control studies were included. The results suggest that in dominant genetic models, the ACE I/D polymorphic variant was associated with a 58% increase in susceptibility risk of PICH (OR = 1.58; 95% CI = 1.07-2.35 for DD vs. DI+II. However, in the subgroup analysis based on race, a significant increased risk was found in Asian DD homozygote carriers (OR = 1.76 and 95% CI = 1.16-2.66 for DD vs. DI+II, but not in Caucasian DD homozygote carriers (OR = 1.18, 95% CI = 0.36-3.88, P = 0.784 for DD vs. DI+II. The heterogeneity between studies was remarkable, and its major sources of heterogeneity were due to the year in which the study was published. No potential publication bias was observed in dominant genetic models.These data demonstrated evidence of a positive association between ACE I/D polymorphism with PICH, and suggested that the ACE gene is a PICH susceptible gene in Asian populations.

  17. Systematic genetic analysis identifies Cis-eQTL target genes associated with glioblastoma patient survival.

    Directory of Open Access Journals (Sweden)

    Qing-Rong Chen

    Full Text Available Prior expression quantitative trait locus (eQTL studies have demonstrated heritable variation determining differences in gene expression. The majority of eQTL studies were based on cell lines and normal tissues. We performed cis-eQTL analysis using glioblastoma multiforme (GBM data sets obtained from The Cancer Genome Atlas (TCGA to systematically investigate germline variation's contribution to tumor gene expression levels. We identified 985 significant cis-eQTL associations (FDR<0.05 mapped to 978 SNP loci and 159 unique genes. Approximately 57% of these eQTLs have been previously linked to the gene expression in cell lines and normal tissues; 43% of these share cis associations known to be associated with functional annotations. About 25% of these cis-eQTL associations are also common to those identified in Breast Cancer from a recent study. Further investigation of the relationship between gene expression and patient clinical information identified 13 eQTL genes whose expression level significantly correlates with GBM patient survival (p<0.05. Most of these genes are also differentially expressed in tumor samples and organ-specific controls (p<0.05. Our results demonstrated a significant relationship of germline variation with gene expression levels in GBM. The identification of eQTLs-based expression associated survival might be important to the understanding of genetic contribution to GBM cancer prognosis.

  18. Analysis of the association between host genetics, smoking, and sputum microbiota in healthy humans

    National Research Council Canada - National Science Library

    Lim, Mi Young; Yoon, Hyo Shin; Rho, Mina; Sung, Joohon; Song, Yun-Mi; Lee, Kayoung; Ko, GwangPyo

    2016-01-01

    .... Here, we report the associations of host genetics and lifestyles such as smoking, alcohol consumption, and physical activity with the composition of the sputum microbiota using 16S rRNA gene sequence...

  19. Retrospective analysis of main and interaction effects in genetic association studies of human complex traits

    DEFF Research Database (Denmark)

    Tan, Qihua; Christiansen, Lene; Brasch-Andersen, Charlotte;

    2007-01-01

    BACKGROUND: The etiology of multifactorial human diseases involves complex interactions between numerous environmental factors and alleles of many genes. Efficient statistical tools are demanded in identifying the genetic and environmental variants that affect the risk of disease development....... This paper introduces a retrospective polytomous logistic regression model to measure both the main and interaction effects in genetic association studies of human discrete and continuous complex traits. In this model, combinations of genotypes at two interacting loci or of environmental exposure...... regression model can be used as a convenient tool for assessing both main and interaction effects in genetic association studies of human multifactorial diseases involving genetic and non-genetic factors as well as categorical or continuous traits....

  20. Association analysis of genetic variants in the myosin IXB gene in acute pancreatitis.

    Directory of Open Access Journals (Sweden)

    Rian M Nijmeijer

    Full Text Available INTRODUCTION: Impairment of the mucosal barrier plays an important role in the pathophysiology of acute pancreatitis. The myosin IXB (MYO9B gene and the two tight-junction adaptor genes, PARD3 and MAGI2, have been linked to gastrointestinal permeability. Common variants of these genes are associated with celiac disease and inflammatory bowel disease, two other conditions in which intestinal permeability plays a role. We investigated genetic variation in MYO9B, PARD3 and MAGI2 for association with acute pancreatitis. METHODS: Five single nucleotide polymorphisms (SNPs in MYO9B, two SNPs in PARD3, and three SNPs in MAGI2 were studied in a Dutch cohort of 387 patients with acute pancreatitis and over 800 controls, and in a German cohort of 235 patients and 250 controls. RESULTS: Association to MYO9B and PARD3 was observed in the Dutch cohort, but only one SNP in MYO9B and one in MAGI2 showed association in the German cohort (p < 0.05. Joint analysis of the combined cohorts showed that, after correcting for multiple testing, only two SNPs in MYO9B remained associated (rs7259292, p = 0.0031, odds ratio (OR 1.94, 95% confidence interval (95% CI 1.35-2.78; rs1545620, p = 0.0006, OR 1.33, 95% CI 1.16-1.53. SNP rs1545620 is a non-synonymous SNP previously suspected to impact on ulcerative colitis. None of the SNPs showed association to disease severity or etiology. CONCLUSION: Variants in MYO9B may be involved in acute pancreatitis, but we found no evidence for involvement of PARD3 or MAGI2.

  1. Genetic analysis of Down syndrome-associated heart defects in mice.

    Science.gov (United States)

    Liu, Chunhong; Morishima, Masae; Yu, Tao; Matsui, Sei-Ichi; Zhang, Li; Fu, Dawei; Pao, Annie; Costa, Alberto C; Gardiner, Katheleen J; Cowell, John K; Nowak, Norma J; Nowak, Normal J; Parmacek, Michael S; Liang, Ping; Baldini, Antonio; Yu, Y Eugene

    2011-11-01

    Human trisomy 21, the chromosomal basis of Down syndrome (DS), is the most common genetic cause of heart defects. Regions on human chromosome 21 (Hsa21) are syntenically conserved with three regions located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. In this study, we have analyzed the impact of duplications of each syntenic region on cardiovascular development in mice and have found that only the duplication on Mmu16, i.e., Dp(16)1Yey, is associated with heart defects. Furthermore, we generated two novel mouse models carrying a 5.43-Mb duplication and a reciprocal deletion between Tiam1 and Kcnj6 using chromosome engineering, Dp(16Tiam1-Kcnj6)Yey/+ and Df(16Tiam1-Kcnj6)Yey/+, respectively, within the 22.9-Mb syntenic region on Mmu16. We found that Dp(16Tiam1-Kcnj6)Yey/+, but not Dp(16)1Yey/Df(16Tiam1-Kcnj6)Yey, resulted in heart defects, indicating that triplication of the Tiam1-Knj6 region is necessary and sufficient to cause DS-associated heart defects. Our transcriptional analysis of Dp(16Tiam1-Kcnj6)Yey/+ embryos confirmed elevated expression levels for the genes located in the Tiam-Kcnj6 region. Therefore, we established the smallest critical genomic region for DS-associated heart defects to lay the foundation for identifying the causative gene(s) for this phenotype.

  2. Association Analysis of Genetic Variants with Type 2 Diabetes in a Mongolian Population in China

    OpenAIRE

    Haihua Bai; Haiping Liu; Suyalatu Suyalatu; Xiaosen Guo; Shandan Chu; Ying Chen; Tianming Lan; Burenbatu Borjigin; Orlov, Yuriy L.; Posukh, Olga L.; Xiuqin Yang; Guilan Guilan; Osipova, Ludmila P.; Qizhu Wu; Narisu Narisu

    2015-01-01

    The large scale genome wide association studies (GWAS) have identified approximately 80 single nucleotide polymorphisms (SNPs) conferring susceptibility to type 2 diabetes (T2D). However, most of these loci have not been replicated in diverse populations and much genetic heterogeneity has been observed across ethnic groups. We tested 28 SNPs previously found to be associated with T2D by GWAS in a Mongolian sample of Northern China (497 diagnosed with T2D and 469 controls) for association with...

  3. Identification of genetic markers linked to anthracnose resistance in sorghum using association analysis.

    Science.gov (United States)

    Upadhyaya, Hari D; Wang, Yi-Hong; Sharma, Rajan; Sharma, Shivali

    2013-06-01

    Anthracnose in sorghum caused by Colletotrichum sublineolum is one of the most destructive diseases affecting sorghum production under warm and humid conditions. Markers and genes linked to resistance to the disease are important for plant breeding. Using 14,739 SNP markers, we have mapped eight loci linked to resistance in sorghum through association analysis of a sorghum mini-core collection consisting of 242 diverse accessions evaluated for anthracnose resistance for 2 years in the field. The mini-core was representative of the International Crops Research Institute for the Semi-Arid Tropics' world-wide sorghum landrace collection. Eight marker loci were associated with anthracnose resistance in both years. Except locus 8, disease resistance-related genes were found in all loci based on their physical distance from linked SNP markers. These include two NB-ARC class of R genes on chromosome 10 that were partially homologous to the rice blast resistance gene Pib, two hypersensitive response-related genes: autophagy-related protein 3 on chromosome 1 and 4 harpin-induced 1 (Hin1) homologs on chromosome 8, a RAV transcription factor that is also part of R gene pathway, an oxysterol-binding protein that functions in the non-specific host resistance, and homologs of menthone:neomenthol reductase (MNR) that catalyzes a menthone reduction to produce the antimicrobial neomenthol. These genes and markers may be developed into molecular tools for genetic improvement of anthracnose resistance in sorghum.

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

    DEFF Research Database (Denmark)

    Tan, Q.

    2013-01-01

    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...... 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....... Our results show that the method efficiently handles relatedness in detecting genetic variations that affect the mean level or the rate of change for a phenotype of interest....

  5. Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects.

    Science.gov (United States)

    Busch, Robert; Hobbs, Brian D; Zhou, Jin; Castaldi, Peter J; McGeachie, Michael J; Hardin, Megan E; Hawrylkiewicz, Iwona; Sliwinski, Pawel; Yim, Jae-Joon; Kim, Woo Jin; Kim, Deog K; Agusti, Alvar; Make, Barry J; Crapo, James D; Calverley, Peter M; Donner, Claudio F; Lomas, David A; Wouters, Emiel F; Vestbo, Jørgen; Tal-Singer, Ruth; Bakke, Per; Gulsvik, Amund; Litonjua, Augusto A; Sparrow, David; Paré, Peter D; Levy, Robert D; Rennard, Stephen I; Beaty, Terri H; Hokanson, John; Silverman, Edwin K; Cho, Michael H

    2017-07-01

    The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine: (1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD; and (2) the impact of genetic risk scores on COPD. We genotyped 3,346 single-nucleotide polymorphisms (SNPs) in 2,588 cases (1,803 severe COPD) and 1,782 control subjects from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 control subjects. In addition, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (P = 1.28 × 10(-8)) and PPP4R4/SERPINA1 (P = 1.01 × 10(-8)) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (area under the curve, ∼0.6), and accounted for a mean 0.9-1.9% lower forced expiratory volume in 1 second percent predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest, but significant, effects on risk of COPD and lung function.

  6. 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

    on the mean level of a phenotype, they are not sufficiently straightforward to handle the kinship correlation on the time-dependent trajectories of a phenotype. We introduce a 2-level hierarchical linear model to separately assess the genetic associations with the mean level and the rate of change...

  7. Comparison of multilevel modeling and the family-based association test for identifying genetic variants associated with systolic and diastolic blood pressure using Genetic Analysis Workshop 18 simulated data.

    Science.gov (United States)

    Wang, Jian; Yu, Robert; Shete, Sanjay

    2014-01-01

    Identifying genetic variants associated with complex diseases is an important task in genetic research. Although association studies based on unrelated individuals (ie, case-control genome-wide association studies) have successfully identified common single-nucleotide polymorphisms for many complex diseases, these studies are not so likely to identify rare genetic variants. In contrast, family-based association studies are particularly useful for identifying rare-variant associations. Recently, there has been some interest in employing multilevel models in family-based genetic association studies. However, the performance of such models in these studies, especially for longitudinal family-based sequence data, has not been fully investigated. Therefore, in this study, we investigated the performance of the multilevel model in the family-based genetic association analysis and compared it with the conventional family-based association test, by examining the powers and type I error rates of the 2 approaches using 3 data sets from the Genetic Analysis Workshop 18 simulated data: genome-wide association single-nucleotide polymorphism data, sequence data, and rare-variants-only data. Compared with the univariate family-based association test, the multilevel model had slightly higher power to identify most of the causal genetic variants using the genome-wide association single-nucleotide polymorphism data and sequence data. However, both approaches had low power to identify most of the causal single-nucleotide polymorphisms, especially those among the relatively rare genetic variants. Therefore, we suggest a unified method that combines both approaches and incorporates collapsing strategy, which may be more powerful than either approach alone for studying genetic associations using family-based data.

  8. A genome-wide analysis of population structure in the Finnish Saami with implications for genetic association studies.

    Science.gov (United States)

    Huyghe, Jeroen R; Fransen, Erik; Hannula, Samuli; Van Laer, Lut; Van Eyken, Els; Mäki-Torkko, Elina; Aikio, Pekka; Sorri, Martti; Huentelman, Matthew J; Van Camp, Guy

    2011-03-01

    The understanding of patterns of genetic variation within and among human populations is a prerequisite for successful genetic association mapping studies of complex diseases and traits. Some populations are more favorable for association mapping studies than others. The Saami from northern Scandinavia and the Kola Peninsula represent a population isolate that, among European populations, has been less extensively sampled, despite some early interest for association mapping studies. In this paper, we report the results of a first genome-wide SNP-based study of genetic population structure in the Finnish Saami. Using data from the HapMap and the human genome diversity project (HGDP-CEPH) and recently developed statistical methods, we studied individual genetic ancestry. We quantified genetic differentiation between the Saami population and the HGDP-CEPH populations by calculating pair-wise F(ST) statistics and by characterizing identity-by-state sharing for pair-wise population comparisons. This study affirms an east Asian contribution to the predominantly European-derived Saami gene pool. Using model-based individual ancestry analysis, the median estimated percentage of the genome with east Asian ancestry was 6% (first and third quartiles: 5 and 8%, respectively). We found that genetic similarity between population pairs roughly correlated with geographic distance. Among the European HGDP-CEPH populations, F(ST) was smallest for the comparison with the Russians (F(ST)=0.0098), and estimates for the other population comparisons ranged from 0.0129 to 0.0263. Our analysis also revealed fine-scale substructure within the Finnish Saami and warns against the confounding effects of both hidden population structure and undocumented relatedness in genetic association studies of isolated populations.

  9. Genetic association analysis between polymorphisms of HAIRY-AND-ENHANCER-OF SPLIT-7 and congenital scoliosis

    OpenAIRE

    Gu, Zuchao; Qiu, Guixing; Zhang, Yu

    2015-01-01

    Objective: We explored the association between genetic polymorphisms of HAIRY-AND-ENHANCER-OF-SPLIT-7 (HES7) and congenital scoliosis (CS) in 246 cases of congenital scoliosis and non-congenital controls, in which the age and sex were fully matched. All participants were Chinese Han population. Methods: The genome DNA was extracted from peripheral blood sample. Two SNPs were defined for HES7 using NCBI database. The genotypes of two SNPs were determined by SNP stream UHT Genotyping System. Re...

  10. Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome

    OpenAIRE

    Zemojtel, T.; Koehler, S; Mackenroth, L; Jaeger, M.; Hecht, J.; Krawitz, P.; Graul-Neumann, L; Doelken, S.; Ehmke, N.; Spielmann, M.; Oien, N.C.; Schweiger, M R; Krueger, U; Frommer, G.; Fischer, B.

    2014-01-01

    Less than half of patients with suspected genetic disease receive a molecular diagnosis. We have therefore integrated next-generation sequencing (NGS), bioinformatics, and clinical data into an effective diagnostic workflow. We used variants in the 2741 established Mendelian disease genes [the disease-associated genome (DAG)] to develop a targeted enrichment DAG panel (7.1 Mb), which achieves a coverage of 20-fold or better for 98% of bases. Furthermore, we established a computational method ...

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

    Directory of Open Access Journals (Sweden)

    Maribel Forero-Castro

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

  12. Genetic analysis of Down syndrome-associated heart defects in mice

    OpenAIRE

    Liu, Chunhong; Morishima, Masae; Yu, Tao; Matsui, Sei-ichi; ZHANG Li; Fu, Dawei; Pao, Annie; Costa, Alberto C.; Gardiner, Katheleen J.; Cowell, John K; Nowak, Norma J; Parmacek, Michael S.; Liang, Ping; Baldini, Antonio; Yu, Y. Eugene

    2011-01-01

    Human trisomy 21, the chromosomal basis of Down syndrome (DS), is the most common genetic cause of heart defects. Regions on human chromosome 21 (Has21) are syntenically conserved with three regions located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. In this study, we have analyzed the impact of duplications of each syntenic region on cardiovascular development in mice and have found that only the duplication on Mmu16, i.e., Dp(16)1Yey, is associated with heart defects. Furthermore, we g...

  13. The association of sport performance with ACE and ACTN3 genetic polymorphisms: a systematic review and meta-analysis.

    Directory of Open Access Journals (Sweden)

    Fang Ma

    Full Text Available BACKGROUND: Genetic polymorphism is suggested to be associated with human physical performance. The angiotensin I-converting enzyme insertion/deletion (ACE I/D polymorphism and the α-actinin-3 gene (ACTN3 R577X polymorphism have been most widely studied for such association analysis. However, the findings are frequently heterogeneous. We aim to summarize the associations of ACE I/D and ACTN3 R577X with sport performance by means of meta-analysis. METHODS: We systematically reviewed and quantitatively summarized published studies, until October 31, 2012, on relationship between ACE/ACTN3 genetic polymorphisms and sports performance, respectively. RESULTS: A total of 366 articles on ACE and 88 articles on ACTN3 were achieved by literature search. A significant association was found for ACE II genotype compared to D allele carriage (DD+ID with increased possibility of physical performance (OR, 1.23; 95% CI, 1.05-1.45. With respect to sport discipline, the II genotype was found to be associated with performance in endurance athletes (OR, 1.35; 95% CI, 1.17-1.55. On the other hand, no significant association was observed for ACTN3 RR genotype as compared to X allele carriage (XX+RX (OR, 1.03; 95% CI, 0.92-1.15. However, when restricted the analyses to power events, a significant association was observed (OR, 1.21; 95% CI, 1.03-1.42. CONCLUSION: Our results provide more solid evidence for the associations between ACE II genotype and endurance events and between ACTN3 R allele and power events. The findings suggest that the genetic profiles might influence human physical performance.

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

    Science.gov (United States)

    2017-01-01

    We propose a novel statistical framework for integrating the result from molecular quantitative trait loci (QTL) mapping into genome-wide genetic association analysis of complex traits, with the primary objectives of quantitatively assessing the enrichment of the molecular QTLs in complex trait-associated genetic variants and the colocalizations of the two types of association signals. We introduce a natural Bayesian hierarchical model that treats the latent association status of molecular QTLs as SNP-level annotations for candidate SNPs of complex traits. We detail a computational procedure to seamlessly perform enrichment, fine-mapping and colocalization analyses, which is a distinct feature compared to the existing colocalization analysis procedures in the literature. The proposed approach is computationally efficient and requires only summary-level statistics. We evaluate and demonstrate the proposed computational approach through extensive simulation studies and analyses of blood lipid data and the whole blood eQTL data from the GTEx project. In addition, a useful utility from our proposed method enables the computation of expected colocalization signals using simple characteristics of the association data. Using this utility, we further illustrate the importance of enrichment analysis on the ability to discover colocalized signals and the potential limitations of currently available molecular QTL data. The software pipeline that implements the proposed computation procedures, enloc, is freely available at https://github.com/xqwen/integrative. PMID:28278150

  15. Effects of environment, genetics and data analysis pitfalls in an esophageal cancer genome-wide association study.

    Directory of Open Access Journals (Sweden)

    Alexander Statnikov

    Full Text Available BACKGROUND: The development of new high-throughput genotyping technologies has allowed fast evaluation of single nucleotide polymorphisms (SNPs on a genome-wide scale. Several recent genome-wide association studies employing these technologies suggest that panels of SNPs can be a useful tool for predicting cancer susceptibility and discovery of potentially important new disease loci. METHODOLOGY/PRINCIPAL FINDINGS: In the present paper we undertake a careful examination of the relative significance of genetics, environmental factors, and biases of the data analysis protocol that was used in a previously published genome-wide association study. That prior study reported a nearly perfect discrimination of esophageal cancer patients and healthy controls on the basis of only genetic information. On the other hand, our results strongly suggest that SNPs in this dataset are not statistically linked to the phenotype, while several environmental factors and especially family history of esophageal cancer (a proxy to both environmental and genetic factors have only a modest association with the disease. CONCLUSIONS/SIGNIFICANCE: The main component of the previously claimed strong discriminatory signal is due to several data analysis pitfalls that in combination led to the strongly optimistic results. Such pitfalls are preventable and should be avoided in future studies since they create misleading conclusions and generate many false leads for subsequent research.

  16. Bayesian analysis of censored response data in family-based genetic association studies.

    Science.gov (United States)

    Del Greco M, Fabiola; Pattaro, Cristian; Minelli, Cosetta; Thompson, John R

    2016-09-01

    Biomarkers are subject to censoring whenever some measurements are not quantifiable given a laboratory detection limit. Methods for handling censoring have received less attention in genetic epidemiology, and censored data are still often replaced with a fixed value. We compared different strategies for handling a left-censored continuous biomarker in a family-based study, where the biomarker is tested for association with a genetic variant, S, adjusting for a covariate, X. Allowing different correlations between X and S, we compared simple substitution of censored observations with the detection limit followed by a linear mixed effect model (LMM), Bayesian model with noninformative priors, Tobit model with robust standard errors, the multiple imputation (MI) with and without S in the imputation followed by a LMM. Our comparison was based on real and simulated data in which 20% and 40% censoring were artificially induced. The complete data were also analyzed with a LMM. In the MICROS study, the Bayesian model gave results closer to those obtained with the complete data. In the simulations, simple substitution was always the most biased method, the Tobit approach gave the least biased estimates at all censoring levels and correlation values, the Bayesian model and both MI approaches gave slightly biased estimates but smaller root mean square errors. On the basis of these results the Bayesian approach is highly recommended for candidate gene studies; however, the computationally simpler Tobit and the MI without S are both good options for genome-wide studies.

  17. Genetic Association Analysis of 30 Genes Related to Obesity in a European American Population

    Science.gov (United States)

    Li, Peng; Tiwari, Hemant K.; Lin, Wan-Yu; Allison, David B.; Chung, Wendy K.; Leibel, Rudolph L.; Yi, Nengjun; Liu, Nianjun

    2013-01-01

    Objective Obesity, which is frequently associated with diabetes, hypertension, and cardiovascular diseases, is primarily the result of a net excess of caloric intake over energy expenditure. Human obesity is highly heritable, but the specific genes mediating susceptibility in non-syndromic obesity remain unclear. We tested candidate genes in pathways related to food intake and energy expenditure for association with body mass index (BMI). Methods We re-analyzed 355 common genetic variants of 30 candidate genes in 7 molecular pathways related to obesity in 1,982 unrelated European Americans from the New York Health Project. Data were analyzed by using a Bayesian hierarchical generalized linear model. The BMIs were log-transformed and then adjusted for covariates including age, age2, gender, and diabetes status. The single nucleotide polymorphisms (SNPs) were modeled as additive effects. Results With the stipulated adjustments, nine SNPs in eight genes were significantly associated with BMI: GHRL (rs35683), AGRP (rs5030980), CPE (rs1946816 and rs4481204), GLP1R (rs2268641), HTR2A (rs912127), NPY5R (Y5R1c52), SOCS3 (rs4969170), and STAT3 (rs4796793). We also found a gender-by-SNP interaction (rs1745837 in HTR2A), which indicated that variants in the gene HTR2A had a stronger association with BMI in males. In addition, NPY1R was detected as having a significant gene effect even though none of the SNPs in this gene was significant. Conclusion Variations in genes AGRP, CPE, GHRL, GLP1R, HTR2A, NPY1R, NPY5R, SOCS3, and STAT3 showed modest associations with BMI in European Americans. The pathways in which these genes participate regulate energy intake and thus these associations are mechanistically plausible in this context. PMID:23900445

  18. Genetic association analysis of 30 genes related to obesity in a European American population.

    Science.gov (United States)

    Li, P; Tiwari, H K; Lin, W-Y; Allison, D B; Chung, W K; Leibel, R L; Yi, N; Liu, N

    2014-05-01

    Obesity, which is frequently associated with diabetes, hypertension and cardiovascular diseases, is primarily the result of a net excess of caloric intake over energy expenditure. Human obesity is highly heritable, but the specific genes mediating susceptibility in non-syndromic obesity remain unclear. We tested candidate genes in pathways related to food intake and energy expenditure for association with body mass index (BMI). We reanalyzed 355 common genetic variants of 30 candidate genes in seven molecular pathways related to obesity in 1982 unrelated European Americans from the New York Cancer Project. Data were analyzed by using a Bayesian hierarchical generalized linear model. The BMIs were log-transformed and then adjusted for covariates, including age, age(2), gender and diabetes status. The single-nucleotide polymorphisms (SNPs) were modeled as additive effects. With the stipulated adjustments, nine SNPs in eight genes were significantly associated with BMI: ghrelin (GHRL; rs35683), agouti-related peptide (AGRP; rs5030980), carboxypeptidase E (CPE; rs1946816 and rs4481204), glucagon-like peptide-1 receptor (GLP1R; rs2268641), serotonin receptors (HTR2A; rs912127), neuropeptide Y receptor (NPY5R;Y5R1c52), suppressor of cytokine signaling 3 (SOCS3; rs4969170) and signal transducer and activator of transcription 3 (STAT3; rs4796793). We also found a gender-by-SNP interaction (rs1745837 in HTR2A), which indicated that variants in the gene HTR2A had a stronger association with BMI in males. In addition, NPY1R was detected as having a significant gene effect even though none of the SNPs in this gene was significant. Variations in genes AGRP, CPE, GHRL, GLP1R, HTR2A, NPY1R, NPY5R, SOCS3 and STAT3 showed modest associations with BMI in European Americans. The pathways in which these genes participate regulate energy intake, and thus these associations are mechanistically plausible in this context.

  19. Genetic model selection in genome-wide association studies: robust methods and the use of meta-analysis.

    Science.gov (United States)

    Bagos, Pantelis G

    2013-06-01

    In genetic association studies (GAS) as well as in genome-wide association studies (GWAS), the mode of inheritance (dominant, additive and recessive) is usually not known a priori. Assuming an incorrect mode of inheritance may lead to substantial loss of power, whereas on the other hand, testing all possible models may result in an increased type I error rate. The situation is even more complicated in the meta-analysis of GAS or GWAS, in which individual studies are synthesized to derive an overall estimate. Meta-analysis increases the power to detect weak genotype effects, but heterogeneity and incompatibility between the included studies complicate things further. In this review, we present a comprehensive summary of the statistical methods used for robust analysis and genetic model selection in GAS and GWAS. We then discuss the application of such methods in the context of meta-analysis. We describe the theoretical properties of the various methods and the foundations on which they are based. We also present the available software implementations of the described methods. Finally, since only few of the available robust methods have been applied in the meta-analysis setting, we present some simple extensions that allow robust meta-analysis of GAS and GWAS. Possible extensions and proposals for future work are also discussed.

  20. Genetic Structure and Relationship Analysis of an Association Population in Jute (Corchorus spp. Evaluated by SSR Markers.

    Directory of Open Access Journals (Sweden)

    Liwu Zhang

    Full Text Available Population structure and relationship analysis is of great importance in the germplasm utilization and association mapping. Jute, comprised of white jute (C. capsularis L and dark jute (C. olitorius L, is second to cotton in its commercial significance in the world. Here, we assessed the genetic structure and relationship in a panel of 159 jute accessions from 11 countries and regions using 63 SSRs. The structure analysis divided the 159 jute accessions from white and dark jute into Co and Cc group, further into Co1, Co2, Cc1 and Cc2 subgroups. Out of Cc1 subgroup, 81 accessions were from China and the remaining 10 accessions were from India (2, Japan (5, Thailand, Vietnam (2 and Pakistan (1. Out of Cc2 subgroup, 35 accessions were from China, and the remaining 3 accessions were from India, Pakistan and Thailand respectively. It can be inferred that the genetic background of these jute accessions was not always correlative with their geographical regions. Similar results were found in Co1 and Co2 subgroups. Analysis of molecular variance revealed 81% molecular variation between groups but it was low (19% within subgroups, which further confirmed the genetic differentiation between the two groups. The genetic relationship analysis showed that the most diverse genotypes were Maliyeshengchangguo and Changguozhongyueyin in dark jute, BZ-2-2, Aidianyehuangma, Yangjuchiyuanguo, Zijinhuangma and Jute 179 in white jute, which could be used as the potential parents in breeding programs for jute improvement. These results would be very useful for association studies and breeding in jute.

  1. Genetic Structure and Relationship Analysis of an Association Population in Jute (Corchorus spp.) Evaluated by SSR Markers.

    Science.gov (United States)

    Zhang, Liwu; Yuan, Minhang; Tao, Aifen; Xu, Jiantang; Lin, Lihui; Fang, Pingping; Qi, Jianmin

    2015-01-01

    Population structure and relationship analysis is of great importance in the germplasm utilization and association mapping. Jute, comprised of white jute (C. capsularis L) and dark jute (C. olitorius L), is second to cotton in its commercial significance in the world. Here, we assessed the genetic structure and relationship in a panel of 159 jute accessions from 11 countries and regions using 63 SSRs. The structure analysis divided the 159 jute accessions from white and dark jute into Co and Cc group, further into Co1, Co2, Cc1 and Cc2 subgroups. Out of Cc1 subgroup, 81 accessions were from China and the remaining 10 accessions were from India (2), Japan (5), Thailand, Vietnam (2) and Pakistan (1). Out of Cc2 subgroup, 35 accessions were from China, and the remaining 3 accessions were from India, Pakistan and Thailand respectively. It can be inferred that the genetic background of these jute accessions was not always correlative with their geographical regions. Similar results were found in Co1 and Co2 subgroups. Analysis of molecular variance revealed 81% molecular variation between groups but it was low (19%) within subgroups, which further confirmed the genetic differentiation between the two groups. The genetic relationship analysis showed that the most diverse genotypes were Maliyeshengchangguo and Changguozhongyueyin in dark jute, BZ-2-2, Aidianyehuangma, Yangjuchiyuanguo, Zijinhuangma and Jute 179 in white jute, which could be used as the potential parents in breeding programs for jute improvement. These results would be very useful for association studies and breeding in jute.

  2. Comparison of artificial neural network analysis with other multimarker methods for detecting genetic association

    Directory of Open Access Journals (Sweden)

    Curtis David

    2007-07-01

    Full Text Available Abstract Background Debate remains as to the optimal method for utilising genotype data obtained from multiple markers in case-control association studies. I and colleagues have previously described a method of association analysis using artificial neural networks (ANNs, whose performance compared favourably to single-marker methods. Here, the perfomance of ANN analysis is compared with other multi-marker methods, comprising different haplotype-based analyses and locus-based analyses. Results Of several methods studied and applied to simulated SNP datasets, heterogeneity testing of estimated haplotype frequencies using asymptotic p values rather than permutation testing had the lowest power of the methods studied and ANN analysis had the highest power. The difference in power to detect association between these two methods was statistically significant (p = 0.001 but other comparisons between methods were not significant. The raw t statistic obtained from ANN analysis correlated highly with the empirical statistical significance obtained from permutation testing of the ANN results and with the p value obtained from the heterogeneity test. Conclusion Although ANN analysis was more powerful than the standard haplotype-based test it is unlikely to be taken up widely. The permutation testing necessary to obtain a valid p value makes it slow to perform and it is not underpinned by a theoretical model relating marker genotypes to disease phenotype. Nevertheless, the superior performance of this method does imply that the widely-used haplotype-based methods for detecting association with multiple markers are not optimal and efforts could be made to improve upon them. The fact that the t statistic obtained from ANN analysis is highly correlated with the statistical significance does suggest a possibility to use ANN analysis in situations where large numbers of markers have been genotyped, since the t value could be used as a proxy for the p value in

  3. Analysis of a p53 Mutation Associated with Cancer Susceptibility for Biochemistry and Genetic Laboratory Courses

    Science.gov (United States)

    Soto-Cruz, Isabel; Legorreta-Herrera, Martha

    2009-01-01

    We have devised and implemented a module for an upper division undergraduate laboratory based on the amplification and analysis of a p53 polymorphism associated with cancer susceptibility. First, students collected a drop of peripheral blood cells using a sterile sting and then used FTA cards to extract the genomic DNA. The p53 region is then PCR…

  4. Analysis of a p53 Mutation Associated with Cancer Susceptibility for Biochemistry and Genetic Laboratory Courses

    Science.gov (United States)

    Soto-Cruz, Isabel; Legorreta-Herrera, Martha

    2009-01-01

    We have devised and implemented a module for an upper division undergraduate laboratory based on the amplification and analysis of a p53 polymorphism associated with cancer susceptibility. First, students collected a drop of peripheral blood cells using a sterile sting and then used FTA cards to extract the genomic DNA. The p53 region is then PCR…

  5. Statistical Analysis of Genetic Data in Twin Studies and Association Studies

    NARCIS (Netherlands)

    Setiawan, A.

    2007-01-01

    In studies in human genetics we want to answer questions such as: how important are genetic effects on a phenotype; what kind of action and interaction exists between gene products in the pathways between genotypes and phenotype; are the genetic effects on a phenotype consistent across sexes; do

  6. Statistical Analysis of Genetic Data in Twin Studies and Association Studies

    NARCIS (Netherlands)

    Setiawan, A.

    2007-01-01

    In studies in human genetics we want to answer questions such as: how important are genetic effects on a phenotype; what kind of action and interaction exists between gene products in the pathways between genotypes and phenotype; are the genetic effects on a phenotype consistent across sexes; do

  7. Genetic analysis of cold tolerance at the germination and booting stages in rice by association mapping.

    Directory of Open Access Journals (Sweden)

    Yinghua Pan

    Full Text Available Low temperature affects the rice plants at all stages of growth. It can cause severe seedling injury and male sterility resulting in severe yield losses. Using a mini core collection of 174 Chinese rice accessions and 273 SSR markers we investigated cold tolerance at the germination and booting stages, as well as the underlying genetic bases, by association mapping. Two distinct populations, corresponding to subspecies indica and japonica showed evident differences in cold tolerance and its genetic basis. Both subspecies were sensitive to cold stress at both growth stages. However, japonica was more tolerant than indica at all stages as measured by seedling survival and seed setting. There was a low correlation in cold tolerance between the germination and booting stages. Fifty one quantitative trait loci (QTLs for cold tolerance were dispersed across all 12 chromosomes; 22 detected at the germination stage and 33 at the booting stage. Eight QTLs were identified by at least two of four measures. About 46% of the QTLs represented new loci. The only QTL shared between indica and japonica for the same measure was qLTSSvR6-2 for SSvR. This implied a complicated mechanism of old tolerance between the two subspecies. According to the relative genotypic effect (RGE of each genotype for each QTL, we detected 18 positive genotypes and 21 negative genotypes in indica, and 19 positive genotypes and 24 negative genotypes in japonica. In general, the negative effects were much stronger than the positive effects in both subspecies. Markers for QTL with positive effects in one subspecies were shown to be effective for selection of cold tolerance in that subspecies, but not in the other subspecies. QTL with strong negative effects on cold tolerance should be avoided during MAS breeding so as to not cancel the effect of favorable QTL at other loci.

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

    Science.gov (United States)

    Chikkagoudar, Satish; Wang, Kai; Li, Mingyao

    2011-05-26

    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. 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. 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/.

  9. Clinical phenotype and genetic mutation of fatty acid hydroxylase - associated neurodegeneration: analysis of four cases

    Directory of Open Access Journals (Sweden)

    Xiao-jun HUANG

    2017-07-01

    Full Text Available Objective To report 4 cases of fatty acid hydroxylase - associated neurodegeneration (FAHN and to summarize the clinical and genetic characteristics of FAHN by literatures review.  Methods Four cases of FAHN patients' clinical and family data were collected in detail. The gDNA of patients and their parents were extracted from peripheral blood. FA2H gene was conducted and followed by Sanger sequencing.  Results Among the 4 cases, 3 cases (Case 2, Case 3, Case 4 presented typical manifestations of FAHN while the other (Case 1 was atypical. Genetic sequencing showed FA2H gene mutation in all affected patients. Compound heterozygous mutation c.461G > A (p.Arg154His and c.794T > G (p.Phe265Cys were seen in Case 1. In Case 2, only one documented heterozygous mutation c.703C > T (p.Arg235Cys was found, and dificit mutation was not found in single nucleotide polymorphism (SNP chip test of the patient and her mother. Compound heterozygous mutation c.688G > A (p.Glu230Lys and insertion mutation c.172_173insGGGCCAGGAC (p.Ile58ArgfsX47 were presented in Case 3. In Case 4, compound heterozygous mutation c.688G > A (p.Glu230Lys, c.968C > A (p.Pro323Gln and c.976G > A (p. Gly326Asp were seen, while his father was the carrier of c.688G > A (p.Glu230Lys mutation and his mother was the carrier of c.968C > A (p.Pro323Gln and c.976G > A (p.Gly326Asp mutation. According to the standard of American College of Medical Genetics and Genomics (ACMG, c.461G > A (p.Arg154His and c.794T > G (p.Phe265Cys in Case 1, and c.703C > T (p.Arg235Cys in Case 2 were considered as "likely pathogenic", while FA2H gene compound heterozygous mutation c.688G > A (p.Glu230Lys, insertion mutation c.172_173insGGGCCAGGAC (p.Ile58ArgfsX47 in Case 3 was as "pathogenic", and in Case 4, the FA2H gene mutation c.688G > A (p.Glu230Lys and c.968C > A (p.Pro323Gln were "pathogenic" and c.976G > A (p.Gly326Asp was "likely pathogenic".  Conclusions FAHN has highly clinical and genetic

  10. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes

    Science.gov (United States)

    Morris, Andrew P; Voight, Benjamin F; Teslovich, Tanya M; Ferreira, Teresa; Segrè, Ayellet V; Steinthorsdottir, Valgerdur; Strawbridge, Rona J; Khan, Hassan; Grallert, Harald; Mahajan, Anubha; Prokopenko, Inga; Kang, Hyun Min; Dina, Christian; Esko, Tonu; Fraser, Ross M; Kanoni, Stavroula; Kumar, Ashish; Lagou, Vasiliki; Langenberg, Claudia; Luan, Jian'an; Lindgren, Cecilia M; Müller-Nurasyid, Martina; Pechlivanis, Sonali; Rayner, N William; Scott, Laura J; Wiltshire, Steven; Yengo, Loic; Kinnunen, Leena; Rossin, Elizabeth J; Raychaudhuri, Soumya; Johnson, Andrew D; Dimas, Antigone S; Loos, Ruth J F; Vedantam, Sailaja; Chen, Han; Florez, Jose C; Fox, Caroline; Liu, Ching-Ti; Rybin, Denis; Couper, David J; Kao, Wen Hong L; Li, Man; Cornelis, Marilyn C; Kraft, Peter; Sun, Qi; van Dam, Rob M; Stringham, Heather M; Chines, Peter S; Fischer, Krista; Fontanillas, Pierre; Holmen, Oddgeir L; Hunt, Sarah E; Jackson, Anne U; Kong, Augustine; Lawrence, Robert; Meyer, Julia; Perry, John RB; Platou, Carl GP; Potter, Simon; Rehnberg, Emil; Robertson, Neil; Sivapalaratnam, Suthesh; Stančáková, Alena; Stirrups, Kathleen; Thorleifsson, Gudmar; Tikkanen, Emmi; Wood, Andrew R; Almgren, Peter; Atalay, Mustafa; Benediktsson, Rafn; Bonnycastle, Lori L; Burtt, Noël; Carey, Jason; Charpentier, Guillaume; Crenshaw, Andrew T; Doney, Alex S F; Dorkhan, Mozhgan; Edkins, Sarah; Emilsson, Valur; Eury, Elodie; Forsen, Tom; Gertow, Karl; Gigante, Bruna; Grant, George B; Groves, Christopher J; Guiducci, Candace; Herder, Christian; Hreidarsson, Astradur B; Hui, Jennie; James, Alan; Jonsson, Anna; Rathmann, Wolfgang; Klopp, Norman; Kravic, Jasmina; Krjutškov, Kaarel; Langford, Cordelia; Leander, Karin; Lindholm, Eero; Lobbens, Stéphane; Männistö, Satu; Mirza, Ghazala; Mühleisen, Thomas W; Musk, Bill; Parkin, Melissa; Rallidis, Loukianos; Saramies, Jouko; Sennblad, Bengt; Shah, Sonia; Sigurðsson, Gunnar; Silveira, Angela; Steinbach, Gerald; Thorand, Barbara; Trakalo, Joseph; Veglia, Fabrizio; Wennauer, Roman; Winckler, Wendy; Zabaneh, Delilah; Campbell, Harry; van Duijn, Cornelia; Uitterlinden89-, Andre G; Hofman, Albert; Sijbrands, Eric; Abecasis, Goncalo R; Owen, Katharine R; Zeggini, Eleftheria; Trip, Mieke D; Forouhi, Nita G; Syvänen, Ann-Christine; Eriksson, Johan G; Peltonen, Leena; Nöthen, Markus M; Balkau, Beverley; Palmer, Colin N A; Lyssenko, Valeriya; Tuomi, Tiinamaija; Isomaa, Bo; Hunter, David J; Qi, Lu; Shuldiner, Alan R; Roden, Michael; Barroso, Ines; Wilsgaard, Tom; Beilby, John; Hovingh, Kees; Price, Jackie F; Wilson, James F; Rauramaa, Rainer; Lakka, Timo A; Lind, Lars; Dedoussis, George; Njølstad, Inger; Pedersen, Nancy L; Khaw, Kay-Tee; Wareham, Nicholas J; Keinanen-Kiukaanniemi, Sirkka M; Saaristo, Timo E; Korpi-Hyövälti, Eeva; Saltevo, Juha; Laakso, Markku; Kuusisto, Johanna; Metspalu, Andres; Collins, Francis S; Mohlke, Karen L; Bergman, Richard N; Tuomilehto, Jaakko; Boehm, Bernhard O; Gieger, Christian; Hveem, Kristian; Cauchi, Stephane; Froguel, Philippe; Baldassarre, Damiano; Tremoli, Elena; Humphries, Steve E; Saleheen, Danish; Danesh, John; Ingelsson, Erik; Ripatti, Samuli; Salomaa, Veikko; Erbel, Raimund; Jöckel, Karl-Heinz; Moebus, Susanne; Peters, Annette; Illig, Thomas; de Faire, Ulf; Hamsten, Anders; Morris, Andrew D; Donnelly, Peter J; Frayling, Timothy M; Hattersley, Andrew T; Boerwinkle, Eric; Melander, Olle; Kathiresan, Sekar; Nilsson, Peter M; Deloukas, Panos; Thorsteinsdottir, Unnur; Groop, Leif C; Stefansson, Kari; Hu, Frank; Pankow, James S; Dupuis, Josée; Meigs, James B; Altshuler, David; Boehnke, Michael; McCarthy, Mark I

    2012-01-01

    To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis. PMID:22885922

  11. Genetic analysis of reelin gene (RELN) SNPs: no association with autism spectrum disorder in the Indian population.

    Science.gov (United States)

    Dutta, Shruti; Sinha, Swagata; Ghosh, Saurabh; Chatterjee, Anindita; Ahmed, Shabina; Usha, Rajamma

    2008-08-15

    Involvement of reelin with Autism spectrum disorder (ASD) has been implicated through several biochemical as well as genetic studies. Reelin is an extracellular signaling protein, which plays a significant role in cytoarchitectonic pattern formation of different brain areas during development. Reelin gene (RELN) is located on chromosome 7q22; an important autism critical region identified through several genome-wide scans. A number of genetic studies have been carried out to investigate the association of reelin with autism. Recently we reported possible paternal effect in the transmission of CGG repeat alleles of RELN in the susceptibility towards autism. Further analysis on other polymorphisms is warranted to validate the status of RELN as a candidate for autism. Therefore in the present study, we have investigated six more SNPs (rs727531, rs2072403, rs2072402, rs362691, rs362719, rs736707) in 102 patients, 182 parents and 101 healthy controls. We have followed DSM-IV criteria and the screening for autism was carried out using CARS. Genomic DNA isolated from blood was used for PCR and subsequent RFLP analysis. Finally, case-control and family-based association studies were carried out to examine the genetic association of these SNP markers with ASD in the Indian population. But, we failed to detect either preferential parental transmission of any alleles of the markers to affected offspring or any biased allelic or genotypic distribution between the cases and controls. Thus the present study suggests that these SNPs of RELN are unlikely to be associated with ASD in the Indian population.

  12. Genetic analysis of polymorphisms in the kalirin gene for association with age-at-onset in European Huntington disease patients

    Directory of Open Access Journals (Sweden)

    Tsai Yu-Chun

    2012-06-01

    Full Text Available Abstract Background Huntington disease (HD is caused by an expanded CAG repeat in the HD gene. Although the length of the CAG repeat strongly correlates with the age-at-onset (AAO, AAO in HD individuals may differ dramatically in spite of similar expanded CAG repeat lengths. Additional genetic or environmental factors are thought to influence the disease onset. Several modifier genes have been discovered so far but they do not fully explain the variability of AAO in HD. To potentially identify a novel genetic modifier, we analyzed single nucleotide polymorphisms (SNPs in the kalirin (KALRN gene. Kalirin is a protein crucially involved in spine plasticity and its interaction with huntingtin-associated protein-1 (HAP-1 and a potential protein dysfunction might contribute to spine pathogenesis in HD. Methods The selected SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP and association of SNPs with AAO was investigated with the framework of linear models in an analysis of variance and covariance. Results Eleven SNPs in the kalirin gene were examined in an association study in European HD patients. The ten coding SNPs under investigation were monomorphic, whereas SNP rs10934657 in the promoter region showed a minor allele frequency >1%. An analysis of covariance together with the influence of the expanded HD allele was applied in 680 HD patients. SNP rs10934657 did not affect the AAO of the examined HD population. Conclusions The results did not reveal an association between the analyzed kalirin polymorphisms and the AAO in HD. However, it does not exclude other SNPs of the kalirin gene as susceptible genetic modifiers.

  13. Analysis of eight genes modulating interferon gamma and human genetic susceptibility to tuberculosis: a case-control association study

    Directory of Open Access Journals (Sweden)

    Hoal Eileen G

    2010-06-01

    Full Text Available Abstract Background Interferon gamma is a major macrophage-activating cytokine during infection with Mycobacterium tuberculosis, the causative pathogen of tuberculosis, and its role has been well established in animal models and in humans. This cytokine is produced by activated T helper 1 cells, which can best deal with intracellular pathogens such as M. tuberculosis. Based on the hypothesis that genes which regulate interferon gamma may influence tuberculosis susceptibility, we investigated polymorphisms in eight candidate genes. Methods Fifty-four polymorphisms in eight candidate genes were genotyped in over 800 tuberculosis cases and healthy controls in a population-based case-control association study in a South African population. Genotyping methods used included the SNPlex Genotyping System™, capillary electrophoresis of fluorescently labelled PCR products, TaqMan® SNP genotyping assays or the amplification mutation refraction system. Single polymorphisms as well as haplotypes of the variants were tested for association with TB using statistical analyses. Results A haplotype in interleukin 12B was nominally associated with tuberculosis (p = 0.02, but after permutation testing, done to assess the significance for the entire analysis, this was not globally significant. In addition a novel allele was found for the interleukin 12B D5S2941 microsatellite. Conclusions This study highlights the importance of using larger sample sizes when attempting validation of previously reported genetic associations. Initial studies may be false positives or may propose a stronger genetic effect than subsequently found to be the case.

  14. Molecular genetic analysis of Type II diabetes associated m.3243A ...

    African Journals Online (AJOL)

    Saidul Abrar

    This study was carried out in 6 suspected diabetic members of a Pakistani family. ... The Egyptian Journal of Medical Human Genetics 18 (2017) 305–308. Contents lists .... mutations in diabetes mellitus patients in Chinese Han family.

  15. 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 and func......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...

  16. Genetic association analysis of ATP binding cassette protein family reveals a novel association of ABCB1 genetic variants with epilepsy risk, but not with drug-resistance.

    Science.gov (United States)

    Balan, Shabeesh; Bharathan, Sumitha Prameela; Vellichiramal, Neetha Nanoth; Sathyan, Sanish; Joseph, Vijai; Radhakrishnan, Kurupath; Banerjee, Moinak

    2014-01-01

    Epilepsy constitutes a heterogeneous group of disorders that is characterized by recurrent unprovoked seizures due to widely different etiologies. Multidrug resistance remains a major issue in clinical epileptology, where one third of patients with epilepsy continue to have seizures. Role of efflux transporters in multidrug resistant epilepsy has been attributed to drug-resistant epilepsy although, with discrepant observation in genetic studies. These discrepancies could be attributed to variety of factors such as variable definition of the anti-epileptic drug (AED)-resistance, variable epilepsy phenotypes and ethnicities among the studies. In the present study we inquired the role of multidrug transporters ABCB1 and ABCG2 variants in determining AED-resistance and susceptibility to epilepsy in three well-characterized cohorts comprising of mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) (prototype for AED-resistant epilepsy); juvenile myoclonic epilepsy (JME) (prototype for AED-responsive epilepsy); and healthy non-epileptic controls, in 738 subjects of Malayalam speaking south Indian ancestry. ABCB1 and ABCG2 variants were not found to be associated with drug resistance when AED-resistant and AED-responsive cohorts were compared. However, a significant association was observed between ABCB1 (C3435T) rs1045642 and risk of having epilepsy (MTLE-HS and JME pooled cohort; genotypic p-value = 0.0002; allelic p-value = 0.004). This association was seen persistent with MTLE-HS (genotypic p-value = 0.0008; allelic p-value = 0.004) and also with JME (genotypic p-value = 0.01; allelic p-value = 0.05) cohort individually. In-silico functional prediction indicated that ABCB1 rs1045642 has a deleterious impact on protein coding function and in splicing regulation. We conclude that the ABCB1 and ABCG2 variants do not confer to AED-resistance in the study population. However, ABCB1 rs1045642 increases vulnerability to epilepsy with greater tendency for MTLE

  17. Genetic association analysis of ATP binding cassette protein family reveals a novel association of ABCB1 genetic variants with epilepsy risk, but not with drug-resistance.

    Directory of Open Access Journals (Sweden)

    Shabeesh Balan

    Full Text Available Epilepsy constitutes a heterogeneous group of disorders that is characterized by recurrent unprovoked seizures due to widely different etiologies. Multidrug resistance remains a major issue in clinical epileptology, where one third of patients with epilepsy continue to have seizures. Role of efflux transporters in multidrug resistant epilepsy has been attributed to drug-resistant epilepsy although, with discrepant observation in genetic studies. These discrepancies could be attributed to variety of factors such as variable definition of the anti-epileptic drug (AED-resistance, variable epilepsy phenotypes and ethnicities among the studies. In the present study we inquired the role of multidrug transporters ABCB1 and ABCG2 variants in determining AED-resistance and susceptibility to epilepsy in three well-characterized cohorts comprising of mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS (prototype for AED-resistant epilepsy; juvenile myoclonic epilepsy (JME (prototype for AED-responsive epilepsy; and healthy non-epileptic controls, in 738 subjects of Malayalam speaking south Indian ancestry. ABCB1 and ABCG2 variants were not found to be associated with drug resistance when AED-resistant and AED-responsive cohorts were compared. However, a significant association was observed between ABCB1 (C3435T rs1045642 and risk of having epilepsy (MTLE-HS and JME pooled cohort; genotypic p-value = 0.0002; allelic p-value = 0.004. This association was seen persistent with MTLE-HS (genotypic p-value = 0.0008; allelic p-value = 0.004 and also with JME (genotypic p-value = 0.01; allelic p-value = 0.05 cohort individually. In-silico functional prediction indicated that ABCB1 rs1045642 has a deleterious impact on protein coding function and in splicing regulation. We conclude that the ABCB1 and ABCG2 variants do not confer to AED-resistance in the study population. However, ABCB1 rs1045642 increases vulnerability to epilepsy with greater tendency

  18. The genetic association between personality and major depression or bipolar disorder. A polygenic score analysis using genome-wide association data.

    Science.gov (United States)

    Middeldorp, C M; de Moor, M H M; McGrath, L M; Gordon, S D; Blackwood, D H; Costa, P T; Terracciano, A; Krueger, R F; de Geus, E J C; Nyholt, D R; Tanaka, T; Esko, T; Madden, P A F; Derringer, J; Amin, N; Willemsen, G; Hottenga, J-J; Distel, M A; Uda, M; Sanna, S; Spinhoven, P; Hartman, C A; Ripke, S; Sullivan, P F; Realo, A; Allik, J; Heath, A C; Pergadia, M L; Agrawal, A; Lin, P; Grucza, R A; Widen, E; Cousminer, D L; Eriksson, J G; Palotie, A; Barnett, J H; Lee, P H; Luciano, M; Tenesa, A; Davies, G; Lopez, L M; Hansell, N K; Medland, S E; Ferrucci, L; Schlessinger, D; Montgomery, G W; Wright, M J; Aulchenko, Y S; Janssens, A C J W; Oostra, B A; Metspalu, A; Abecasis, G R; Deary, I J; Räikkönen, K; Bierut, L J; Martin, N G; Wray, N R; van Duijn, C M; Smoller, J W; Penninx, B W J H; Boomsma, D I

    2011-10-18

    The relationship between major depressive disorder (MDD) and bipolar disorder (BD) remains controversial. Previous research has reported differences and similarities in risk factors for MDD and BD, such as predisposing personality traits. For example, high neuroticism is related to both disorders, whereas openness to experience is specific for BD. This study examined the genetic association between personality and MDD and BD by applying polygenic scores for neuroticism, extraversion, openness to experience, agreeableness and conscientiousness to both disorders. Polygenic scores reflect the weighted sum of multiple single-nucleotide polymorphism alleles associated with the trait for an individual and were based on a meta-analysis of genome-wide association studies for personality traits including 13,835 subjects. Polygenic scores were tested for MDD in the combined Genetic Association Information Network (GAIN-MDD) and MDD2000+ samples (N=8921) and for BD in the combined Systematic Treatment Enhancement Program for Bipolar Disorder and Wellcome Trust Case-Control Consortium samples (N=6329) using logistic regression analyses. At the phenotypic level, personality dimensions were associated with MDD and BD. Polygenic neuroticism scores were significantly positively associated with MDD, whereas polygenic extraversion scores were significantly positively associated with BD. The explained variance of MDD and BD, ∼0.1%, was highly comparable to the variance explained by the polygenic personality scores in the corresponding personality traits themselves (between 0.1 and 0.4%). This indicates that the proportions of variance explained in mood disorders are at the upper limit of what could have been expected. This study suggests shared genetic risk factors for neuroticism and MDD on the one hand and for extraversion and BD on the other.

  19. Genetic modifiers of neurofibromatosis type 1-associated cafe-au-lait macule count identified using multi-platform analysis.

    Directory of Open Access Journals (Sweden)

    Alexander Pemov

    2014-10-01

    Full Text Available Neurofibromatosis type 1 (NF1 is an autosomal dominant, monogenic disorder of dysregulated neurocutaneous tissue growth. Pleiotropy, variable expressivity and few NF1 genotype-phenotype correlates limit clinical prognostication in NF1. Phenotype complexity in NF1 is hypothesized to derive in part from genetic modifiers unlinked to the NF1 locus. In this study, we hypothesized that normal variation in germline gene expression confers risk for certain phenotypes in NF1. In a set of 79 individuals with NF1, we examined the association between gene expression in lymphoblastoid cell lines with NF1-associated phenotypes and sequenced select genes with significant phenotype/expression correlations. In a discovery cohort of 89 self-reported European-Americans with NF1 we examined the association between germline sequence variants of these genes with café-au-lait macule (CALM count, a tractable, tumor-like phenotype in NF1. Two correlated, common SNPs (rs4660761 and rs7161 between DPH2 and ATP6V0B were significantly associated with the CALM count. Analysis with tiled regression also identified SNP rs4660761 as significantly associated with CALM count. SNP rs1800934 and 12 rare variants in the mismatch repair gene MSH6 were also associated with CALM count. Both SNPs rs7161 and rs4660761 (DPH2 and ATP6V0B were highly significant in a mega-analysis in a combined cohort of 180 self-reported European-Americans; SNP rs1800934 (MSH6 was near-significant in a meta-analysis assuming dominant effect of the minor allele. SNP rs4660761 is predicted to regulate ATP6V0B, a gene associated with melanosome biology. Individuals with homozygous mutations in MSH6 can develop an NF1-like phenotype, including multiple CALMs. Through a multi-platform approach, we identified variants that influence NF1 CALM count.

  20. Genetic modifiers of neurofibromatosis type 1-associated café-au-lait macule count identified using multi-platform analysis.

    Directory of Open Access Journals (Sweden)

    Alexander Pemov

    2014-10-01

    Full Text Available Neurofibromatosis type 1 (NF1 is an autosomal dominant, monogenic disorder of dysregulated neurocutaneous tissue growth. Pleiotropy, variable expressivity and few NF1 genotype-phenotype correlates limit clinical prognostication in NF1. Phenotype complexity in NF1 is hypothesized to derive in part from genetic modifiers unlinked to the NF1 locus. In this study, we hypothesized that normal variation in germline gene expression confers risk for certain phenotypes in NF1. In a set of 79 individuals with NF1, we examined the association between gene expression in lymphoblastoid cell lines with NF1-associated phenotypes and sequenced select genes with significant phenotype/expression correlations. In a discovery cohort of 89 self-reported European-Americans with NF1 we examined the association between germline sequence variants of these genes with café-au-lait macule (CALM count, a tractable, tumor-like phenotype in NF1. Two correlated, common SNPs (rs4660761 and rs7161 between DPH2 and ATP6V0B were significantly associated with the CALM count. Analysis with tiled regression also identified SNP rs4660761 as significantly associated with CALM count. SNP rs1800934 and 12 rare variants in the mismatch repair gene MSH6 were also associated with CALM count. Both SNPs rs7161 and rs4660761 (DPH2 and ATP6V0B were highly significant in a mega-analysis in a combined cohort of 180 self-reported European-Americans; SNP rs1800934 (MSH6 was near-significant in a meta-analysis assuming dominant effect of the minor allele. SNP rs4660761 is predicted to regulate ATP6V0B, a gene associated with melanosome biology. Individuals with homozygous mutations in MSH6 can develop an NF1-like phenotype, including multiple CALMs. Through a multi-platform approach, we identified variants that influence NF1 CALM count.

  1. The Association Between Genetic Variants in the Dopaminergic System and Posttraumatic Stress Disorder: A Meta-Analysis.

    Science.gov (United States)

    Li, Lizhuo; Bao, Yijun; He, Songbai; Wang, Gang; Guan, Yanlei; Ma, Dexuan; Wang, Pengfei; Huang, Xiaolong; Tao, Shanwei; Zhang, Dewei; Liu, Qiwen; Wang, Yunjie; Yang, Jingyun

    2016-03-01

    Posttraumatic stress disorder (PTSD) is a complex mental disorder and can severely interfere with the normal life of the affected people. Previous studies have examined the association of PTSD with genetic variants in multiple dopaminergic genes with inconsistent results. To perform a systematic literature search and conduct meta-analysis to examine whether genetic variants in the dopaminergic system is associated with PTSD. Data Sources: PubMed, Cochrane Library, Embase, Google Scholar, and HuGE. Study eligibility criteria and participants: The studies included subjects who had been screened for the presence of PTSD; the studies provided data for genetic variants of genes involved in the dopaminergic system; the outcomes of interest included diagnosis status of PTSD; and the studies were case-control studies. Study appraisal and synthesis methods: Odds ratio was used as a measure of association. We used random-effects model in all the meta-analyses. Between-study heterogeneity was assessed using I², and publication bias was evaluated using Egger test. Findings from meta-analyses were confirmed using random-effects meta-analyses under the framework of generalized linear model (GLM). A total of 19 studies met the eligibility criteria and were included in our analyses. We found that rs1800497 in DRD2 was significantly associated with PTSD (OR = 1.96, 95% CI: 1.15-3.33; P = 0.014). The 3'-UTR variable number tandem repeat (VNTR) in SLC6A3 also showed significant association with PTSD (OR = 1.62, 95% CI: 1.12-2.35; P = 0.010), but there was no association of rs4680 in COMT with PTSD (P = 0.595). Sample size is limited for some studies; type and severity of traumatic events varied across studies; we could not control for potential confounding factors, such as age at traumatic events and gender; and we could not examine gene-environment interaction due to lack of data. We found that rs1800497 in DRD2 and the VNTR in SLC6A3 showed significant

  2. A Co-Association Network Analysis of the Genetic Determination of Pig Conformation, Growth and Fatness

    NARCIS (Netherlands)

    Puig-Oliveras, A.; Ballester, M.; Corominas, J.; Revilla, M.; Estelle, J.; Fernandez, A.I.; Ramayo-Caldas, Y.; Folch, J.M.

    2014-01-01

    BACKGROUND: Several QTLs have been identified for major economically relevant traits in livestock, such as growth and meat quality, revealing the complex genetic architecture of these traits. The use of network approaches considering the interactions of multiple molecules and traits provides useful

  3. 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); 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. 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. D

  4. Genomic analysis of genetic markers associated with inherited cardiomyopathy (round heart disease) in the turkey (Meleagris gallopavo).

    Science.gov (United States)

    Reed, K M; Mendoza, K M; Hu, G R; Sullivan, L R; Grace, M W; Chaves, L D; Kooyman, D L

    2007-06-01

    In turkeys, spontaneous cardiomyopathy or round heart (RH) disease is characterised by dilated ventricles and cardiac muscle hypertrophy. Although the aetiology of RH is still unknown, the disease can have a significant economic impact on turkey producers. In an initial attempt to identify genomic regions associated with RH, we utilised the chicken genome sequence to target short DNA sequences (sequence-characterised amplified regions, SCARs) identified in previous studies that had significant differences in frequency distribution between RH+ and RH- turkeys. SCARs were comparatively aligned with the chicken whole-genome sequence to identify flanking regions for primer design. Primers from 32 alignments were tested and target sequences were successfully amplified for 30 loci (94%). Comparative re-sequencing identified putative SNPs in 20 of the 30 loci (67%). Genetically informative SNPs at 16 loci were genotyped in the UMN/NTBF turkey mapping population. As a result of this study, 34 markers were placed on the turkey/chicken comparative map and 15 markers were added to the turkey genetic linkage map. The position of these markers relative to cardiac-related genes is presented. In addition, analysis of genotypes at 109 microsatellite loci presumed to flank the SCAR sequences in the turkey genome identified four significant associations with RH.

  5. Genetic association analysis of polymorphisms in PSD3 gene with obesity, type 2 diabetes, and HDL cholesterol.

    Science.gov (United States)

    Gong, Shaoqing; Xu, Chun; Wang, Liang; Liu, Ying; Owusu, Daniel; Bailey, Beth A; Li, Yujing; Wang, Kesheng

    2017-04-01

    The pleckstrin and Sec7 domain-containing 3 (PSD3) gene has been linked to immune diseases. We examined whether the genetic variants within the PSD3 gene are associated with obesity, type 2 diabetes (T2D), and high-density lipoprotein (HDL) cholesterol level. Multiple logistic regression model and linear regression model were used to examine the associations of 259 single nucleotide polymorphisms (SNPs) within the PSD3 gene with obesity and T2D as binary traits, and HDL level as a continuous trait using the Marshfield data, respectively. A replication study of obesity was conducted using the Health Aging and Body Composition (Health ABC) sample. 23SNPs were associated with obesity (pHDL level (top SNP rs13254772 with p=2.79×10(-3)) in the Marshfield data; meanwhile rs7009615 was associated with both T2D (p=0.038) and HDL level (p=4.44×10(-3)). In addition, haplotype analyses further supported the results of single SNP analysis. Common variants in PSD3 were associated with obesity, T2D and HDL level. These findings add important new insights into the pathogenesis of obesity, T2D and HDL cholesterol. Published by Elsevier B.V.

  6. Genetic Control of Canine Leishmaniasis: Genome-Wide Association Study and Genomic Selection Analysis

    OpenAIRE

    Javier Quilez; Verónica Martínez; Woolliams, John A; Armand Sanchez; Ricardo Pong-Wong; Kennedy, Lorna J.; Quinnell, Rupert J.; Ollier, William E R; Xavier Roura; Lluís Ferrer; Laura Altet; Olga Francino

    2012-01-01

    BACKGROUND: The current disease model for leishmaniasis suggests that only a proportion of infected individuals develop clinical disease, while others are asymptomatically infected due to immune control of infection. The factors that determine whether individuals progress to clinical disease following Leishmania infection are unclear, although previous studies suggest a role for host genetics. Our hypothesis was that canine leishmaniasis is a complex disease with multiple loci responsible for...

  7. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes

    DEFF Research Database (Denmark)

    Morris, Andrew P; Voight, Benjamin F; Teslovich, Tanya M

    2012-01-01

    To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D suscep...

  8. Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia.

    Science.gov (United States)

    Meda, Shashwath A; Ruaño, Gualberto; Windemuth, Andreas; O'Neil, Kasey; Berwise, Clifton; Dunn, Sabra M; Boccaccio, Leah E; Narayanan, Balaji; Kocherla, Mohan; Sprooten, Emma; Keshavan, Matcheri S; Tamminga, Carol A; Sweeney, John A; Clementz, Brett A; Calhoun, Vince D; Pearlson, Godfrey D

    2014-05-13

    The brain's default mode network (DMN) is highly heritable and is compromised in a variety of psychiatric disorders. However, genetic control over the DMN in schizophrenia (SZ) and psychotic bipolar disorder (PBP) is largely unknown. Study subjects (n = 1,305) underwent a resting-state functional MRI scan and were analyzed by a two-stage approach. The initial analysis used independent component analysis (ICA) in 324 healthy controls, 296 SZ probands, 300 PBP probands, 179 unaffected first-degree relatives of SZ probands (SZREL), and 206 unaffected first-degree relatives of PBP probands to identify DMNs and to test their biomarker and/or endophenotype status. A subset of controls and probands (n = 549) then was subjected to a parallel ICA (para-ICA) to identify imaging-genetic relationships. ICA identified three DMNs. Hypo-connectivity was observed in both patient groups in all DMNs. Similar patterns observed in SZREL were restricted to only one network. DMN connectivity also correlated with several symptom measures. Para-ICA identified five sub-DMNs that were significantly associated with five different genetic networks. Several top-ranking SNPs across these networks belonged to previously identified, well-known psychosis/mood disorder genes. Global enrichment analyses revealed processes including NMDA-related long-term potentiation, PKA, immune response signaling, axon guidance, and synaptogenesis that significantly influenced DMN modulation in psychoses. In summary, we observed both unique and shared impairments in functional connectivity across the SZ and PBP cohorts; these impairments were selectively familial only for SZREL. Genes regulating specific neurodevelopment/transmission processes primarily mediated DMN disconnectivity. The study thus identifies biological pathways related to a widely researched quantitative trait that might suggest novel, targeted drug treatments for these diseases.

  9. Genetic Associations of Interleukin-related Genes with Graves’ Ophthalmopathy: a Systematic Review and Meta-analysis

    Science.gov (United States)

    Wong, Kah Hie; Rong, Shi Song; Chong, Kelvin K. L.; Young, Alvin L.; Pang, Chi Pui; Chen, Li Jia

    2015-01-01

    Graves’ ophthalmopathy (GO) is the commonest extra-thyroidal manifestation of Graves’ disease (GD). Associations between interleukin-related (IL) gene polymorphisms and GO have been reported in different populations. We aim to confirm such associations by conducting a meta-analysis. Totally 382 publications were retrieved in MEDLINE and EMBASE up to 25/2/2015. After removing the duplicates and assessing the studies, we retrieved 16 studies that met the selection criteria for meta-analysis, involving 12 polymorphisms in 8 IL-related genes, and 1650 GO cases and 2909 GD controls. The summary odds ratio (OR) and 95% confidence intervals (CI) were estimated. We found one polymorphism in IL1A (rs1800587, c.-889C>T) showing a suggestive association with GO in the meta-analysis (allelic model [T vs. C]: OR = 1.62, 95% CI: 1.00–2.62, P = 0.050, I2 = 53.7%; recessive model [TT vs. TC + CC]: OR = 2.39, 95% CI: 1.07–5.37, P = 0.039, I2 = 23.6%; heterozygous model [TC vs. CC]: OR = 1.52, 95% CI: 1.04–2.22, P = 0.034, I2 = 37.0%). No association with GO was detected for the other 7 genes (IL1B, IL1RA, IL4, IL6, IL12B, IL13 and IL23R). Our results thus indicate that IL1A is likely to be a genetic biomarker for GO. Further studies with larger sample sizes are warranted to confirm the associations of IL1A and other IL-related genes with GO. PMID:26578206

  10. Integrating pathway analysis and genetics of gene expression for genome-wide association study of basal cell carcinoma.

    Science.gov (United States)

    Zhang, Mingfeng; Liang, Liming; Morar, Nilesh; Dixon, Anna L; Lathrop, G Mark; Ding, Jun; Moffatt, Miriam F; Cookson, William O C; Kraft, Peter; Qureshi, Abrar A; Han, Jiali

    2012-04-01

    Genome-wide association studies (GWASs) have primarily focused on marginal effects for individual markers and have incorporated external functional information only after identifying robust statistical associations. We applied a new approach combining the genetics of gene expression and functional classification of genes to the GWAS of basal cell carcinoma (BCC) to identify potential biological pathways associated with BCC. We first identified 322,324 expression-associated single-nucleotide polymorphisms (eSNPs) from two existing GWASs of global gene expression in lymphoblastoid cell lines (n = 955), and evaluated the association of these functionally annotated SNPs with BCC among 2,045 BCC cases and 6,013 controls in Caucasians. We then grouped them into 99 KEGG pathways for pathway analysis and identified two pathways associated with BCC with p value <0.05 and false discovery rate (FDR) <0.5: the autoimmune thyroid disease pathway (mainly HLA class I and II antigens, p < 0.001, FDR = 0.24) and Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway (p = 0.02, FDR = 0.49). Seventy-nine (25.7%) out of 307 significant eSNPs in the JAK-STAT pathway were associated with BCC risk (p < 0.05) in an independent replication set of 278 BCC cases and 1,262 controls. In addition, the association of JAK-STAT signaling pathway was marginally validated using 16,691 eSNPs identified from 110 normal skin samples (p = 0.08). Based on the evidence of biological functions of the JAK-STAT pathway on oncogenesis, it is plausible that this pathway is involved in BCC pathogenesis.

  11. Cumulative association between age-related macular degeneration and less studied genetic variants in PLEKHA1/ARMS2/HTRA1: a meta and gene-cluster analysis.

    Science.gov (United States)

    Yu, Weihong; Dong, Shuqian; Zhao, Chuntao; Wang, Haina; Dai, Fei; Yang, Jingyun

    2013-10-01

    The objective of this study is to examine the cumulative effect of the less studied genetic variants in PLEKHA1/ARMS2/HTRA1 on age-related macular degeneration (AMD). We performed an extensive literature search for studies on the association between AMD and the less studied genetic variants in PLEKHA1/ARMS2/HTRA1. Multiple meta-analyses were performed to evaluate the association between individual genetic variants and AMD. A gene-cluster analysis was used to investigate the cumulative effect of these less studied genetic variants on AMD. A total of 23 studies from 20 published papers met the eligibility criteria and were included in our analyses. Several genetic variants in the gene cluster are significantly associated with AMD in our meta-analyses or in individual studies. Gene-cluster analysis reveals a strong cumulative association between these genetic variants in this gene cluster and AMD (p studies in our meta-analyses; and rs3793917, the SNP with the largest sample size, were not significantly associated with AMD (both p's > 0.12). Sensitivity analyses reveal significant association of AMD with rs2736911 in Chinese but not in Caucasian, with c.372_815del443ins54 in Caucasian but not in Chinese, and with rs1049331 in both ethnic groups. These less studied genetic variants have a significant cumulative effect on wet AMD. Our study provides evidence of the joint contribution of genetic variants in PLEKHA1/ARMS2/HTRA1 to AMD risk, in addition to the two widely studied genetic variants whose association with AMD was well established.

  12. Systems genetics and genome-wide association approaches for analysis of feed intake, feed efficiency, and performance in beef cattle

    DEFF Research Database (Denmark)

    Santana, M. H. A.; Freua, M. C.; Do, D. N.

    2016-01-01

    and 943,577 single nucleotide polymorphisms (SNPs), a genome-wide association analysis was performed for dry matter intake, average daily weight gain, feed conversion ratio, and residual feed intake with a Bayesian Lasso procedure. Genes within 50-kb SNPs, most relevant for explaining the genomic variance......Feed intake, feed efficiency, and weight gain are important economic traits of beef cattle in feed lots. In the present study, we investigated the physiological processes underlying such traits from the point of view of systems genetics. Firstly, using data from 1334 Nellore (Bos indicus) cattle...... phenotypes and showed that almost all genomic variances were in the SNPs located in the intergenic and intronic regions. We further identified five main metabolic pathways related to ion transport, body composition, and feed intake control, which influenced the four phenotypes simultaneously. The systems...

  13. Genetic distribution and association analysis of DRD2 gene polymorphisms with major depressive disorder in the Chinese Han population.

    Science.gov (United States)

    He, Mei; Yan, Hong; Duan, Zhao-Xia; Qu, Wei; Gong, Hai-Yan; Fan, Zheng-Li; Kang, Jian-Yi; Li, Bing-Cang; Wang, Jian-Min

    2013-01-01

    Dopamine D2 receptor is involved in reward-mediating mesocorticolimbic pathways. It plays an important role in major depressive disorder (MDD). Three gene polymorphisms Taq1A, C957T and -141C ins/del, were identified in the DRD2 gene among the Western population. These variants in the DRD2 gene might be associated with the susceptibility of MDD patients through affecting the bioeffects of endogenous dopamine neurotransmission. However, little is known about their occurrence in Chinese population and their association with the susceptibility of patients with major depressive disorder. In this study, a total of 338 unrelated adult Chinese Han population, including 224 healthy volunteers and 114 patients with major depressive disorder, were recruited. DRD2 polymorphisms (Taq1A and -141C ins/del) were detected using restriction fragment length polymorphism (RFLP) analysis and the C957T were detected by sequencing directly. As a result, three polymorphisms were identified in Chinese Han population and all were common SNP. However, we could detect no evidence of genetic association between 3 markers in DRD2 and major depressive disorder in the Chinese Han population. To conclude, this result suggests that Taq1A, C957T and -141C ins/del of DRD2 gene may not be associated with major depressive disorder, also may be the sample sizes too small to allow a meaningful test.

  14. Genetic and biochemical analysis of the adenylyl cyclase-associated protein, cap, in Schizosaccharomyces pombe.

    OpenAIRE

    Kawamukai, M; Gerst, J; Field, J.; Riggs, M.; Rodgers, L; Wigler, M; Young, D

    1992-01-01

    We have identified, cloned, and studied a gene, cap, encoding a protein that is associated with adenylyl cyclase in the fission yeast Schizosaccharomyces pombe. This protein shares significant sequence homology with the adenylyl cyclase-associated CAP protein in the yeast Saccharomyces cerevisiae. CAP is a bifunctional protein; the N-terminal domain appears to be involved in cellular responsiveness to RAS, whereas loss of the C-terminal portion is associated with morphological and nutritional...

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

    Directory of Open Access Journals (Sweden)

    Sarah L. Kerns

    2016-08-01

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

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

    Science.gov (United States)

    Kerns, Sarah L; Dorling, Leila; Fachal, Laura; Bentzen, Søren; Pharoah, Paul D P; Barnes, Daniel R; Gómez-Caamaño, Antonio; Carballo, Ana M; Dearnaley, David P; Peleteiro, Paula; Gulliford, Sarah L; Hall, Emma; Michailidou, Kyriaki; Carracedo, Ángel; Sia, Michael; Stock, Richard; Stone, Nelson N; Sydes, Matthew R; Tyrer, Jonathan P; Ahmed, Shahana; Parliament, Matthew; Ostrer, Harry; Rosenstein, Barry S; Vega, Ana; Burnet, Neil G; Dunning, Alison M; Barnett, Gillian C; West, Catharine M L

    2016-08-01

    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.

  17. Genetic diversity and genome-wide association analysis of cooking time in dry bean (Phaseolus vulgaris L.).

    Science.gov (United States)

    Cichy, Karen A; Wiesinger, Jason A; Mendoza, Fernando A

    2015-08-01

    Fivefold diversity for cooking time found in a panel of 206 Phaseolus vulgaris accessions. Fastest accession cooks nearly 20 min faster than average.   SNPs associated with cooking time on Pv02, 03, and 06. Dry beans (Phaseolus vulgaris L.) are a nutrient dense food and a dietary staple in parts of Africa and Latin America. One of the major factors that limits greater utilization of beans is their long cooking times compared to other foods. Cooking time is an important trait with implications for gender equity, nutritional value of diets, and energy utilization. Very little is known about the genetic diversity and genomic regions involved in determining cooking time. The objective of this research was to assess cooking time on a panel of 206 P. vulgaris accessions, use genome- wide association analysis (GWAS) to identify genomic regions influencing this trait, and to test the ability to predict cooking time by raw seed characteristics. In this study 5.5-fold variation for cooking time was found and five bean accessions were identified which cook in less than 27 min across 2 years, where the average cooking time was 37 min. One accession, ADP0367 cooked nearly 20 min faster than average. Four of these five accessions showed close phylogenetic relationship based on a NJ tree developed with ~5000 SNP markers, suggesting a potentially similar underlying genetic mechanism. GWAS revealed regions on chromosomes Pv02, Pv03, and Pv06 associated with cooking time. Vis/NIR scanning of raw seed explained 68 % of the phenotypic variation for cooking time, suggesting with additional experimentation, it may be possible to use this spectroscopy method to non-destructively identify fast cooking lines as part of a breeding program.

  18. Identification of autophagosome-associated proteins and regulators by quantitative proteomic analysis and genetic screens

    DEFF Research Database (Denmark)

    Dengjel, Jörn; Høyer-Hansen, Maria; Nielsen, Maria;

    2012-01-01

    deprivation or rapamycin or concanamycin A treatment. The autophagosome-associated proteins were dependent on stimulus, but a core set of proteins was stimulus-independent. Remarkably, proteasomal proteins were abundant among the stimulus-independent common autophagosome-associated proteins...

  19. Identification of a genetic marker associated with the resistance to Schistosoma mansoni infection using random amplified polymorphic DNA analysis

    Directory of Open Access Journals (Sweden)

    Abdel-Hamid Z Abdel-Hamid

    2006-12-01

    Full Text Available In schistosomiasis, the host/parasite interaction remains not completely understood. Many questions related to the susceptibility of snails to infection by respective trematode still remain unanswered. The control of schistosomiasis requires a good understanding of the host/parasite association. In this work, the susceptibility/resistance to Schistosoma mansoni infection within Biomphalaria alexandrina snails were studied starting one month post infection and continuing thereafter weekly up to 10 weeks after miracidia exposure. Genetic variations between susceptible and resistant strains to Schistosoma infection within B. alexandrina snails using random amplified polymorphic DNA analysis technique were also carried out. The results showed that 39.8% of the examined field snails were resistant, while 60.2% of these snails showed high infection rates.In the resistant genotype snails, OPA-02 primer produced a major low molecular weight marker 430 bp. Among the two snail strains there were interpopulational variations, while the individual specimens from the same snail strain, either susceptible or resistant, record semi-identical genetic bands. Also, the resistant character was ascendant in contrast to a decline in the susceptibility of snails from one generation to the next.

  20. Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies.

    Directory of Open Access Journals (Sweden)

    Ilja M Nolte

    Full Text Available To identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS including 3,558 subjects from the TwinsUK and BRIGHT cohorts in the UK and the DCCT/EDIC cohort from North America. Five loci were significantly associated with QT interval at P<1x10(-6. To validate these findings we performed an in silico comparison with data from two QT consortia: QTSCD (n = 15,842 and QTGEN (n = 13,685. Analysis confirmed the association between common variants near NOS1AP (P = 1.4x10(-83 and the phospholamban (PLN gene (P = 1.9x10(-29. The most associated SNP near NOS1AP (rs12143842 explains 0.82% variance; the SNP near PLN (rs11153730 explains 0.74% variance of QT interval duration. We found no evidence for interaction between these two SNPs (P = 0.99. PLN is a key regulator of cardiac diastolic function and is involved in regulating intracellular calcium cycling, it has only recently been identified as a susceptibility locus for QT interval. These data offer further mechanistic insights into genetic influence on the QT interval which may predispose to life threatening arrhythmias and sudden cardiac death.

  1. New genetic variants associated with prostate cancer

    Science.gov (United States)

    Researchers have newly identified 23 common genetic variants -- one-letter changes in DNA known as single-nucleotide polymorphisms or SNPs -- that are associated with risk of prostate cancer. These results come from an analysis of more than 10 million SNP

  2. Principal component analysis of breeding values for growth and reproductive traits and genetic association with adult size in beef cattle.

    Science.gov (United States)

    Boligon, A A; Vicente, I S; Vaz, R Z; Campos, G S; Souza, F R P; Carvalheiro, R; Albuquerque, L G

    2016-12-01

    Principal component analysis was applied to evaluate the variability and relationships among univariate breeding values predicted for 9 weaning and yearling traits, as well as suggest functions of the traits that would promote a particular breeding objective. Phenotypic and pedigree information from 600,132 Nelore animals was used. Genetic parameters and breeding values were obtained from univariate analyses of birth to weaning weight gain; weaning to yearling weight gain; conformation, finishing precocity, and muscling scores at weaning and at yearling; and yearling scrotal circumference. The principal component mainly associated with maturity (precocious vs. late animals) was used as a pseudophenotype in bivariate analyses with either adult weight or adult height of cows. Direct heritability estimates ranging from 0.19 ± 0.01 to 0.41 ± 0.01 indicate that these 9 traits are all heritable to varying degrees. Correlations between the breeding values for the various traits ranged from 0.14 to 0.88. Principal component analysis was performed on the standardized breeding values. The first 3 principal components attained the Kaiser criterion, retaining 48.06%, 18.03%, and 12.97% of the total breeding value variance, respectively. The first component was characterized by positive coefficients for all traits. The second component contrasted weaning traits with yearling traits. The third component represented a contrast between late maturity animals (better for weight gain and conformation) and early maturity animals (better for finishing precocity, muscling, and scrotal circumference). Thus, the first 3 components represent 3 different potential selection criteria. Selecting for the first principal component would identify animals with positive breeding values for all studied traits. The second principal component may be used to identify animals with higher or lower maturation rates (precocity). Animals with negative values in the third principal component are regarded

  3. Mining Outcome-relevant Brain Imaging Genetic Associations via Three-way Sparse Canonical Correlation Analysis in Alzheimer’s Disease

    Science.gov (United States)

    Hao, Xiaoke; Li, Chanxiu; Du, Lei; Yao, Xiaohui; Yan, Jingwen; Risacher, Shannon L.; Saykin, Andrew J.; Shen, Li; Zhang, Daoqiang; Weiner, Michael W.; Aisen, Paul; Petersen, Ronald; Jack, Clifford R.; Mason, Sara S.; Albers, Colleen S.; Knopman, David; Johnson, Kris; Jagust, William; Trojanowki, John Q.; Toga, Arthur W.; Beckett, Laurel; Green, Robert C.; Farlow, Martin R.; Marie Hake, Ann; Matthews, Brandy R.; Brosch, Jared R.; Herring, Scott; Hunt, Cynthia; Shaw, Leslie M.; Ances, Beau; Morris, John C.; Carroll, Maria; Creech, Mary L.; Franklin, Erin; Mintun, Mark A.; Schneider, Stacy; Oliver, Angela; Kaye, Jeffrey; Quinn, Joseph; Silbert, Lisa; Lind, Betty; Carter, Raina; Dolen, Sara; Schneider, Lon S.; Pawluczyk, Sonia; Beccera, Mauricio; Teodoro, Liberty; Spann, Bryan M.; Brewer, James; Vanderswag, Helen; Fleisher, Adam; Tariot, Pierre; Burke, Anna; Trncic, Nadira; Reeder, Stephanie; Heidebrink, Judith L.; Lord, Joanne L.; Doody, Rachelle S.; Villanueva-Meyer, Javier; Chowdhury, Munir; Rountree, Susan; Dang, Mimi; Stern, Yaakov; Honig, Lawrence S.; Bell, Karen L.; Marson, Daniel; Griffith, Randall; Clark, David; Geldmacher, David; Brockington, John; Roberson, Erik; Love, Marissa Natelson; Grossman, Hillel; Mitsis, Effie; Shah, Raj C.; deToledo-Morrell, Leyla; Duara, Ranjan; Varon, Daniel; Greig, Maria T.; Roberts, Peggy; Albert, Marilyn; Onyike, Chiadi; D’Agostino, Daniel; Kielb, Stephanie; Galvin, James E.; Cerbone, Brittany; Michel, Christina A.; Pogorelec, Dana M.; Rusinek, Henry; de Leon, Mony J.; Glodzik, Lidia; De Santi, Susan; Doraiswamy, P. Murali; Petrella, Jeffrey R.; Borges-Neto, Salvador; Wong, Terence Z.; Coleman, Edward; Smith, Charles D.; Jicha, Greg; Hardy, Peter; Sinha, Partha; Oates, Elizabeth; Conrad, Gary; Porsteinsson, Anton P.; Goldstein, Bonnie S.; Martin, Kim; Makino, Kelly M.; Ismail, M. Saleem; Brand, Connie; Mulnard, Ruth A.; Thai, Gaby; Mc-Adams-Ortiz, Catherine; Womack, Kyle; Mathews, Dana; Quiceno, Mary; Levey, Allan I.; Lah, James J.; Cellar, Janet S.; Burns, Jeffrey M.; Swerdlow, Russell H.; Brooks, William M.; Apostolova, Liana; Tingus, Kathleen; Woo, Ellen; Silverman, Daniel H. S.; Lu, Po H.; Bartzokis, George; Graff-Radford, Neill R.; Parfitt, Francine; Kendall, Tracy; Johnson, Heather; van Dyck, Christopher H.; Carson, Richard E.; MacAvoy, Martha G.; Varma, Pradeep; Chertkow, Howard; Bergman, Howard; Hosein, Chris; Black, Sandra; Stefanovic, Bojana; Caldwell, Curtis; Hsiung, Ging-Yuek Robin; Feldman, Howard; Mudge, Benita; Assaly, Michele; Finger, Elizabeth; Pasternack, Stephen; Rachisky, Irina; Trost, Dick; Kertesz, Andrew; Bernick, Charles; Munic, Donna; Mesulam, Marek-Marsel; Lipowski, Kristine; Weintraub, Sandra; Bonakdarpour, Borna; Kerwin, Diana; Wu, Chuang-Kuo; Johnson, Nancy; Sadowsky, Carl; Villena, Teresa; Turner, Raymond Scott; Johnson, Kathleen; Reynolds, Brigid; Sperling, Reisa A.; Johnson, Keith A.; Marshall, Gad; Yesavage, Jerome; Taylor, Joy L.; Lane, Barton; Rosen, Allyson; Tinklenberg, Jared; Sabbagh, Marwan N.; Belden, Christine M.; Jacobson, Sandra A.; Sirrel, Sherye A.; Kowall, Neil; Killiany, Ronald; Budson, Andrew E.; Norbash, Alexander; Johnson, Patricia Lynn; Obisesan, Thomas O.; Wolday, Saba; Allard, Joanne; Lerner, Alan; Ogrocki, Paula; Tatsuoka, Curtis; Fatica, Parianne; Fletcher, Evan; Maillard, Pauline; Olichney, John; DeCarli, Charles; Carmichael, Owen; Kittur, Smita; Borrie, Michael; Lee, T.-Y.; Bartha, Rob; Johnson, Sterling; Asthana, Sanjay; Carlsson, Cynthia M.; Potkin, Steven G.; Preda, Adrian; Nguyen, Dana; Bates, Vernice; Capote, Horacio; Rainka, Michelle; Scharre, Douglas W.; Kataki, Maria; Adeli, Anahita; Zimmerman, Earl A.; Celmins, Dzintra; Brown, Alice D.; Pearlson, Godfrey D.; Blank, Karen; Anderson, Karen; Flashman, Laura A.; Seltzer, Marc; Hynes, Mary L.; Santulli, Robert B.; Sink, Kaycee M.; Gordineer, Leslie; Williamson, Jeff D.; Garg, Pradeep; Watkins, Franklin; Ott, Brian R.; Querfurth, Henry; Tremont, Geoffrey; Salloway, Stephen; Malloy, Paul; Correia, Stephen; Rosen, Howard J.; Miller, Bruce L.; Perry, David; Mintzer, Jacobo; Spicer, Kenneth; Bachman, David; Pomara, Nunzio; Hernando, Raymundo; Sarrael, Antero; Relkin, Norman; Chaing, Gloria; Lin, Michael; Ravdin, Lisa; Smith, Amanda; Raj, Balebail Ashok; Fargher, Kristin

    2017-01-01

    Neuroimaging genetics is an emerging field that aims to identify the associations between genetic variants (e.g., single nucleotide polymorphisms (SNPs)) and quantitative traits (QTs) such as brain imaging phenotypes. In recent studies, in order to detect complex multi-SNP-multi-QT associations, bi-multivariate techniques such as various structured sparse canonical correlation analysis (SCCA) algorithms have been proposed and used in imaging genetics studies. However, associations between genetic markers and imaging QTs identified by existing bi-multivariate methods may not be all disease specific. To bridge this gap, we propose an analytical framework, based on three-way sparse canonical correlation analysis (T-SCCA), to explore the intrinsic associations among genetic markers, imaging QTs, and clinical scores of interest. We perform an empirical study using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort to discover the relationships among SNPs from AD risk gene APOE, imaging QTs extracted from structural magnetic resonance imaging scans, and cognitive and diagnostic outcomes. The proposed T-SCCA model not only outperforms the traditional SCCA method in terms of identifying strong associations, but also discovers robust outcome-relevant imaging genetic patterns, demonstrating its promise for improving disease-related mechanistic understanding. PMID:28291242

  4. Meta-analysis of Genome-Wide Association Studies for Extraversion: Findings from the Genetics of Personality Consortium

    NARCIS (Netherlands)

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

    2016-01-01

    textabstractExtraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to

  5. Genetic Syndromes Associated with Craniosynostosis.

    Science.gov (United States)

    Ko, Jung Min

    2016-05-01

    Craniosynostosis is defined as the premature fusion of one or more of the cranial sutures. It leads not only to secondary distortion of skull shape but to various complications including neurologic, ophthalmic and respiratory dysfunction. Craniosynostosis is very heterogeneous in terms of its causes, presentation, and management. Both environmental factors and genetic factors are associated with development of craniosynostosis. Nonsyndromic craniosynostosis accounts for more than 70% of all cases. Syndromic craniosynostosis with a certain genetic cause is more likely to involve multiple sutures or bilateral coronal sutures. FGFR2, FGFR3, FGFR1, TWIST1 and EFNB1 genes are major causative genes of genetic syndromes associated with craniosynostosis. Although most of syndromic craniosynostosis show autosomal dominant inheritance, approximately half of patients are de novo cases. Apert syndrome, Pfeiffer syndrome, Crouzon syndrome, and Antley-Bixler syndrome are related to mutations in FGFR family (especially in FGFR2), and mutations in FGFRs can be overlapped between different syndromes. Saethre-Chotzen syndrome, Muenke syndrome, and craniofrontonasal syndrome are representative disorders showing isolated coronal suture involvement. Compared to the other types of craniosynostosis, single gene mutations can be more frequently detected, in one-third of coronal synostosis patients. Molecular diagnosis can be helpful to provide adequate genetic counseling and guidance for patients with syndromic craniosynostosis.

  6. Genetic Association Analysis of Dopamine DRD3 Ser9Gly Polymorphism and Schizophrenia in Malay Population

    Directory of Open Access Journals (Sweden)

    SF Tee

    2011-06-01

    Full Text Available "nBackground: Molecular components of the dopamine receptor (DRD3 play an important role in the pathophysiology of schizophrenia (SCZ. Previous studies have demonstrated an association between the DRD3 Ser9Gly polymorphism and SCZ but the results have been inconclusive. "nMethod: In this study, we investigated this controversial association between the Ser9Gly (A/G polymorphism and SCZ using Malay cases-control (261 cases/157 controls samples. PCR-RFLP was performed to genotype the distribu­tion of the DRD3 Ser9Gly polymorphism."nResults: Both healthy control and SCHZ patient groups were in of Hardy-Weinberg equilibrium for the analyzed ge­netic variability. There was a significant association between the genotype distribution DRD3 polymorphisms and SCZ (χ2= 9.359; df= 2; P= 0.009."nConclusion: We believe that further studies are required to examine the association between others dopamine-related genes and the behavioral phenotypes of SCZ.  

  7. Multilocus sequence analysis reveals genetic diversity in xanthomonads associated with poinsettia production

    Science.gov (United States)

    Xanthomonas axonopodis pv. poinsettiicola is traditionally identified as the primary causal agent of bacterial leaf spot on poinsettia (Family Euphorbiaceae). Sixty-seven strains of xanthomonads isolated from lesions associated with several species within Euphorbia were collected over a 64 year peri...

  8. Analysis of the Putative Role of CR1 in Alzheimer's Disease: Genetic Association, Expression and Function.

    Directory of Open Access Journals (Sweden)

    Maria I Fonseca

    Full Text Available Chronic activation of the complement system and induced inflammation are associated with neuropathology in Alzheimer's disease (AD. Recent large genome wide association studies (GWAS have identified single nucleotide polymorphisms (SNPs in the C3b/C4b receptor (CR1 or CD35 that are associated with late onset AD. Here, anti-CR1 antibodies (Abs directed against different epitopes of the receptor, were used to localize CR1 in brain, and relative binding affinities of the CR1 ligands, C1q and C3b, were assessed by ELISA. Most Abs tested stained red blood cells in blood vessels but showed no staining in brain parenchyma. However, two monoclonal anti-CR1 Abs labeled astrocytes in all of the cases tested, and this reactivity was preabsorbed by purified recombinant human CR1. Human brain-derived astrocyte cultures were also reactive with both mAbs. The amount of astrocyte staining varied among the samples, but no consistent difference was conferred by diagnosis or the GWAS-identified SNPs rs4844609 or rs6656401. Plasma levels of soluble CR1 did not correlate with diagnosis but a slight increase was observed with rs4844609 and rs6656401 SNP. There was also a modest but statistically significant increase in relative binding activity of C1q to CR1 with the rs4844609 SNP compared to CR1 without the SNP, and of C3b to CR1 in the CR1 genotypes containing the rs6656401 SNP (also associated with the larger isoform of CR1 regardless of clinical diagnosis. These results suggest that it is unlikely that astrocyte CR1 expression levels or C1q or C3b binding activity are the cause of the GWAS identified association of CR1 variants with AD. Further careful functional studies are needed to determine if the variant-dictated number of CR1 expressed on red blood cells contributes to the role of this receptor in the progression of AD, or if another mechanism is involved.

  9. Genetic Association Analysis of NOS3 and Methamphetamine-Induced Psychosis Among Japanese.

    Science.gov (United States)

    Okochi, T; Kishi, T; Ikeda, M; Kitajima, T; Kinoshita, Y; Kawashima, K; Okumura, T; Tsunoka, T; Fukuo, Y; Inada, T; Yamada, M; Uchimura, N; Iyo, M; Sora, I; Ozaki, N; Ujike, H; Iwata, N

    2011-03-01

    Endothelial nitric oxide synthase (NOS3) is one of the enzymes influencing nitric oxide (NO) function in the human brain. NO is a gaseous neurotransmitter that is involved in a variety of mechanisms in the central nervous system, such as N-methyl-D-aspartate receptor activation and oxidative stress. The evidence from animal pharmacological studies and postmortem studies supports an association between NO and psychotic disorders. Methamphetamine (METH) use disorder is a known psychotic disorder, and we therefore conducted a gene-based case-control study between tagging single nucleotide polymorphisms (SNPs) (rs2070744, rs1799983) in NOS3 and METH-induced psychosis in Japanese subjects (183 with METH-induced psychosis and 267 controls). Written informed consent was obtained from each subject. No significant association was found between any tagging SNP in NOS3 and METH-induced psychosis in the allele/genotype-wise or haplotype-wise analyses. In conclusion, we suggest that NOS3 might not contribute to the risk of METH-induced psychosis in the Japanese population.

  10. A general semi-parametric approach to the analysis of genetic association studies in population-based designs.

    Science.gov (United States)

    Lutz, Sharon; Yip, Wai-Ki; Hokanson, John; Laird, Nan; Lange, Christoph

    2013-02-28

    For genetic association studies in designs of unrelated individuals, current statistical methodology typically models the phenotype of interest as a function of the genotype and assumes a known statistical model for the phenotype. In the analysis of complex phenotypes, especially in the presence of ascertainment conditions, the specification of such model assumptions is not straight-forward and is error-prone, potentially causing misleading results. In this paper, we propose an alternative approach that treats the genotype as the random variable and conditions upon the phenotype. Thereby, the validity of the approach does not depend on the correctness of assumptions about the phenotypic model. Misspecification of the phenotypic model may lead to reduced statistical power. Theoretical derivations and simulation studies demonstrate both the validity and the advantages of the approach over existing methodology. In the COPDGene study (a GWAS for Chronic Obstructive Pulmonary Disease (COPD)), we apply the approach to a secondary, quantitative phenotype, the Fagerstrom nicotine dependence score, that is correlated with COPD affection status. The software package that implements this method is available. The flexibility of this approach enables the straight-forward application to quantitative phenotypes and binary traits in ascertained and unascertained samples. In addition to its robustness features, our method provides the platform for the construction of complex statistical models for longitudinal data, multivariate data, multi-marker tests, rare-variant analysis, and others.

  11. Comparative population genetic analysis of bocaccio rockfish Sebastes paucispinis using anonymous and gene-associated simple sequence repeat loci.

    Science.gov (United States)

    Buonaccorsi, Vincent P; Kimbrell, Carol A; Lynn, Eric A; Hyde, John R

    2012-01-01

    Comparative population genetic analyses of traditional and emergent molecular markers aid in determining appropriate use of new technologies. The bocaccio rockfish Sebastes paucispinis is a high gene-flow marine species off the west coast of North America that experienced strong population decline over the past 3 decades. We used 18 anonymous and 13 gene-associated simple sequence repeat (SSR) loci (expressed sequence tag [EST]-SSRs) to characterize range-wide population structure with temporal replicates. No F(ST)-outliers were detected using the LOSITAN program, suggesting that neither balancing nor divergent selection affected the loci surveyed. Consistent hierarchical structuring of populations by geography or year class was not detected regardless of marker class. The EST-SSRs were less variable than the anonymous SSRs, but no correlation between F(ST) and variation or marker class was observed. General linear model analysis showed that low EST-SSR variation was attributable to low mean repeat number. Comparative genomic analysis with Gasterosteus aculeatus, Takifugu rubripes, and Oryzias latipes showed consistently lower repeat number in EST-SSRs than SSR loci that were not in ESTs. Purifying selection likely imposed functional constraints on EST-SSRs resulting in low repeat numbers that affected diversity estimates but did not affect the observed pattern of population structure.

  12. Genetic analysis and ecological association of Hina genes based on single nucleotide polymorphisms (SNPs) in wild barley, Hordeum spontaneum.

    Science.gov (United States)

    Li, Wei-Tao; Huang, Xia; Wang, Ji-Rui; Chen, Guo-Yue; Nevo, Eviatar; Zheng, You-Liang; Wei, Yu-Ming

    2010-02-01

    Specific primers were designed to amplify the sequences of Hina genes from 121 wild barley (Hordeum spontaneum) accessions belonging to 18 populations from Iran, Israel and Turkey. Forty-nine single nucleotide polymorphisms (SNPs), nine indels, and 26 haplotypes were determined by sequence analysis. The genetic polymorphism (P), genetic diversity (He), and Shannon's information index (I) in the 18 populations were 0.486, 0.181 and 0.269, respectively. Approximately 2/3 genetic variations of Hina genes were presented within populations, while approximately 1/3 genetic variations were observed between populations. Broad gene flow (Nm= 3.31) and low genetic variation (Gst= 0.0702) were detected. However, the genetic differentiation between populations was independent of geographical distances according to the Mantel test (p = 0.478). The result of Spearman rank correlations (r(s)) showed that the genetic indices (P, He and I) of Hina were not significantly correlated with ecological factors. Only eight SNP positions correlated significantly with ecological factors. Of the eight SNP positions that positively correlated with ecological factors, only one SNP (769, T-C) was located in the coding region; however, it was not responsible for the amino acid change.

  13. Genetic differentiation and genetic diversity of Castanopsis (Fagaceae), the dominant tree species in Japanese broadleaved evergreen forests, revealed by analysis of EST-associated microsatellites.

    Science.gov (United States)

    Aoki, Kyoko; Ueno, Saneyoshi; Kamijo, Takashi; Setoguchi, Hiroaki; Murakami, Noriaki; Kato, Makoto; Tsumura, Yoshihiko

    2014-01-01

    The broadleaved evergreen forests of the East Asian warm temperate zone are characterised by their high biodiversity and endemism, and there is therefore a need to extend our understanding of its genetic diversity and phylogeographic patterns. Castanopsis (Fagaceae) is one of the dominant tree species in the broadleaved evergreen forests of Japan. In this study we investigate the genetic diversity, genetic structure and leaf epidermal morphology of 63 natural populations of C. sieboldii and C. cuspidata, using 32 Expressed Sequence Tag associated microsatellites. The overall genetic differentiation between populations was low (GST = 0.069 in C. sieboldii and GST = 0.057 in C. cuspidata). Neighbor-joining tree and Bayesian clustering analyses revealed that the populations of C. sieboldii and C. cuspidata were genetically clearly differentiated, a result which is consistent with the morphology of their epidermal cell layers. This suggests that C. sieboldii and C. cuspidata should be treated as independent species, although intermediate morphologies are often observed, especially at sites where the two species coexist. The higher level of genetic diversity observed in the Kyushu region (for both species) and the Ryukyu Islands (for C. sieboldii) is consistent with the available fossil pollen data for Castanopsis-type broadleaved evergreen trees during the Last Glacial Maximum and suggests the existence of refugia for Castanopsis forests in southern Japan. Within the C. sieboldii populations, Bayesian clustering analyses detected three clusters, in the western and eastern parts of the main islands and in the Ryukyu Islands. The west-east genetic differentiation observed for this species in the main islands, a pattern which is also found in several plant and animal species inhabiting Castanopsis forests in Japan, suggests that they have been isolated from each other in the western and eastern populations for an extended period of time, and may imply the

  14. Is the ballan wrasse (Labrus bergylta) two species? Genetic analysis reveals within-species divergence associated with plain and spotted morphotype frequencies.

    Science.gov (United States)

    Quintela, María; Danielsen, Elin Annie; Lopez, Lua; Barreiro, Rodolfo; Svåsand, Terje; Knutsen, Halvor; Skiftesvik, Anne Berit; Glover, Kevin A

    2016-03-01

    The ballan wrasse (Labrus bergylta) is a marine fish belonging to the family Labridae characterized by 2 main morphotypes that occur in sympatry: spotty and plain. Previous studies have revealed differences in their life-history traits, such as growth and maturation; however, the genetic relationship between forms is presently unknown. Using 20 recently developed microsatellite markers, we conducted a genetic analysis of 41 and 48 spotty and plain ballan wrasse collected in Galicia (northwest Spain). The 2 morphotypes displayed highly significant genetic differences to each other (FST = 0.018, P morphotypes was significantly different (χ(2) = 9.46, P = 0.002). It is concluded that there is significant genetic heterogeneity within this species, which appears to be highly associated with the spotty and plain forms, but not completely explained by them. Given the previously demonstrated biological differences between morphotypes, and the present genetic analyses, we speculate about the convenience of a taxonomic re-evaluation of this species.

  15. 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.

  16. Genetic mapping and QTL analysis of growth-related traits in Pinctada fucata using restriction-site associated DNA sequencing.

    Directory of Open Access Journals (Sweden)

    Yaoguo Li

    Full Text Available The pearl oyster, Pinctada fucata (P. fucata, is one of the marine bivalves that is predominantly cultured for pearl production. To obtain more genetic information for breeding purposes, we constructed a high-density linkage map of P. fucata and identified quantitative trait loci (QTL for growth-related traits. One F1 family, which included the two parents, 48 largest progeny and 50 smallest progeny, was sampled to construct a linkage map using restriction site-associated DNA sequencing (RAD-Seq. With low coverage data, 1956.53 million clean reads and 86,342 candidate RAD loci were generated. A total of 1373 segregating SNPs were used to construct a sex-average linkage map. This spanned 1091.81 centimorgans (cM, with 14 linkage groups and an average marker interval of 1.41 cM. The genetic linkage map coverage, Coa, was 97.24%. Thirty-nine QTL-peak loci, for seven growth-related traits, were identified using the single-marker analysis, nonparametric mapping Kruskal-Wallis (KW test. Parameters included three for shell height, six for shell length, five for shell width, four for hinge length, 11 for total weight, eight for soft tissue weight and two for shell weight. The QTL peak loci for shell height, shell length and shell weight were all located in linkage group 6. The genotype frequencies of most QTL peak loci showed significant differences between the large subpopulation and the small subpopulation (P<0.05. These results highlight the effectiveness of RAD-Seq as a tool for generation of QTL-targeted and genome-wide marker data in the non-model animal, P. fucata, and its possible utility in marker-assisted selection (MAS.

  17. Genetic analysis of the ELOVL6 gene polymorphism associated with type 2 diabetes mellitus

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Y.; Wang, F.; Yu, X.L.; Miao, Z.M.; Wang, Z.C.; Chen, Y.; Wang, Y.G. [Department of Endocrinology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao (China)

    2013-08-10

    Recent animal studies have indicated that overexpression of the elongation of long-chain fatty acids family member 6 (Elovl6) gene can cause insulin resistance and β-cell dysfunction. These are the major factors involved in the development of type 2 diabetes mellitus (T2DM). To identify the relationship between single nucleotide polymorphisms (SNP) of ELOVL6 and T2DM pathogenesis, we conducted a case-control study of 610 Han Chinese individuals (328 newly diagnosed T2DM and 282 healthy subjects). Insulin resistance and islet first-phase secretion function were evaluated by assessment of insulin resistance in a homeostasis model (HOMA-IR) and an arginine stimulation test. Three SNPs of the ELOVL6 gene were genotyped with polymerase chain reaction-restriction fragment length polymorphism, with DNA sequencing used to confirm the results. Only genotypes TT and CT of the ELOVL6 SNP rs12504538 were detected in the samples. Genotype CC was not observed. The T2DM group had a higher frequency of the C allele and the CT genotype than the control group. Subjects with the CT genotype had higher HOMA-IR values than those with the TT genotype. In addition, no statistical significance was observed between the genotype and allele frequencies of the control and T2DM groups for SNPs rs17041272 and rs6824447. The study indicated that the ELOVL6 gene polymorphism rs12504538 is associated with an increased risk of T2DM, because it causes an increase in insulin resistance.

  18. Association analysis of genetic and environmental risk factors in the cuticular drusen subtype of age-related macular degeneration.

    NARCIS (Netherlands)

    Ven, J.P.H. van de; Smailhodzic, D.; Boon, C.J.F.; Fauser, S.; Groenewoud, J.M.M.; Chong, N.V.; Hoyng, C.B.; Klevering, B.J.; Hollander, A.I. den

    2012-01-01

    PURPOSE: To assess the association of gender, cigarette smoking, body-mass index, and nine genetic risk variants with cuticular drusen (CD), a well recognized subtype of age-related macular degeneration (AMD). METHODS: A total of 757 patients with AMD, including 217 patients with CD, and 553 control

  19. SNP discovery in common bean by restriction-associated DNA (RAD) sequencing for genetic diversity and population structure analysis.

    Science.gov (United States)

    Valdisser, Paula Arielle M R; Pappas, Georgios J; de Menezes, Ivandilson P P; Müller, Bárbara S F; Pereira, Wendell J; Narciso, Marcelo G; Brondani, Claudio; Souza, Thiago L P O; Borba, Tereza C O; Vianello, Rosana P

    2016-06-01

    Researchers have made great advances into the development and application of genomic approaches for common beans, creating opportunities to driving more real and applicable strategies for sustainable management of the genetic resource towards plant breeding. This work provides useful polymorphic single-nucleotide polymorphisms (SNPs) for high-throughput common bean genotyping developed by RAD (restriction site-associated DNA) sequencing. The RAD tags were generated from DNA pooled from 12 common bean genotypes, including breeding lines of different gene pools and market classes. The aligned sequences identified 23,748 putative RAD-SNPs, of which 3357 were adequate for genotyping; 1032 RAD-SNPs with the highest ADT (assay design tool) score are presented in this article. The RAD-SNPs were structurally annotated in different coding (47.00 %) and non-coding (53.00 %) sequence components of genes. A subset of 384 RAD-SNPs with broad genome distribution was used to genotype a diverse panel of 95 common bean germplasms and revealed a successful amplification rate of 96.6 %, showing 73 % of polymorphic SNPs within the Andean group and 83 % in the Mesoamerican group. A slightly increased He (0.161, n = 21) value was estimated for the Andean gene pool, compared to the Mesoamerican group (0.156, n = 74). For the linkage disequilibrium (LD) analysis, from a group of 580 SNPs (289 RAD-SNPs and 291 BARC-SNPs) genotyped for the same set of genotypes, 70.2 % were in LD, decreasing to 0.10 %in the Andean group and 0.77 % in the Mesoamerican group. Haplotype patterns spanning 310 Mb of the genome (60 %) were characterized in samples from different origins. However, the haplotype frameworks were under-represented for the Andean (7.85 %) and Mesoamerican (5.55 %) gene pools separately. In conclusion, RAD sequencing allowed the discovery of hundreds of useful SNPs for broad genetic analysis of common bean germplasm. From now, this approach provides an excellent panel

  20. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

    NARCIS (Netherlands)

    I.M. Heid (Iris); A.U. Jackson (Anne); J.C. Randall (Joshua); T.W. Winkler (Thomas); L. Qi (Lu); V. Ssteinthorsdottir (Valgerdur); G. Tthorleifsson (Ggudmar); M.C. Zillikens (Carola); E.K. Sspeliotes (Eelizabeth); R. Mägi (Reedik); T. Workalemahu (Tsegaselassie); C.C. White (Charles); N. Bouatia-Naji (Nabila); T.B. Harris (Tamara); S.I. Berndt (Sonja); E. Ingelsson (Erik); C.J. Willer (Cristen); J. Luan; S. Vedantam (Sailaja); T. Eesko (Tõnu); T.O. Kilpeläinen (Tuomas); Z. Kutalik (Zoltán); S. Li (Shengxu); K.L. Monda (Keri); A.L. Dixon (Anna); C. Holmes (Christopher); R.C. Kaplan (Robert); L. Liang (Liming); J. Min (Josine); M.F. Moffatt (Miriam); C. Molony (Cliona); G. Nicholson (Ggeorge); E.E. Sschadt (Eeric); K.T. Zondervan (Krina); M.F. Feitosa (Mary Furlan); T. Ferreira (Teresa); H.L. Allen; R.J. Weyant (Robert); E. Wheeler (Eleanor); A.R. Wood (Andrew); K. Eestrada (Karol); M.E. Goddard (Michael); G. Lettre (Guillaume); M. Mangino (Massimo); D.R. Nyholt (Dale); S. Purcell (Shaun); A.V. Ssmith; P.M. Visscher (Peter); J. Yang (Joanna); S.A. McCcarroll (Ssteven); J. Nemesh (James); B.F. Voight (Benjamin); D. Absher (Devin); N. Amin (Najaf); T. Aspelund (Thor); L. Coin (Lachlan); N.L. Glazer (Nicole); C. Hayward (Caroline); N. Heard-Ccosta (Nancy); J.J. Hottenga (Jouke Jan); A. Johansson (Åsa); T. Johnson (Toby); M. Kaakinen (Marika); K. Kapur (Karen); S. Ketkar (Shamika); J.W. Knowles (Joshua); P. Kraft (Peter); A. Kraja (Aldi); C. Lamina (Claudia); M.F. Leitzmann (Michael); B. McKknight (Barbara); A.D. Morris (Andrew); K. Oong (Ken); J.R.B. Perry (John); M.J. Peters (Marjolein); O. Polasek (Ozren); I. Prokopenko (Inga); N.W. Rayner (Nigel William); S. Ripatti (Samuli); F. Rivadeneira Ramirez (Fernando); N.R. Robertson (Neil); S. Sanna (Serena); U. Sovio (Ulla); I. Surakka (Ida); A. Teumer (Alexander); S. van Wingerden (Sophie); V. Vitart (Veronique); J.H. Zhao; C. Cavalcanti-Proença (Christine); P.S. Chines (Peter); E. Fisher (Eeva); J.R. Kulzer (Jennifer); C. Lecoeur (Cécile); N. Narisu (Narisu); C. Sandholt (Camilla); L.J. Scott (Laura); K. Silander (Kaisa); K. Stark (Klaus); M.L. Tammesoo; T.M. Teslovich (Tanya); N. Timpson (Nicholas); R.P. Welch (Ryan); D.I. Chasman (Daniel); M.N. Cooper (Matthew); J.O. Jansson; J. Kettunen (Johannes); R. Wlawrence (Robert); N. Pellikka (Niina); M. Perola (Markus); L. Vandenput (Liesbeth); H. Alavere (Helene); P. Almgren (Peter); L.D. Atwood (Larry); A.J. Bennett (Amanda); R. Biffar (Reiner); L.L. Bonnycastle (Lori); S.R. Bornstein (Stefan); T.A. Buchanan (Thomas); H. Campbell (Harry); I.N.M. Day (Ian); M. Dei (Mariano); M. Dörr (Marcus); P. Eelliott (Paul); M.R. Eerdos (Micheal); J.G. Eeriksson (Johan); N.B. Freimer (Nelson); M. Fu (Mao); S. Gaget (Stefan); E.J.C. Geus (Eco); A.P. Gjesing (Anette); H. Grallert (Harald); J. Gräßler (Jürgen); C.J. Groves (Christopher); C. Guiducci (Candace); A.L. Hartikainen; N. Hassanali (Neelam); A.S. Havulinna (Aki); K.H. Herzig; A.A. Hicks (Andrew); J. Hui (Jennie); W. Igl (Wilmar); P. Jousilahti (Pekka); A. Jula (Antti); E. Kajantie (Eero); L. Kinnunen (Leena); I. Kolcic (Ivana); S. Koskinen (Seppo); P. Kovacs (Peter); H.K. Kroemer (Heyo); V. Krzelj (Vjekoslav); J. Kuusisto (Johanna); K. Kvaløy (Kirsti); J. Laitinen (Jaana); O. Lantieri (Olivier); G.M. Lathrop (Mark); M.L. Lokki; R.N. Luben (Robert); B. Ludwig (Barbara); W.L. McArdle (Wendy); A. McCcarthy (Anne); M.A. Morken (Mario); M. Nelis (Mari); M.J. Neville (Matthew); G. Paré (Guillaume); A.N. Parker (Alex); J. Peden (John); I. Pichler (Irene); K.H. Pietilainen (Kirsi Hannele); C.P. Platou (Carl); A. Pouta (Anneli); M. Ridderstråle (Martin); N.J. Samani (Nilesh); J. Saramies (Jouko); J. Sinisalo (Juha); J.H. Smit (Jan); R.J. Strawbridge (Rona); H.M. Stringham (Heather); A.J. Swift (Amy); M. Teder-Llaving (Maris); B. Thomson (Brian); G. Usala; J.B.J. van Meurs (Joyce); G.J. van Ommen (Gert); V. Vatin (Vincent); C.B. Volpato; H. Wallaschofski (Henri); G.B. Walters (Bragi); E. Widen (Elisabeth); S.H. Wild (Sarah); G.A.H.M. Willemsen (Gonneke); D.R. Witte (Deniel); L. Zgaga (Lina); P. Zitting (Paavo); J.P. Beilby (John); A. James (Alan); M. Kähönen (Mika); T. Lehtimäki (Terho); M.S. Nieminen (Markku); C. Ohlsson (Claes); C. Palmer (Cameron); O. Raitakari (Olli); P.M. Ridker (Paul); M. Stumvoll (Michael); A. Tönjes (Anke); J. Viikari (Jorma); B. Balkau (Beverley); Y. Ben-Shlomo; R.N. Bergman (Richard); H. Boeing (Heiner); A.V. Smith (Albert Vernon); S. Eebrahim (Shah); P. Froguel (Philippe); T. Hansen (Torben); C. Hengstenberg (Christian); K. Hveem (Kristian); B. Isomaa (Bo); T. Jørgensen (Torben); F. Karpe (Fredrik); K-T. Khaw (Kay-Tee); M. Laakso (Markku); D.A. Lawlor (Debbie); M. Marre (Michel); T. Meitinger (Thomas); A. Metspalu (Andres); K. Midthjell (Kristian); O. Pedersen (Oluf); V. Salomaa (Veikko); P.E.H. Schwarz (Peter); T. Tuomi (Tiinamaija); J. Tuomilehto (Jaakko); T.T. Valle (Timo); N.J. Wareham (Nick); A.M. Arnold (Alice); J.S. Beckmann (Jacques); S.M. Bergmann (Sven); E.A. Boerwinkle (Eric); D.I. Boomsma (Dorret); M. Caulfield (Mark); F.S. Collins (Francis); G. Eeiriksdottir (Gudny); V. Gudnason (Vilmundur); U. Gyllensten (Ulf); A. Hamsten (Anders); A.T. Hattersley (Andrew); A. Hofman (Albert); F.B. Hu (Frank); T. Illig (Thomas); C. Iribarren (Carlos); M.R. Järvelin; W.H.L. Kao (Wen); J. Kaprio (Jaakko); L.J. Launer (Lenore); P. Munroe (Patricia); B.A. Oostra (Ben); B.W.J.H. Penninx (Brenda); P.P. Pramstaller (Peter Paul); B.M. Psaty (Bruce); T. Quertermous (Thomas); A. Rissanen (Aila); I. Rudan (Igor); A.R. Shuldiner (Alan); N. Soranzo (Nicole); T.D. Spector (Timothy); A.C. Syvanen; M. Uda (Manuela); A.G. Uitterlinden (André); H. Völzke (Henry); P. Vollenweider (Peter); J.F. Wilson (James); J.C.M. Witteman (Jacqueline); A.F. Wright (Alan); G.R. Abecasis (Gonçalo); M. Boehnke (Michael); I.B. Borecki (Ingrid); P. Deloukas (Panagiotis); T.M. Frayling (Timothy); L. Groop (Leif); T. Haritunians (Talin); D.J. Hunter (David); K.E. North (Kari); J.R. O'Cconnell (Jeffrey); L. Peltonen (Leena Johanna); D. Schlessinger; D.P. Strachan (David); J.N. Hirschhorn (Joel); T.L. Assimes (Themistocles); H.E. Wichmann (Heinz Erich); U. Thorsteinsdottir (Unnur); C.M. van Duijn (Cock); K. Stefansson (Kari); L.A. Cupples (Adrienne); R.J.F. Loos (Ruth); I. Barroso (Inês); C.S. Fox (Caroline); K.L. Mohlke (Karen); C.M. Lindgren (Cecilia); R.M. Watanabe (Richard); M.N. Weedon (Michael)

    2010-01-01

    textabstractWaist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studi

  1. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

    NARCIS (Netherlands)

    Heid, Iris M.; Jackson, Anne U.; Randall, Joshua C.; Winkler, Thomas W.; Qi, Lu; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Zillikens, M. Carola; Speliotes, Elizabeth K.; Maegi, Reedik; Workalemahu, Tsegaselassie; White, Charles C.; Bouatia-Naji, Nabila; Harris, Tamara B.; Berndt, Sonja I.; Ingelsson, Erik; Willer, Cristen J.; Weedon, Michael N.; Luan, Jianan; Vedantam, Sailaja; Esko, Tonu; Kilpelaeinen, Tuomas O.; Kutalik, Zoltan; Li, Shengxu; Monda, Keri L.; Dixon, Anna L.; Holmes, Christopher C.; Kaplan, Lee M.; Liang, Liming; Min, Josine L.; Moffatt, Miriam F.; Molony, Cliona; Nicholson, George; Schadt, Eric E.; Zondervan, Krina T.; Feitosa, Mary F.; Ferreira, Teresa; Allen, Hana Lango; Weyant, Robert J.; Wheeler, Eleanor; Wood, Andrew R.; Estrada, Karol; Goddard, Michael E.; Lettre, Guillaume; Mangino, Massimo; Nyholt, Dale R.; Purcell, Shaun; Smith, Albert Vernon; Visscher, Peter M.; Yang, Jian; McCarroll, Steven A.; Nemesh, James; Voight, Benjamin F.; Absher, Devin; Amin, Najaf; Aspelund, Thor; Coin, Lachlan; Glazer, Nicole L.; Hayward, Caroline; Heard-Costa, Nancy L.; Hottenga, Jouke-Jan; Johansson, Asa; Johnson, Toby; Kaakinen, Marika; Kapur, Karen; Ketkar, Shamika; Knowles, Joshua W.; Kraft, Peter; Kraja, Aldi T.; Lamina, Claudia; Leitzmann, Michael F.; McKnight, Barbara; Morris, Andrew P.; Ong, Ken K.; Perry, John R. B.; Peters, Marjolein J.; Polasek, Ozren; Prokopenko, Inga; Rayner, Nigel W.; Ripatti, Samuli; Rivadeneira, Fernando; Robertson, Neil R.; Sanna, Serena; Sovio, Ulla; Surakka, Ida; Teumer, Alexander; van Wingerden, Sophie; Vitart, Veronique; Zhao, Jing Hua; Cavalcanti-Proenca, Christine; Chines, Peter S.; Fisher, Eva; Kulzer, Jennifer R.; Lecoeur, Cecile; Narisu, Narisu; Sandholt, Camilla; Scott, Laura J.; Silander, Kaisa; Stark, Klaus; Tammesoo, Mari-Liis; Teslovich, Tanya M.; Timpson, Nicholas John; Watanabe, Richard M.; Welch, Ryan; Chasman, Daniel I.; Cooper, Matthew N.; Jansson, John-Olov; Kettunen, Johannes; Lawrence, Robert W.; Pellikka, Niina; Perola, Markus; Vandenput, Liesbeth; Alavere, Helene; Almgren, Peter; Atwood, Larry D.; Bennett, Amanda J.; Biffar, Reiner; Bonnycastle, Lori L.; Bornstein, Stefan R.; Buchanan, Thomas A.; Campbell, Harry; Day, Ian N. M.; Dei, Mariano; Doerr, Marcus; Elliott, Paul; Erdos, Michael R.; Eriksson, Johan G.; Freimer, Nelson B.; Fu, Mao; Gaget, Stefan; Geus, Eco J. C.; Gjesing, Anette P.; Grallert, Harald; Graessler, Juergen; Groves, Christopher J.; Guiducci, Candace; Hartikainen, Anna-Liisa; Hassanali, Neelam; Havulinna, Aki S.; Herzig, Karl-Heinz; Hicks, Andrew A.; Hui, Jennie; Igl, Wilmar; Jousilahti, Pekka; Jula, Antti; Kajantie, Eero; Kinnunen, Leena; Kolcic, Ivana; Koskinen, Seppo; Kovacs, Peter; Kroemer, Heyo K.; Krzelj, Vjekoslav; Kuusisto, Johanna; Kvaloy, Kirsti; Laitinen, Jaana; Lantieri, Olivier; Lathrop, G. Mark; Lokki, Marja-Liisa; Luben, Robert N.; Ludwig, Barbara; McArdle, Wendy L.; McCarthy, Anne; Morken, Mario A.; Nelis, Mari; Neville, Matt J.; Pare, Guillaume; Parker, Alex N.; Peden, John F.; Pichler, Irene; Pietilainen, Kirsi H.; Platou, Carl G. P.; Pouta, Anneli; Ridderstrale, Martin; Samani, Nilesh J.; Saramies, Jouko; Sinisalo, Juha; Smit, Jan H.; Strawbridge, Rona J.; Stringham, Heather M.; Swift, Amy J.; Teder-Laving, Maris; Thomson, Brian; Usala, Gianluca; van Meurs, Joyce B. J.; van Ommen, Gert-Jan; Vatin, Vincent; Volpato, Claudia B.; Wallaschofski, Henri; Walters, G. Bragi; Widen, Elisabeth; Wild, Sarah H.; Willemsen, Gonneke; Witte, Daniel R.; Zgaga, Lina; Zitting, Paavo; Beilby, John P.; James, Alan L.; Kahonen, Mika; Lehtimaki, Terho; Nieminen, Markku S.; Ohlsson, Claes; Palmer, Lyle J.; Raitakari, Olli; Ridker, Paul M.; Stumvoll, Michael; Toenjes, Anke; Viikari, Jorma; Balkau, Beverley; Ben-Shlomo, Yoav; Bergman, Richard N.; Boeing, Heiner; Smith, George Davey; Ebrahim, Shah; Froguel, Philippe; Hansen, Torben; Hengstenberg, Christian; Hveem, Kristian; Isomaa, Bo; Jorgensen, Torben; Karpe, Fredrik; Khaw, Kay-Tee; Laakso, Markku; Lawlor, Debbie A.; Marre, Michel; Meitinger, Thomas; Metspalu, Andres; Midthjell, Kristian; Pedersen, Oluf; Salomaa, Veikko; Schwarz, Peter E. H.; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Valle, Timo T.; Wareham, Nicholas J.; Arnold, Alice M.; Beckmann, Jacques S.; Bergmann, Sven; Boerwinkle, Eric; Boomsma, Dorret I.; Caulfield, Mark J.; Collins, Francis S.; Eiriksdottir, Gudny; Gudnason, Vilmundur; Gyllensten, Ulf; Hamsten, Anders; Hattersley, Andrew T.; Hofman, Albert; Hu, Frank B.; Illig, Thomas; Iribarren, Carlos; Jarvelin, Marjo-Riitta; Kao, W. H. Linda; Kaprio, Jaakko

    2010-01-01

    Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR a

  2. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

    DEFF Research Database (Denmark)

    Heid, Iris M; Jackson, Anne U; Randall, Joshua C

    2010-01-01

    Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WH...

  3. Genetic analysis of completely sequenced disease-associated MHC haplotypes identifies shuffling of segments in recent human history.

    Directory of Open Access Journals (Sweden)

    James A Traherne

    2006-01-01

    Full Text Available The major histocompatibility complex (MHC is recognised as one of the most important genetic regions in relation to common human disease. Advancement in identification of MHC genes that confer susceptibility to disease requires greater knowledge of sequence variation across the complex. Highly duplicated and polymorphic regions of the human genome such as the MHC are, however, somewhat refractory to some whole-genome analysis methods. To address this issue, we are employing a bacterial artificial chromosome (BAC cloning strategy to sequence entire MHC haplotypes from consanguineous cell lines as part of the MHC Haplotype Project. Here we present 4.25 Mb of the human haplotype QBL (HLA-A26-B18-Cw5-DR3-DQ2 and compare it with the MHC reference haplotype and with a second haplotype, COX (HLA-A1-B8-Cw7-DR3-DQ2, that shares the same HLA-DRB1, -DQA1, and -DQB1 alleles. We have defined the complete gene, splice variant, and sequence variation contents of all three haplotypes, comprising over 259 annotated loci and over 20,000 single nucleotide polymorphisms (SNPs. Certain coding sequences vary significantly between different haplotypes, making them candidates for functional and disease-association studies. Analysis of the two DR3 haplotypes allowed delineation of the shared sequence between two HLA class II-related haplotypes differing in disease associations and the identification of at least one of the sites that mediated the original recombination event. The levels of variation across the MHC were similar to those seen for other HLA-disparate haplotypes, except for a 158-kb segment that contained the HLA-DRB1, -DQA1, and -DQB1 genes and showed very limited polymorphism compatible with identity-by-descent and relatively recent common ancestry (<3,400 generations. These results indicate that the differential disease associations of these two DR3 haplotypes are due to sequence variation outside this central 158-kb segment, and that shuffling of

  4. Genetic correlates of brain aging on MRI and cognitive test measures: a genome-wide association and linkage analysis in the Framingham study

    OpenAIRE

    2007-01-01

    Abstract Background Brain magnetic resonance imaging (MRI) and cognitive tests can identify heritable endophenotypes associated with an increased risk of developing stroke, dementia and Alzheimer's disease (AD). We conducted a genome-wide association (GWA) and linkage analysis exploring the genetic basis of these endophenotypes in a community-based sample. Methods A total of 705 stroke- and dementia-free Framingham participants (age 62 +9 yrs, 50% male) who underwent volumetric brain MRI and ...

  5. 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, WT; Mitchell, Braxton D.; Psaty, Bruce M.; Kooperberg, Charles; Reiner, Alexander; Worrall, Bradford B.; Fornage, Myriam

    2015-01-01

    Background and Purpose 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. Methods Using METAL, we conducted meta-analyses of GWAS in 14,746 African-Americans (1,365 ischemic and 1,592 total stroke cases) from COMPASS, and tested SNPs with Pstroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations. Results 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 pre-splicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, 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. Conclusions We identified a novel SNP 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. PMID:26089329

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

    NARCIS (Netherlands)

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

    2011-01-01

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

  7. 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

  8. Genetic Structure and Molecular Variability Analysis of Citrus sudden death-associated virus Isolates from Infected Plants Grown in Brazil

    Directory of Open Access Journals (Sweden)

    Emilyn Emy Matsumura

    2016-12-01

    Full Text Available Citrus sudden death-associated virus (CSDaV is a monopartite positive-sense single-stranded RNA virus that was suggested to be associated with citrus sudden death (CSD disease in Brazil. Here, we report the first study of the genetic structure and molecular variability among 31 CSDaV isolates collected from both symptomatic and asymptomatic trees in CSD-affected areas. Analyses of partial nucleotide sequences of five domains of the CSDaV genomic RNA, including those encoding for the methyltransferase, the multi-domain region (MDR, the helicase, the RNA-dependent RNA polymerase and the coat protein, showed that the MDR coding region was the most diverse region assessed here, and a possible association between this region and virus adaption to different host or plant tissues is considered. Overall, the nucleotide diversity (π was low for CSDaV isolates, but the phylogenetic analyses revealed the predominance of two main groups, one of which showed a higher association with CSD-symptomatic plants. Isolates obtained from CSD-symptomatic plants, compared to those obtained from asymptomatic plants, showed higher nucleotide diversity, nonsynonymous and synonymous substitution rates and number of amino acid changes on the coding regions located closer to the 5’ end region of the genomic RNA. This work provides new insights into the genetic diversity of the CSDaV, giving support for further epidemiological studies.

  9. Genetic Structure and Molecular Variability Analysis of Citrus sudden death-associated virus Isolates from Infected Plants Grown in Brazil

    Science.gov (United States)

    Matsumura, Emilyn Emy; Coletta Filho, Helvécio Della; de Oliveira Dorta, Silvia; Nouri, Shahideh; Machado, Marcos Antonio

    2016-01-01

    Citrus sudden death-associated virus (CSDaV) is a monopartite positive-sense single-stranded RNA virus that was suggested to be associated with citrus sudden death (CSD) disease in Brazil. Here, we report the first study of the genetic structure and molecular variability among 31 CSDaV isolates collected from both symptomatic and asymptomatic trees in CSD-affected areas. Analyses of partial nucleotide sequences of five domains of the CSDaV genomic RNA, including those encoding for the methyltransferase, the multi-domain region (MDR), the helicase, the RNA-dependent RNA polymerase and the coat protein, showed that the MDR coding region was the most diverse region assessed here, and a possible association between this region and virus adaption to different host or plant tissues is considered. Overall, the nucleotide diversity (π) was low for CSDaV isolates, but the phylogenetic analyses revealed the predominance of two main groups, one of which showed a higher association with CSD-symptomatic plants. Isolates obtained from CSD-symptomatic plants, compared to those obtained from asymptomatic plants, showed higher nucleotide diversity, nonsynonymous and synonymous substitution rates and number of amino acid changes on the coding regions located closer to the 5’ end region of the genomic RNA. This work provides new insights into the genetic diversity of the CSDaV, giving support for further epidemiological studies. PMID:27999249

  10. 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; Pol, Hilleke E. Hulshoff; Ikeda, Masashi; Jack Jr, 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

    2017-01-01

    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 (rg=−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness. PMID:28098162

  11. Associations of two common genetic variants with breast cancer risk in a chinese population: a stratified interaction analysis.

    Directory of Open Access Journals (Sweden)

    Yuxiang Lin

    Full Text Available Recent genome-wide association studies (GWAS have identified a series of new genetic susceptibility loci for breast cancer (BC. However, the correlations between these variants and breast cancer are still not clear. In order to explore the role of breast cancer susceptibility variants in a Southeast Chinese population, we genotyped two common SNPs at chromosome 6q25 (rs2046210 and in TOX3 (rs4784227 in a case-control study with a total of 702 breast cancer cases and 794 healthy-controls. In addition, we also evaluated the multiple interactions among genetic variants, risk factors, and tumor subtypes. Associations of genotypes with breast cancer risk was evaluated using multivariate logistic regression to estimate odds ratios (OR and their 95% confidence intervals (95% CI. The results indicated that both polymorphisms were significantly associated with the risk of breast cancer, with per allele OR = 1.35, (95%CI = 1.17-1.57 for rs2046210 and per allele OR = 1.24 (95%CI = 1.06-1.45 for rs4784227. Furthermore, in subgroup stratified analyses, we observed that the T allele of rs4784227 was significantly associated with elevated OR among postmenopausal populations (OR = 1.44, 95%CI 1.11-1.87 but not in premenopausal populations, with the heterogeneity P value of P = 0.064. These findings suggest that the genetic variants at chromosome 6q25 and in the TOX3 gene may play important roles in breast cancer development in a Chinese population and the underlying biological mechanisms need to be further elucidated.

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

    DEFF Research Database (Denmark)

    Ng, Maggie C Y; Shriner, Daniel; Chen, Brian H

    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 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs...... × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23)

  13. Analysis of 19 genes for association with type I diabetes in the Type I Diabetes Genetics Consortium families.

    Science.gov (United States)

    Howson, J M M; Walker, N M; Smyth, D J; Todd, J A

    2009-12-01

    In recent years the pace of discovery of genetic associations with type I diabetes (T1D) has accelerated, with the total number of confirmed loci, including the major histocompatibility complex (MHC) region, reaching 43. However, much of the deciphering of the associations at these, and the established T1D loci, has yet to be performed in sufficient numbers of samples or with sufficient markers. Here, 257 single-nucleotide polymorphisms (SNPs) have been genotyped in 19 candidate genes (INS, PTPN22, IL2RA, CTLA4, IFIH1, SUMO4, VDR, PAX4, OAS1, IRS1, IL4, IL4R, IL13, IL12B, CEACAM21, CAPSL, Q7Z4c4(5Q), FOXP3, EFHB) in 2300 affected sib-pair families and tested for association with T1D as part of the Type I Diabetes Genetics Consortium's candidate gene study. The study had approximately 80% power at alpha=0.002 and a minor allele frequency of 0.2 to detect an effect with a relative risk (RR) of 1.20, which drops to just 40% power for a RR of 1.15. At the INS gene, rs689 (-23 HphI) was the most associated SNP (P=3.8 x 10(-31)), with the estimated RR=0.57 (95% confidence interval, 0.52-0.63). In addition, rs689 was associated with age-at-diagnosis of T1D (P=0.001), with homozygosity for the T1D protective T allele, delaying the onset of T1D by approximately 2 years in these families. At PTPN22, rs2476601 (R620W), in agreement with previous reports, was the most significantly associated SNP (P=6.9 x 10(-17)), with RR=1.55 (1.40-1.72). Evidence for association with T1D was observed for the IFIH1 SNP, rs1990760 (P=7.0 x 10(-4)), with RR=0.88 (0.82-0.95) and the CTLA4 SNP rs1427676 (P=0.0005), with RR=1.14 (1.06-1.23). In contrast, no convincing evidence of association was obtained for SUMO4, VDR, PAX4, OAS1, IRS1, IL4, IL4R, IL13, IL12B, CEACAM21 or CAPSL gene regions (http://www.T1DBase.org).

  14. A Cross-Cancer Genetic Association Analysis of the DNA repair and DNA Damage Signaling Pathways for Lung, Ovary, Prostate, Breast and Colorectal Cancer

    Science.gov (United States)

    Scarbrough, Peter M.; Weber, Rachel Palmieri; Iversen, Edwin S.; Brhane, Yonathan; Amos, Christopher I.; Kraft, Peter; Hung, Rayjean J.; Sellers, Thomas A.; Witte, John S.; Pharoah, Paul; Henderson, Brian E.; Gruber, Stephen B.; Hunter, David J.; Garber, Judy E.; Joshi, Amit D.; McDonnell, Kevin; Easton, Doug F.; Eeles, Ros; Kote-Jarai, Zsofia; Muir, Kenneth; Doherty, Jennifer A.; Schildkraut, Joellen M.

    2015-01-01

    Background DNA damage is an established mediator of carcinogenesis, though GWAS have identified few significant loci. This cross-cancer site, pooled analysis was performed to increase the power to detect common variants of DNA repair genes associated with cancer susceptibility. Methods We conducted a cross-cancer analysis of 60,297 SNPs, at 229 DNA repair gene regions, using data from the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) Network. Our analysis included data from 32 GWAS and 48,734 controls and 51,537 cases across five cancer sites (breast, colon, lung, ovary, and prostate). Because of the unavailability of individual data, data were analyzed at the aggregate level. Meta-analysis was performed using the Association analysis for SubSETs (ASSET) software. To test for genetic associations that might escape individual variant testing due to small effect sizes, pathway analysis of eight DNA repair pathways was performed using hierarchical modeling. Results We identified three susceptibility DNA repair genes, RAD51B (p < 5.09 × 10−6), MSH5 (p < 5.09 × 10−6) and BRCA2 (p = 5.70 × 10−6). Hierarchical modeling identified several pleiotropic associations with cancer risk in the base excision repair, nucleotide excision repair, mismatch repair, and homologous recombination pathways. Conclusions Only three susceptibility loci were identified which had all been previously reported. In contrast, hierarchical modeling identified several pleiotropic cancer risk associations in key DNA repair pathways. Impact Results suggest that many common variants in DNA repair genes are likely associated with cancer susceptibility through small effect sizes that do not meet stringent significance testing criteria. PMID:26637267

  15. Association Between Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis.

    Science.gov (United States)

    Lotta, Luca A; Sharp, Stephen J; Burgess, Stephen; Perry, John R B; Stewart, Isobel D; Willems, Sara M; Luan, Jian'an; Ardanaz, Eva; Arriola, Larraitz; Balkau, Beverley; Boeing, Heiner; Deloukas, Panos; Forouhi, Nita G; Franks, Paul W; Grioni, Sara; Kaaks, Rudolf; Key, Timothy J; Navarro, Carmen; Nilsson, Peter M; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Quirós, Jose-Ramón; Riboli, Elio; Rolandsson, Olov; Sacerdote, Carlotta; Salamanca, Elena C; Slimani, Nadia; Spijkerman, Annemieke Mw; Tjonneland, Anne; Tumino, Rosario; van der A, Daphne L; van der Schouw, Yvonne T; McCarthy, Mark I; Barroso, Inês; O'Rahilly, Stephen; Savage, David B; Sattar, Naveed; Langenberg, Claudia; Scott, Robert A; Wareham, Nicholas J

    2016-10-04

    heterogeneity in genetic associations; P = .93). However, associations with type 2 diabetes were heterogeneous (I2 = 77.2%; P = .002), indicating gene-specific associations with metabolic risk of LDL-C-lowering alleles. In this meta-analysis, exposure to LDL-C-lowering genetic variants in or near NPC1L1 and other genes was associated with a higher risk of type 2 diabetes. These data provide insights into potential adverse effects of LDL-C-lowering therapy.

  16. PedGenie: an analysis approach for genetic association testing in extended pedigrees and genealogies of arbitrary size

    Directory of Open Access Journals (Sweden)

    Camp Nicola J

    2006-04-01

    Full Text Available Abstract Background We present a general approach to perform association analyses in pedigrees of arbitrary size and structure, which also allows for a mixture of pedigree members and independent individuals to be analyzed together, to test genetic markers and qualitative or quantitative traits. Our software, PedGenie, uses Monte Carlo significance testing to provide a valid test for related individuals that can be applied to any test statistic, including transmission disequilibrium statistics. Single locus at a time, composite genotype tests, and haplotype analyses may all be performed. We illustrate the validity and functionality of PedGenie using simulated and real data sets. For the real data set, we evaluated the role of two tagging-single nucleotide polymorphisms (tSNPs in the DNA repair gene, NBS1, and their association with female breast cancer in 462 cases and 572 controls selected to be BRCA1/2 mutation negative from 139 high-risk Utah breast cancer families. Results The results from PedGenie were shown to be valid both for accurate p-value calculations and consideration of pedigree structure in the simulated data set. A nominally significant association with breast cancer was observed with the NBS1 tSNP rs709816 for carriage of the rare allele (OR = 1.61, 95% CI = 1.10–2.35, p = 0.019. Conclusion PedGenie is a flexible and valid statistical tool that is intuitively simple to understand, makes efficient use of all the data available from pedigrees without requiring trimming, and is flexible to the types of tests to which it can be applied. Further, our analyses of real data indicate NBS1 may play a role in the genetic etiology of heritable breast cancer.

  17. Genetic association studies in lumbar disc degeneration

    DEFF Research Database (Denmark)

    Eskola, Pasi J; Lemmelä, Susanna; Kjaer, Per

    2012-01-01

    Low back pain is associated with lumbar disc degeneration, which is mainly due to genetic predisposition. The objective of this study was to perform a systematic review to evaluate genetic association studies in lumbar disc degeneration as defined on magnetic resonance imaging (MRI) in humans....

  18. Genetic Association Between Androgen Receptor Gene CAG Repeat Length Polymorphism and Male Infertility: A Meta-Analysis

    OpenAIRE

    Pan, Bihui; Li, Rui; CHEN, YAO; Tang, Qiuqin; Wu, Wei; Chen, Liping; Lu, Chuncheng; Pan, Feng; Hongjuan DING; Xia,Yankai; Hu, Lingqing; Chen, Daozhen; Sha, Jiahao; Wang, Xinru

    2016-01-01

    Abstract The association between polymorphism of androgen receptor gene CAG (AR-CAG) and male infertility in several studies was controversial. Based on studies on association between AR-CAG repeat length and male infertility in recent years, an updated meta-analysis is needed. We aimed to evaluate the association between AR-CAG repeat length and male infertility in advantage of the data in all published reports. We searched for reports published before August 2015 using PubMed, CNKI, VIP, an...

  19. MicroRNA Genetic Variation: From Population Analysis to Functional Implications of Three Allele Variants Associated with Cancer.

    Science.gov (United States)

    Torruella-Loran, Ignasi; Laayouni, Hafid; Dobon, Begoña; Gallego, Alicia; Balcells, Ingrid; Garcia-Ramallo, Eva; Espinosa-Parrilla, Yolanda

    2016-10-01

    Nucleotide variants in microRNA regions have been associated with disease; nevertheless, few studies still have addressed the allele-dependent effect of these changes. We studied microRNA genetic variation in human populations and found that while low-frequency variants accumulate indistinctly in microRNA regions, the mature and seed regions tend to be depleted of high-frequency variants, probably as a result of purifying selection. Comparison of pairwise population fixation indexes among regions showed that the seed had higher population fixation indexes than the other regions, suggesting the existence of local adaptation in the seed region. We further performed functional studies of three microRNA variants associated with cancer (rs2910164:C > G in MIR146A, rs11614913:C > T in MIR196A2, and rs3746444:A > G in both MIR499A and MIR499B). We found differences in the expression between alleles and in the regulation of several genes involved in cancer, such as TP53, KIT, CDH1, CLH, and TERT, which may result in changes in regulatory networks related to tumorigenesis. Furthermore, luciferase-based assays showed that MIR499A could be regulating the cadherin CDH1 and the cell adhesion molecule CLH1 in an allele-dependent fashion. A better understanding of the effect of microRNA variants associated with disease could be key in our way to a more personalized medicine.

  20. Association of genetic polymorphisms in ADH and ALDH2 with risk of coronary artery disease and myocardial infarction: a meta-analysis.

    Science.gov (United States)

    Han, Hongguang; Wang, Huishan; Yin, Zongtao; Jiang, Hui; Fang, Minhua; Han, Jingsong

    2013-09-10

    Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the major enzymes responsible for alcohol metabolism in humans. Emerging evidences have shown that functional polymorphisms in ADH and ALDH genes might play a critical role in increasing coronary artery disease (CAD) and myocardial infarction (MI) risks; however, individually published studies showed inconclusive results. The aim of this meta-analysis is to evaluate the associations between the genetic polymorphisms of ADH and ALDH genes with susceptibility to CAD and MI. A literature search was conducted on PubMed, Embase, Web of Science and Chinese BioMedical databases from inception through December 1st, 2012. Crude relative risks (RRs) with 95% confidence intervals (CIs) were calculated. Twelve case-control studies were included with a total of 9616 subjects, including 2053 CAD patients, 1436 MI patients, and 6127 healthy controls. Meta-analysis showed that mutant genotypes (GA+AA) of the rs671 polymorphism in the ALDH2 gene were associated with increased risk of both CAD and MI (CAD: RR=1.20, 95%CI: 1.03-1.40, P=0.021; MI: RR=1.32, 95%CI: 1.11-1.57, P=0.002). However, there were no significant associations of ADH genetic polymorphisms to CAD and MI risks (CAD: RR=0.92, 95%CI: 0.73-1.15, P=0.445; MI: RR=0.93, 95%CI: 0.84-1.03, P=0.148). In conclusion, this meta-analysis provides strong evidence that ALDH2 rs671 polymorphism may be associated with increased risks of CAD and MI. However, further studies are still needed to accurately determine whether ADH genetic polymorphisms are associated with susceptibility to CAD and MI.

  1. Genome-Wide Association Analysis for Blood Lipid Traits Measured in Three Pig Populations Reveals a Substantial Level of Genetic Heterogeneity.

    Directory of Open Access Journals (Sweden)

    Hui Yang

    Full Text Available Serum lipids are associated with myocardial infarction and cardiovascular disease in humans. Here we dissected the genetic architecture of blood lipid traits by applying genome-wide association studies (GWAS in 1,256 pigs from Laiwu, Erhualian and Duroc × (Landrace × Yorkshire populations, and a meta-analysis of GWAS in more than 2,400 pigs from five diverse populations. A total of 22 genomic loci surpassing the suggestive significance level were detected on 11 pig chromosomes (SSC for six blood lipid traits. Meta-analysis of GWAS identified 5 novel loci associated with blood lipid traits. Comparison of GWAS loci across the tested populations revealed a substantial level of genetic heterogeneity for porcine blood lipid levels. We further evaluated the causality of nine polymorphisms nearby or within the APOB gene on SSC3 for serum LDL-C and TC levels. Of the 9 polymorphisms, an indel showed the most significant association with LDL-C and TC in Laiwu pigs. But the significant association was not identified in the White Duroc × Erhualian F2 resource population, in which the QTL for LDL-C and TC was also detected on SSC3. This indicates that population-specific signals may exist for the SSC3 QTL. Further investigations are warranted to validate this assumption.

  2. Genome-Wide Association Analysis for Blood Lipid Traits Measured in Three Pig Populations Reveals a Substantial Level of Genetic Heterogeneity.

    Science.gov (United States)

    Yang, Hui; Huang, Xiaochang; Zeng, Zhijun; Zhang, Wanchang; Liu, Chenlong; Fang, Shaoming; Huang, Lusheng; Chen, Congying

    2015-01-01

    Serum lipids are associated with myocardial infarction and cardiovascular disease in humans. Here we dissected the genetic architecture of blood lipid traits by applying genome-wide association studies (GWAS) in 1,256 pigs from Laiwu, Erhualian and Duroc × (Landrace × Yorkshire) populations, and a meta-analysis of GWAS in more than 2,400 pigs from five diverse populations. A total of 22 genomic loci surpassing the suggestive significance level were detected on 11 pig chromosomes (SSC) for six blood lipid traits. Meta-analysis of GWAS identified 5 novel loci associated with blood lipid traits. Comparison of GWAS loci across the tested populations revealed a substantial level of genetic heterogeneity for porcine blood lipid levels. We further evaluated the causality of nine polymorphisms nearby or within the APOB gene on SSC3 for serum LDL-C and TC levels. Of the 9 polymorphisms, an indel showed the most significant association with LDL-C and TC in Laiwu pigs. But the significant association was not identified in the White Duroc × Erhualian F2 resource population, in which the QTL for LDL-C and TC was also detected on SSC3. This indicates that population-specific signals may exist for the SSC3 QTL. Further investigations are warranted to validate this assumption.

  3. Combining microarrays and genetic analysis

    NARCIS (Netherlands)

    Alberts, Rudi; Fu, Jingyuan; Swertz, Morris A.; Lubbers, L. Alrik; Albers, Casper J.; Jansen, Ritsert C.

    2005-01-01

    Gene expression can be studied at a genome-wide scale with the aid of modern microarray technologies. Expression profiling of tens to hundreds of individuals in a genetic population can reveal the consequences of genetic variation. In this paper it is argued that the design and analysis of such a

  4. Combining microarrays and genetic analysis

    NARCIS (Netherlands)

    Alberts, Rudi; Fu, Jingyuan; Swertz, Morris A.; Lubbers, L. Alrik; Albers, Casper J.; Jansen, Ritsert C.

    2005-01-01

    Gene expression can be studied at a genome-wide scale with the aid of modern microarray technologies. Expression profiling of tens to hundreds of individuals in a genetic population can reveal the consequences of genetic variation. In this paper it is argued that the design and analysis of such a st

  5. Genetic Association Between Androgen Receptor Gene CAG Repeat Length Polymorphism and Male Infertility: A Meta-Analysis.

    Science.gov (United States)

    Pan, Bihui; Li, Rui; Chen, Yao; Tang, Qiuqin; Wu, Wei; Chen, Liping; Lu, Chuncheng; Pan, Feng; Ding, Hongjuan; Xia, Yankai; Hu, Lingqing; Chen, Daozhen; Sha, Jiahao; Wang, Xinru

    2016-03-01

    The association between polymorphism of androgen receptor gene CAG (AR-CAG) and male infertility in several studies was controversial. Based on studies on association between AR-CAG repeat length and male infertility in recent years, an updated meta-analysis is needed. We aimed to evaluate the association between AR-CAG repeat length and male infertility in advantage of the data in all published reports.We searched for reports published before August 2015 using PubMed, CNKI, VIP, and WanFang. Data on sample size, mean, and standard deviation (SD) of AR-CAG repeat length were extracted independently by 3 investigators.Forty-four reports were selected based on criteria. The overall infertile patients and azoospermic patients were found to have longer AR-CAG repeat length (standard mean difference (SMD) = 0.19, 95% confidence interval (CI): 0.10-0.28, P CAG repeat length was longer in infertile men in Asian, Caucasian, and mixed races (SMD = 0.25, 95% CI: 0.08-0.43, P CAG repeat length was associated with male infertility. The subgroup study on races shows that increased AR-CAG repeat length was associated with male infertility in Asian, Caucasian, and mixed races. Increased AR-CAG repeat length was also associated with azoospermia.This meta-analysis supports that increased androgen receptor CAG length is capable of causing male infertility susceptibility.

  6. Genetic Characterization by RAPD Analysis of Isolates of Fusarium oxysporum f. sp. erythroxyli Associated with an Emerging Epidemic in Peru.

    Science.gov (United States)

    Nelson, A J; Elias, K S; Arévalo G, E; Darlington, L C; Bailey, B A

    1997-12-01

    ABSTRACT An epidemic of vascular wilt caused by Fusarium oxysporum f. sp. erythroxyli is currently occurring on Erythroxylum coca var. coca in the coca-growing regions of the Huallaga Valley in Peru. Random amplified polymorphic DNA (RAPD) analysis of isolates of the pathogen was undertaken to elucidate its genetic complexity, as well as to identify a specific DNA fingerprint for the pathogen. Two hundred isolates of Fusarium were collected from 10 coca-growing regions in Peru. Of these, 187 were confirmed to be F. oxysporum, and 143 of the F. oxysporum were shown to be pathogens of coca by a root-dip pathogenicity test. The pathogens could be grouped into two subpopulations based on RAPD analysis, and no polymorphism in RAPD pattern was observed among isolates of either subpopulation. Both subpopulations were present in the central Huallaga Valley, where earliest reports of the epidemic occurred. RAPD analysis could easily distinguish the isolates of F. oxysporum f. sp. erythroxyli from the nonpathogenic isolates of F. oxysporum from E. coca var. coca, indicating its utility in DNA fingerprinting.

  7. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies

    Science.gov (United States)

    Traylor, Matthew; Farrall, Martin; Holliday, Elizabeth G; Sudlow, Cathie; Hopewell, Jemma C; Cheng, Yu-Ching; Fornage, Myriam; Ikram, M Arfan; Malik, Rainer; Bevan, Steve; Thorsteinsdottir, Unnur; Nalls, Mike A; Longstreth, WT; Wiggins, Kerri L; Yadav, Sunaina; Parati, Eugenio A; DeStefano, Anita L; Worrall, Bradford B; Kittner, Steven J; Khan, Muhammad Saleem; Reiner, Alex P; Helgadottir, Anna; Achterberg, Sefanja; Fernandez-Cadenas, Israel; Abboud, Sherine; Schmidt, Reinhold; Walters, Matthew; Chen, Wei-Min; Ringelstein, E Bernd; O'Donnell, Martin; Ho, Weang Kee; Pera, Joanna; Lemmens, Robin; Norrving, Bo; Higgins, Peter; Benn, Marianne; Sale, Michele; Kuhlenbäumer, Gregor; Doney, Alexander S F; Vicente, Astrid M; Delavaran, Hossein; Algra, Ale; Davies, Gail; Oliveira, Sofia A; Palmer, Colin N A; Deary, Ian; Schmidt, Helena; Pandolfo, Massimo; Montaner, Joan; Carty, Cara; de Bakker, Paul I W; Kostulas, Konstantinos; Ferro, Jose M; van Zuydam, Natalie R; Valdimarsson, Einar; Nordestgaard, Børge G; Lindgren, Arne; Thijs, Vincent; Slowik, Agnieszka; Saleheen, Danish; Paré, Guillaume; Berger, Klaus; Thorleifsson, Gudmar; Hofman, Albert; Mosley, Thomas H; Mitchell, Braxton D; Furie, Karen; Clarke, Robert; Levi, Christopher; Seshadri, Sudha; Gschwendtner, Andreas; Boncoraglio, Giorgio B; Sharma, Pankaj; Bis, Joshua C; Gretarsdottir, Solveig; Psaty, Bruce M; Rothwell, Peter M; Rosand, Jonathan; Meschia, James F; Stefansson, Kari; Dichgans, Martin; Markus, Hugh S

    2012-01-01

    Summary Background Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes. Methods We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls. Findings We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10−16) and ZFHX3 (p=2·28×10−8), and for large-vessel stroke at a 9p21 locus (p=3·32×10−5) and HDAC9 (p=2·03×10−12). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at pgenetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes. Funding Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH

  8. Genetic association and gene expression analysis identify FGFR1 as a new susceptibility gene for human obesity.

    Science.gov (United States)

    Jiao, Hong; Arner, Peter; Dickson, Suzanne L; Vidal, Hubert; Mejhert, Niklas; Henegar, Corneliu; Taube, Magdalena; Hansson, Caroline; Hinney, Anke; Galan, Pilar; Simon, Chantal; Silveira, Angela; Benrick, Anna; Jansson, John-Olov; Bouloumié, Anne; Langin, Dominique; Laville, Martine; Debard, Cyrille; Axelsson, Tomas; Rydén, Mikael; Kere, Juha; Dahlman-Wright, Karin; Hamsten, Anders; Clement, Karine; Dahlman, Ingrid

    2011-06-01

    Previous studies suggest a role for fibroblast growth factor receptor 1 (FGFR1) in the regulation of energy balance. Our objective was to investigate whether FGFR1 is an obesity gene by genetic association and functional studies. The study was designed to genotype common FGFR1 single-nucleotide polymorphisms (SNP) in large cohorts, confirm significant results in additional cohorts, and measure FGFR1 expression in human adipose tissue and in rodent hypothalamus. General community and referral centers for specialized care was the setting for the study. We genotyped FGFR1 SNP in 2438 obese and 2115 lean adults and 985 obese and 532 population-based children. Results were confirmed in 928 obese and 2738 population-based adults and 487 obese and 441 lean children. Abdominal sc adipose tissue was investigated in 202 subjects. We also investigated diet-induced, obese fasting, and fed rats. We analyzed the association between FGFR1 SNP and obesity. In secondary analyses, we related adipose FGFR1 expression to genotype, obesity, and degree of fat cell differentiation and related hypothalamic FGFR1 to energy balance. FGFR1 rs7012413*T was nominally associated with obesity in all four cohorts; metaanalysis odds ratio = 1.17 (95% confidence interval = 1.10-1.25), and P = 1.8 × 10(-6), which was P = 7.0 × 10(-8) in the recessive model. rs7012413*T was associated with FGFR1 expression in adipose tissue (P obesity. In rats, hypothalamic expression of FGFR1 declined after fasting (P obesity (P obesity gene that may promote obesity by influencing adipose tissue and the hypothalamic control of appetite.

  9. Synopsis and meta-analysis of genetic association studies in osteoporosis for the focal adhesion family genes: the CUMAGAS-OSTEOporosis information system

    Directory of Open Access Journals (Sweden)

    Kastanis Alkibiadis

    2011-01-01

    Full Text Available Abstract Background Focal adhesion (FA family genes have been studied as candidate genes for osteoporosis, but the results of genetic association studies (GASs are controversial. To clarify these data, a systematic assessment of GASs for FA genes in osteoporosis was conducted. Methods We developed Cumulative Meta-Analysis of GAS-OSTEOporosis (CUMAGAS-OSTEOporosis, a web-based information system that allows the retrieval, analysis and meta-analysis (for allele contrast, recessive, dominant, additive and codominant models of data from GASs on osteoporosis with the capability of update. GASs were identified by searching the PubMed and HuGE PubLit databases. Results Data from 72 studies involving 13 variants of 6 genes were analyzed and catalogued in CUMAGAS-OSTEOporosis. Twenty-two studies produced significant associations with osteoporosis risk under any genetic model. All studies were underpowered (1 (COL1A1 G2046T (all genetic models, COL1A1 G-1997T (allele contrast and dominant model and integrin β-chain β3 (ITGB3 T176C (recessive and additive models. In COL1A1 G2046T, subgroup analysis has shown significant associations for Caucasians, adults, females, males and postmenopausal women. A differential magnitude of effect in large versus small studies (that is, indication of publication bias was detected for the variant COL1A1 G2046T. Conclusion There is evidence of an implication of FA family genes in osteoporosis. CUMAGAS-OSTEOporosis could be a useful tool for current genomic epidemiology research in the field of osteoporosis.

  10. Common genetic variation near the phospholamban gene is associated with cardiac repolarisation : Meta-analysis of three genome-wide association studies

    NARCIS (Netherlands)

    I.M. Nolte (Ilja); C. Wallace (Chris); S.J. Newhouse (Stephen); D. Waggott (Daryl); J. Fu (Jingyuan); N. Soranzo (Nicole); R. Gwilliam (Rhian); S. Demissie (Serkalem); I. Savelieva (Irina); D. Zheng (Dongling); C. Dalageorgou (Chrysoula); M. Farrall (Martin); N.J. Samani (Nilesh); J. Connell (John); M.J. Brown (Morris); A. Dominiczak (Anna); M. Lathrop (Mark); E. Zeggini (Eleftheria); L.V. Wain (Louise); C. Newton-Cheh (Christopher); M. Eijgelsheim (Mark); K. Rice (Kenneth); P.I.W. de Bakker (Paul); A. Pfeufer (Arne); S. Sanna (Serena); D.E. Arking (Dan); F.W. Asselbergs (Folkert); T.D. Spector (Tim); N.D. Carter (Nicholas); S. Jeffery (Steve); M. Tobin (Martin); M. Caulfield (Mark); H. Snieder (Harold); A.D. Paterson (Andrew); P. Munroe (Patricia); Y. Jamshidi (Yalda)

    2009-01-01

    textabstractTo identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the Tw

  11. Common Genetic Variation Near the Phospholamban Gene Is Associated with Cardiac Repolarisation : Meta-Analysis of Three Genome-Wide Association Studies

    NARCIS (Netherlands)

    Nolte, Ilja M.; Wallace, Chris; Newhouse, Stephen J.; Waggott, Daryl; Fu, Jingyuan; Soranzo, Nicole; Gwilliam, Rhian; Deloukas, Panos; Savelieva, Irina; Zheng, Dongling; Dalageorgou, Chrysoula; Farrall, Martin; Samani, Nilesh J.; Connell, John; Brown, Morris; Dominiczak, Anna; Lathrop, Mark; Zeggini, Eleftheria; Wain, Louise V.; Newton-Cheh, Christopher; Eijgelsheim, Mark; Rice, Kenneth; de Bakker, Paul I. W.; Pfeufer, Arne; Sanna, Serena; Arking, Dan E.; Asselbergs, Folkert W.; Spector, Tim D.; Carter, Nicholas D.; Jeffery, Steve; Tobin, Martin; Caulfield, Mark; Snieder, Harold; Paterson, Andrew D.; Munroe, Patricia B.; Jamshidi, Yalda

    2009-01-01

    To identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the TwinsUK and BR

  12. Common genetic variation near the phospholamban gene is associated with cardiac repolarisation : Meta-analysis of three genome-wide association studies

    NARCIS (Netherlands)

    I.M. Nolte (Ilja); C. Wallace (Chris); S.J. Newhouse (Stephen); D. Waggott (Daryl); J. Fu (Jingyuan); N. Soranzo (Nicole); R. Gwilliam (Rhian); S. Demissie (Serkalem); I. Savelieva (Irina); D. Zheng (Dongling); C. Dalageorgou (Chrysoula); M. Farrall (Martin); N.J. Samani (Nilesh); J. Connell (John); M.J. Brown (Morris); A. Dominiczak (Anna); M. Lathrop (Mark); E. Zeggini (Eleftheria); L.V. Wain (Louise); C. Newton-Cheh (Christopher); M. Eijgelsheim (Mark); K. Rice (Kenneth); P.I.W. de Bakker (Paul); A. Pfeufer (Arne); S. Sanna (Serena); D.E. Arking (Dan); F.W. Asselbergs (Folkert); T.D. Spector (Tim); N.D. Carter (Nicholas); S. Jeffery (Steve); M. Tobin (Martin); M. Caulfield (Mark); H. Snieder (Harold); A.D. Paterson (Andrew); P. Munroe (Patricia); Y. Jamshidi (Yalda)

    2009-01-01

    textabstractTo identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the

  13. Common Genetic Variation Near the Phospholamban Gene Is Associated with Cardiac Repolarisation : Meta-Analysis of Three Genome-Wide Association Studies

    NARCIS (Netherlands)

    Nolte, Ilja M.; Wallace, Chris; Newhouse, Stephen J.; Waggott, Daryl; Fu, Jingyuan; Soranzo, Nicole; Gwilliam, Rhian; Deloukas, Panos; Savelieva, Irina; Zheng, Dongling; Dalageorgou, Chrysoula; Farrall, Martin; Samani, Nilesh J.; Connell, John; Brown, Morris; Dominiczak, Anna; Lathrop, Mark; Zeggini, Eleftheria; Wain, Louise V.; Newton-Cheh, Christopher; Eijgelsheim, Mark; Rice, Kenneth; de Bakker, Paul I. W.; Pfeufer, Arne; Sanna, Serena; Arking, Dan E.; Asselbergs, Folkert W.; Spector, Tim D.; Carter, Nicholas D.; Jeffery, Steve; Tobin, Martin; Caulfield, Mark; Snieder, Harold; Paterson, Andrew D.; Munroe, Patricia B.; Jamshidi, Yalda

    2009-01-01

    To identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the TwinsUK and

  14. Multilocus analysis indicates that Trypanosoma cruzi I genetic substructure associated with sylvatic and domestic cycles is not an attribute conserved throughout Colombia.

    Science.gov (United States)

    Gómez-Palacio, Andrés; Lopera, Juan; Rojas, Winston; Bedoya, Gabriel; Cantillo-Barraza, Omar; Marín-Suarez, Johana; Triana-Chávez, Omar; Mejía-Jaramillo, Ana

    2016-03-01

    Trypanosoma cruzi, the causative agent of Chagas disease, has been classified into six discrete typing units (DTUs) named TcI to TcVI. Furthermore, subcontinental scale studies based on analysis of the splice leader intergenic region (SL-IR) of the mini-exon gene have subdivided TcI in five genetic groups (Ia-Ie) related to the domestic and non-domestic cycles. However, a current review of this marker among all the sequences deposited in the GenBank demonstrates no correlation between the genetic structure and the eco-epidemiological features of parasite transmission. In this study, we performed a multilocus analysis of TcI isolates from a diverse array of hosts and vectors in a wide eco-geographical area of Colombia. Sequences from SL-IR and mitochondrial cyt b genes as well as PCR-RFLP profiles for four nuclear genes were analyzed. Multilocus analysis indicates that genetic structuration associated with sylvatic and domestic cycles in Colombia is not an attribute conserved across the entire eco-geography where TcI can be found.

  15. Genetic association between the cyclin-dependent kinase inhibitor gene p27/Kip1 polymorphism (rs34330) and cancer susceptibility: a meta-analysis

    Science.gov (United States)

    Cheng, Xiao-Ke; Wang, Xue-Jun; Li, Xiao-Dong; Ren, Xue-Qun

    2017-01-01

    The p27 rs34330 (-79C/T) polymorphism has been widely studied for human cancer susceptibility. The current findings, however, still remained controversial. Therefore, we performed the meta-analysis to provide a more accurate result. Eligible studies were identified from PubMed database up to June 2015. The association of p27 rs34330 polymorphism and cancer susceptibility was estimated with odds ratios and corresponding 95% confidence intervals. The meta-analysis was performed with Stata 12. A total of ten studies with 11,214 cases and more than 8,776 controls were included in the meta-analysis (including breast, lung, thyroid, endometrial, and hepatocellular cancer). In pooled analysis, p27 gene rs34330 polymorphism significantly increased the cancer susceptibility. Subgroup analysis indicated that the elevated risk was observed under all the genetic models for Asians and under three genetic models for Caucasians. Results of sensitivity analysis were similar to the overall results. The results suggested that the p27 rs34330 polymorphism increased the cancer susceptibility, especially in Asians. Further well-designed and large sample size studies are warranted to verify the conclusion. PMID:28317869

  16. GACT: a Genome build and Allele definition Conversion Tool for SNP imputation and meta-analysis in genetic association studies.

    Science.gov (United States)

    Sulovari, Arvis; Li, Dawei

    2014-07-19

    Genome-wide association studies (GWAS) have successfully identified genes associated with complex human diseases. Although much of the heritability remains unexplained, combining single nucleotide polymorphism (SNP) genotypes from multiple studies for meta-analysis will increase the statistical power to identify new disease-associated variants. Meta-analysis requires same allele definition (nomenclature) and genome build among individual studies. Similarly, imputation, commonly-used prior to meta-analysis, requires the same consistency. However, the genotypes from various GWAS are generated using different genotyping platforms, arrays or SNP-calling approaches, resulting in use of different genome builds and allele definitions. Incorrect assumptions of identical allele definition among combined GWAS lead to a large portion of discarded genotypes or incorrect association findings. There is no published tool that predicts and converts among all major allele definitions. In this study, we have developed a tool, GACT, which stands for Genome build and Allele definition Conversion Tool, that predicts and inter-converts between any of the common SNP allele definitions and between the major genome builds. In addition, we assessed several factors that may affect imputation quality, and our results indicated that inclusion of singletons in the reference had detrimental effects while ambiguous SNPs had no measurable effect. Unexpectedly, exclusion of genotypes with missing rate > 0.001 (40% of study SNPs) showed no significant decrease of imputation quality (even significantly higher when compared to the imputation with singletons in the reference), especially for rare SNPs. GACT is a new, powerful, and user-friendly tool with both command-line and interactive online versions that can accurately predict, and convert between any of the common allele definitions and between genome builds for genome-wide meta-analysis and imputation of genotypes from SNP-arrays or deep

  17. Genetic Diversity and Association Analysis for Salinity Tolerance,Heading Date and Plant Height of Barley Germplasm Using Simple Sequence Repeat Markers

    Institute of Scientific and Technical Information of China (English)

    Lilia Eleuch; Abderrazek Jilal; Stefania Grando; Salvatore Ceccarelli; Maria von Korff Schmising; Hisashi Tsujimoto; Amara Hajer; Abderrazek Daaloul; Michael Baum

    2008-01-01

    The objective of this study was to investigate the genetic diversity of barley accessions.Additionally,association trait analysis was conducted for grain yield under salinity,heading date and plant height.For this purpose,48 barley genotypes were analyzed with 22 microsatellite simple sequence repeat (SSR) markers.Four of the 22 markers (Bmac316,scssr03907,HVM67 and Bmag770) were able to differentiate all barley genotypes.Cluster and principal coordinate analysis allowed a clear grouping between countries from the same region.The genotypes used in this study have been evaluated for agronomic performance in different environments.Conducting association analysis for grain yield under salinity conditions using TASSEL software revealed a close association of the marker Bmag749 (2H,bin 13) in two different environments with common significant alleles (175,177),whereas the HVHOTR1 marker (2H,bin 3) was only significant in Sakhar_Egypt with alleles size being 158 and 161.Heading date also showed an association with scssr03907 through the common significant specific allele 111 and EBmacO415 markers in three different agro climatic locations,whereas HVCMA,scssr00103 and HVM67 were linked to heading date in the Egyptian environment only.The plant height association analysis revealed significant markers Bmag770 via the significant allele 152 and scssr09398.

  18. Genetic polymorphisms of the main transcription factors for adiponectin gene promoter in regulation of adiponectin levels: association analysis in three European cohorts.

    Directory of Open Access Journals (Sweden)

    Lyudmyla Kedenko

    Full Text Available Adiponectin serum concentrations are an important biomarker in cardiovascular epidemiology with heritability etimates of 30-70%. However, known genetic variants in the adiponectin gene locus (ADIPOQ account for only 2%-8% of its variance. As transcription factors are thought to play an under-acknowledged role in carrying functional variants, we hypothesized that genetic polymorphisms in genes coding for the main transcription factors for the ADIPOQ promoter influence adiponectin levels. Single nucleotide polymorphisms (SNPs at these genes were selected based on the haplotype block structure and previously published evidence to be associated with adiponectin levels. We performed association analyses of the 24 selected SNPs at forkhead box O1 (FOXO1, sterol-regulatory-element-binding transcription factor 1 (SREBF1, sirtuin 1 (SIRT1, peroxisome-proliferator-activated receptor gamma (PPARG and transcription factor activating enhancer binding protein 2 beta (TFAP2B gene loci with adiponectin levels in three different European cohorts: SAPHIR (n = 1742, KORA F3 (n = 1636 and CoLaus (n = 5355. In each study population, the association of SNPs with adiponectin levels on log-scale was tested using linear regression adjusted for age, sex and body mass index, applying both an additive and a recessive genetic model. A pooled effect size was obtained by meta-analysis assuming a fixed effects model. We applied a significance threshold of 0.0033 accounting for the multiple testing situation. A significant association was only found for variants within SREBF1 applying an additive genetic model (smallest p-value for rs1889018 on log(adiponectin = 0.002, β on original scale = -0.217 µg/ml, explaining ~0.4% of variation of adiponectin levels. Recessive genetic models or haplotype analyses of the FOXO1, SREBF1, SIRT1, TFAPB2B genes or sex-stratified analyses did not reveal additional information on the regulation of adiponectin levels. The role of genetic

  19. Genetic Polymorphisms of the Main Transcription Factors for Adiponectin Gene Promoter in Regulation of Adiponectin Levels: Association Analysis in Three European Cohorts

    Science.gov (United States)

    Kiesslich, Tobias; Kapur, Karen; Bergmann, Sven; Waterworth, Dawn; Heid, Iris M.; Wichmann, H.-Erich; Kedenko, Igor; Kronenberg, Florian; Paulweber, Bernhard

    2012-01-01

    Adiponectin serum concentrations are an important biomarker in cardiovascular epidemiology with heritability etimates of 30–70%. However, known genetic variants in the adiponectin gene locus (ADIPOQ) account for only 2%–8% of its variance. As transcription factors are thought to play an under-acknowledged role in carrying functional variants, we hypothesized that genetic polymorphisms in genes coding for the main transcription factors for the ADIPOQ promoter influence adiponectin levels. Single nucleotide polymorphisms (SNPs) at these genes were selected based on the haplotype block structure and previously published evidence to be associated with adiponectin levels. We performed association analyses of the 24 selected SNPs at forkhead box O1 (FOXO1), sterol-regulatory-element-binding transcription factor 1 (SREBF1), sirtuin 1 (SIRT1), peroxisome-proliferator-activated receptor gamma (PPARG) and transcription factor activating enhancer binding protein 2 beta (TFAP2B) gene loci with adiponectin levels in three different European cohorts: SAPHIR (n = 1742), KORA F3 (n = 1636) and CoLaus (n = 5355). In each study population, the association of SNPs with adiponectin levels on log-scale was tested using linear regression adjusted for age, sex and body mass index, applying both an additive and a recessive genetic model. A pooled effect size was obtained by meta-analysis assuming a fixed effects model. We applied a significance threshold of 0.0033 accounting for the multiple testing situation. A significant association was only found for variants within SREBF1 applying an additive genetic model (smallest p-value for rs1889018 on log(adiponectin) = 0.002, β on original scale = −0.217 µg/ml), explaining ∼0.4% of variation of adiponectin levels. Recessive genetic models or haplotype analyses of the FOXO1, SREBF1, SIRT1, TFAPB2B genes or sex-stratified analyses did not reveal additional information on the regulation of adiponectin levels. The

  20. Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium.

    Directory of Open Access Journals (Sweden)

    Rozenn N Lemaitre

    2011-07-01

    Full Text Available Long-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 association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases were associated with higher levels of ALA (p = 3 x 10⁻⁶⁴ and lower levels of eicosapentaenoic acid (EPA, p = 5 x 10⁻⁵⁸ and docosapentaenoic acid (DPA, p = 4 x 10⁻¹⁵⁴. Minor alleles of SNPs in ELOVL2 (elongase were associated with higher EPA (p = 2 x 10⁻¹² and DPA (p = 1 x 10⁻⁴³ and lower docosahexaenoic acid (DHA, p = 1 x 10⁻¹⁵. In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1 x 10⁻⁸. We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535, suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.

  1. Genetic Association of CHAT rs3810950 and rs2177369 Polymorphisms with the Risk of Alzheimer’s Disease: A Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Yong Liu

    2016-01-01

    Full Text Available Choline acetyltransferase (CHAT rs3810950 and rs2177369 polymorphisms have been implicated in susceptibility to Alzheimer’s disease (AD. Due to the inconsistent results from previous studies, a meta-analysis was performed to estimate the association between these polymorphisms and AD risk more precisely. Pooled results of our meta-analysis indicated CHAT rs2177369 polymorphism was correlated with decreasing AD risk in one of five genetic models (dominant: OR = 0.77, 95% CI: 0.62–0.96, while rs3810950 mutant was associated with AD development in three models (allelic: OR = 1.18, 95% CI: 1.01–1.37, homozygous: OR = 1.63, 95% CI: 1.09–2.42, and recessive: OR = 1.65, 95% CI: 1.20–2.26. In subgroup analysis by ethnicity, the association between CHAT rs3810950 polymorphism and AD risk was just found in the recessive model (OR = 1.47, 95% CI: 1.05–2.07 among Caucasians, while four genetic models (allelic: OR = 1.23, 95% CI: 1.01–1.48; homozygous: OR = 2.24, 95% CI: 1.48–3.39; dominant: OR = 1.21, 95% CI: 1.06–1.40; and recessive: OR = 2.18, 95% CI: 1.45–3.29 assumed this association in Asians. In conclusion, our meta-analysis indicated CHAT rs2177369 polymorphism might play a protective role in AD, while rs3810950 variant was a risk factor for AD but its single heterozygous mutations might not influence susceptibility to AD.

  2. Association of SSR markers with contents of fatty acids in olive oil and genetic diversity analysis of an olive core collection.

    Science.gov (United States)

    Ipek, M; Ipek, A; Seker, M; Gul, M K

    2015-03-27

    The purpose of this research was to characterize an olive core collection using some agronomic characters and simple sequence repeat (SSR) markers and to determine SSR markers associated with the content of fatty acids in olive oil. SSR marker analysis demonstrated the presence of a high amount of genetic variation between the olive cultivars analyzed. A UPGMA dendrogram demonstrated that olive cultivars did not cluster on the basis of their geographic origin. Fatty acid components of olive oil in these cultivars were determined. The results also showed that there was a great amount of variation between the olive cultivars in terms of fatty acid composition. For example, oleic acid content ranged from 57.76 to 76.9% with standard deviation of 5.10%. Significant correlations between fatty acids of olive oil were observed. For instance, a very high negative correlation (-0.812) between oleic and linoleic acids was detected. A structured association analysis between the content of fatty acids in olive oil and SSR markers was performed. STRUCTURE analysis assigned olive cultivars to two gene pools (K = 2). Assignment of olive cultivars to these gene pools was not based on geographical origin. Association between fatty acid traits and SSR markers was evaluated using the general linear model of TASSEL. Significant associations were determined between five SSR markers and stearic, oleic, linoleic, and linolenic acids of olive oil. Very high associations (P olive.

  3. Association between Prostinogen (KLK15 genetic variants and prostate cancer risk and aggressiveness in Australia and a meta-analysis of GWAS data.

    Directory of Open Access Journals (Sweden)

    Jyotsna Batra

    Full Text Available BACKGROUND: Kallikrein 15 (KLK15/Prostinogen is a plausible candidate for prostate cancer susceptibility. Elevated KLK15 expression has been reported in prostate cancer and it has been described as an unfavorable prognostic marker for the disease. OBJECTIVES: We performed a comprehensive analysis of association of variants in the KLK15 gene with prostate cancer risk and aggressiveness by genotyping tagSNPs, as well as putative functional SNPs identified by extensive bioinformatics analysis. METHODS AND DATA SOURCES: Twelve out of 22 SNPs, selected on the basis of linkage disequilibrium pattern, were analyzed in an Australian sample of 1,011 histologically verified prostate cancer cases and 1,405 ethnically matched controls. Replication was sought from two existing genome wide association studies (GWAS: the Cancer Genetic Markers of Susceptibility (CGEMS project and a UK GWAS study. RESULTS: Two KLK15 SNPs, rs2659053 and rs3745522, showed evidence of association (p<0.05 but were not present on the GWAS platforms. KLK15 SNP rs2659056 was found to be associated with prostate cancer aggressiveness and showed evidence of association in a replication cohort of 5,051 patients from the UK, Australia, and the CGEMS dataset of US samples. A highly significant association with Gleason score was observed when the data was combined from these three studies with an Odds Ratio (OR of 0.85 (95% CI = 0.77-0.93; p = 2.7×10(-4. The rs2659056 SNP is predicted to alter binding of the RORalpha transcription factor, which has a role in the control of cell growth and differentiation and has been suggested to control the metastatic behavior of prostate cancer cells. CONCLUSIONS: Our findings suggest a role for KLK15 genetic variation in the etiology of prostate cancer among men of European ancestry, although further studies in very large sample sets are necessary to confirm effect sizes.

  4. Association of GST genetic polymorphisms with the susceptibility to hepatocellular carcinoma (HCC in Chinese population evaluated by an updated systematic meta-analysis.

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    Kui Liu

    Full Text Available BACKGROUND: Due to the possible involvement of Glutathione S-transferase Mu-1 (GSTM1 and Glutathione S-transferase theta-1 (GSTT1 in the detoxification of environmental carcinogens, environmental toxins, and oxidative stress products, genetic polymorphisms of these two genes may play important roles in the susceptibility of human being to hepatocellular carcinoma. However, the existing research results are not conclusive. METHODS: A systematic literature search using databases (PubMed, Scopus, Embase, Chinese Biomedical Database, Chinese National Knowledge Infrastructure, Wanfang Data, etc. for the eligible studies meeting the inclusion criteria including case-control studies or cohort studies is evaluated using an updated systematic meta-analysis. RESULTS: Significant increase in the risk of HCC in the Chinese population is found in GSTM1 null genotype (OR = 1.47, 95% CI: 1.21 to 1.79, P<0.001 and GSTT1 null genotype (OR = 1.38, 95% CI: 1.14 to 1.65, P<0.001. Analysis using the random-effects model found an increased risk of HCC in GSTM1-GSTT1 dual null population (OR = 1.79, 95% CI: 1.26 to 2.53, P<0.001. In addition, subgroup analyses showed a significant increase in the association of GST genetic polymorphisms (GSTM1, GSTT1, and GSTM1-GSTT1 with HCC in southeast and central China mainland. However, available data collected by this study fail to show an association between GST genetic polymorphisms and HCC in people from the Taiwan region (for GSTM1: OR = 0.78, 95% CI: 0.60 to 1.01, P = 0.06; for GSTT1: OR = 0.94, 95% CI: 0.78 to 1.14, P = 0.546; for GSTM1-GSTT1: OR = 1.04, 95% CI: 0.81 to 1.32, P = 0.77. Sensitivity analysis and publication bias diagnostics confirmed the reliability and stability of this meta-analysis. CONCLUSIONS: Our results indicate that both GSTM1 and GSTT1 null genotypes are associated with an increased HCC risk in Chinese population. Peoples with dual null genotypes of GSTM1-GSTT1

  5. Human parainfluenza virus-associated respiratory tract infection among children and genetic analysis of HPIV-3 strains in Beijing, China.

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    Naiying Mao

    Full Text Available The relevance of human parainfluenza viruses (HPIVs to the epidemiology of acute respiratory infections (ARI in China is unclear. From May 2008 to September 2010, 443 nasopharyngeal aspirates (NPAs from hospitalized pediatric patients (age from 1 to 93 months in Beijing were collected and screened for HPIVs and other common respiratory viruses by real-time RT-PCR. Sixty-two of 443 samples were positive for HPIVs with 4 positive for HPIV-2 and 58 positive for HPIV-3, indicating that HPIV-3 was the predominant virus present during the study period. A phylogenetic tree based on all the available HN (hemagglutinin-neuraminidase sequences of HPIV-3 indicated that three distinct clusters (A,B, and C were circulating with some temporal and regional clustering. Cluster C was further divided into sub-clusters, C1, C2, C3 and C4. HPIV-3 from Beijing isolates belonged to sub-cluster C3, and were grouped with the isolates from two Provinces of China and the neighboring country of Japan. Genetic analysis based on entire HN gene revealed that the HPIV-3 isolates from Beijing were highly similar with 97.2%-100% identity at the nucleotide level and these could be divided into two closely related lineages, C3a and C3b. These findings suggested that there was co-circulation of multiple lineages of HPIV-3 in the Beijing region during the study period. This is the first study to describe the epidemiology and molecular characterization of HPIVs in China.

  6. Association between Genetic Polymorphisms in Interleukin Genes and Recurrent Pregnancy Loss - A Systematic Review and Meta-Analysis.

    Science.gov (United States)

    Zhang, Meixiang; Xu, Jiawei; Bao, Xiao; Niu, Wenbin; Wang, Linlin; Du, Linqing; Zhang, Nan; Sun, Yingpu

    2017-01-01

    Interleukins are a group of immunomodulatory proteins that mediate a variety of immune reactions in the human body. To investigate the association between interleukin gene polymorphisms and recurrent pregnancy loss (RPL), we reviewed 21 studies from MEDLINE, EMBASE, OVID SP and PubMed to evaluate RPL-related interleukin gene polymorphisms. Meta-analysis was performed on 12 of the polymorphisms, and a review included the others. Our integrated results indicated that IL-1β (-511C/T) (P = 0.02, 95% CI 0.77[0.62,0.96]), IL-6 (-634C/G) (P<0.001, 95% CI 2.91[2.01,4.22]), IL-10 (-1082G/A, -819T/C) (P = 0.01, 95% CI 0.80[0.67,0.96]; P<0.01, 95% CI 0.66[0.49,0.89]), and IL-18 (-137G/C, -105G/A) (P<0.01, 95% CI 1.69[1.24,2.31]; P = <0.01, 95% CI 1.41[1.17,1.70]) consistently associated with RPL after meta-analysis. IL-17A rs2275913 and IL-17F rs763780, IL-21 rs2055979 and rs13143866, IL-1β (-31C/T), IL-6 (-2954G/C), and IL-10 (-536A/G) were reported only once as having a significant association with RPL. The potential mechanism underlying miscarriage and these polymorphisms and future research directions are also discussed.

  7. Low mannose-binding lectin (MBL) levels and MBL genetic polymorphisms associated with the risk of neonatal sepsis: An updated meta-analysis.

    Science.gov (United States)

    Luo, Jun; Xu, Fen; Lu, Guang-Jin; Lin, Hung-Chih; Feng, Zhi-Chun

    2014-10-01

    Relatively low serum mannose-binding lectin (MBL) levels and MBL genetic polymorphisms have been implicated as high risk factors for neonatal sepsis. However, different studies have reported conflicting findings and have generally been underpowered to exclude modest effect sizes. Standard methodology of systematic reviews and meta-analyses was followed. PubMed, Embase, Cochrane, Web of Science, and Scopus databases were searched from January 1996 to December 2013. The eligible studies were collected and analyzed using Review Manager 5.2. Meta-Disc version 1.4 was used to describe and calculate sensitivity, specificity, summary receiver operator characteristic (SROC) curves and area under the curve. SROC curve analysis was used to summarize the overall performance. Funnel plots, Egger's test and Begg's test were used to investigate publication bias. Seven studies addressing low MBL levels and MBL genetic polymorphisms (structure variant A/O, A/B of Exon1) were analyzed for susceptibility to neonatal sepsis, respectively. All of these control studies were of reasonable methodological quality. The pooled unadjusted odds ratio showed that low MBL levels were significantly associated with neonatal sepsis (P=0.0002; odds ratio=4.94, 95% confidence interval=2.16-11.29) and MBL genetic polymorphisms were also significantly associated with neonatal sepsis (P=0.03; odds ratio=1.41, 95% confidence interval=1.03-1.94). In subgroup analysis based on gestational age, increased risk was found in the preterm infants in the dominant model (RR 2.33, 95%CI 1.06-5.13, P=0.03). However, no association was observed for term infants in subgroup analysis. Additionally, the SROC curve of low MBL levels in the prediction of neonatal sepsis indicated a poor predictive ability. The area under curve was 0.80 (95% confidence interval=0.74-0.86). Currently available evidence shows that neonates with low serum MBL levels are more than four times more likely to have neonatal sepsis compared to

  8. GENETIC FACTORS ASSOCIATED WITH AMYOTROPHIC LATERAL SCLEROSIS

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    Katarina Vrabec

    2015-10-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a rare complex neurodegenerative disease characterized by degeneration of motor neurons in the cerebral cortex, brainstem and spinal cord. The disease mainly occurs in adults, typically between 50. and 60. years and presents with symptoms like muscular weakness, atrophy and later on paralysis which lead to death due to respiratory failure within 2-5 years from onset and remains incurable. The symptoms typically start in the muscles of arms or legs (spinal onset or bulbary (bulbar onset. Most ALS cases are sporadic although about 5% are familiar. Genetic factors contribute to the disease in sporadic form as well as in familial form. Mutations have been found in 116 genes among which SOD1, TARDBP, FUS and C9ORF72 are represented in highest frequencies. Besides those four genes we are also describing 13 other genes involved in the disease process. Oligogenic model has been proposed for ALS that considers mutations in two or more genes in one patient. We emphasize the convergence between hereditary and sporadic form, which are clinically inseparable, and other neurodegenerative diseases that share with ALS genetic and clinical characteristics. Because about 2/3 of familial cases and only about 11% of sporadic cases are explained by mutations the research have been aimed at discovering new candidate genes using  genome –wide association studies and at the epigenetic causes of the disease. We have recently completed the first representative genetic analysis of patients with ALS in Slovenia and research on methylation and microRNAs is currently in progress.

  9. Genetic variant in MTRR, but not MTR, is associated with risk of congenital heart disease: an integrated meta-analysis.

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    Bingxi Cai

    Full Text Available BACKGROUND: Congenital heart disease (CHD is one of the most common birth defects and the leading cause of deaths among individuals with congenital structural abnormalities worldwide. Both Methionine synthase reductase (MTRR and Methionine synthase (MTR are key enzymes involved in the metabolic pathway of homocysteine, which are significant in the earlier period embryogenesis, particularly in the cardiac development. Evidence is mounting for the association between MTRR A66G (rs1801394/MTR A2756G (rs1805087 and the CHD risk, but results are controversial. Therefore, we conducted a meta-analysis integrating case-control and transmitted disequilibrium test (TDT studies to obtain more precise estimate of the associations of these two variants with the CHD risk. METHODS: To combine case-control and TDT studies, we used the Catmap package of R software to calculate odds ratios (ORs and 95% confidence intervals (CIs. RESULTS: A total of 9 reports were included in the final meta-analysis. Eight of them comprised of 914 cases, 964 controls, and 441 families that were germane to MTRR A66G polymorphism; and 4 reports comprised of 250 cases, 205 controls, and 53 families that were relevant to MTR A2756G polymorphism. The pooled OR for the MTRR 66 G allele versus A allele was 1.35 (95% CI = 1.14-1.59, P<0.001, Pheterogeneity = 0.073. For MTR A2756G, the G allele conferred a pooled OR of 1.10 (95% CI = 0.78-1.57, P = 0.597, Pheterogeneity = 0.173 compared with the A allele. Sensitivity analyses were carried out to asses the effects of each individual study on the pooled OR, indicating the stability of the outcome. Moreover, positive results were also obtained in all subgroups stratified by study type and ethnicity except the subgroup of TDT studies in MTRR A66G variant. CONCLUSIONS: This meta-analysis demonstrated a suggestive result that the A66G variant in MTRR, but not the A2756G in MTR, may be associated with the increase of CHD risks.

  10. Analysis of genome-wide association studies of Alzheimer disease and of Parkinson disease to determine if these 2 diseases share a common genetic risk.

    Science.gov (United States)

    Moskvina, Valentina; Harold, Denise; Russo, GianCarlo; Vedernikov, Alexey; Sharma, Manu; Saad, Mohamed; Holmans, Peter; Bras, Jose M; Bettella, Francesco; Keller, Margaux F; Nicolaou, Nayia; Simón-Sánchez, Javier; Gibbs, J Raphael; Schulte, Claudia; Durr, Alexandra; Guerreiro, Rita; Hernandez, Dena; Brice, Alexis; Stefánsson, Hreinn; Majamaa, Kari; Gasser, Thomas; Heutink, Peter; Wood, Nick; Martinez, Maria; Singleton, Andrew B; Nalls, Michael A; Hardy, John; Owen, Michael J; O'Donovan, Michael C; Williams, Julie; Morris, Huw R; Williams, Nigel M

    2013-10-01

    Despite Alzheimer disease (AD) and Parkinson disease (PD) being clinically distinct entities, there is a possibility of a pathological overlap, with some genome-wide association (GWA) studies suggesting that the 2 diseases represent a biological continuum. The application of GWA studies to idiopathic forms of AD and PD have identified a number of loci that contain genetic variants that increase the risk of these disorders. To assess the genetic overlap between PD and AD by testing for the presence of potentially pleiotropic loci in 2 recent GWA studies of PD and AD. Combined GWA analysis. Data sets from the United Kingdom, Germany, France, and the United States. Thousands of patients with AD or PD and their controls. Meta-analysis of GWA studies of AD and PD. To identify evidence for potentially pleiotropic alleles that increased the risk for both PD and AD, we performed a combined PD-AD meta-analysis and compared the results with those obtained in the primary GWA studies.We also tested for a net effect of potentially polygenic alleles that were shared by both disorders by performing a polygenic score analysis. Finally, we also performed a gene-based association analysis that was aimed at detecting genes that harbor multiple disease-causing single-nucleotide polymorphisms, some of which confer a risk of PD and some a risk of AD. Detailed interrogation of the single-nucleotide polymorphism, polygenic, and gene-based analyses resulted in no significant evidence that supported the presence of loci that increase the risk of both PD and AD. Our findings therefore imply that loci that increase the risk of both PD and AD are not widespread and that the pathological overlap could instead be “downstream” of the primary susceptibility genes that increase the risk of each disease.

  11. Genetic Associations with Gestational Duration and Spontaneous Preterm Birth

    DEFF Research Database (Denmark)

    Zhang, Ge; Feenstra, Bjarke; Bacelis, Jonas

    2017-01-01

    Background Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations....... Methods We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total...... of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother-infant dyads suggested that these variants act at the level...

  12. Associations between the Genetic Polymorphisms of Osteopontin Promoter and Susceptibility to Cancer in Chinese Population: A Meta-Analysis.

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    Yulan Liu

    Full Text Available Several studies have been conducted to examine the associations between osteopontin (OPN promoter gene SPP1 polymorphisms with human cancers in Chinese population, but the results remain inconsistent. The aim of this meta-analysis is to clarify the associations between SPP1 polymorphisms and cancer susceptibility.All eligible case-control studies published up to March 2015 were identified by searching PubMed, Web of Science, Embase, and Cochrane Library without language restrictions. Pooled odds ratio (OR and 95% confidence interval (95% CI were calculated using fixed- or random-effect model.A total of 11 case-control studies were included; of those, there were eleven studies (3130 cases and 3828 controls for -443T>C polymorphism, ten studies (3019 cases and 3615 controls for -156G>GG polymorphism, eight studies (2258 cases and 2846 controls for -66T>G polymorphism. Overall, no evidence indicated that the -443 T>C polymorphism was associated with cancer risk (OR = 0.93, 95%CI 0.62-1.38 for dominant model, OR = 1.06, 95%CI 0.73-1.55 for recessive model, OR = 0.88, 95%CI 0.62-1.26 for CT vs TT model, OR = 1.03, 95%CI 0.61-1.73 for CC vs TT model. While, a significantly increase risk was found for -156 G>GG polymorphism (OR = 1.22, 95%CI 1.10-1.35 for dominant model, OR = 1.25, 95%CI 1.10-1.41 for recessive model, OR = 1.18, 95%CI 1.06-1.32 for GGG vs GG model, OR = 1.35, 95%CI 1.09-1.68 for GGGG vs GG model. For -66T>G polymorphism, we found a decrease risk of cancer (OR = 0.84, 95% CI 0.71-0.98 for dominant model, but this result changed (OR = 0.93, 95% CI 0.77-1.12 for dominant model when we excluded a study.This meta-analysis suggests that in Chinese population the -156G>GG polymorphism of SPP1 might be a risk factor for human cancers, while -443T>C mutation is not associated with cancer risk. For -66T>G polymorphism, it may be a protective factor for human cancers.

  13. Associations between the Genetic Polymorphisms of Osteopontin Promoter and Susceptibility to Cancer in Chinese Population: A Meta-Analysis.

    Science.gov (United States)

    Liu, Yulan; Lei, Hongbo; Zhang, Jixiang; Wang, Jun; Li, Kui; Dong, Weiguo

    2015-01-01

    Several studies have been conducted to examine the associations between osteopontin (OPN) promoter gene SPP1 polymorphisms with human cancers in Chinese population, but the results remain inconsistent. The aim of this meta-analysis is to clarify the associations between SPP1 polymorphisms and cancer susceptibility. All eligible case-control studies published up to March 2015 were identified by searching PubMed, Web of Science, Embase, and Cochrane Library without language restrictions. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated using fixed- or random-effect model. A total of 11 case-control studies were included; of those, there were eleven studies (3130 cases and 3828 controls) for -443T>C polymorphism, ten studies (3019 cases and 3615 controls) for -156G>GG polymorphism, eight studies (2258 cases and 2846 controls) for -66T>G polymorphism. Overall, no evidence indicated that the -443 T>C polymorphism was associated with cancer risk (OR = 0.93, 95%CI 0.62-1.38 for dominant model, OR = 1.06, 95%CI 0.73-1.55 for recessive model, OR = 0.88, 95%CI 0.62-1.26 for CT vs TT model, OR = 1.03, 95%CI 0.61-1.73 for CC vs TT model). While, a significantly increase risk was found for -156 G>GG polymorphism (OR = 1.22, 95%CI 1.10-1.35 for dominant model, OR = 1.25, 95%CI 1.10-1.41 for recessive model, OR = 1.18, 95%CI 1.06-1.32 for GGG vs GG model, OR = 1.35, 95%CI 1.09-1.68 for GGGG vs GG model). For -66T>G polymorphism, we found a decrease risk of cancer (OR = 0.84, 95% CI 0.71-0.98 for dominant model), but this result changed (OR = 0.93, 95% CI 0.77-1.12 for dominant model) when we excluded a study. This meta-analysis suggests that in Chinese population the -156G>GG polymorphism of SPP1 might be a risk factor for human cancers, while -443T>C mutation is not associated with cancer risk. For -66T>G polymorphism, it may be a protective factor for human cancers.

  14. Multi-variant pathway association analysis reveals the importance of genetic determinants of estrogen metabolism in breast and endometrial cancer susceptibility.

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    Yen Ling Low

    2010-07-01

    Full Text Available Despite the central role of estrogen exposure in breast and endometrial cancer development and numerous studies of genes in the estrogen metabolic pathway, polymorphisms within the pathway have not been consistently associated with these cancers. We posit that this is due to the complexity of multiple weak genetic effects within the metabolic pathway that can only be effectively detected through multi-variant analysis. We conducted a comprehensive association analysis of the estrogen metabolic pathway by interrogating 239 tagSNPs within 35 genes of the pathway in three tumor samples. The discovery sample consisted of 1,596 breast cancer cases, 719 endometrial cancer cases, and 1,730 controls from Sweden; and the validation sample included 2,245 breast cancer cases and 1,287 controls from Finland. We performed admixture maximum likelihood (AML-based global tests to evaluate the cumulative effect from multiple SNPs within the whole metabolic pathway and three sub-pathways for androgen synthesis, androgen-to-estrogen conversion, and estrogen removal. In the discovery sample, although no single polymorphism was significant after correction for multiple testing, the pathway-based AML global test suggested association with both breast (p(global = 0.034 and endometrial (p(global = 0.052 cancers. Further testing revealed the association to be focused on polymorphisms within the androgen-to-estrogen conversion sub-pathway, for both breast (p(global = 0.008 and endometrial cancer (p(global = 0.014. The sub-pathway association was validated in the Finnish sample of breast cancer (p(global = 0.015. Further tumor subtype analysis demonstrated that the association of the androgen-to-estrogen conversion sub-pathway was confined to postmenopausal women with sporadic estrogen receptor positive tumors (p(global = 0.0003. Gene-based AML analysis suggested CYP19A1 and UGT2B4 to be the major players within the sub-pathway. Our study indicates that the composite

  15. Distinguishing Hypertrophic Cardiomyopathy-Associated Mutations from Background Genetic Noise

    Science.gov (United States)

    Kapplinger, Jamie D.; Landstrom, Andrew P.; Bos, J. Martijn; Salisbury, Benjamin A.; Callis, Thomas E.; Ackerman, Michael J.

    2014-01-01

    Despite the significant progress that has been made in identifying disease-associated mutations, the utility of the Hypertrophic Cardiomyopathy (HCM) genetic test is limited by a lack of understanding of the background genetic variation inherent to these sarcomeric genes in seemingly healthy subjects. This study represents the first comprehensive analysis of genetic variation in 427 ostensibly healthy individuals for the HCM genetic test using the “Gold Standard” Sanger sequencing method validating the background rate identified in the publically available exomes. While mutations are clearly over-represented in disease, a background rate as high as ~5% among healthy individuals prevents diagnostic certainty. To this end, we have identified a number of estimated predictive value-based associations including gene-specific, topology, and conservation methods generating an algorithm aiding in the probabilistic interpretation of an HCM genetic test. PMID:24510615

  16. Genetic diversity and association mapping in a collection of selected Chinese soybean accessions based on SSR marker analysis

    NARCIS (Netherlands)

    Li, Y.H.; Smulders, M.J.M.; Chang, R.Z.; Qiu, L.J.

    2011-01-01

    For broadening the narrow genetic base of modern soybean cultivars, 159 accessions were selected from the Chinese soybean collection which contained at least one of seven important agronomic traits: resistance to soybean cyst nematode (SCN) or soybean mosaic virus (SMV), tolerance to salt, cold, or

  17. Genetic analysis of the estrogen-related receptor alpha and studies of association with obesity and type 2 diabetes

    DEFF Research Database (Denmark)

    Larsen, L H; Rose, C S; Sparsø, T;

    2007-01-01

    The estrogen-related receptor alpha (ERRalpha or NR3B1) is a transcription factor from the nuclear receptor super-family, group III. The gene encoding ERRalpha (ESRRA) is located on chromosome 11q13, a region showing genetic linkage to body mass index and fat percentage. Through interaction with ...

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

    NARCIS (Netherlands)

    Verweij, C.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 a

  19. Using Ambystoma mexicanum (Mexican axolotl) embryos, chemical genetics, and microarray analysis to identify signaling pathways associated with tissue regeneration.

    Science.gov (United States)

    Ponomareva, Larissa V; Athippozhy, Antony; Thorson, Jon S; Voss, S Randal

    2015-12-01

    Amphibian vertebrates are important models in regenerative biology because they present exceptional regenerative capabilities throughout life. However, it takes considerable effort to rear amphibians to juvenile and adult stages for regeneration studies, and the relatively large sizes that frogs and salamanders achieve during development make them difficult to use in chemical screens. Here, we introduce a new tail regeneration model using late stage Mexican axolotl embryos. We show that axolotl embryos completely regenerate amputated tails in 7days before they exhaust their yolk supply and begin to feed. Further, we show that axolotl embryos can be efficiently reared in microtiter plates to achieve moderate throughput screening of soluble chemicals to investigate toxicity and identify molecules that alter regenerative outcome. As proof of principle, we identified integration 1 / wingless (Wnt), transforming growth factor beta (Tgf-β), and fibroblast growth factor (Fgf) pathway antagonists that completely block tail regeneration and additional chemicals that significantly affected tail outgrowth. Furthermore, we used microarray analysis to show that inhibition of Wnt signaling broadly affects transcription of genes associated with Wnt, Fgf, Tgf-β, epidermal growth factor (Egf), Notch, nerve growth factor (Ngf), homeotic gene (Hox), rat sarcoma/mitogen-activated protein kinase (Ras/Mapk), myelocytomatosis viral oncogene (Myc), tumor protein 53 (p53), and retinoic acid (RA) pathways. Punctuated changes in the expression of genes known to regulate vertebrate development were observed; this suggests the tail regeneration transcriptional program is hierarchically structured and temporally ordered. Our study establishes the axolotl as a chemical screening model to investigate signaling pathways associated with tissue regeneration.

  20. On the replication of genetic associations: timing can be everything!

    Science.gov (United States)

    Lasky-Su, Jessica; Lyon, Helen N; Emilsson, Valur; Heid, Iris M; Molony, Cliona; Raby, Benjamin A; Lazarus, Ross; Klanderman, Barbara; Soto-Quiros, Manuel E; Avila, Lydiana; Silverman, Edwin K; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Kronenberg, Florian; Vollmert, Caren; Illig, Thomas; Fox, Caroline S; Levy, Daniel; Laird, Nan; Ding, Xiao; McQueen, Matt B; Butler, Johannah; Ardlie, Kristin; Papoutsakis, Constantina; Dedoussis, George; O'Donnell, Christopher J; Wichmann, H-Erich; Celedón, Juan C; Schadt, Eric; Hirschhorn, Joel; Weiss, Scott T; Stefansson, Kari; Lange, Christoph

    2008-04-01

    The failure of researchers to replicate genetic-association findings is most commonly attributed to insufficient statistical power, population stratification, or various forms of between-study heterogeneity or environmental influences.(1) Here, we illustrate another potential cause for nonreplications that has so far not received much attention in the literature. We illustrate that the strength of a genetic effect can vary by age, causing "age-varying associations." If not taken into account during the design and the analysis of a study, age-varying genetic associations can cause nonreplication. By using the 100K SNP scan of the Framingham Heart Study, we identified an age-varying association between a SNP in ROBO1 and obesity and hypothesized an age-gene interaction. This finding was followed up in eight independent samples comprising 13,584 individuals. The association was replicated in five of the eight studies, showing an age-dependent relationship (one-sided combined p = 3.92 x 10(-9), combined p value from pediatric cohorts = 2.21 x 10(-8), combined p value from adult cohorts = 0.00422). Furthermore, this study illustrates that it is difficult for cross-sectional study designs to detect age-varying associations. If the specifics of age- or time-varying genetic effects are not considered in the selection of both the follow-up samples and in the statistical analysis, important genetic associations may be missed.

  1. Attitudes towards genetic testing: analysis of contradictions

    DEFF Research Database (Denmark)

    Jallinoja, P; Hakonen, A; Aro, A R

    1998-01-01

    A survey study was conducted among 1169 people to evaluate attitudes towards genetic testing in Finland. Here we present an analysis of the contradictions detected in people's attitudes towards genetic testing. This analysis focuses on the approval of genetic testing as an individual choice...... and on the confidence in control of the process of genetic testing and its implications. Our analysis indicated that some of the respondents have contradictory attitudes towards genetic testing. It is proposed that contradictory attitudes towards genetic testing should be given greater significance both in scientific...... studies on attitudes towards genetic testing as well as in the health care context, e.g. in genetic counselling....

  2. Genetic association studies in lumbar disc degeneration: a systematic review.

    Directory of Open Access Journals (Sweden)

    Pasi J Eskola

    Full Text Available OBJECTIVE: Low back pain is associated with lumbar disc degeneration, which is mainly due to genetic predisposition. The objective of this study was to perform a systematic review to evaluate genetic association studies in lumbar disc degeneration as defined on magnetic resonance imaging (MRI in humans. METHODS: A systematic literature search was conducted in MEDLINE, MEDLINE In-Process, SCOPUS, ISI Web of Science, The Genetic Association Database and The Human Genome Epidemiology Network for information published between 1990-2011 addressing genes and lumbar disc degeneration. Two investigators independently identified studies to determine inclusion, after which they performed data extraction and analysis. The level of cumulative genetic association evidence was analyzed according to The HuGENet Working Group guidelines. RESULTS: Fifty-two studies were included for review. Forty-eight studies reported at least one positive association between a genetic marker and lumbar disc degeneration. The phenotype definition of lumbar disc degeneration was highly variable between the studies and replications were inconsistent. Most of the associations presented with a weak level of evidence. The level of evidence was moderate for ASPN (D-repeat, COL11A1 (rs1676486, GDF5 (rs143383, SKT (rs16924573, THBS2 (rs9406328 and MMP9 (rs17576. CONCLUSIONS: Based on this first extensive systematic review on the topic, the credibility of reported genetic associations is mostly weak. Clear definition of lumbar disc degeneration phenotypes and large population-based cohorts are needed. An international consortium is needed to standardize genetic association studies in relation to disc degeneration.

  3. An integrated system for genetic analysis

    Directory of Open Access Journals (Sweden)

    Duan Xiao

    2006-04-01

    Full Text Available Abstract Background Large-scale genetic mapping projects require data management systems that can handle complex phenotypes and detect and correct high-throughput genotyping errors, yet are easy to use. Description We have developed an Integrated Genotyping System (IGS to meet this need. IGS securely stores, edits and analyses genotype and phenotype data. It stores information about DNA samples, plates, primers, markers and genotypes generated by a genotyping laboratory. Data are structured so that statistical genetic analysis of both case-control and pedigree data is straightforward. Conclusion IGS can model complex phenotypes and contain genotypes from whole genome association studies. The database makes it possible to integrate genetic analysis with data curation. The IGS web site http://bioinformatics.well.ox.ac.uk/project-igs.shtml contains further information.

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

    Directory of Open Access Journals (Sweden)

    Maggie C Y Ng

    2014-08-01

    Full Text Available Type 2 diabetes (T2D is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1 and two novel loci (HLA-B and INS-IGF2 at genome-wide significance (4.15 × 10(-94association (2.2 × 10(-23 < locus-wide P<0.05. These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.

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

    Science.gov (United States)

    Holliday, Elizabeth G; Smith, Albert V; Cornes, Belinda K; Buitendijk, Gabriëlle H S; Jensen, Richard A; Sim, Xueling; Aspelund, Thor; Aung, Tin; Baird, Paul N; Boerwinkle, Eric; Cheng, Ching Yu; van Duijn, Cornelia M; Eiriksdottir, Gudny; Gudnason, Vilmundur; Harris, Tamara; Hewitt, Alex W; Inouye, Michael; Jonasson, Fridbert; Klein, Barbara E K; Launer, Lenore; Li, Xiaohui; Liew, Gerald; Lumley, Thomas; McElduff, Patrick; McKnight, Barbara; Mitchell, Paul; Psaty, Bruce M; Rochtchina, Elena; Rotter, Jerome I; Scott, Rodney J; Tay, Wanting; Taylor, Kent; Teo, Yik Ying; Uitterlinden, André G; Viswanathan, Ananth; Xie, Sophia; Vingerling, Johannes R; Klaver, Caroline C W; Tai, E Shyong; Siscovick, David; Klein, Ronald; Cotch, Mary Frances; Wong, Tien Y; Attia, John; Wang, Jie Jin

    2013-01-01

    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.

  6. 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

  7. No association of genetic polymorphisms in CYP1B1 with primary open-angle glaucoma: a meta- and gene-based analysis

    OpenAIRE

    Dong, Shuqian; Yang, Jingyun; Yu, Weihong; Kota, Pravina; Xia, Xiaobo; Xu, Huizhuo

    2012-01-01

    Purpose To examine the effects of genetic polymorphisms in cytochrome P450, subfamily 1, polypeptide 1 (C1P1B1) on primary open-angle glaucoma (POAG). Methods A systematic literature search was performed, and random-effects meta-analyses were used to evaluate genetic polymorphisms in CYP1B1 with POAG. A gene-based analysis was conducted to investigate the cumulative effects of genetic polymorphisms in CYP1B1. Results A total of six studies from published papers were included in our analysis. ...

  8. Complement genetics, deficiencies, and disease associations.

    Science.gov (United States)

    Mayilyan, Karine R

    2012-07-01

    The complement system is a key component of innate immunity. More than 45 genes encoding the proteins of complement components or their isotypes and subunits, receptors, and regulators have been discovered. These genes are distributed throughout different chromosomes, with 19 genes comprising three significant complement gene clusters in the human genome. Genetic deficiency of any early component of the classical pathway (C1q, C1r/s, C2, C4, and C3) is associated with autoimmune diseases due to the failure of clearance of immune complexes (IC) and apoptotic materials, and the impairment of normal humoral response. Deficiencies of mannan-binding lectin (MBL) and the early components of the alternative (factor D, properdin) and terminal pathways (from C3 onward components: C5, C6, C7, C8, C9) increase susceptibility to infections and their recurrence. While the association of MBL deficiency with a number of autoimmune and infectious disorders has been well established, the effects of the deficiency of other lectin pathway components (ficolins, MASPs) have been less extensively investigated due to our incomplete knowledge of the genetic background of such deficiencies and the functional activity of those components. For complement regulators and receptors, the consequences of their genetic deficiency vary depending on their specific involvement in the regulatory or signalling steps within the complement cascade and beyond. This article reviews current knowledge and concepts about the genetic load of complement component deficiencies and their association with diseases. An integrative presentation of genetic data with the latest updates provides a background to further investigations of the disease association investigations of the complement system from the perspective of systems biology and systems genetics.

  9. The Prothrombin G20210A Mutation is Associated with Young-Onset Stroke: The Genetics of Early Onset Stroke Study and Meta-Analysis

    Science.gov (United States)

    Jiang, Baijia; Ryan, Kathleen A.; Hamedani, Ali; Cheng, Yuching; Sparks, Mary J.; Koontz, Deborah; Bean, Christopher J.; Gallagher, Margaret; Hooper, W. Craig; McArdle, Patrick F.; O'Connell, Jeffrey R.; Stine, O. Colin; Wozniak, Marcella A.; Stern, Barney J.; Mitchell, Braxton D.; Kittner, Steven J.; Cole, John W.

    2014-01-01

    Background and Purpose Although the prothrombin G20210A mutation has been implicated as a risk factor for venous thrombosis, its role in arterial ischemic stroke is unclear, particularly among young-adults. To address this issue, we examined the association between prothrombin G20210A and ischemic stroke in a Caucasian case-control population and additionally performed a meta-analysis Methods From the population-based Genetics of Early Onset Stroke (GEOS) study we identified 397 individuals of European ancestry aged 15-49 years with first-ever ischemic stroke and 426 matched-controls. Logistic regression was used to calculate odds ratios in the entire population and for subgroups stratified by gender, age, oral contraceptive use, migraine and smoking status. A meta-analysis of 17 case-control studies (n=2305 cases stroke did not achieve statistical significance (OR=2.5,95%CI=0.9-6.5,p=0.07). However, among adults aged 15-42 (younger than median age), cases were significantly more likely than controls to have the mutation (OR=5.9,95%CI=1.2-28.1,p=0.03), whereas adults ages 42-49 were not (OR=1.4,95%CI=0.4-5.1,p=0.94). In our meta-analysis, the mutation was associated with significantly increased stroke risk in adults stroke in young-adults and may have an even stronger association among those with earlier onset strokes. Our finding of a stronger association in the younger-young adult population requires replication. PMID:24619398

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

    Directory of Open Access Journals (Sweden)

    Petr Volkov

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

  11. A genetic association analysis of cognitive ability and cognitive ageing using 325 markers for 109 genes associated with oxidative stress or cognition

    Directory of Open Access Journals (Sweden)

    Whalley Lawrence J

    2007-07-01

    Full Text Available Abstract Background Non-pathological cognitive ageing is a distressing condition affecting an increasing number of people in our 'ageing society'. Oxidative stress is hypothesised to have a major role in cellular ageing, including brain ageing. Results Associations between cognitive ageing and 325 single nucleotide polymorphisms (SNPs, located in 109 genes implicated in oxidative stress and/or cognition, were examined in a unique cohort of relatively healthy older people, on whom we have cognitive ability scores at ages 11 and 79 years (LBC1921. SNPs showing a significant positive association were then genotyped in a second cohort for whom we have cognitive ability scores at the ages of 11 and 64 years (ABC1936. An intronic SNP in the APP gene (rs2830102 was significantly associated with cognitive ageing in both LBC1921 and a combined LBC1921/ABC1936 analysis (p Conclusion This study suggests a possible role for APP in normal cognitive ageing, in addition to its role in Alzheimer's disease.

  12. A weighted U statistic for association analyses considering genetic heterogeneity.

    Science.gov (United States)

    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.

  13. Understanding Salesforce Behavior using Genetic Association Studies

    NARCIS (Netherlands)

    W.E. van den Berg (Wouter)

    2014-01-01

    markdownabstract__Abstract__ Using genetic association studies, this thesis aims to investigate the drivers of successful customer-salesperson interactions in a context where knowledge development has become crucial to the value creation process. Central to this thesis is the developing role of the

  14. Understanding Salesforce Behavior using Genetic Association Studies

    NARCIS (Netherlands)

    W.E. van den Berg (Wouter)

    2014-01-01

    markdownabstract__Abstract__ Using genetic association studies, this thesis aims to investigate the drivers of successful customer-salesperson interactions in a context where knowledge development has become crucial to the value creation process. Central to this thesis is the developing role of the

  15. Genetic variants associated with lung function

    DEFF Research Database (Denmark)

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

    2014-01-01

    BACKGROUND: Reduced forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) are strong predictors of mortality and lung function is higher among individuals with exceptional longevity. However, genetic factors associated with lung function in individuals...... 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...... used the residuals of the FEV1 and FEV1/FVC, adjusted for age, sex, height, ancestry principal components (PCs), smoking status, pack-years, and field center. RESULTS: We identified nine SNPs in strong linkage disequilibrium in the CYP2U1 gene to be associated with FEV1 and a novel SNP (rs889574...

  16. Genetic Associations with Gestational Length and Spontaneous Preterm Birth

    Science.gov (United States)

    Zhang, Ge; Feenstra, Bjarke; Bacelis, Jonas; Liu, Xueping; Muglia, Lisa M.; Juodakis, Julius; Miller, Daniel E.; Litterman, Nadia; Jiang, Pan-Pan; Russell, Laura; Hinds, David A.; Hu, Youna; Weirauch, Matthew T.; Chen, Xiaoting; Chavan, Arun R.; Wagner, Günter P.; Pavličev, Mihaela; Nnamani, Mauris C.; Maziarz, Jamie; Karjalainen, Minna K.; Rämet, Mika; Sengpiel, Verena; Geller, D Frank; Boyd, Heather A.; Palotie, Aarno; Momany, Allison; Bedell, Bruce; Ryckman, Kelli K.; Huusko, Johanna M.; Forney, Carmy R.; Kottyan, Leah C.; Hallman, Mikko; Teramo, Kari; Nohr, Ellen A.; Davey-Smith, George; Melbye, Mads; Jacobsson, Bo; Muglia, Louis J.

    2017-01-01

    BackgroundDespite evidence that genetic factors contribute to gestational length and preterm birth, robust associations with genetic variants have not been identified. We hypothesized that analyzing larger data sets with gestational length information by genomewide association would reveal trait-influencing variants.MethodsWe performed a genomewide association study in a discovery data set of 43,568 women of European ancestry from 23andMe, Inc., for gestational length as a continuous trait and for term or preterm (preterm birth with genomewide significance. Analysis of mother-infant dyads indicated that these findings likely resulted from maternal genome actions.ConclusionsOur study is the first to identify maternal genetic variants robustly associated with gestational length and preterm birth. Roles of these loci in uterine development, maternal nutrition, and vascular control support their mechanistic involvement and create opportunities to investigate new risk factors for prevention of preterm birth. PMID:28877031

  17. Genetic association analysis of 13 nuclear-encoded mitochondrial candidate genes with type II diabetes mellitus: the DAMAGE study

    DEFF Research Database (Denmark)

    Reiling, Erwin; van Vliet-Ostaptchouk, Jana V; van 't Riet, Esther;

    2009-01-01

    ). After a meta-analysis, only one SNP in SIRT4 (rs2522138) remained significant (P=0.01). Extending the second stage with samples from the Danish Steno Study (n=1220 participants) resulted in a common odds ratio (OR) of 0.92 (0.85-1.00), P=0.06. Moreover, in a large meta-analysis of three genome...

  18. Genetic Diversity and Association Analysis for Solvent Retention Capacity in the Accessions Derived from Soft Wheat Ningmai 9

    Science.gov (United States)

    Jiang, Peng; Zhang, Ping-Ping

    2017-01-01

    Solvent retention capacity (SRC) test is an effective method for quality evaluation of soft wheat. Ningmai 9 is a founder in soft wheat breeding. The SRC and genotype of Ningmai 9 and its 117 derivatives were tested. Association mapping was employed to identify the quantitative trait loci (QTL) associated with SRCs. Ningmai 9 had the allele frequency of 75.60% and 67.81% to its first- and second-generation derivatives, respectively, indicating higher contribution than theoretical expectation. Neighbor-joining cluster based on the genotyping data showed that Ningmai 9 and most of its first-generation derivatives were clustered together, whereas its second-generation derivatives were found in another group. The variation coefficients of SRCs in the derivatives ranged from 5.35% to 8.63%. A total of 29 markers on 13 chromosomes of the genome were associated with the SRCs. There were 6 markers associated with more than one SRC or detected in two years. The results suggested that QTL controlling SRCs in Ningmai 9 might be different from other varieties. Markers Xgwm44, Xbarc126, Xwmc790, and Xgwm232 associated with SRCs in Ningmai 9 might be used for quality improvement in soft wheat breeding.

  19. Genetic Analysis with the Immunochip Platform in Behçet Disease. Identification of Residues Associated in the HLA Class I Region and New Susceptibility Loci

    Science.gov (United States)

    Montes-Cano, Marco-Antonio; García-Lozano, José-Raúl; Conde-Jaldón, Marta; Ortego-Centeno, Norberto; Castillo, María Jesús; Sánchez-Bursón, Juan; Juliá, María Rosa; Solans, Roser; Blanco, Ricardo; Barnosi-Marín, Ana-Celia; Gómez de la Torre, Ricardo; Fanlo, Patricia; Rodríguez-Carballeira, Mónica; Camps, Teresa; Castañeda, Santos; Alegre-Sancho, Juan-Jose; Martín, Javier; González-Escribano, María Francisca

    2016-01-01

    Behcet's disease (BD) is an immuno-mediated vasculitis in which knowledge of its etiology and genetic basis is limited. To improve the current knowledge, a genetic analysis performed with the Immunochip platform was carried out in a population from Spain. A discovery cohort comprising 278 BD cases and 1,517 unaffected controls were genotyped using the Immunochip platform. The validation step was performed on an independent replication cohort composed of 130 BD cases and 600 additional controls. The strongest association signals were observed in the HLA class I region, being HLA-B*51 the highest peak (overall P = 6.82E-32, OR = 3.82). A step-wise conditional logistic regression with classical alleles identified HLA-B*57 and HLA-A*03 as additional independent markers. The amino acid model that best explained the association, includes the position 97 of the HLA-B molecule and the position 66 of the HLA-A. Among the non-HLA loci, the most significant in the discovery analysis were: IL23R (rs10889664: P = 3.81E-12, OR = 2.00), the JRKL/CNTN5 region (rs2848479: P = 5.00E-08, OR = 1.68) and IL12A (rs1874886: P = 6.67E-08, OR = 1.72), which were confirmed in the validation phase (JRKL/CNTN5 rs2848479: P = 3.29E-10, OR = 1.66; IL12A rs1874886: P = 1.62E-08, OR = 1.61). Our results confirm HLA-B*51 as a primary-association marker in predisposition to BD and suggest additional independent signals within the class I region, specifically in the genes HLA-A and HLA-B. Regarding the non-HLA genes, in addition to IL-23R, previously reported in our population; IL12A, described in other populations, was found to be a BD susceptibility factor also in Spaniards; finally, a new associated locus was found in the JRKL/CNTN5 region. PMID:27548383

  20. Network-based analysis of genetic variants associated with hippocampal volume in Alzheimer’s disease: a study of ADNI cohorts

    OpenAIRE

    2016-01-01

    Background Alzheimer’s disease (AD) is a neurodegenerative disease that causes dementia. While molecular basis of AD is not fully understood, genetic factors are expected to participate in the development and progression of the disease. Our goal was to uncover novel genetic underpinnings of Alzheimer’s disease with a bioinformatics approach that accounts for tissue specificity. Findings We performed genome-wide association studies (GWAS) for hippocampal volume in two Alzheimer’s Disease Neuro...

  1. A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control.

    Science.gov (United States)

    Bartha, István; Carlson, Jonathan M; Brumme, Chanson J; McLaren, Paul J; Brumme, Zabrina L; John, Mina; Haas, David W; Martinez-Picado, Javier; Dalmau, Judith; López-Galíndez, Cecilio; Casado, Concepción; Rauch, Andri; Günthard, Huldrych F; Bernasconi, Enos; Vernazza, Pietro; Klimkait, Thomas; Yerly, Sabine; O'Brien, Stephen J; Listgarten, Jennifer; Pfeifer, Nico; Lippert, Christoph; Fusi, Nicolo; Kutalik, Zoltán; Allen, Todd M; Müller, Viktor; Harrigan, P Richard; Heckerman, David; Telenti, Amalio; Fellay, Jacques

    2013-10-29

    HIV-1 sequence diversity is affected by selection pressures arising from host genomic factors. Using paired human and viral data from 1071 individuals, we ran >3000 genome-wide scans, testing for associations between host DNA polymorphisms, HIV-1 sequence variation and plasma viral load (VL), while considering human and viral population structure. We observed significant human SNP associations to a total of 48 HIV-1 amino acid variants (pgenome-to-genome approach highlights sites of genomic conflict and is a strategy generally applicable to studies of host-pathogen interaction. DOI:http://dx.doi.org/10.7554/eLife.01123.001.

  2. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes

    DEFF Research Database (Denmark)

    McKay, James D; Hung, Rayjean J; Han, Younghun

    2017-01-01

    Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genomewide association s...

  3. Genetic variants associated with Crohn's disease

    Directory of Open Access Journals (Sweden)

    Michail S

    2013-07-01

    Full Text Available Sonia Michail,1 Gilberto Bultron,1 R William DePaolo2 1The University of Southern California, Children's Hospital of Los Angeles, Los Angeles, CA, USA; 2Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Abstract: Crohn's disease is an immune-related disorder characterized by inflammation of the gastrointestinal mucosa, which can occur in any area throughout the digestive tract. This life-long disease commonly presents with abdominal pain, diarrhea, vomiting, and weight loss. While the exact etiology of this disease is largely unknown, it is thought to arise from an interaction between microbial, immunological, and environmental factors in a genetically susceptible host, whereby the immune system attacks the intestine as it cross reacts against gut microbial antigens. The study of genetic variants associated with Crohn's disease has shed light on our understanding of disease pathophysiology. A large number of genetic variants identified in Crohn's disease are related to genes targeting microbial recognition and bacterial wall sensing, the most common being NOD2/CARD15 gene. This review will discuss the recent advance in our knowledge of genetic variants of this disease and how they influence the disease course and prognosis. Keywords: Crohn's disease, genetics, autophagy

  4. Prothrombin G20210A mutation is associated with young-onset stroke: the genetics of early-onset stroke study and meta-analysis.

    Science.gov (United States)

    Jiang, Baijia; Ryan, Kathleen A; Hamedani, Ali; Cheng, Yuching; Sparks, Mary J; Koontz, Deborah; Bean, Christopher J; Gallagher, Margaret; Hooper, W Craig; McArdle, Patrick F; O'Connell, Jeffrey R; Stine, O Colin; Wozniak, Marcella A; Stern, Barney J; Mitchell, Braxton D; Kittner, Steven J; Cole, John W

    2014-04-01

    Although the prothrombin G20210A mutation has been implicated as a risk factor for venous thrombosis, its role in arterial ischemic stroke is unclear, particularly among young adults. To address this issue, we examined the association between prothrombin G20210A and ischemic stroke in a white case-control population and additionally performed a meta-analysis. From the population-based Genetics of Early Onset Stroke (GEOS) study, we identified 397 individuals of European ancestry aged 15 to 49 years with first-ever ischemic stroke and 426 matched controls. Logistic regression was used to calculate odds ratios (ORs) in the entire population and for subgroups stratified by sex, age, oral contraceptive use, migraine, and smoking status. A meta-analysis of 17 case-control studies (n=2305 cases <55 years) was also performed with and without GEOS data. Within GEOS, the association of the prothrombin G20210A mutation with ischemic stroke did not achieve statistical significance (OR=2.5; 95% confidence interval [CI]=0.9-6.5; P=0.07). However, among adults aged 15 to 42 years (younger than median age), cases were significantly more likely than controls to have the mutation (OR=5.9; 95% CI=1.2-28.1; P=0.03), whereas adults aged 42 to 49 years were not (OR=1.4; 95% CI=0.4-5.1; P=0.94). In our meta-analysis, the mutation was associated with significantly increased stroke risk in adults ≤55 years (OR=1.4; 95% CI=1.1-1.9; P=0.02), with significance increasing with addition of the GEOS results (OR=1.5; 95% CI=1.1-2.0; P=0.005). The prothrombin G20210A mutation is associated with ischemic stroke in young adults and may have an even stronger association among those with earlier onset strokes. Our finding of a stronger association in the younger young adult population requires replication.

  5. Genetic Analysis with the Immunochip Platform in Behçet Disease. Identification of Residues Associated in the HLA Class I Region and New Susceptibility Loci

    OpenAIRE

    Ortiz-Fernández, Lourdes; Carmona, F.D.; Montes-Cano, Marco-Antonio; García-Lozano, J R; Conde_Jaldón, Marta; Ortego-Centeno, N.; Castillo, María Jesús; Espinosa, Gerard; Graña-Gil, Genaro; Sánchez-Bursón, Juan; Juliá, María Rosa; Solans, Roser; Blanco, Ricardo; Barnosi-Marín, Ana C.; Gómez de la Torre, Ricardo

    2016-01-01

    Behcet's disease (BD) is an immuno-mediated vasculitis in which knowledge of its etiology and genetic basis is limited. To improve the current knowledge, a genetic analysis performed with the Immunochip platform was carried out in a population from Spain. A discovery cohort comprising 278 BD cases and 1,517 unaffected controls were genotyped using the Immunochip platform. The validation step was performed on an independent replication cohort composed of 130 BD cases and 600 additional control...

  6. A Survey of Association Rule Mining Using Genetic Algorithm

    Directory of Open Access Journals (Sweden)

    Anubha Sharma

    2012-08-01

    Full Text Available Data mining is the analysis step of the "Knowledge Discovery in Databases" process, or KDD. It is the process that results in the discovery of new patterns in large data sets. It utilizes methods at the intersection of artificial intelligence, machine learning, statistics, and database systems. The overall goal of the data mining process is to extract knowledge from an existing data set and transform it into a human-understandable structure. In data mining, association rule learning is a popular and well researched method for discovering interesting relations between variables in large databases. Association rules are usually required to satisfy a user-specified minimum support and a user-specified minimum confidence at the same time. Genetic algorithm (GA is a search heuristic that mimics the process of natural evolution. This heuristic is routinely used to generate useful solutions to optimization and search problems. Genetic algorithms belong to the larger class of evolutionary algorithms, which generate solutions to optimization problems using techniques inspired by natural evolution, such as inheritance, mutation, selection, and crossover. In previous, many researchers have proposed Genetic Algorithms for mining interesting association rules from quantitative data. In this paper we represent a survey of Association Rule Mining Using Genetic Algorithm. The techniques are categorized based upon different approaches. This paper provides the major advancement in the approaches for association rule mining using genetic algorithms.

  7. Associations between two genetic variants in NKX2-5 and risk of congenital heart disease in Chinese population: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Zhenling Wang

    Full Text Available BACKGROUND: NKX2-5 is a transcriptional factor, which plays an important role in heart formation and development. Two genetic variants in the coding region of NKX2-5, 63A>G (rs2277923 and 606G>C (rs3729753, have been investigated in the risk of congenital heart disease (CHD, although with inconsistent results. Thus, a meta-analysis was performed to clarify the associations between the two variants and CHD risk in the Chinese population. METHODS AND RESULTS: Relevant studies were identified by searching PubMed, ISI Web of Science and CNKI databases and by reviewing the reference lists of retrieved articles. Then, the data from eligible studies were combined in an allelic model. A total of 7 and 4 studies were ultimately included for 63A>G and 606G>C, respectively. The results of overall meta-analyses showed that significant association was detected for 63A>G (OR = 1.26, 95% CI = 1.02-1.56, P(heterogeneity = 0.009, I (2 = 65.1%, but not for 606G>C (OR = 1.22, 95% CI = 0.75-1.96, P(heterogeneity =  0.412, I (2 = 0.0%. Regarding 63A>G variant, positive results were also obtained in the subgroups of atrial septal defect and large-sample-size study. Besides, the sensitivity analysis indicated that significant association was still detected after deletion of the individual studies with positive result and striking heterogeneity. CONCLUSION: Our results revealed that the 63A>G variant in NKX2-5, but not the 606G>C, may contribute to CHD risk for Chinese.

  8. Full-length genome characterization and genetic relatedness analysis of hepatitis A virus outbreak strains associated with acute liver failure among children.

    Science.gov (United States)

    Vaughan, Gilberto; Forbi, Joseph C; Xia, Guo-Liang; Fonseca-Ford, Maureen; Vazquez, Roberto; Khudyakov, Yury E; Montiel, Sonia; Waterman, Steve; Alpuche, Celia; Gonçalves Rossi, Livia Maria; Luna, Norma

    2014-02-01

    Clinical infection by hepatitis A virus (HAV) is generally self-limited but in some cases can progress to liver failure. Here, an HAV outbreak investigation among children with acute liver failure in a highly endemic country is presented. In addition, a sensitive method for HAV whole genome amplification and sequencing suitable for analysis of clinical samples is described. In this setting, two fatal cases attributed to acute liver failure and two asymptomatic cases living in the same household were identified. In a second household, one HAV case was observed with jaundice which resolved spontaneously. Partial molecular characterization showed that both households were infected by HAV subtype IA; however, the infecting strains in the two households were different. The HAV outbreak strains recovered from all cases grouped together within cluster IA1, which contains closely related HAV strains from the United States commonly associated with international travelers. Full-genome HAV sequences obtained from the household with the acute liver failure cases were related (genetic distances ranging from 0.01% to 0.04%), indicating a common-source infection. Interestingly, the strain recovered from the asymptomatic household contact was nearly identical to the strain causing acute liver failure. The whole genome sequence from the case in the second household was distinctly different from the strains associated with acute liver failure. Thus, infection with almost identical HAV strains resulted in drastically different clinical outcomes.

  9. Genetic correlates of brain aging on MRI and cognitive test measures: a genome-wide association and linkage analysis in the Framingham study

    Science.gov (United States)

    Seshadri, Sudha; DeStefano, Anita L; Au, Rhoda; Massaro, Joseph M; Beiser, Alexa S; Kelly-Hayes, Margaret; Kase, Carlos S; D'Agostino, Ralph B; DeCarli, Charles; Atwood, Larry D; Wolf, Philip A

    2007-01-01

    Background Brain magnetic resonance imaging (MRI) and cognitive tests can identify heritable endophenotypes associated with an increased risk of developing stroke, dementia and Alzheimer's disease (AD). We conducted a genome-wide association (GWA) and linkage analysis exploring the genetic basis of these endophenotypes in a community-based sample. Methods A total of 705 stroke- and dementia-free Framingham participants (age 62 +9 yrs, 50% male) who underwent volumetric brain MRI and cognitive testing (1999–2002) were genotyped. We used linear models adjusting for first degree relationships via generalized estimating equations (GEE) and family based association tests (FBAT) in additive models to relate qualifying single nucleotide polymorphisms (SNPs, 70,987 autosomal on Affymetrix 100K Human Gene Chip with minor allele frequency ≥ 0.10, genotypic call rate ≥ 0.80, and Hardy-Weinberg equilibrium p-value ≥ 0.001) to multivariable-adjusted residuals of 9 MRI measures including total cerebral brain (TCBV), lobar, ventricular and white matter hyperintensity (WMH) volumes, and 6 cognitive factors/tests assessing verbal and visuospatial memory, visual scanning and motor speed, reading, abstract reasoning and naming. We determined multipoint identity-by-descent utilizing 10,592 informative SNPs and 613 short tandem repeats and used variance component analyses to compute LOD scores. Results The strongest gene-phenotype association in FBAT analyses was between SORL1 (rs1131497; p = 3.2 × 10-6) and abstract reasoning, and in GEE analyses between CDH4 (rs1970546; p = 3.7 × 10-8) and TCBV. SORL1 plays a role in amyloid precursor protein processing and has been associated with the risk of AD. Among the 50 strongest associations (25 each by GEE and FBAT) were other biologically interesting genes. Polymorphisms within 28 of 163 candidate genes for stroke, AD and memory impairment were associated with the endophenotypes studied at p < 0.001. We confirmed our previously

  10. Molecular Analysis of a Genetic Variants Panel Related to Nutrients and Metabolism: Association with Susceptibility to Gestational Diabetes and Cardiometabolic Risk in Affected Women

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    Marica Franzago

    2017-01-01

    Full Text Available Gestational diabetes mellitus (GDM is the most frequent metabolic disorder in pregnancy. Women with a GDM history are at increased risk of developing diabetes and cardiovascular diseases. Studies have demonstrated a significant correlation between several genes involved in the metabolic pathway of insulin and environmental factors. The aim of this study was to investigate the relationship between clinical parameters in GDM and variants in genes involved with nutrients and metabolism. Several variants PPARG2 rs1801282 (C>G; PPARGC1A rs8192678 (C>T; TCF7L2 rs7903146 (C>T; LDLR rs2228671 (C>T; MTHFR rs1801133 (C>T; APOA5 rs662799 (T>C; GCKR rs1260326 (C>T; FTO rs9939609 (T>A; MC4R rs17782313 (T>C were genotyped in 168 pregnant Caucasian women with or without GDM by High Resolution Melting (HRM analysis. A significant correlation was observed between TT genotype of TCF7L2 gene and increased risk of GDM (OR 5.4 [95% CI 1.5–19.3]. Moreover, a significant correlation was observed between lipid parameters and genetic variations in additional genes, namely, PPARG2 [p = 0,02], APOA5 [p = 0,02], MC4R [p = 0,03], LDLR [p = 0,01], and FTO [p = 0,02]. Our findings support the association between TCF7L2 rs7903146 variant and an increased GDM risk. Results about the investigated genetic variants provide important information about cardiometabolic risk in GDM and help to plan future prevention studies.

  11. Molecular Analysis of a Genetic Variants Panel Related to Nutrients and Metabolism: Association with Susceptibility to Gestational Diabetes and Cardiometabolic Risk in Affected Women

    Science.gov (United States)

    Nicolucci, Antonio; Celentano, Claudio; Liberati, Marco; Stuppia, Liborio

    2017-01-01

    Gestational diabetes mellitus (GDM) is the most frequent metabolic disorder in pregnancy. Women with a GDM history are at increased risk of developing diabetes and cardiovascular diseases. Studies have demonstrated a significant correlation between several genes involved in the metabolic pathway of insulin and environmental factors. The aim of this study was to investigate the relationship between clinical parameters in GDM and variants in genes involved with nutrients and metabolism. Several variants PPARG2 rs1801282 (C>G); PPARGC1A rs8192678 (C>T); TCF7L2 rs7903146 (C>T); LDLR rs2228671 (C>T); MTHFR rs1801133 (C>T); APOA5 rs662799 (T>C); GCKR rs1260326 (C>T); FTO rs9939609 (T>A); MC4R rs17782313 (T>C) were genotyped in 168 pregnant Caucasian women with or without GDM by High Resolution Melting (HRM) analysis. A significant correlation was observed between TT genotype of TCF7L2 gene and increased risk of GDM (OR 5.4 [95% CI 1.5–19.3]). Moreover, a significant correlation was observed between lipid parameters and genetic variations in additional genes, namely, PPARG2 [p = 0,02], APOA5 [p = 0,02], MC4R [p = 0,03], LDLR [p = 0,01], and FTO [p = 0,02]. Our findings support the association between TCF7L2 rs7903146 variant and an increased GDM risk. Results about the investigated genetic variants provide important information about cardiometabolic risk in GDM and help to plan future prevention studies. PMID:28133617

  12. Association of genetic variants with diabetic nephropathy

    Institute of Scientific and Technical Information of China (English)

    Saliha; Rizvi; Syed; Tasleem; Raza; Farzana; Mahdi

    2014-01-01

    Diabetic nephropathy accounts for the most serious microvascular complication of diabetes mellitus. It is suggested that the prevalence of diabetic nephropathy will continue to increase in future posing a major challenge to the healthcare system resulting in increased morbidity and mortality. It occurs as a result of interaction between both genetic and environmental factors in individuals with both type 1 and type 2 diabetes. Genetic susceptibility has been proposed as an important factor for the development and progression of diabetic nephropathy, and various research efforts are being executed worldwide to identify the susceptibility gene for diabetic nephropathy. Numerous single nucleotide polymorphisms have been found in various genes giving rise to various gene variants which have been found to play a major role in genetic susceptibility to diabetic nephropathy. The risk of developing diabetic nephropathy is increased several times by inheriting risk alleles at susceptibility loci of various genes like ACE, IL, TNF-α, COL4A1, e NOS, SOD2, APOE, GLUT, etc. The identification of these genetic variants at a biomarker level could thus, allow the detection of those individuals at high risk for diabetic nephropathy which could thus help in the treatment, diagnosis and early prevention of the disease. The present review discusses about the various gene variants found till date to be associated with diabetic nephropathy.

  13. Association of genetic variants with diabetic nephropathy.

    Science.gov (United States)

    Rizvi, Saliha; Raza, Syed Tasleem; Mahdi, Farzana

    2014-12-15

    Diabetic nephropathy accounts for the most serious microvascular complication of diabetes mellitus. It is suggested that the prevalence of diabetic nephropathy will continue to increase in future posing a major challenge to the healthcare system resulting in increased morbidity and mortality. It occurs as a result of interaction between both genetic and environmental factors in individuals with both type 1 and type 2 diabetes. Genetic susceptibility has been proposed as an important factor for the development and progression of diabetic nephropathy, and various research efforts are being executed worldwide to identify the susceptibility gene for diabetic nephropathy. Numerous single nucleotide polymorphisms have been found in various genes giving rise to various gene variants which have been found to play a major role in genetic susceptibility to diabetic nephropathy. The risk of developing diabetic nephropathy is increased several times by inheriting risk alleles at susceptibility loci of various genes like ACE, IL, TNF-α, COL4A1, eNOS, SOD2, APOE, GLUT, etc. The identification of these genetic variants at a biomarker level could thus, allow the detection of those individuals at high risk for diabetic nephropathy which could thus help in the treatment, diagnosis and early prevention of the disease. The present review discusses about the various gene variants found till date to be associated with diabetic nephropathy.

  14. Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies

    Science.gov (United States)

    Grallert, Harald; Dupuis, Josée; Bis, Joshua C.; Dehghan, Abbas; Barbalic, Maja; Baumert, Jens; Lu, Chen; Smith, Nicholas L.; Uitterlinden, André G.; Roberts, Robert; Khuseyinova, Natalie; Schnabel, Renate B.; Rice, Kenneth M.; Rivadeneira, Fernando; Hoogeveen, Ron C.; Fontes, João Daniel; Meisinger, Christa; Keaney, John F.; Lemaitre, Rozenn; Aulchenko, Yurii S.; Vasan, Ramachandran S.; Ellis, Stephen; Hazen, Stanley L.; van Duijn, Cornelia M.; Nelson, Jeanenne J.; März, Winfried; Schunkert, Heribert; McPherson, Ruth M.; Stirnadel-Farrant, Heide A.; Psaty, Bruce M.; Gieger, Christian; Siscovick, David; Hofman, Albert; Illig, Thomas; Cushman, Mary; Yamamoto, Jennifer F.; Rotter, Jerome I.; Larson, Martin G.; Stewart, Alexandre F.R.; Boerwinkle, Eric; Witteman, Jacqueline C.M.; Tracy, Russell P.; Koenig, Wolfgang; Benjamin, Emelia J.; Ballantyne, Christie M.

    2012-01-01

    Aims Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Methods and results In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 × 10−23, log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE–APOC1–APOC4–APOC2 cluster [P = 4.9 × 10−30; log Lp-PLA2 difference per allele (beta): −0.054]. There were no significant gene–environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study. Conclusion Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels. PMID:22003152

  15. Arthritis Genetics Analysis Aids Drug Discovery

    Science.gov (United States)

    ... Matters NIH Research Matters January 13, 2014 Arthritis Genetics Analysis Aids Drug Discovery An international research team ... may play a role in triggering the disease. Genetic factors are also thought to play a role. ...

  16. Analysis of t(9;17)(q33.2;q25.3) chromosomal breakpoint regions and genetic association reveals novel candidate genes for bipolar disorder

    DEFF Research Database (Denmark)

    Rajkumar, A.P.; Christensen, Jane H.; Mattheisen, Manuel

    2015-01-01

    ,856) data. Genetic associations between these disorders and single nucleotide polymorphisms within these breakpoint regions were analysed by BioQ, FORGE, and RegulomeDB programmes. RESULTS: Four protein-coding genes [coding for (endonuclease V (ENDOV), neuronal pentraxin I (NPTX1), ring finger protein 213...

  17. MCPerm: a Monte Carlo permutation method for accurately correcting the multiple testing in a meta-analysis of genetic association studies.

    Directory of Open Access Journals (Sweden)

    Yongshuai Jiang

    Full Text Available Traditional permutation (TradPerm tests are usually considered the gold standard for multiple testing corrections. However, they can be difficult to complete for the meta-analyses of genetic association studies based on multiple single nucleotide polymorphism loci as they depend on individual-level genotype and phenotype data to perform random shuffles, which are not easy to obtain. Most meta-analyses have therefore been performed using summary statistics from previously published studies. To carry out a permutation using only genotype counts without changing the size of the TradPerm P-value, we developed a Monte Carlo permutation (MCPerm method. First, for each study included in the meta-analysis, we used a two-step hypergeometric distribution to generate a random number of genotypes in cases and controls. We then carried out a meta-analysis using these random genotype data. Finally, we obtained the corrected permutation P-value of the meta-analysis by repeating the entire process N times. We used five real datasets and five simulation datasets to evaluate the MCPerm method and our results showed the following: (1 MCPerm requires only the summary statistics of the genotype, without the need for individual-level data; (2 Genotype counts generated by our two-step hypergeometric distributions had the same distributions as genotype counts generated by shuffling; (3 MCPerm had almost exactly the same permutation P-values as TradPerm (r = 0.999; P<2.2e-16; (4 The calculation speed of MCPerm is much faster than that of TradPerm. In summary, MCPerm appears to be a viable alternative to TradPerm, and we have developed it as a freely available R package at CRAN: http://cran.r-project.org/web/packages/MCPerm/index.html.

  18. Genetic analysis of bleeding disorders.

    Science.gov (United States)

    Edison, E; Konkle, B A; Goodeve, A C

    2016-07-01

    Molecular genetic analysis of inherited bleeding disorders has been practised for over 30 years. Technological changes have enabled advances, from analyses using extragenic linked markers to next-generation DNA sequencing and microarray analysis. Two approaches for genetic analysis are described, each suiting their environment. The Christian Medical Centre in Vellore, India, uses conformation-sensitive gel electrophoresis mutation screening of multiplexed PCR products to identify candidate mutations, followed by Sanger sequencing confirmation of variants identified. Specific analyses for F8 intron 1 and 22 inversions are also undertaken. The MyLifeOurFuture US project between the American Thrombosis and Hemostasis Network, the National Hemophilia Foundation, Bloodworks Northwest and Biogen uses molecular inversion probes (MIP) to capture target exons, splice sites plus 5' and 3' sequences and to detect F8 intron 1 and 22 inversions. This allows screening for all F8 and F9 variants in one sequencing run of multiple samples (196 or 392). Sequence variants identified are subsequently confirmed by a diagnostic laboratory. After having identified variants in genes of interest through these processes, a systematic procedure determining their likely pathogenicity should be applied. Several scientific societies have prepared guidelines. Systematic analysis of the available evidence facilitates reproducible scoring of likely pathogenicity. Documentation of frequency in population databases of variant prevalence and in locus-specific mutation databases can provide initial information on likely pathogenicity. Whereas null mutations are often pathogenic, missense and splice site variants often require in silico analyses to predict likely pathogenicity and using an accepted suite of tools can help standardize their documentation.

  19. Microsatellite data analysis for population genetics.

    Science.gov (United States)

    Kim, Kyung Seok; Sappington, Thomas W

    2013-01-01

    Theories and analytical tools of population genetics have been widely applied for addressing various questions in the fields of ecological genetics, conservation biology, and any context where the role of dispersal or gene flow is important. Underlying much of population genetics is the analysis of variation at selectively neutral marker loci, and microsatellites continue to be a popular choice of marker. In recent decades, software programs to estimate population genetics parameters have been developed at an increasing pace as computational science and theoretical knowledge advance. Numerous population genetics software programs are presently available to analyze microsatellite genotype data, but only a handful are commonly employed for calculating parameters such as genetic variation, genetic structure, patterns of spatial and temporal gene flow, population demography, individual population assignment, and genetic relationships within and between populations. In this chapter, we introduce statistical analyses and relevant population genetic software programs that are commonly employed in the field of population genetics and molecular ecology.

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

    NARCIS (Netherlands)

    G. Davies (Gail); N.J. Armstrong (Nicola J.); J.C. Bis (Joshua); J. Bressler (Jan); V. Chouraki (Vincent); S. Giddaluru (Sudheer); E. Hofer; C.A. Ibrahim-Verbaas (Carla); M. Kirin (Mirna); J. Lahti; S. van der Lee (Sven); S. Le Hellard (Stephanie); T. Liu; R.E. Marioni (Riccardo); C. Oldmeadow (Christopher); D. Postmus (Douwe); G.D. Smith; J.A. Smith (Jennifer A); A. Thalamuthu (Anbupalam); R. Thomson (Russell); V. Vitart (Veronique); J. Wang; L. Yu; L. Zgaga (Lina); W. Zhao (Wei); R. Boxall (Ruth); S.E. Harris (Sarah); W.D. Hill (W. David); D.C. Liewald (David C.); M. Luciano (Michelle); H.H.H. Adams (Hieab); D. Ames; N. Amin (Najaf); P. Amouyel (Philippe); A.A. Assareh; R. Au; J.T. Becker; A. Beiser; C. Berr (Claudine); L. Bertram (Lars); E.A. Boerwinkle (Eric); B.M. Buckley (Brendan M.); H. Campbell (Harry); J. Corley; P.L. De Jager; C. Dufouil (Carole); J.G. Eriksson (Johan G.); T. Espeseth (Thomas); J.D. Faul; I. Ford; G. Scotland (Generation); R.F. Gottesman (Rebecca); M.D. Griswold (Michael); V. Gudnason (Vilmundur); T.B. Harris; G. Heiss (Gerardo); A. Hofman (Albert); E.G. Holliday (Elizabeth); J.E. Huffman (Jennifer); S.L.R. Kardia (Sharon); N.A. Kochan (Nicole A.); D.S. Knopman (David); J.B. Kwok; J.-C. Lambert; T. Lee; G. Li; S.-C. Li; M. Loitfelder (Marisa); O.L. Lopez (Oscar); A.J. Lundervold; A. Lundqvist; R. Mather; S.S. Mirza (Saira S.aeed); L. Nyberg; B.A. Oostra (Ben); A. Palotie (Aarno); G. Papenberg; A. Pattie (Alison); K. Petrovic (Katja); O. Polasek (Ozren); B.M. Psaty (Bruce); P. Redmond (Paul); S. Reppermund; J.I. Rotter; R. Schmidt (Reinhold); M. Schuur (Maaike); P.W. Schofield; R.J. Scott; V.M. Steen (Vidar); D.J. Stott (David J.); J.C. van Swieten (John); K.D. Taylor (Kent); J. Trollor; S. Trompet (Stella); A.G. Uitterlinden (André); G. Weinstein; E. Widen (Elisabeth); B.G. Windham (B Gwen); J.W. Jukema (Jan Wouter); A. Wright (Alan); M.J. Wright (Margaret); Q. Yang (Qiong Fang); H. Amieva (Hélène); J. Attia (John); D.A. Bennett (David); H. Brodaty (Henry); A.J. de Craen (Anton); C. Hayward; M.A. Ikram (Arfan); U. Lindenberger; L.-G. Nilsson; D.J. Porteous (David J.); K. Räikkönen (Katri); I. Reinvang (Ivar); I. Rudan (Igor); P.S. Sachdev (Perminder); R. Schmidt; P. Schofield (Peter); V. Srikanth; J.M. Starr (John); S.T. Turner (Stephen); D.R. Weir (David R.); J.F. Wilson (James F); C.M. van Duijn (Cornelia M.); L.J. Launer (Lenore); A.L. Fitzpatrick (Annette); S. Seshadri (Sudha); T.H. Mosley (Thomas H.); I.J. Deary (Ian J.)

    2015-01-01

    textabstractGeneral cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of g

  1. Short communication: Genetic association between schizophrenia and cannabis use.

    Science.gov (United States)

    Verweij, Karin J H; Abdellaoui, Abdel; Nivard, Michel G; Sainz Cort, Alberto; Ligthart, Lannie; Draisma, Harmen H M; Minică, Camelia C

    2017-02-01

    Previous studies have shown a relationship between schizophrenia and cannabis use. As both traits are substantially heritable, a shared genetic liability could explain the association. We use two recently developed genomics methods to investigate the genetic overlap between schizophrenia and cannabis use. Firstly, polygenic risk scores for schizophrenia were created based on summary statistics from the largest schizophrenia genome-wide association (GWA) meta-analysis to date. We analysed the association between these schizophrenia polygenic scores and multiple cannabis use phenotypes (lifetime use, regular use, age at initiation, and quantity and frequency of use) in a sample of 6,931 individuals. Secondly, we applied LD-score regression to the GWA summary statistics of schizophrenia and lifetime cannabis use to calculate the genome-wide genetic correlation. Polygenic risk scores for schizophrenia were significantly (αschizophrenia and lifetime cannabis use. Common genetic variants underlying schizophrenia and lifetime cannabis use are partly overlapping. Individuals with a stronger genetic predisposition to schizophrenia are more likely to initiate cannabis use, use cannabis more regularly, and consume more cannabis over their lifetime. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. [An analysis of the prevalence of isolated dental anomalies and of those associated with hereditary syndromes: a model for evaluating the genetic control of the dentition characteristics].

    Science.gov (United States)

    Baccetti, T

    1993-06-01

    Tooth ontogenesis, morphogenesis, and eruption are under a multifactorial (genetic, epigenetic, environmental) control. The aim of this study has been a genetic appraisal of tooth developmental characteristics by means of the prevalence and patterns of association of tooth anomalies in a large sample of hereditary syndromes. MATERIALS AND METHODS. A sample of 169 hereditary syndromes exhibiting tooth abnormalities was collected from the literature: original articles were controlled in order to achieve uniformity of judgement about the definition of the dental defects. Tooth anomalies were classified according to anatomoclinical criteria: number (hypodontia/hyperdontia), shape, position, structure (enamel/dentin/cementum), size (micro-/macrodontism), eruption (precocious/delayed including unerupted teeth). Prevalence data were calculated for: 1) modes of syndrome inheritance; 2) syndromes exhibiting a single dental anomaly vs. syndromes exhibiting associated tooth abnormalities; 3) different types of tooth abnormalities; 4) isolated and associated tooth abnormalities.

  3. Genetics in psychiatry: common variant association studies

    Directory of Open Access Journals (Sweden)

    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.

  4. Genetic analysis of 103 candidate genes for coronary artery disease and associated phenotypes in a founder population reveals a new association between endothelin-1 and high-density lipoprotein cholesterol.

    Science.gov (United States)

    Pare, Guillaume; Serre, David; Brisson, Diane; Anand, Sonia S; Montpetit, Alexandre; Tremblay, Gerald; Engert, James C; Hudson, Thomas J; Gaudet, Daniel

    2007-04-01

    Coronary artery disease (CAD) is a major health concern in both developed and developing countries. With a heritability estimated at ~50%, there is a strong rationale to better define the genetic contribution to CAD. This project involves the analysis of 884 individuals from 142 families (with average sibships of 5.7) as well as 558 case and control subjects from the Saguenay Lac St-Jean region of northeastern Quebec, with the use of 1,536 single-nucleotide polymorphisms (SNPs) in 103 candidate genes for CAD. By use of clusters of SNPs to generate multiallelic haplotypes at candidate loci for segregation studies within families, suggestive linkage for high-density lipoprotein (HDL) cholesterol is observed on chromosome 1p36.22. Furthermore, several associations that remain significant after Bonferroni correction are observed with lipoprotein-related traits as well as plasma concentrations of adiponectin. Of note, HDL cholesterol levels are associated with an amino acid substitution (lysine/asparagine) at codon 198 (rs5370) of endothelin-1 (EDN1) in a sex-specific manner, as well as with a SNP (rs2292318) located 7.7 kb upstream of lecithin cholesterol acyl-transferase (LCAT). Whereas the other observed associations are described in the current literature, these two are new. Using an independent validation sample of 806 individuals, we confirm the EDN1 association (P<.005), whereas the LCAT association was nonsignificant (P=.12).

  5. 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.

  6. Genetic syndromes associated with overgrowth in childhood.

    Science.gov (United States)

    Ko, Jung Min

    2013-09-01

    Overgrowth syndromes comprise a diverse group of conditions with unique clinical, behavioral and molecular genetic features. While considerable overlap in presentation sometimes exists, advances in identification of the precise etiology of specific overgrowth disorders continue to improve clinicians' ability to make an accurate diagnosis. Among them, this paper introduces two classic genetic overgrowth syndromes: Sotos syndrome and Beckwith-Wiedemann syndrome. Historically, the diagnosis was based entirely on clinical findings. However, it is now understood that Sotos syndrome is caused by a variety of molecular genetic alterations resulting in haploinsufficiency of the NSD1 gene at chromosome 5q35 and that Beckwith-Wiedemann syndrome is caused by heterogeneous abnormalities in the imprinting of a number of growth regulatory genes within chromosome 11p15 in the majority of cases. Interestingly, the 11p15 imprinting region is also associated with Russell-Silver syndrome which is a typical growth retardation syndrome. Opposite epigenetic alterations in 11p15 result in opposite clinical features shown in Beckwith-Wiedemann syndrome and Russell-Silver syndrome. Although the exact functions of the causing genes have not yet been completely understood, these overgrowth syndromes can be good models to clarify the complex basis of human growth and help to develop better-directed therapies in the future.

  7. Disease-Concordant Twins Empower Genetic Association Studies.

    Science.gov (United States)

    Tan, Qihua; Li, Weilong; Vandin, Fabio

    2017-01-01

    Genome-wide association studies with moderate sample sizes are underpowered, especially when testing SNP alleles with low allele counts, a situation that may lead to high frequency of false-positive results and lack of replication in independent studies. Related individuals, such as twin pairs concordant for a disease, should confer increased power in genetic association analysis because of their genetic relatedness. We conducted a computer simulation study to explore the power advantage of the disease-concordant twin design, which uses singletons from disease-concordant twin pairs as cases and ordinary healthy samples as controls. We examined the power gain of the twin-based design for various scenarios (i.e., cases from monozygotic and dizygotic twin pairs concordant for a disease) and compared the power with the ordinary case-control design with cases collected from the unrelated patient population. Simulation was done by assigning various allele frequencies and allelic relative risks for different mode of genetic inheritance. In general, for achieving a power estimate of 80%, the sample sizes needed for dizygotic and monozygotic twin cases were one half and one fourth of the sample size of an ordinary case-control design, with variations depending on genetic mode. Importantly, the enriched power for dizygotic twins also applies to disease-concordant sibling pairs, which largely extends the application of the concordant twin design. Overall, our simulation revealed a high value of disease-concordant twins in genetic association studies and encourages the use of genetically related individuals for highly efficiently identifying both common and rare genetic variants underlying human complex diseases without increasing laboratory cost. © 2016 John Wiley & Sons Ltd/University College London.

  8. Whole genome sequence analysis indicates recent diversification of mammal-associated Campylobacter fetus and implicates a genetic factor associated with H

    NARCIS (Netherlands)

    Graaf-van Bloois, van der Linda; Duim, Birgitta; Miller, William G.; Forbes, Ken J.; Wagenaar, Jaap A.; Zomer, Aldert

    2016-01-01

    Background: Campylobacter fetus (C. fetus) can cause disease in both humans and animals. C. fetus has been divided into three subspecies: C. fetus subsp. fetus (Cff), C. fetus subsp. venerealis (Cfv) and C. fetus subsp. testudinum (Cft). Subspecies identification of mammal-associated C. fetus

  9. Whole genome sequence analysis indicates recent diversification of mammal-associated Campylobacter fetus and implicates a genetic factor associated with H2S production

    NARCIS (Netherlands)

    van der Graaf-van Bloois, Linda|info:eu-repo/dai/nl/336455798; Duim, Birgitta|info:eu-repo/dai/nl/143855352; Miller, William G; Forbes, Ken J; Wagenaar, Jaap A|info:eu-repo/dai/nl/126613354; Zomer, Aldert

    2016-01-01

    BACKGROUND: Campylobacter fetus (C. fetus) can cause disease in both humans and animals. C. fetus has been divided into three subspecies: C. fetus subsp. fetus (Cff), C. fetus subsp. venerealis (Cfv) and C. fetus subsp. testudinum (Cft). Subspecies identification of mammal-associated C. fetus

  10. Dietary fatty acids modulate associations between genetic variants and circulating fatty acids in plasma and erythrocyte membranes: meta-analysis of 9 studies in the CHARGE consortium

    Science.gov (United States)

    Smith, Caren E.; Follis, Jack L.; Nettleton, Jennifer A.; Foy, Millennia; Wu, Jason H.Y.; Ma, Yiyi; Tanaka, Toshiko; Manichakul, Ani W.; Wu, Hongyu; Chu, Audrey Y.; Steffen, Lyn M.; Fornage, Myriam; Mozaffarian, Dariush; Kabagambe, Edmond K.; Ferruci, Luigi; da Chen, Yii-Der I; Rich, Stephen S.; Djoussé, Luc; Ridker, Paul M.; Tang, Weihong; McKnight, Barbara; Tsai, Michael Y.; Bandinelli, Stefania; Rotter, Jerome I.; Hu, Frank B.; Chasman, Daniel I.; Psaty, Bruce M.; Arnett, Donna K.; King, Irena B.; Sun, Qi; Wang, Lu; Lumley, Thomas; Chiuve, Stephanie E.; Siscovick, David S; Ordovás, José M.; Lemaitre, Rozenn N.

    2015-01-01

    Scope Tissue concentrations of omega-3 fatty acids may reduce cardiovascular disease risk, and genetic variants are associated with circulating fatty acids concentrations. Whether dietary fatty acids interact with genetic variants to modify circulating omega-3 fatty acids is unclear. Objective We evaluated interactions between genetic variants and fatty acid intakes for circulating alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). Methods and Results We conducted meta-analyses (N to 11,668) evaluating interactions between dietary fatty acids and genetic variants (rs174538 and rs174548 in FADS1 (fatty acid desaturase 1), rs7435 in AGPAT3 (1-acyl-sn-glycerol-3-phosphate), rs4985167 in PDXDC1 (pyridoxal-dependent decarboxylase domain-containing 1), rs780094 in GCKR (glucokinase regulatory protein) and rs3734398 in ELOVL2 (fatty acid elongase 2)). Stratification by measurement compartment (plasma vs. erthyrocyte) revealed compartment-specific interactions between FADS1 rs174538 and rs174548 and dietary ALA and linoleic acid for DHA and DPA. Conclusion Our findings reinforce earlier reports that genetically-based differences in circulating fatty acids may be partially due to differences in the conversion of fatty acid precursors. Further, fatty acids measurement compartment may modify gene-diet relationships, and considering compartment may improve the detection of gene-fatty acids interactions for circulating fatty acid outcomes. PMID:25626431

  11. Integrative Lifecourse and Genetic Analysis of Military Working Dogs

    Science.gov (United States)

    2013-10-01

    1 Award Number: W81XWH-11-2-0226 TITLE: Integrative Lifecourse and Genetic Analysis of Military Working Dogs PRINCIPAL...insight into gene environment interactions. It leverages the simplified genetics and detailed records of the military working dog population. There are...regions associated with phenotypic variation between dog breeds using selection mapping. PLoS Genet . 7(10):e1002316. PubMed PMID: 22022279). In the

  12. Microsatellite data analysis for population genetics

    Science.gov (United States)

    Theories and analytical tools of population genetics have been widely applied for addressing various questions in the fields of ecological genetics, conservation biology, and any context where the role of dispersal or gene flow is important. Underlying much of population genetics is the analysis of ...

  13. Genetic analysis of environmental variation

    NARCIS (Netherlands)

    Hill, W.G.; Mulder, H.A.

    2010-01-01

    Environmental variation (VE) in a quantitative trait – variation in phenotype that cannot be explained by genetic variation or identifiable genetic differences – can be regarded as being under some degree of genetic control. Such variation may be either between repeated expressions of the same trait

  14. Genetic analysis of environmental variation

    NARCIS (Netherlands)

    Hill, W.G.; Mulder, H.A.

    2010-01-01

    Environmental variation (VE) in a quantitative trait – variation in phenotype that cannot be explained by genetic variation or identifiable genetic differences – can be regarded as being under some degree of genetic control. Such variation may be either between repeated expressions of the same trait

  15. Genetic and Molecular Network Analysis of Behavior

    OpenAIRE

    Williams, Robert W.; Mulligan, Megan K.

    2012-01-01

    This chapter provides an introduction into the genetic control and analysis of behavioral variation using powerful online resources. We introduce you to the new field of systems genetics using "case studies" drawn from the world of behavioral genetics that exploit populations of genetically diverse lines of mice. These lines differ very widely in patterns of gene and protein expression in the brain and in patterns of behavior. In this chapter we address the following set of related questions:...

  16. Molecular Genetic Alterations in Renal Cell Carcinomas With Tubulocystic Pattern: Tubulocystic Renal Cell Carcinoma, Tubulocystic Renal Cell Carcinoma With Heterogenous Component and Familial Leiomyomatosis-associated Renal Cell Carcinoma. Clinicopathologic and Molecular Genetic Analysis of 15 Cases.

    Science.gov (United States)

    Ulamec, Monika; Skenderi, Faruk; Zhou, Ming; Krušlin, Božo; Martínek, Petr; Grossmann, Petr; Peckova, Kvetoslava; Alvarado-Cabrero, Isabel; Kalusova, Kristyna; Kokoskova, Bohuslava; Rotterova, Pavla; Hora, Milan; Daum, Ondrej; Dubova, Magdalena; Bauleth, Kevin; Slouka, David; Sperga, Maris; Davidson, Whitney; Rychly, Boris; Perez Montiel, Delia; Michal, Michal; Hes, Ondrej

    2016-08-01

    The characteristic morphologic spectrum of tubulocystic renal cell carcinoma (TC-RCC) may include areas resembling papillary RCC (PRCC). Our study includes 15 RCCs with tubulocystic pattern: 6 TC-RCCs, 1 RCC-high grade with tubulocystic architecture, 5 TC-RCCs with foci of PRCC, 2 with high-grade RCC (HGRCC) not otherwise specified, and 1 with a clear cell papillary RCC/renal angiomyoadenomatous tumor-like component. We analyzed aberrations of chromosomes 7, 17, and Y; mutations of VHL and FH genes; and loss of heterozygosity at chromosome 3p. Genetic analysis was performed separately in areas of classic TC-RCC and in those with other histologic patterns. The TC-RCC component demonstrated disomy of chromosome 7 in 9/15 cases, polysomy of chromosome 17 in 7/15 cases, and loss of Y in 1 case. In the PRCC component, 2/3 analyzable cases showed disomy of chromosome 7 and polysomy of chromosome 17 with normal Y. One case with focal HGRCC exhibited only disomy 7, whereas the case with clear cell papillary RCC/renal angiomyoadenomatous tumor-like pattern showed polysomies of 7 and 17, mutation of VHL, and loss of heterozygosity 3p. FH gene mutation was identified in a single case with an aggressive clinical course and predominant TC-RCC pattern. The following conclusions were drawn: (1) TC-RCC demonstrates variable status of chromosomes 7, 17, and Y even in cases with typical/uniform morphology. (2) The biological nature of PRCC/HGRCC-like areas within TC-RCC remains unclear. Our data suggest that heterogenous TC-RCCs may be associated with an adverse clinical outcome. (3) Hereditary leiomyomatosis-associated RCC can be morphologically indistinguishable from "high-grade" TC-RCC; therefore, in TC-RCC with high-grade features FH gene status should be tested.

  17. Genetics of homocysteine metabolism and associated disorders

    Directory of Open Access Journals (Sweden)

    S. Brustolin

    2010-01-01

    Full Text Available Homocysteine is a sulfur-containing amino acid derived from the metabolism of methionine, an essential amino acid, and is metabolized by one of two pathways: remethylation or transsulfuration. Abnormalities of these pathways lead to hyperhomocysteinemia. Hyperhomocysteinemia is observed in approximately 5% of the general population and is associated with an increased risk for many disorders, including vascular and neurodegenerative diseases, autoimmune disorders, birth defects, diabetes, renal disease, osteoporosis, neuropsychiatric disorders, and cancer. We review here the correlation between homocysteine metabolism and the disorders described above with genetic variants on genes coding for enzymes of homocysteine metabolism relevant to clinical practice, especially common variants of the MTHFR gene, 677C>T and 1298A>C. We also discuss the management of hyperhomocysteinemia with folic acid supplementation and fortification of folic acid and the impact of a decrease in the prevalence of congenital anomalies and a decline in the incidence of stroke mortality.

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

    Science.gov (United States)

    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)

  19. Disease-Concordant Twins Empower Genetic Association Studies

    DEFF Research Database (Denmark)

    Tan, Qihua; Li, Weilong; Vandin, Fabio

    2017-01-01

    Genome-wide association studies with moderate sample sizes are underpowered, especially when testing SNP alleles with low allele counts, a situation that may lead to high frequency of false-positive results and lack of replication in independent studies. Related individuals, such as twin pairs...... concordant for a disease, should confer increased power in genetic association analysis because of their genetic relatedness. We conducted a computer simulation study to explore the power advantage of the disease-concordant twin design, which uses singletons from disease-concordant twin pairs as cases...... and ordinary healthy samples as controls. We examined the power gain of the twin-based design for various scenarios (i.e., cases from monozygotic and dizygotic twin pairs concordant for a disease) and compared the power with the ordinary case-control design with cases collected from the unrelated patient...

  20. 'Smoking genes': a genetic association study.

    Directory of Open Access Journals (Sweden)

    Zoraida Verde

    Full Text Available Some controversy exists on the specific genetic variants that are associated with nicotine dependence and smoking-related phenotypes. The purpose of this study was to analyse the association of smoking status and smoking-related phenotypes (included nicotine dependence with 17 candidate genetic variants: CYP2A6*1×2, CYP2A6*2 (1799T>A [rs1801272], CYP2A6*9 (-48T>G [rs28399433], CYP2A6*12, CYP2A13*2 (3375C>T [rs8192789], CYP2A13*3 (7520C>G, CYP2A13*4 (579G>A, CYP2A13*7 (578C>T [rs72552266], CYP2B6*4 (785A>G, CYP2B6*9 (516G>T, CHRNA3 546C>T [rs578776], CHRNA5 1192G>A [rs16969968], CNR1 3764C>G [rs6928499], DRD2-ANKK1 2137G>A (Taq1A [rs1800497], 5HTT LPR, HTR2A -1438A>G [rs6311] and OPRM1 118A>G [rs1799971]. We studied the genotypes of the aforementioned polymorphisms in a cohort of Spanish smokers (cases, N = 126 and ethnically matched never smokers (controls, N = 80. The results showed significant between-group differences for CYP2A6*2 and CYP2A6*12 (both PA (Taq1A polymorphisms was 3.60 (95%CI: 1.75, 7.44 and 2.63 (95%CI: 1.41, 4.89 respectively. Compared with the wild-type genotype, the OR for being a non-smoker in carriers of the minor CYP2A6*2 allele was 1.80 (95%CI: 1.24, 2.65. We found a significant genotype effect (all P≤0.017 for the following smoking-related phenotypes: (i cigarettes smoked per day and CYP2A13*3; (ii pack years smoked and CYP2A6*2, CYP2A6*1×2, CYP2A13*7, CYP2B6*4 and DRD2-ANKK1 2137G>A (Taq1A; (iii nicotine dependence (assessed with the Fagestrom test and CYP2A6*9. Overall, our results suggest that genetic variants potentially involved in nicotine metabolization (mainly, CYP2A6 polymorphisms are those showing the strongest association with smoking-related phenotypes, as opposed to genetic variants influencing the brain effects of nicotine, e.g., through nicotinic acetylcholine (CHRNA5, serotoninergic (HTR2A, opioid (OPRM1 or cannabinoid receptors (CNR1.

  1. Analysis of t(9;17)(q33.2;q25.3) chromosomal breakpoint regions and genetic association reveals novel candidate genes for bipolar disorder

    DEFF Research Database (Denmark)

    Rajkumar, A.P.; Christensen, Jane H.; Mattheisen, Manuel

    2015-01-01

    OBJECTIVES: Breakpoints of chromosomal abnormalities facilitate identification of novel candidate genes for psychiatric disorders. Genome-wide significant evidence supports the linkage between chromosome 17q25.3 and bipolar disorder (BD). Co-segregation of translocation t(9;17)(q33.2;q25.......3) with psychiatric disorders has been reported. We aimed to narrow down these chromosomal breakpoint regions and to investigate the associations between single nucleotide polymorphisms within these regions and BD as well as schizophrenia (SZ) in large genome-wide association study samples. METHODS: We cross......,856) data. Genetic associations between these disorders and single nucleotide polymorphisms within these breakpoint regions were analysed by BioQ, FORGE, and RegulomeDB programmes. RESULTS: Four protein-coding genes [coding for (endonuclease V (ENDOV), neuronal pentraxin I (NPTX1), ring finger protein 213...

  2. Multivariate Analysis of Genotype-Phenotype Association.

    Science.gov (United States)

    Mitteroecker, Philipp; Cheverud, James M; Pavlicev, Mihaela

    2016-04-01

    With the advent of modern imaging and measurement technology, complex phenotypes are increasingly represented by large numbers of measurements, which may not bear biological meaning one by one. For such multivariate phenotypes, studying the pairwise associations between all measurements and all alleles is highly inefficient and prevents insight into the genetic pattern underlying the observed phenotypes. We present a new method for identifying patterns of allelic variation (genetic latent variables) that are maximally associated-in terms of effect size-with patterns of phenotypic variation (phenotypic latent variables). This multivariate genotype-phenotype mapping (MGP) separates phenotypic features under strong genetic control from less genetically determined features and thus permits an analysis of the multivariate structure of genotype-phenotype association, including its dimensionality and the clustering of genetic and phenotypic variables within this association. Different variants of MGP maximize different measures of genotype-phenotype association: genetic effect, genetic variance, or heritability. In an application to a mouse sample, scored for 353 SNPs and 11 phenotypic traits, the first dimension of genetic and phenotypic latent variables accounted for >70% of genetic variation present in all 11 measurements; 43% of variation in this phenotypic pattern was explained by the corresponding genetic latent variable. The first three dimensions together sufficed to account for almost 90% of genetic variation in the measurements and for all the interpretable genotype-phenotype association. Each dimension can be tested as a whole against the hypothesis of no association, thereby reducing the number of statistical tests from 7766 to 3-the maximal number of meaningful independent tests. Important alleles can be selected based on their effect size (additive or nonadditive effect on the phenotypic latent variable). This low dimensionality of the genotype-phenotype map

  3. 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

    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...

  4. Periodontal disease associated to systemic genetic disorders.

    Science.gov (United States)

    Nualart Grollmus, Zacy Carola; Morales Chávez, Mariana Carolina; Silvestre Donat, Francisco Javier

    2007-05-01

    A number of systemic disorders increase patient susceptibility to periodontal disease, which moreover evolves more rapidly and more aggressively. The underlying factors are mainly related to alterations in immune, endocrine and connective tissue status. These alterations are associated with different pathologies and syndromes that generate periodontal disease either as a primary manifestation or by aggravating a pre-existing condition attributable to local factors. This is where the role of bacterial plaque is subject to debate. In the presence of qualitative or quantitative cellular immune alterations, periodontal disease may manifest early on a severe localized or generalized basis--in some cases related to the presence of plaque and/or specific bacteria (severe congenital neutropenia or infantile genetic agranulocytosis, Chediak-Higiashi syndrome, Down syndrome and Papillon-Lefévre syndrome). In the presence of humoral immune alterations, periodontal damage may result indirectly as a consequence of alterations in other systems. In connective tissue disorders, bacterial plaque and alterations of the periodontal tissues increase patient susceptibility to gingival inflammation and alveolar resorption (Marfan syndrome and Ehler-Danlos syndrome). The management of periodontal disease focuses on the control of infection and bacterial plaque by means of mechanical and chemical methods. Periodontal surgery and even extraction of the most seriously affected teeth have also been suggested. There are variable degrees of consensus regarding the background systemic disorder, as in the case of Chediak-Higiashi syndrome, where antibiotic treatment proves ineffective; in severe congenital neutropenia or infantile genetic agranulocytosis, where antibiotic prophylaxis is suggested; and in Papillon-Lefévre syndrome, where an established treatment protocol is available.

  5. Longitudinal Genetic Analysis of Anxiety Sensitivity

    Science.gov (United States)

    Zavos, Helena M. S.; Gregory, Alice M.; Eley, Thalia C.

    2012-01-01

    Anxiety sensitivity is associated with both anxiety and depression and has been shown to be heritable. Little, however, is known about the role of genetic influence on continuity and change of symptoms over time. The authors' aim was to examine the stability of anxiety sensitivity during adolescence. By using a genetically sensitive design, the…

  6. Genetic Analysis in Translational Medicine: The 2010 GOLDEN HELIX Symposium.

    Science.gov (United States)

    Patrinos, George P; Innocenti, Federico; Cox, Nancy; Fortina, Paolo

    2011-06-01

    The 2010 GOLDEN HELIX Symposium "Genetic Analysis in Translational Medicine" was held in Athens, Greece, 1-4 December 2010. The scientific program covered all aspects of this discipline, including genome-wide association studies, genomics of cancer and human disorders, molecular cytogenetics, advances in genomic technology, next-generation sequencing applications, pharmacogenomics, and bioinformatics. In addition, various topics on genetics and society and genetic analysis in clinical practice were discussed. We provide an overview of the plenary lectures and the topics discussed in the symposium.

  7. Functional relevance for associations between osteoporosis and genetic variants

    Science.gov (United States)

    Tan, Li-Jun; Wang, Peng; Chen, Xiang-Ding; Zhu, Li-Hua; Zeng, Qin; Hu, Yuan; Deng, Hong-Wen

    2017-01-01

    Osteoporosis is characterized by increased bone loss and deterioration of bone microarchitecture, which will lead to reduced bone strength and increased risk of fragility fractures. Previous studies have identified many genetic loci associated with osteoporosis, but functional mechanisms underlying the associations have rarely been explored. In order to explore the potential molecular functional mechanisms underlying the associations for osteoporosis, we performed integrative analyses by using the publically available datasets and resources. We searched 128 identified osteoporosis associated SNPs (Posteoporosis. This study may provide novel insights into the functional mechanisms underlying the osteoporosis associated genetic variants, which will help us to comprehend the potential mechanisms underlying the genetic association for osteoporosis. PMID:28369098

  8. Are genetic variants for tobacco smoking associated with cannabis involvement?

    Science.gov (United States)

    Agrawal, Arpana; Lynskey, Michael T; Kapoor, Manav; Bucholz, Kathleen K; Edenberg, Howard J; Schuckit, Marc; Brooks, Andrew; Hesselbrock, Victor; Kramer, John; Saccone, Nancy; Tischfield, Jay; Bierut, Laura J

    2015-05-01

    Cannabis users are highly likely to also be tobacco cigarette smokers and a proportion of this comorbidity is attributable to shared genetic influences. Three large meta-analyses of genomewide association studies (GWAS) of tobacco smoking have identified multiple genomewide significant (psmoking and with cannabis involvement in an independent sample. Eleven SNPs associated with cigarettes per day (CPD), ever versus never smoking and current smoking/smoking cessation at psmoking measures in 2716 European-American subjects from the Study of Addictions Genes and Environment (SAGE) and with lifetime and current cannabis use and DSM-IV cannabis abuse/dependence. Cannabis use and tobacco smoking correlated at 0.54. Rs16969968 in CHRNA5 (and its proxy, rs1051730 in CHRNA3) and rs1451240, a proxy for rs13280604 in CHRNB3, were associated with CPD after Bonferroni correction (psmoking initiation, as in the original meta-analysis and also with lifetime cannabis use. Associations with cannabis involvement were no longer significant upon adjustment for the tobacco smoking measures. The modest associations between cannabis involvement and SNPs for tobacco smoking were not independent of the comorbidity between tobacco and cannabis involvement. Larger samples of individuals might be required to articulate the specific genetic architecture of cannabis involvement. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  9. Multivariate Analysis of Genotype–Phenotype Association

    Science.gov (United States)

    Mitteroecker, Philipp; Cheverud, James M.; Pavlicev, Mihaela

    2016-01-01

    With the advent of modern imaging and measurement technology, complex phenotypes are increasingly represented by large numbers of measurements, which may not bear biological meaning one by one. For such multivariate phenotypes, studying the pairwise associations between all measurements and all alleles is highly inefficient and prevents insight into the genetic pattern underlying the observed phenotypes. We present a new method for identifying patterns of allelic variation (genetic latent variables) that are maximally associated—in terms of effect size—with patterns of phenotypic variation (phenotypic latent variables). This multivariate genotype–phenotype mapping (MGP) separates phenotypic features under strong genetic control from less genetically determined features and thus permits an analysis of the multivariate structure of genotype–phenotype association, including its dimensionality and the clustering of genetic and phenotypic variables within this association. Different variants of MGP maximize different measures of genotype–phenotype association: genetic effect, genetic variance, or heritability. In an application to a mouse sample, scored for 353 SNPs and 11 phenotypic traits, the first dimension of genetic and phenotypic latent variables accounted for >70% of genetic variation present in all 11 measurements; 43% of variation in this phenotypic pattern was explained by the corresponding genetic latent variable. The first three dimensions together sufficed to account for almost 90% of genetic variation in the measurements and for all the interpretable genotype–phenotype association. Each dimension can be tested as a whole against the hypothesis of no association, thereby reducing the number of statistical tests from 7766 to 3—the maximal number of meaningful independent tests. Important alleles can be selected based on their effect size (additive or nonadditive effect on the phenotypic latent variable). This low dimensionality of the

  10. Associative Analysis in Statistics

    Directory of Open Access Journals (Sweden)

    Mihaela Muntean

    2015-03-01

    Full Text Available In the last years, the interest in technologies such as in-memory analytics and associative search has increased. This paper explores how you can use in-memory analytics and an associative model in statistics. The word “associative” puts the emphasis on understanding how datasets relate to one another. The paper presents the main characteristics of “associative” data model. Also, the paper presents how to design an associative model for labor market indicators analysis. The source is the EU Labor Force Survey. Also, this paper presents how to make associative analysis.

  11. Genetic analysis of rare disorders

    DEFF Research Database (Denmark)

    van den Berg, Stéphanie M; von Bornemann Hjelmborg, Jacob

    2012-01-01

    Twin concordance rates provide insight into the possibility of a genetic background for a disease. These concordance rates are usually estimated within a frequentistic framework. Here we take a Bayesian approach. For rare diseases, estimation methods based on asymptotic theory cannot be applied due...

  12. The genetic variant on chromosome 10p14 is associated with risk of colorectal cancer: results from a case-control study and a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Qin Qin

    Full Text Available BACKGROUND: A common single nucleotide polymorphism (SNP, rs10795668, located at 10p14, was first identified to be significantly associated with risk of colorectal cancer (CRC by a genome-wide association study (GWAS in 2008; however, another GWAS and following replication studies yielded conflicting results. METHODS: We conducted a case-control study of 470 cases and 475 controls in a Chinese population and then performed a meta-analysis, integrating the current study and 9 publications to evaluate the association between rs10795668 and CRC risk. Heterogeneity among studies and publication bias were assessed by the χ²-based Q statistic test and Egger's test, respectively. RESULTS: In the case-control study, significant association between the SNP and CRC risk was observed, with per-A-allele OR of 0.71 (95%CI: 0.54-0.94, P = 0.017. The following meta-analysis further confirmed the significant association, with per-A-allele OR of 0.91 (95%CI: 0.89-0.93, P(heterogeneity >0.05 in European population and 0.86 (95%CI: 0.78-0.96, P(heterogeneity <0.05 in Asian population. Besides, sensitivity analyses and publication bias assessment indicated the robust stability and reliability of the results. CONCLUSIONS: Results from our case-control study and the followed meta-analysis confirmed the significant association of rs10795668 with CRC risk.

  13. Genetic association signal near NTN4 in Tourette Syndrome

    Science.gov (United States)

    Paschou, Peristera; Yu, Dongmei; Gerber, Gloria; Evans, Patrick; Tsetsos, Fotis; Davis, Lea K.; Karagiannidis, Iordanis; Chaponis, Jonathan; Gamazon, Eric; Mueller-Vahl, Kirsten; Stuhrmann, Manfred; Schloegelhofer, Monika; Stamenkovic, Mara; Hebebrand, Johannes; Noethen, Markus; Nagy, Peter; Barta, Csaba; Tarnok, Zsanett; Rizzo, Renata; Depienne, Christel; Worbe, Yulia; Hartmann, Andreas; Cath, Danielle C.; Budman, Cathy L.; Sandor, Paul; Barr, Cathy; Wolanczyk, Thomas; Singer, Harvey; Chou, I-Ching; Grados, Marco; Posthuma, Danielle; Rouleau, Guy A.; Aschauer, Harald; Freimer, Nelson B.; Pauls, David L.; Cox, Nancy J.; Mathews, Carol A.; Scharf, Jeremiah M.

    2014-01-01

    Tourette Syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (SNPs)(p<10−3) from the recent TS genome-wide association study (GWAS) in 609 independent cases and 610 ancestry-matched controls. Only rs2060546 on chromosome 12q22 (p=3.3×10−4) remained significant after Bonferroni correction. Meta-analysis with the original GWAS yielded the strongest association to date (p=5.8×10−7). Although its functional significance is unclear, rs2060546 lies closest to NTN4, an axon guidance molecule expressed in developing striatum. Risk score analysis significantly predicted case/control status (p=0.042), suggesting that many of these variants are true TS risk alleles. PMID:25042818

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    mediate their effects on metabolic traits (e.g. BMI, cholesterol, high-density lipoprotein (HDL), hemoglobin A1c (HbA1c) and homeostatic model assessment of insulin resistance (HOMA-IR)) via altered DNA methylation in human adipose tissue. This study identifies genome-wide interactions between genetic......Little is known about the extent to which interactions between genetics and epigenetics may affect the risk of complex metabolic diseases and/or their intermediary phenotypes. We performed a genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human adipose tissue of 119 men......, where 592,794 single nucleotide polymorphisms (SNPs) were related to DNA methylation of 477,891 CpG sites, covering 99% of RefSeq genes. SNPs in significant mQTLs were further related to gene expression in adipose tissue and obesity related traits. We found 101,911 SNP-CpG pairs (mQTLs) in cis and 5...

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

    African Journals Online (AJOL)

    Methods: We identified three eligible studies, 499 prostate cancer cases and 571 ... Conclusions: Results from this meta-analysis indicate that the XRCC3 Thr241Met genetic variant is associated with prostate cancer risk. ... Article Metrics.

  16. Recommendations for using standardised phenotypes in genetic association studies

    Directory of Open Access Journals (Sweden)

    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.

  17. Determining the pathogenicity of genetic variants associated with cardiac channelopathies.

    Science.gov (United States)

    Campuzano, Oscar; Allegue, Catarina; Fernandez, Anna; Iglesias, Anna; Brugada, Ramon

    2015-01-22

    Advancements in genetic screening have generated massive amounts of data on genetic variation; however, a lack of clear pathogenic stratification has left most variants classified as being of unknown significance. This is a critical limitation for translating genetic data into clinical practice. Genetic screening is currently recommended in the guidelines for diagnosis and treatment of cardiac channelopathies, which are major contributors to sudden cardiac death in young people. We propose to characterize the pathogenicity of genetic variants associated with cardiac channelopathies using a stratified scoring system. The development of this system was considered by using all of the tools currently available to define pathogenicity. The use of this scoring system could help clinicians to understand the limitations of genetic associations with a disease, and help them better define the role that genetics can have in their clinical routine.

  18. Novel genetic loci associated with hippocampal volume

    NARCIS (Netherlands)

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

    2017-01-01

    textabstractThe 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 underpi

  19. Novel genetic loci associated with hippocampal volume

    NARCIS (Netherlands)

    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|info:eu-repo/dai/nl/34549072X; 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|info:eu-repo/dai/nl/286852071; 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|info:eu-repo/dai/nl/344497569; 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|info:eu-repo/dai/nl/304811432; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Bulayeva, Kazima B; Cahn, Wiepke|info:eu-repo/dai/nl/250566370; 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; Pol, Hilleke E Hulshoff|info:eu-repo/dai/nl/142348228; Ikeda, Masashi; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Jönsson, Erik G; Jukema, J Wouter; Kahn, René S|info:eu-repo/dai/nl/073778532; 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|info:eu-repo/dai/nl/271562161; 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

    2017-01-01

    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 hi

  20. Novel genetic loci associated with hippocampal volume

    NARCIS (Netherlands)

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

    2017-01-01

    textabstractThe 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 underpi

  1. Fine genetic mapping of the Batten disease locus (CLN3) by haplotype analysis and demonstration of allelic association with chromosome 16p microsatellite loci

    Energy Technology Data Exchange (ETDEWEB)

    Mitchison, H.M.; McKay, T.R. [Univ. College London Medical School (United Kingdom); Thompson, A.D.; Mulley, J.C.; Kozman, H.M.; Richards, R.I.; Callen, D.F. [Women and Children`s Hospital, Adelaide (Australia); Stallings, R.L.; Doggett, N.A. [Los Alamos National Lab., NM (United States); Attwood, J. [Galton Lab., London (United Kingdom)] [and others

    1993-05-01

    Batten disease, juvenile onset neuronal ceroid lipofuscinosis, is an autosomal recessive neurodegenerative disorder characterized by accumulation of autofluorescent lipopigment in neurons and other cell types. The disease locus (CLN3) has previously been assigned to chromosome 16p. The genetic localization of CLN3 has been refined by analyzing 70 families using a high-resolution map of 15 marker loci encompassing the CLN3 region on 16p. Crossovers in three maternal meioses allowed localization of CLN3 to the interval between D16S297 and D16S57. Within that interval alleles at three highly polymorphic dinucleotide repeat loci (D16S288, D16S298, D16S299) were found to be in strong linkage disequilibrium with CLN3. Analysis of haplotypes suggests that a majority of CLN3 chromosomes have arisen from a single founder mutation. 15 refs., 2 figs., 5 tabs.

  2. Evolutionary triangulation: informing genetic association studies with evolutionary evidence.

    Science.gov (United States)

    Huang, Minjun; Graham, Britney E; Zhang, Ge; Harder, Reed; Kodaman, Nuri; Moore, Jason H; Muglia, Louis; Williams, Scott M

    2016-01-01

    Genetic studies of human diseases have identified many variants associated with pathogenesis and severity. However, most studies have used only statistical association to assess putative relationships to disease, and ignored other factors for evaluation. For example, evolution is a factor that has shaped disease risk, changing allele frequencies as human populations migrated into and inhabited new environments. Since many common variants differ among populations in frequency, as does disease prevalence, we hypothesized that patterns of disease and population structure, taken together, will inform association studies. Thus, the population distributions of allelic risk variants should reflect the distributions of their associated diseases. Evolutionary Triangulation (ET) exploits this evolutionary differentiation by comparing population structure among three populations with variable patterns of disease prevalence. By selecting populations based on patterns where two have similar rates of disease that differ substantially from a third, we performed a proof of principle analysis for this method. We examined three disease phenotypes, lactase persistence, melanoma, and Type 2 diabetes mellitus. We show that for lactase persistence, a phenotype with a simple genetic architecture, ET identifies the key gene, lactase. For melanoma, ET identifies several genes associated with this disease and/or phenotypes related to it, such as skin color genes. ET was less obviously successful for Type 2 diabetes mellitus, perhaps because of the small effect sizes in known risk loci and recent environmental changes that have altered disease risk. Alternatively, ET may have revealed new genes involved in conferring disease risk for diabetes that did not meet nominal GWAS significance thresholds. We also compared ET to another method used to filter for phenotype associated genes, population branch statistic (PBS), and show that ET performs better in identifying genes known to associate with

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

    NARCIS (Netherlands)

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

    2011-01-01

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

  4. Integrated analysis of genetic data with R

    Directory of Open Access Journals (Sweden)

    Zhao Jing

    2006-01-01

    Full Text Available Abstract Genetic data are now widely available. There is, however, an apparent lack of concerted effort to produce software systems for statistical analysis of genetic data compared with other fields of statistics. It is often a tremendous task for end-users to tailor them for particular data, especially when genetic data are analysed in conjunction with a large number of covariates. Here, R http://www.r-project.org, a free, flexible and platform-independent environment for statistical modelling and graphics is explored as an integrated system for genetic data analysis. An overview of some packages currently available for analysis of genetic data is given. This is followed by examples of package development and practical applications. With clear advantages in data management, graphics, statistical analysis, programming, internet capability and use of available codes, it is a feasible, although challenging, task to develop it into an integrated platform for genetic analysis; this will require the joint efforts of many researchers.

  5. Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium

    DEFF Research Database (Denmark)

    Pearce, C L; Near, A M; Van Den Berg, D J;

    2009-01-01

    The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had...... been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P... and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted....

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

    Directory of Open Access Journals (Sweden)

    Lisette J. A. Kogelman

    2014-07-01

    Full Text Available Obesity is a complex condition with world-wide exponentially rising prevalence rates, linked with severe diseases like Type 2 Diabetes. Economic and welfare consequences have led to a raised interest in a better understanding of the biological and genetic background. To date, whole genome 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 of haplotype blocks. We built Weighted Interaction SNP Hub (WISH and differentially wired (DW networks using genotypic correlations amongst obesity-associated SNPs resulting from GWA analysis. GWA results and SNP modules detected by WISH and DW analyses were further investigated by functional enrichment analyses. The functional annotation of SNPs revealed several genes associated with obesity, e.g. NPC2 and OR4D10. Moreover, gene enrichment analyses identified several significantly associated pathways, over and above the GWA study results, that may influence obesity and obesity related diseases, e.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 and employ systems genetics in a porcine model to provide important insights into the complex genetic architecture associated with obesity and many biological pathways

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

    Science.gov (United States)

    Kogelman, Lisette J A; Pant, Sameer D; Fredholm, Merete; Kadarmideen, Haja N

    2014-01-01

    Obesity is a complex condition with world-wide exponentially rising prevalence rates, linked with severe diseases like Type 2 Diabetes. Economic and welfare consequences have led to a raised interest in a better understanding of the biological and genetic background. To date, whole genome 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 of haplotype blocks. We built Weighted Interaction SNP Hub (WISH) and differentially wired (DW) networks using genotypic correlations amongst obesity-associated SNPs resulting from GWA analysis. GWA results and SNP modules detected by WISH and DW analyses were further investigated by functional enrichment analyses. The functional annotation of SNPs revealed several genes associated with obesity, e.g., NPC2 and OR4D10. Moreover, gene enrichment analyses identified several significantly associated pathways, over and above the GWA study results, that may influence obesity and obesity related diseases, e.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 and employ systems genetics in a porcine model to provide important insights into the complex genetic architecture associated with obesity and many biological pathways that underlie

  8. Resistance to gray leaf spot of maize: genetic architecture and mechanisms elucidated through nested association mapping and near-isogenic line analysis.

    Directory of Open Access Journals (Sweden)

    Jacqueline M Benson

    2015-03-01

    Full Text Available Gray leaf spot (GLS, caused by Cercospora zeae-maydis and Cercospora zeina, is one of the most important diseases of maize worldwide. The pathogen has a necrotrophic lifestyle and no major genes are known for GLS. Quantitative resistance, although poorly understood, is important for GLS management. We used genetic mapping to refine understanding of the genetic architecture of GLS resistance and to develop hypotheses regarding the mechanisms underlying quantitative disease resistance (QDR loci. Nested association mapping (NAM was used to identify 16 quantitative trait loci (QTL for QDR to GLS, including seven novel QTL, each of which demonstrated allelic series with significant effects above and below the magnitude of the B73 reference allele. Alleles at three QTL, qGLS1.04, qGLS2.09, and qGLS4.05, conferred disease reductions of greater than 10%. Interactions between loci were detected for three pairs of loci, including an interaction between iqGLS4.05 and qGLS7.03. Near-isogenic lines (NILs were developed to confirm and fine-map three of the 16 QTL, and to develop hypotheses regarding mechanisms of resistance. qGLS1.04 was fine-mapped from an interval of 27.0 Mb to two intervals of 6.5 Mb and 5.2 Mb, consistent with the hypothesis that multiple genes underlie highly significant QTL identified by NAM. qGLS2.09, which was also associated with maturity (days to anthesis and with resistance to southern leaf blight, was narrowed to a 4-Mb interval. The distance between major leaf veins was strongly associated with resistance to GLS at qGLS4.05. NILs for qGLS1.04 were treated with the C. zeae-maydis toxin cercosporin to test the role of host-specific toxin in QDR. Cercosporin exposure increased expression of a putative flavin-monooxygenase (FMO gene, a candidate detoxification-related gene underlying qGLS1.04. This integrated approach to confirming QTL and characterizing the potential underlying mechanisms advances the understanding of QDR and will

  9. Association Analysis between g.18873C>T and g.27522G>A Genetic Polymorphisms of OPG and Bone Mineral Density in Chinese Postmenopausal Women

    Directory of Open Access Journals (Sweden)

    Fei Wang

    2014-01-01

    Full Text Available Several studies report that the OPG is an important candidate gene in the pathogenesis of osteoporosis. This study aimed to detect the potential association of OPG gene polymorphisms with osteoporosis in postmenopausal women. We recruited 928 subjects containing 463 with primary postmenopausal osteoporosis and 465 healthy volunteers as controls. The BMD of neck hip, lumbar spine (L2–4, and total hip were assessed by dual-energy X-ray absorptiometry (DEXA. Through the created restriction site-polymerase chain reaction (CRS-PCR, PCR-restriction fragment length polymorphism (PCR-RFLP, and DNA sequencing methods, the g.18873C>T and g.27522G>A have been investigated. As for g.18873C>T, our data indicated that subjects with CC genotype have significantly higher BMD value than those of CT and TT genotypes (all P values A, the BMD values of subjects with GG genotype were significantly higher than those of GA and AA genotypes (all P values T and g.27522G>A genetic polymorphisms are associated with the decreased risk for osteoporosis in Chinese postmenopausal women.

  10. Optimal Trend Tests for Genetic Association Studies of Heterogeneous Diseases.

    Science.gov (United States)

    Lee, Wen-Chung

    2016-06-09

    The Cochran-Armitage trend test is a standard procedure in genetic association studies. It is a directed test with high power to detect genetic effects that follow the gene-dosage model. In this paper, the author proposes optimal trend tests for genetic association studies of heterogeneous diseases. Monte-Carlo simulations show that the power gain of the optimal trend tests over the conventional Cochran-Armitage trend test is striking when the genetic effects are heterogeneous. The easy-to-use R 3.1.2 software (R Foundation for Statistical Computing, Vienna, Austria) code is provided. The optimal trend tests are recommended for routine use.

  11. Genetic Loci Associated With Plasma Concentration of Low-Density Lipoprotein Cholesterol, High-Density Lipoprotein Cholesterol, Triglycerides, Apolipoprotein A1, and Apolipoprotein B Among 6382 White Women in Genome-Wide Analysis With Replication

    National Research Council Canada - National Science Library

    Chasman, Daniel I; Pare, Guillaume; Zee, Robert Y.L; Parker, Alex N; Cook, Nancy R; Buring, Julie E; Kwiatkowski, David J; Rose, Lynda M; Smith, Joshua D; Williams, Paul T; Rieder, Mark J; Rotter, Jerome I; Nickerson, Deborah A; Krauss, Ronald M; Miletich, Joseph P; Ridker, Paul M

    2008-01-01

    Genetic Loci Associated With Plasma Concentration of Low-Density Lipoprotein Cholesterol, High-Density Lipoprotein Cholesterol, Triglycerides, Apolipoprotein A1, and Apolipoprotein B Among 6382 White...

  12. Genetic variants of CD209 associated with Kawasaki disease susceptibility.

    Directory of Open Access Journals (Sweden)

    Ho-Chang Kuo

    Full Text Available BACKGROUND: Kawasaki disease (KD is a systemic vasculitis with unknown etiology mainly affecting children in Asian countries. Dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN, CD209 in humans was showed to trigger an anti-inflammatory cascade and associated with KD susceptibility. This study was conducted to investigate the association between genetic polymorphisms of CD209 and the risk KD. METHODS: A total of 948 subjects (381 KD and 567 controls were recruited. Nine tagging SNPs (rs8112310, rs4804800, rs11465421, rs1544766, rs4804801, rs2287886, rs735239, rs735240, rs4804804 were selected for TaqMan allelic discrimination assay. Clinical phenotypes, coronary artery lesions (CAL and intravenous immunoglobulin (IVIG treatment outcomes were collected for analysis. RESULTS: Significant associations were found between CD209 polymorphisms (rs4804800, rs2287886, rs735240 and the risk of KD. Haplotype analysis for CD209 polymorphisms showed that A/A/G haplotype (P = 0.0002, OR = 1.61 and G/A/G haplotype (P = 0.0365, OR = 1.52 had higher risk of KD as compared with G/G/A haplotype in rs2287886/rs735239/rs735240 pairwise allele analysis. There were no significant association in KD with regards to CAL formation and IVIG treatment responses. CONCLUSION: CD209 polymorphisms were responsible for the susceptibility of KD, but not CAL formation and IVIG treatment responsiveness.

  13. Event History Analysis in Quantitative Genetics

    DEFF Research Database (Denmark)

    Maia, Rafael Pimentel

    Event history analysis is a clas of statistical methods specially designed to analyze time-to-event characteristics, e.g. the time until death. The aim of the thesis was to present adequate multivariate versions of mixed survival models that properly represent the genetic aspects related to a given...... time-to-event characteristic of interest. Real genetic longevity studies based on female animals of different species (sows, dairy cows, and sheep) exemplifies the use of the methods. Moreover these studies allow to understand som genetic mechanisms related to the lenght of the productive life...

  14. Genetic Association Study of KCNQ5 Polymorphisms with High Myopia

    Directory of Open Access Journals (Sweden)

    Xuan Liao

    2017-01-01

    Full Text Available Identification of genetic variations related to high myopia may advance our knowledge of the etiopathogenesis of refractive error. This study investigated the role of potassium channel gene (KCNQ5 polymorphisms in high myopia. We performed a case-control study of 1563 unrelated Han Chinese subjects (809 cases of high myopia and 754 emmetropic controls. Five tag single-nucleotide polymorphisms (SNPs of KCNQ5 were genotyped, and association testing with high myopia was conducted using logistic regression analysis adjusted for sex and age to give Pasym values, and multiple comparisons were corrected by permutation test to give Pemp values. All five noncoding SNPs were associated with high myopia. The SNP rs7744813, previously shown to be associated with refractive error and myopia in two GWAS, showed an odds ratio of 0.75 (95% CI 0.63–0.90; Pemp = 0.0058 for the minor allele. The top SNP rs9342979 showed an odds ratio of 0.75 (95% CI 0.64–0.89; Pemp = 0.0045 for the minor allele. Both SNPs are located within enhancer histone marks and DNase-hypersensitive sites. Our data support the involvement of KCNQ5 gene polymorphisms in the genetic susceptibility to high myopia and further exploration of KCNQ5 as a risk factor for high myopia.

  15. Rapid Genetic Analysis in Congenital Hyperinsulinism

    DEFF Research Database (Denmark)

    Christesen, Henrik Thybo; Brusgaard, Klaus; Alm, Jan

    2007-01-01

    . METHODS: In 4 patients, a rapid genetic analysis of the ABBC8 and KCNJ11 genes was performed within 2 weeks on request prior to the decision of pancreatic surgery. RESULTS: Two patients had no mutations, rendering the genetic analysis non-informative. Peroperative multiple biopsies showed diffuse disease....... One patient had a paternal KCNJ11 mutation and focal disease confirmed by positron emission tomography scan and biopsies. One patient had a de novo heterozygous ABBC8 mutation and unexplained diffuse disease confirmed by positron emission tomography scan and biopsies. CONCLUSION: A rapid analysis...

  16. Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians12

    Science.gov (United States)

    Fretts, Amanda M; Follis, Jack L; Nettleton, Jennifer A; Lemaitre, Rozenn N; Ngwa, Julius S; Wojczynski, Mary K; Kalafati, Ioanna Panagiota; Varga, Tibor V; Frazier-Wood, Alexis C; Houston, Denise K; Lahti, Jari; Ericson, Ulrika; van den Hooven, Edith H; Mikkilä, Vera; Kiefte-de Jong, Jessica C; Mozaffarian, Dariush; Rice, Kenneth; Renström, Frida; North, Kari E; McKeown, Nicola M; Feitosa, Mary F; Kanoni, Stavroula; Smith, Caren E; Garcia, Melissa E; Tiainen, Anna-Maija; Sonestedt, Emily; Manichaikul, Ani; van Rooij, Frank JA; Dimitriou, Maria; Raitakari, Olli; Pankow, James S; Djoussé, Luc; Province, Michael A; Hu, Frank B; Lai, Chao-Qiang; Keller, Margaux F; Perälä, Mia-Maria; Rotter, Jerome I; Hofman, Albert; Graff, Misa; Kähönen, Mika; Mukamal, Kenneth; Johansson, Ingegerd; Ordovas, Jose M; Liu, Yongmei; Männistö, Satu; Uitterlinden, André G; Deloukas, Panos; Seppälä, Ilkka; Psaty, Bruce M; Cupples, L Adrienne; Borecki, Ingrid B; Franks, Paul W; Arnett, Donna K; Nalls, Mike A; Eriksson, Johan G; Orho-Melander, Marju; Franco, Oscar H; Lehtimäki, Terho; Dedoussis, George V; Meigs, James B; Siscovick, David S

    2015-01-01

    Background: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown. Objective: We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus. Design: Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined 1) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations. Results: Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049–ln-pmol/L (95% CI: 0.035, 0.063–ln-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic

  17. Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians.

    Science.gov (United States)

    Fretts, Amanda M; Follis, Jack L; Nettleton, Jennifer A; Lemaitre, Rozenn N; Ngwa, Julius S; Wojczynski, Mary K; Kalafati, Ioanna Panagiota; Varga, Tibor V; Frazier-Wood, Alexis C; Houston, Denise K; Lahti, Jari; Ericson, Ulrika; van den Hooven, Edith H; Mikkilä, Vera; Kiefte-de Jong, Jessica C; Mozaffarian, Dariush; Rice, Kenneth; Renström, Frida; North, Kari E; McKeown, Nicola M; Feitosa, Mary F; Kanoni, Stavroula; Smith, Caren E; Garcia, Melissa E; Tiainen, Anna-Maija; Sonestedt, Emily; Manichaikul, Ani; van Rooij, Frank J A; Dimitriou, Maria; Raitakari, Olli; Pankow, James S; Djoussé, Luc; Province, Michael A; Hu, Frank B; Lai, Chao-Qiang; Keller, Margaux F; Perälä, Mia-Maria; Rotter, Jerome I; Hofman, Albert; Graff, Misa; Kähönen, Mika; Mukamal, Kenneth; Johansson, Ingegerd; Ordovas, Jose M; Liu, Yongmei; Männistö, Satu; Uitterlinden, André G; Deloukas, Panos; Seppälä, Ilkka; Psaty, Bruce M; Cupples, L Adrienne; Borecki, Ingrid B; Franks, Paul W; Arnett, Donna K; Nalls, Mike A; Eriksson, Johan G; Orho-Melander, Marju; Franco, Oscar H; Lehtimäki, Terho; Dedoussis, George V; Meigs, James B; Siscovick, David S

    2015-11-01

    Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown. We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus. Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined 1) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations. Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049-ln-pmol/L (95% CI: 0.035, 0.063-ln-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic loci known to influence fasting glucose or

  18. Analysis of gender differences in genetic risk: association of TNFAIP3 polymorphism with male childhood-onset systemic lupus erythematosus in the Japanese population.

    Directory of Open Access Journals (Sweden)

    Keisuke Kadota

    Full Text Available BACKGROUND: Systemic lupus erythematosus (SLE is a systemic multisystem autoimmune disorder influenced by genetic background and environmental factors. Our aim here was to replicate findings of associations between 7 of the implicated single nucleotide polymorphisms (SNPs in IRF5, BLK, STAT4, TNFAIP3, SPP1, TNIP1 and ETS1 genes with susceptibility to childhood-onset SLE in the Japanese population. In particular, we focused on gender differences in allelic frequencies. METHODOLOGY/PRINCIPAL FINDINGS: The 7 SNPs were genotyped using TaqMan assays in 75 patients with childhood-onset SLE and in 190 healthy controls. The relationship between the cumulative number of risk alleles and SLE manifestations was explored in childhood-onset SLE. Logistic regression was used to test the effect of each polymorphism on susceptibility to SLE, and Wilcoxon rank sum testing was used for comparison of total risk alleles. Data on rs7574865 in the STAT4 gene and rs9138 in SPP1 were replicated for associations with SLE when comparing cases and controls (corrected P values ranging from 0.0043 to 0.027. The rs2230926 allele of TNFAIP3 was associated with susceptibility to SLE in males, but after Bonferroni correction there were no significant associations with any of the other four SNPs in IRF5, BLK, TNIP1 and ETS1 genes. The cumulative number of risk alleles was significantly increased in childhood-onset SLE relative to healthy controls (P = 0.0000041. Male SLE patients had a slightly but significantly higher frequency of the TNFAIP3 (rs2230926G risk allele than female patients (odds ratio [OR] = 4.05, 95% confidence interval [95%CI] = 1.46-11.2 P<0.05. CONCLUSIONS: Associations of polymorphisms in STAT4 and SPP1 with childhood-onset SLE were confirmed in a Japanese population. Although these are preliminary results for a limited number of cases, TNFAIP3 rs2230926G may be an important predictor of disease onset in males. We also replicated findings that the

  19. Association of established hypothyroidism-associated genetic variants with Hashimoto's thyroiditis.

    Science.gov (United States)

    Barić, A; Brčić, L; Gračan, S; Torlak Lovrić, V; Gunjača, I; Šimunac, M; Brekalo, M; Boban, M; Polašek, O; Barbalić, M; Zemunik, T; Punda, A; Boraska Perica, V

    2017-04-05

    Hashimoto's thyroiditis (HT) as a chronic autoimmune disease of the thyroid gland is the most common cause of hypothyroidism. Since HT and hypothyroidism are closely related, the main aim of this study was to explore the association of established hypothyroidism single-nucleotide polymorphisms (SNPs) with HT. The case-control dataset included 200 HT cases and 304 controls. Diagnosis of HT cases was based on clinical examination, measurement of thyroid antibodies (TgAb, TPOAb), hormones (TSH and FT4) and ultrasound examination. We genotyped and analysed 11 known hypothyroidism-associated genetic variants. Case-control association analysis was performed in order to test each SNP for the association with HT using logistic regression model. Additionally, each SNP was tested for the association with thyroid-related quantitative traits (TPOAb levels, TgAb levels and thyroid volume) in HT cases only using linear regression. We identified two genetic variants nominally associated with HT rs3184504 in SH2B3 gene (P = 0.0135, OR = 0.74, 95% CI = 0.57-0.95) and rs4704397 in PDE8B gene (P = 0.0383, OR = 1.32, 95% CI = 1.01-1.74). The SH2B3 genetic variant also showed nominal association with TPOAb levels (P = 0.0163, β = -0.46) and rs4979402 inside DFNB31 gene was nominally associated with TgAb levels (P = 0.0443, β = 0.41). SH2B3 gene has previously been associated with susceptibility to several autoimmune diseases, whereas PDE8B has been associated with TSH levels and suggested to modulate thyroid physiology that may influence the manifestation of thyroid disease. Identified loci are novel and biologically plausible candidates for HT development and represent good basis for further exploration of HT susceptibility.

  20. 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

    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...... 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...

  1. Association of CD14 −159 (−260C/T) polymorphism and asthma risk: an updated genetic meta-analysis study

    Science.gov (United States)

    Wang, Duan; Yang, Yang; Xu, Jin; Zhou, Zong-Ke; Yu, Hai-Yang

    2016-01-01

    Abstract Background: It has been reported that the cluster of differentiation 14 (CD14) gene −159C/T variant may be associated with asthma risk. However, some studies yielded conflicting results. Therefore, a comprehensive meta-analysis was designed to assess the precise association. Methods: A systematic search in PubMed, Embase (Ovid), China National Knowledge Internet (CNKI), and Wan fang databases was conducted up to August 15, 2015. Odds ratio (OR) and 95% confidence interval (CI) were used to pool the effect size. We used I2 to assess heterogeneity, and a funnel plot and Egger test to assess publication bias. Results: In total, 34 studies involving 15,641 subjects were included in this meta-analysis. There was a statistically significant association between CD14 −159C/T polymorphism and asthma risk observed in dominant model (TT+TC vs CC: OR = 0.86, 95% CI = 0.77–0.97, P = 0.012) and codominant model (TC vs CC: OR = 0.88, 95% CI = 0.78–0.99, P = 0.035) in adults. However, there may be no significant association between CD14 159C/T and atopic and nonatopic asthma risk. Conclusion: In summary, the overall results suggested that the CD14 −159C/T variant may decrease the risk of asthma susceptibility in adults. However, no significant association between CD14 159C/T and atopic and nonatopic asthma susceptibility was identified. More studies with larger sample size are needed to validate the findings from this study. PMID:27684840

  2. Improving Phenotypic Prediction by Combining Genetic and Epigenetic Associations

    NARCIS (Netherlands)

    Shah, Sonia; Bonder, Marc J.; Marioni, Riccardo E.; Zhu, Zhihong; McRae, Allan F.; Zhernakova, Alexandra; Harris, Sarah E.; Liewald, Dave; Henders, Anjali K.; Mendelson, Michael M.; Liu, Chunyu; Joehanes, Roby; Liang, Liming; Levy, Daniel; Martin, Nicholas G.; Starr, John M.; Wijmenga, Cisca; Wray, Naomi R.; Yang, Jian; Montgomery, Grant W.; Franke, Lude; Deary, Ian J.; Visscher, Peter M.

    2015-01-01

    We tested whether DNA-methylation profiles account for inter-individual variation in body mass index (BMI) and height and whether they predict these phenotypes over and above genetic factors. Genetic predictors were derived from published summary results from the largest genome-wide association stud

  3. Higher magnesium intake is associated with lower fasting glucose and insulin, with no evidence of interaction with select genetic loci, in a meta-analysis of 15 charge consortium studies

    Science.gov (United States)

    Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) assoc...

  4. Psoriasis and cardiometabolic traits: modest association but distinct genetic architectures

    Science.gov (United States)

    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

  5. Genetic variants associated with increased risk of malignant pleural mesothelioma: a genome-wide association study.

    Directory of Open Access Journals (Sweden)

    Giuseppe Matullo

    Full Text Available Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM, a rare aggressive tumor. Nevertheless, only 5-17% of those exposed to asbestos develop MPM, suggesting the involvement of other environmental and genetic risk factors. To identify the genetic risk factors that may contribute to the development of MPM, we conducted a genome-wide association study (GWAS; 370,000 genotyped SNPs, 5 million imputed SNPs in Italy, among 407 MPM cases and 389 controls with a complete history of asbestos exposure. A replication study was also undertaken and included 428 MPM cases and 1269 controls from Australia. Although no single marker reached the genome-wide significance threshold, several associations were supported by haplotype-, chromosomal region-, gene- and gene-ontology process-based analyses. Most of these SNPs were located in regions reported to harbor aberrant alterations in mesothelioma (SLC7A14, THRB, CEBP350, ADAMTS2, ETV1, PVT1 and MMP14 genes, causing at most a 2-3-fold increase in MPM risk. The Australian replication study showed significant associations in five of these chromosomal regions (3q26.2, 4q32.1, 7p22.2, 14q11.2, 15q14. Multivariate analysis suggested an independent contribution of 10 genetic variants, with an Area Under the ROC Curve (AUC of 0.76 when only exposure and covariates were included in the model, and of 0.86 when the genetic component was also included, with a substantial increase of asbestos exposure risk estimation (odds ratio, OR: 45.28, 95% confidence interval, CI: 21.52-95.28. These results showed that genetic risk factors may play an additional role in the development of MPM, and that these should be taken into account to better estimate individual MPM risk in individuals who have been exposed to asbestos.

  6. Genetic variants associated with increased risk of malignant pleural mesothelioma: a genome-wide association study.

    Science.gov (United States)

    Matullo, Giuseppe; Guarrera, Simonetta; Betti, Marta; Fiorito, Giovanni; Ferrante, Daniela; Voglino, Floriana; Cadby, Gemma; Di Gaetano, Cornelia; Rosa, Fabio; Russo, Alessia; Hirvonen, Ari; Casalone, Elisabetta; Tunesi, Sara; Padoan, Marina; Giordano, Mara; Aspesi, Anna; Casadio, Caterina; Ardissone, Francesco; Ruffini, Enrico; Betta, Pier Giacomo; Libener, Roberta; Guaschino, Roberto; Piccolini, Ezio; Neri, Monica; Musk, Arthur W B; de Klerk, Nicholas H; Hui, Jennie; Beilby, John; James, Alan L; Creaney, Jenette; Robinson, Bruce W; Mukherjee, Sutapa; Palmer, Lyle J; Mirabelli, Dario; Ugolini, Donatella; Bonassi, Stefano; Magnani, Corrado; Dianzani, Irma

    2013-01-01

    Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, only 5-17% of those exposed to asbestos develop MPM, suggesting the involvement of other environmental and genetic risk factors. To identify the genetic risk factors that may contribute to the development of MPM, we conducted a genome-wide association study (GWAS; 370,000 genotyped SNPs, 5 million imputed SNPs) in Italy, among 407 MPM cases and 389 controls with a complete history of asbestos exposure. A replication study was also undertaken and included 428 MPM cases and 1269 controls from Australia. Although no single marker reached the genome-wide significance threshold, several associations were supported by haplotype-, chromosomal region-, gene- and gene-ontology process-based analyses. Most of these SNPs were located in regions reported to harbor aberrant alterations in mesothelioma (SLC7A14, THRB, CEBP350, ADAMTS2, ETV1, PVT1 and MMP14 genes), causing at most a 2-3-fold increase in MPM risk. The Australian replication study showed significant associations in five of these chromosomal regions (3q26.2, 4q32.1, 7p22.2, 14q11.2, 15q14). Multivariate analysis suggested an independent contribution of 10 genetic variants, with an Area Under the ROC Curve (AUC) of 0.76 when only exposure and covariates were included in the model, and of 0.86 when the genetic component was also included, with a substantial increase of asbestos exposure risk estimation (odds ratio, OR: 45.28, 95% confidence interval, CI: 21.52-95.28). These results showed that genetic risk factors may play an additional role in the development of MPM, and that these should be taken into account to better estimate individual MPM risk in individuals who have been exposed to asbestos.

  7. Cancer genetic association studies in the genome-wide age

    OpenAIRE

    Savage, Sharon A

    2008-01-01

    Genome-wide association studies of hundreds of thousands of SNPs have led to a deluge of studies of genetic variation in cancer and other common diseases. Large case–control and cohort studies have identified novel SNPs as markers of cancer risk. Genome-wide association study SNP data have also advanced understanding of population-specific genetic variation. While studies of risk profiles, combinations of SNPs that may increase cancer risk, are not yet clinically applicable, future, large-sca...

  8. Integrative analysis of mRNA expression and half-life data reveals trans-acting genetic variants associated with increased expression of stable transcripts.

    Directory of Open Access Journals (Sweden)

    Thong T Nguyen

    Full Text Available Genetic variation in gene expression makes an important contribution to phenotypic variation and susceptibility to disease. Recently, a subset of cis-acting expression quantitative loci (eQTLs has been found to result from polymorphisms that affect RNA stability. Here we carried out a search for trans-acting variants that influence RNA stability. We first demonstrate that differences in the activity of trans-acting factors that stabilize RNA can be detected by comparing the expression levels of long-lived (stable and short-lived (unstable transcripts in high-throughput gene expression experiments. Using gene expression microarray data generated from eight HapMap3 populations, we calculated the relative expression ranks of long-lived transcripts versus short-lived transcripts in each sample. Treating this as a quantitative trait, we applied genome-wide association and identified a single nucleotide polymorphism (SNP, rs6137010, on chromosome 20p13 with which it is strongly associated in two Asian populations (p = 4×10(-10 in CHB - Han Chinese from Beijing; p = 1×10(-4 in JPT - Japanese from Tokyo. This SNP is a cis-eQTL for SNRPB in CHB and JPT but not in the other six HapMap3 populations. SNRPB is a core component of the spliceosome, and has previously been shown to affect the expression of many RNA processing factors. We propose that a cis-eQTL of SNRPB may be directly responsible for inter-individual variation in relative expression of long-lived versus short-lived transcript in Asian populations. In support of this hypothesis, knockdown of SNRPB results in a significant reduction in the relative expression of long-lived versus short-lived transcripts. Samples with higher relative expression of long-lived transcripts also had higher relative expression of coding compared to non-coding RNA and of RNA from housekeeping compared to non-housekeeping genes, due to the lower decay rates of coding RNAs, particularly those that perform

  9. 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

    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...... 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...... for each setting of the specified allele risk and frequency parameters under different modes of inheritance and for different sample sizes. The indirect genetic association analysis is a valid approach for studying gene-longevity association, but the sample size requirement is about 3-4 time larger than...

  10. Multiple comparisons in genetic association studies: a hierarchical modeling approach.

    Science.gov (United States)

    Yi, Nengjun; Xu, Shizhong; Lou, Xiang-Yang; Mallick, Himel

    2014-02-01

    Multiple comparisons or multiple testing has been viewed as a thorny issue in genetic association studies aiming to detect disease-associated genetic variants from a large number of genotyped variants. We alleviate the problem of multiple comparisons by proposing a hierarchical modeling approach that is fundamentally different from the existing methods. The proposed hierarchical models simultaneously fit as many variables as possible and shrink unimportant effects towards zero. Thus, the hierarchical models yield more efficient estimates of parameters than the traditional methods that analyze genetic variants separately, and also coherently address the multiple comparisons problem due to largely reducing the effective number of genetic effects and the number of statistically "significant" effects. We develop a method for computing the effective number of genetic effects in hierarchical generalized linear models, and propose a new adjustment for multiple comparisons, the hierarchical Bonferroni correction, based on the effective number of genetic effects. Our approach not only increases the power to detect disease-associated variants but also controls the Type I error. We illustrate and evaluate our method with real and simulated data sets from genetic association studies. The method has been implemented in our freely available R package BhGLM (http://www.ssg.uab.edu/bhglm/).

  11. Optimization of genetic analysis for single cell

    Directory of Open Access Journals (Sweden)

    hussein mouawia

    2012-12-01

    Full Text Available The molecular genetic analysis of microdissected cells by laser, a method for selecting a starting material of pure DNA or RNA uncontaminated. Our study focuses on technical pre-PCR (polymerase chain reaction for the amplification of DNA from a single cell (leukocyte isolated from human blood after laser microdissection and aims to optimize the yield of DNA extracted of this cell to be amplified without errors and provide reliable genetic analyzes. This study has allowed us to reduce the duration of cell lysis in order to perform the step of expanding genomic PEP (primer extension preamplification directly after lysis the same day and the quality of genomic amplification and eliminate purification step of the product PEP, step with a risk of contamination and risk of loss of genetic material related to manipulation. This approach has shown that the combination of at least 3 STR (short tandem repeat markers for genetic analysis of single cell improves the efficiency and accuracy of PCR and minimizes the loss of allele (allele drop out; ADO. This protocol can be applied to large scale and an effective means suitable for genetic testing for molecular diagnostic from isolated single cell (cancerous - fetal.

  12. Methods for genetic linkage analysis using trisomies

    Energy Technology Data Exchange (ETDEWEB)

    Feingold, E.; Lamb, N.E.; Sherman, S.L. [Emory Univ., Atlanta, GA (United States)

    1994-09-01

    Certain genetic disorders (e.g. congenital cataracts, duodenal atresia) are rare in the general population, but more common in people with Down`s syndrome. We present a method for using individuals with trisomy 21 to map genes for such traits. Our methods are analogous to methods for mapping autosomal dominant traits using affected relative pairs by looking for markers with greater than expected identity-by-descent. In the trisomy case, one would take trisomic individuals and look for markers with greater than expected reduction to homozygosity in the chromosomes inherited form the non-disjoining parent. We present statistical methods for performing such a linkage analysis, including a test for linkage to a marker, a method for estimating the distance from the marker to the gene, a confidence interval for that distance, and methods for computing power and sample sizes. The methods are described in the context of gene-dosage model for the etiology of the disorder, but can be extended to other models. We also resolve some practical issues involved in implementing the methods, including how to use partially informative markers, how to test candidate genes, and how to handle the effect of reduced recombination associated with maternal meiosis I non-disjunction.

  13. APOL1 kidney risk alleles: population genetics and disease associations.

    Science.gov (United States)

    Limou, Sophie; Nelson, George W; Kopp, Jeffrey B; Winkler, Cheryl A

    2014-09-01

    APOL1 kidney disease is a unique case in the field of the genetics of common disease: 2 variants (termed G1 and G2) with high population frequency have been repeatedly associated with nondiabetic CKDs, with very strong effect size (odds ratios 3-29) in populations of sub-Saharan African descent. This review provides an update on the spectrum of APOL1 kidney disease and on the worldwide distribution of these kidney risk variants. We also summarize the proper way to run a recessive analysis on joint and independent effects of APOL1 G1 and G2 kidney risk variants. Copyright © 2014 National Kidney Foundation, Inc. All rights reserved.

  14. Methods for Analyzing Multivariate Phenotypes in Genetic Association Studies

    Directory of Open Access Journals (Sweden)

    Qiong Yang

    2012-01-01

    Full Text Available Multivariate phenotypes are frequently encountered in genetic association studies. The purpose of analyzing multivariate phenotypes usually includes discovery of novel genetic variants of pleiotropy effects, that is, affecting multiple phenotypes, and the ultimate goal of uncovering the underlying genetic mechanism. In recent years, there have been new method development and application of existing statistical methods to such phenotypes. In this paper, we provide a review of the available methods for analyzing association between a single marker and a multivariate phenotype consisting of the same type of components (e.g., all continuous or all categorical or different types of components (e.g., some are continuous and others are categorical. We also reviewed causal inference methods designed to test whether the detected association with the multivariate phenotype is truly pleiotropy or the genetic marker exerts its effects on some phenotypes through affecting the others.

  15. [Genetic variants associated to male infertility in Mexican patients].

    Science.gov (United States)

    Piña-Aguilar, Raúl Eduardo; Chima-Galán, María del Carmen; Yerena-de-vega, María de la Concepción A; Regalado-Hernández, Miguel Angel; Sánchez-Guerrero, Cecilia; García-Ortiz, Liliana; Santillán-Hernández, Yuritzi; Moreno-García, Jesús Daniel

    2013-05-01

    Recently Mexican Federation of Obstetrics and Gynecology Colleges (Federación Mexicana de Colegios de Obstetricia y Ginecologia, FEMECOG) published the Mexican guideline forthe management of male infertility, which suggests performing genetic laboratory tests as part of diagnosis and management of infertile patients and states that these should receive genetic counseling. This paper reviews the genetic approach proposed by Mexican guideline. A systematic review of medical literature was performed in Pubmed and Web of Knowledge from 1980 to 2012 in order to find reports of genetic variants associated to male infertility in Mexican patients. Also it is discussed the current knowledge of these variants, their clinical implications and finally the guidelines and recommendations for their molecular diagnosis. Most genetic variants in Mexican infertile patients are chromosome abnormalities. In relation to other variants there is only a report of Y chromosome microdeletions, repeated CAG in androgen receptor and more common mutations in CFTR, and other article reporting mutations in CFTR in patients with congenital absence of vas deferens. Little is known about the genetics of Mexican infertile patients apart from chromosome abnormalities. However, the contribution of genetics as etiology of male infertility is taking more relevance and currently the consensual management of infertile male should include the screening of genetic background. This review pretends to be a quick guide for clinicians who want to know about reports of genetic variants related to male infertility in Mexican population and how to approach their diagnosis.

  16. Analysis of Variance Components for Genetic Markers with Unphased Genotypes.

    Science.gov (United States)

    Wang, Tao

    2016-01-01

    An ANOVA type general multi-allele (GMA) model was proposed in Wang (2014) on analysis of variance components for quantitative trait loci or genetic markers with phased or unphased genotypes. In this study, by applying the GMA model, we further examine estimation of the genetic variance components for genetic markers with unphased genotypes based on a random sample from a study population. In one locus and two loci cases, we first derive the least square estimates (LSE) of model parameters in fitting the GMA model. Then we construct estimators of the genetic variance components for one marker locus in a Hardy-Weinberg disequilibrium population and two marker loci in an equilibrium population. Meanwhile, we explore the difference between the classical general linear model (GLM) and GMA based approaches in association analysis of genetic markers with quantitative traits. We show that the GMA model can retain the same partition on the genetic variance components as the traditional Fisher's ANOVA model, while the GLM cannot. We clarify that the standard F-statistics based on the partial reductions in sums of squares from GLM for testing the fixed allelic effects could be inadequate for testing the existence of the variance component when allelic interactions are present. We point out that the GMA model can reduce the confounding between the allelic effects and allelic interactions at least for independent alleles. As a result, the GMA model could be more beneficial than GLM for detecting allelic interactions.

  17. Genetics of homocysteine metabolism and associated disorders

    National Research Council Canada - National Science Library

    Brustolin, S; Giugliani, R; Félix, T.M

    2010-01-01

    .... Hyperhomocysteinemia is observed in approximately 5% of the general population and is associated with an increased risk for many disorders, including vascular and neurodegenerative diseases, autoimmune disorders, birth defects, diabetes, renal disease...

  18. Family-Based Genetic Association for Molar-Incisor Hypomineralization.

    Science.gov (United States)

    Jeremias, Fabiano; Pierri, Ricardo A G; Souza, Juliana F; Fragelli, Camila Maria B; Restrepo, Manuel; Finoti, Livia S; Bussaneli, Diego G; Cordeiro, Rita C L; Secolin, Rodrigo; Maurer-Morelli, Claudia V; Scarel-Caminaga, Raquel M; Santos-Pinto, Lourdes

    2016-01-01

    Despite some evidence of genetic and environmental factors on molar-incisor hypomineralization (MIH), its aetiology remains unclear. This family-based genetic association study aimed more comprehensively to investigate the genetic carriage potentially involved in MIH development. DNA was obtained from buccal cells of 391 individuals who were birth family members of 101 Brazilian nuclear families. Sixty-three single nucleotide polymorphisms (SNPs) were investigated in 21 candidate genes related to amelogenesis using the TaqMan™ OpenArray™ Genotyping platform. All SNPs were genotyped in 165 birth family members unaffected by MIH, 96 with unknown MIH status and 130 affected individuals (50.7% with severe MIH). Association analysis was performed by the transmission/disequilibrium test (TDT), and statistical results were corrected using the false discovery rate. Significant results were obtained for SNPs rs7821494 (FAM83H gene, OR = 3.7; 95% CI = 1.75-7.78), rs34367704 (AMBN gene, OR = 2.7; 95% CI = 1.16-6.58), rs3789334 (BMP2 gene, OR = 2.9; 95% CI = 1.34-6.35), rs6099486 (BMP7 gene, OR = 2.2; 95% CI = 1.14-4.38), rs762642 (BMP4 gene, OR = 2.3; 95% CI = 1.38-3.65), rs7664896 (ENAM gene, OR = 2.1; 95% CI = 1.19-3.51), rs1711399 (MMP20 gene, OR = 0.4; 95% CI = 0.20-0.72), rs1711423 (MMP20 gene, OR = 2.1; 95% CI = 1.18-3.61), rs2278163 (DLX3 gene, OR = 2.8; 95% CI = 1.26-6.41), rs6996321 (FGFR1 gene, OR = 2.7; 95% CI = 1.20-5.88), and rs5979395 (AMELX gene, OR = 11.7; 95% CI = 1.63-84.74). Through this family-based association study, we concluded that variations in genes related to amelogenesis were associated with the susceptibility to develop MIH. This result is in agreement with the multifactorial idea of the MIH aetiology, but further studies are necessary to investigate more thoroughly the factors that could influence MIH.

  19. 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.

  20. Genetic variability, character association, and path analysis for economic traits in menthofuran rich half-sib seed progeny of Mentha piperita L.

    Science.gov (United States)

    Kumar, Birendra; Mali, Himanshi; Gupta, Ekta

    2014-01-01

    Menthofuran rich eight half-sib seed progeny of Mentha piperita (MPS-36) were studied for various genetic parameters, namely, coefficient of variation, heritability, genetic advance, correlation, and path of various plant and oil attributes, namely, plant height, L:S ratio, herb yield, β -myrcene, limonene, 1,8-cineole, menthone, menthofuran, neomenthone, pulegone, and menthol. Maximum genotypic coefficient of variation and genetic advance as percentage of mean were recorded for pulegone, followed by menthofuran and 1,8-cineole. The genotypic correlation in general was higher than phenotypic; positive significant correlation was recorded for limonene with 1,8-cineole and menthone, β -myrcene with limonene, and 1,8-cineole and menthofuran with neomenthol. A high direct positive effect on menthofuran was of neomenthol.

  1. Genetic algorithm applied to hierarchically coupled associative memories.

    Science.gov (United States)

    Gomes, Rogério Martins; Braga, Antônio Pádua; Borges, Henrique E

    2010-01-01

    Inspired by the theory of neuronal group selection (TNGS), we have carried out an analysis of the capacity of convergence of a multi-level associative memory based on coupled generalized-brain-state-in-a-box (GBSB) networks through evolutionary computation. The TNGS establishes that a memory process can be described as being organized functionally in hierarchical levels where higher levels coordinate sets of functions of lower levels. According to this theory, the most basic units in the cortical area of the brain are called neuronal groups or first-level blocks of memories and the higher-level memories are formed through selective strengthening or weakening of the synapses amongst the neuronal groups. In order to analyse this effect, we propose that the higher levels should emerge through a learning mechanism as correlations of lower level memories. According to this proposal, this paper describes a method of acquiring the inter-group synapses based on a genetic algorithm. Thus the results show that genetic algorithms are feasible as they allow the emergence of complex behaviours which could be potentially excluded in other learning process.

  2. Genetic analysis and association of simple sequence repeat markers with storage root yield, dry matter, starch and β-carotene content in sweetpotato.

    Science.gov (United States)

    Yada, Benard; Brown-Guedira, Gina; Alajo, Agnes; Ssemakula, Gorrettie N; Owusu-Mensah, Eric; Carey, Edward E; Mwanga, Robert O M; Yencho, G Craig

    2017-03-01

    Molecular markers are needed for enhancing the development of elite sweetpotato (Ipomoea batatas (L.) Lam) cultivars with a wide range of commercially important traits in sub-Saharan Africa. This study was conducted to estimate the heritability and determine trait correlations of storage root yield, dry matter, starch and β-carotene content in a cross between 'New Kawogo' × 'Beauregard'. The study was also conducted to identify simple sequence repeat (SSR) markers associated with these traits. A total of 287 progeny and the parents were evaluated for two seasons at three sites in Uganda and genotyped with 250 SSR markers. Broad sense heritability (H(2)) for storage root yield, dry matter, starch and β-carotene content were 0.24, 0.68, 0.70 and 0.90, respectively. Storage root β-carotene content was negatively correlated with dry matter (r = -0.59, P content, while storage root yield was positively correlated with dry matter (r = 0.57, P = 0.029) and starch (r = 0.41, P = 0.008) content. Through logistic regression, a total of 12, 4, 6 and 8 SSR markers were associated with storage root yield, dry matter, starch and β-carotene content, respectively. The SSR markers used in this study may be useful for quantitative trait loci analysis and selection for these traits in future.

  3. Are there common genetic and environmental factors behind the endophenotypes associated with the metabolic syndrome?

    DEFF Research Database (Denmark)

    Benyamin, B.; Sørensen, T.I.A.; Schousboe, K.

    2007-01-01

    AIMS/HYPOTHESIS: The cluster of obesity, insulin resistance, dyslipidaemia and hypertension, called the metabolic syndrome, has been suggested as a risk factor for cardiovascular disease and type 2 diabetes. The aim of the present study was to evaluate whether there are common genetic...... and environmental factors influencing this cluster in a general population of twin pairs. MATERIALS AND METHODS: A multivariate genetic analysis was performed on nine endophenotypes associated with the metabolic syndrome from 625 adult twin pairs of the GEMINAKAR study of the Danish Twin Registry. RESULTS: All......, the endophenotypes associated with the metabolic syndrome apparently do not share a substantial common genetic or familial environmental background....

  4. 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

  5. Promoting Utilization of Saccharum spp. Genetic Resources through Genetic Diversity Analysis and Core Collection Construction

    Science.gov (United States)

    Pathak, Bhuvan; Ayala-Silva, Tomas; Yang, Xiping; Todd, James; Glynn, Neil C.; Kuhn, David N.; Glaz, Barry; Gilbert, Robert A.; Comstock, Jack C.; Wang, Jianping

    2014-01-01

    Sugarcane (Saccharum spp.) and other members of Saccharum spp. are attractive biofuel feedstocks. One of the two World Collections of Sugarcane and Related Grasses (WCSRG) is in Miami, FL. This WCSRG has 1002 accessions, presumably with valuable alleles for biomass, other important agronomic traits, and stress resistance. However, the WCSRG has not been fully exploited by breeders due to its lack of characterization and unmanageable population. In order to optimize the use of this genetic resource, we aim to 1) genotypically evaluate all the 1002 accessions to understand its genetic diversity and population structure and 2) form a core collection, which captures most of the genetic diversity in the WCSRG. We screened 36 microsatellite markers on 1002 genotypes and recorded 209 alleles. Genetic diversity of the WCSRG ranged from 0 to 0.5 with an average of 0.304. The population structure analysis and principal coordinate analysis revealed three clusters with all S. spontaneum in one cluster, S. officinarum and S. hybrids in the second cluster and mostly non-Saccharum spp. in the third cluster. A core collection of 300 accessions was identified which captured the maximum genetic diversity of the entire WCSRG which can be further exploited for sugarcane and energy cane breeding. Sugarcane and energy cane breeders can effectively utilize this core collection for cultivar improvement. Further, the core collection can provide resources for forming an association panel to evaluate the traits of agronomic and commercial importance. PMID:25333358

  6. Promoting utilization of Saccharum spp. genetic resources through genetic diversity analysis and core collection construction.

    Directory of Open Access Journals (Sweden)

    Spurthi N Nayak

    Full Text Available Sugarcane (Saccharum spp. and other members of Saccharum spp. are attractive biofuel feedstocks. One of the two World Collections of Sugarcane and Related Grasses (WCSRG is in Miami, FL. This WCSRG has 1002 accessions, presumably with valuable alleles for biomass, other important agronomic traits, and stress resistance. However, the WCSRG has not been fully exploited by breeders due to its lack of characterization and unmanageable population. In order to optimize the use of this genetic resource, we aim to 1 genotypically evaluate all the 1002 accessions to understand its genetic diversity and population structure and 2 form a core collection, which captures most of the genetic diversity in the WCSRG. We screened 36 microsatellite markers on 1002 genotypes and recorded 209 alleles. Genetic diversity of the WCSRG ranged from 0 to 0.5 with an average of 0.304. The population structure analysis and principal coordinate analysis revealed three clusters with all S. spontaneum in one cluster, S. officinarum and S. hybrids in the second cluster and mostly non-Saccharum spp. in the third cluster. A core collection of 300 accessions was identified which captured the maximum genetic diversity of the entire WCSRG which can be further exploited for sugarcane and energy cane breeding. Sugarcane and energy cane breeders can effectively utilize this core collection for cultivar improvement. Further, the core collection can provide resources for forming an association panel to evaluate the traits of agronomic and commercial importance.

  7. Promoting utilization of Saccharum spp. genetic resources through genetic diversity analysis and core collection construction.

    Science.gov (United States)

    Nayak, Spurthi N; Song, Jian; Villa, Andrea; Pathak, Bhuvan; Ayala-Silva, Tomas; Yang, Xiping; Todd, James; Glynn, Neil C; Kuhn, David N; Glaz, Barry; Gilbert, Robert A; Comstock, Jack C; Wang, Jianping

    2014-01-01

    Sugarcane (Saccharum spp.) and other members of Saccharum spp. are attractive biofuel feedstocks. One of the two World Collections of Sugarcane and Related Grasses (WCSRG) is in Miami, FL. This WCSRG has 1002 accessions, presumably with valuable alleles for biomass, other important agronomic traits, and stress resistance. However, the WCSRG has not been fully exploited by breeders due to its lack of characterization and unmanageable population. In order to optimize the use of this genetic resource, we aim to 1) genotypically evaluate all the 1002 accessions to understand its genetic diversity and population structure and 2) form a core collection, which captures most of the genetic diversity in the WCSRG. We screened 36 microsatellite markers on 1002 genotypes and recorded 209 alleles. Genetic diversity of the WCSRG ranged from 0 to 0.5 with an average of 0.304. The population structure analysis and principal coordinate analysis revealed three clusters with all S. spontaneum in one cluster, S. officinarum and S. hybrids in the second cluster and mostly non-Saccharum spp. in the third cluster. A core collection of 300 accessions was identified which captured the maximum genetic diversity of the entire WCSRG which can be further exploited for sugarcane and energy cane breeding. Sugarcane and energy cane breeders can effectively utilize this core collection for cultivar improvement. Further, the core collection can provide resources for forming an association panel to evaluate the traits of agronomic and commercial importance.

  8. Preimplantation genetic diagnosis associated to Duchenne muscular dystrophy.

    Science.gov (United States)

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

    2017-09-21

    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. RESUMO A distrofia muscular de Duchenne é a doença muscular mais comum observadas em crianças do sexo masculino. Atualmente, não há terapia eficaz disponível para distrofia muscular de Duchenne, portanto, é essencial o diagnóstico pré-natal e o aconselhamento genético para reduzir o nascimento desses meninos. Relatamos um caso de diagnóstico genético pré-implantação associado à distrofia muscular de Duchenne. O casal E.P.R., 38 anos, heterozigota, sintomática para uma mutação de deleção dos éxons 2 a 47 no gene

  9. Genetic changes associated with testicular cancer susceptibility.

    Science.gov (United States)

    Pyle, Louise C; Nathanson, Katherine L

    2016-10-01

    Testicular germ cell tumor (TGCT) is a highly heritable cancer primarily affecting young white men. Genome-wide association studies (GWAS) have been particularly effective in identifying multiple common variants with strong contribution to TGCT risk. These loci identified through association studies have implicated multiple genes as associated with TGCT predisposition, many of which are unique among cancer types, and regulate processes such as pluripotency, sex specification, and microtubule assembly. Together these biologically plausible genes converge on pathways involved in male germ cell development and maturation, and suggest that perturbation of them confers susceptibility to TGCT, as a developmental defect of germ cell differentiation. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Genome-wide association data reveal a global map of genetic interactions among protein complexes.

    Directory of Open Access Journals (Sweden)

    Gregory Hannum

    2009-12-01

    Full Text Available This work demonstrates how gene association studies can be analyzed to map a global landscape of genetic interactions among protein complexes and pathways. Despite the immense potential of gene association studies, they have been challenging to analyze because most traits are complex, involving the combined effect of mutations at many different genes. Due to lack of statistical power, only the strongest single markers are typically identified. Here, we present an integrative approach that greatly increases power through marker clustering and projection of marker interactions within and across protein complexes. Applied to a recent gene association study in yeast, this approach identifies 2,023 genetic interactions which map to 208 functional interactions among protein complexes. We show that such interactions are analogous to interactions derived through reverse genetic screens and that they provide coverage in areas not yet tested by reverse genetic analysis. This work has the potential to transform gene association studies, by elevating the analysis from the level of individual markers to global maps of genetic interactions. As proof of principle, we use synthetic genetic screens to confirm numerous novel genetic interactions for the INO80 chromatin remodeling complex.

  11. Genetic association, seasonal infections and autoimmune basis of narcolepsy

    Science.gov (United States)

    Singh, Abinav Kumar; Mahlios, Josh; Mignot, Emmanuel

    2014-01-01

    In recent years, a growing number of potential autoimmune disorders affecting neurons in the central nervous system have been identified, including narcolepsy. Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness with irresistible sleep attacks, cataplexy (sudden bilateral loss of muscle tone), hypnagogic hallucinations, and abnormalities of Rapid Eye Movement sleep. Narcolepsy is generally a sporadic disorder and is caused by the loss of hypocretin (orexin)-producing neurons in the hypothalamus region of the brain. Studies have established that more than 90% of patients have a genetic association with HLA DQB1*06:02. Genome-wide association analysis shows a strong association between narcolepsy and polymorphisms in the TCRα locus and weaker associations within TNFSF4 (also called OX40L), Cathepsin H and the P2RY11-DNMT1 (purinergic receptor subtype P2Y11 to DNMT1, a DNA methytransferase) loci, suggesting an autoimmune basis. Mutations in DNMT1 have also been reported to cause narcolepsy in association with a complex neurological syndrome, suggesting the importance of DNA methylation in the pathology. More recently, narcolepsy was identified in association with seasonal streptococcus, H1N1 infections and following AS03-adjuvanted pH1N1 influenza vaccination in Northern Europe. Potential immunological pathways responsible for the loss of hypocretin producing neurons in these cases may be molecular mimicry or bystander activation. Specific autoantibodies or T cells cross-reactive with hypocretin neurons have not yet been identified, however, thus narcolepsy does not meet Witebsky’s criteria for an autoimmune disease. As the brain is not an easily accessible organ, mechanisms of disease initiation and progression remain a challenge to researchers. PMID:23497937

  12. Boosting Principal Component Analysis by Genetic Algorithm

    Directory of Open Access Journals (Sweden)

    Divya Somvanshi

    2010-07-01

    Full Text Available This paper presents a new method of feature extraction by combining principal component analysis and genetic algorithm. Use of multiple pre-processors in combination with principal component analysis generates alternate feature spaces for data representation. The present method works out the fusion of these multiple spaces to create higher dimensionality feature vectors. The fused feature vectors are given chromosome representation by taking feature components to be genes. Then these feature vectors are allowed to undergo genetic evolution individually. For genetic algorithm, initial population is created by calculating probability distance matrix, and by applying a probability distance metric such that all the genes which lie farther than a defined threshold are tripped to zero. The genetic evolution of fused feature vector brings out most significant feature components (genes as survivours. A measure of significance is adapted on the basis of frequency of occurrence of the surviving genes in the current population. Finally, the feature vector is obtained by weighting the original feature components in proportion to their significance. The present algorithm is validated in combination with a neural network classifier based on error backpropagation algorithm, and by analysing a number of benchmark datasets available in the open sources.Defence Science Journal, 2010, 60(4, pp.392-398, DOI:http://dx.doi.org/10.14429/dsj.60.495

  13. Biological insights from 108 schizophrenia-associated genetic loci

    NARCIS (Netherlands)

    Ripke, Stephan; Neale, Benjamin M.; Corvin, Aiden; Walters, James T. R.; Farh, Kai-How; Holmans, Peter A.; Lee, Phil; Bulik-Sullivan, Brendan; Collier, David A.; Huang, Hailiang; Pers, Tune H.; Agartz, Ingrid; Agerbo, Esben; Albus, Margot; Alexander, Madeline; Amin, Farooq; Bacanu, Silviu A.; Begemann, Martin; Belliveau, Richard A.; Bene, Judit; Bergen, Sarah E.; Bevilacqua, Elizabeth; Bigdeli, Tim B.; Black, Donald W.; Bruggeman, Richard; Buccola, Nancy G.; Buckner, Randy L.; Byerley, William; Cahn, Wiepke; Cai, Guiqing; Campion, Dominique; Cantor, Rita M.; Carr, Vaughan J.; Carrera, Noa; Catts, Stanley V.; Chambert, Kimberly D.; Chan, Raymond C. K.; Chen, Ronald Y. L.; Chen, Eric Y. H.; Cheng, Wei; Cheung, Eric F. C.; Chong, Siow Ann; Cloninger, C. Robert; Cohen, David; Cohen, Nadine; Cormican, Paul; Craddock, Nick; Crowley, James J.; Curtis, David; Davidson, Michael; Davis, Kenneth L.; Degenhardt, Franziska; Del Favero, Jurgen; Demontis, Ditte; Dikeos, Dimitris; Dinan, Timothy; Djurovic, Srdjan; Donohoe, Gary; Drapeau, Elodie; Duan, Jubao; Dudbridge, Frank; Durmishi, Naser; Eichhammer, Peter; Eriksson, Johan; Escott-Price, Valentina; Essioux, Laurent; Fanous, Ayman H.; Farrell, Martilias S.; Frank, Josef; Franke, Lude; Freedman, Robert; Freimer, Nelson B.; Friedl, Marion; Friedman, Joseph I.; Fromer, Menachem; Genovese, Giulio; Georgieva, Lyudmila; Giegling, Ina; Giusti-Rodriguez, Paola; Godard, Stephanie; Goldstein, Jacqueline I.; Golimbet, Vera; Gopal, Srihari; Gratten, Jacob; de Haan, Lieuwe; Hammer, Christian; Hamshere, Marian L.; Hansen, Mark; Hansen, Thomas; Haroutunian, Vahram; Hartmann, Annette M.; Henskens, Frans A.; Herms, Stefan; Hirschhorn, Joel N.; Hoffmann, Per; Hofman, Andrea; Hollegaard, Mads V.; Hougaard, David M.; Ikeda, Masashi; Joa, Inge; Julia, Antonio; Kahn, Rene S.; Kalaydjieva, Luba; Karachanak-Yankova, Sena; Karjalainen, Juha; Kavanagh, David; Keller, Matthew C.; Kennedy, James L.; Khrunin, Andrey; Kim, Yunjung; Klovins, Janis; Knowles, James A.; Konte, Bettina; Kucinskas, Vaidutis; Kucinskiene, Zita Ausrele; Kuzelova-Ptackova, Hana; Kahler, Anna K.; Laurent, Claudine; Keong, Jimmy Lee Chee; Lee, S. Hong; Legge, Sophie E.; Lerer, Bernard; Li, Miaoxin; Li, Tao; Liang, Kung-Yee; Lieberman, Jeffrey; Limborska, Svetlana; Loughland, Carmel M.; Lubinski, Jan; Lonnqvist, Jouko; Macek, Milan; Magnusson, Patrik K. E.; Maher, Brion S.; Maier, Wolfgang; Mallet, Jacques; Marsal, Sara; Mattheisen, Manuel; Mattingsdal, Morten; McCarley, Robert W.; McDonald, Colm; McIntosh, Andrew M.; Meier, Sandra; Meijer, Carin J.; Melegh, Bela; Melle, Ingrid; Mesholam-Gately, Raquelle I.; Metspalu, Andres; Michie, Patricia T.; Milani, Lili; Milanova, Vihra; Mokrab, Younes; Morris, Derek W.; Mors, Ole; Murphy, Kieran C.; Murray, Robin M.; Myin-Germeys, Inez; Mueller-Myhsok, Bertram; Nelis, Mari; Nenadic, Igor; Nertney, Deborah A.; Nestadt, Gerald; Nicodemus, Kristin K.; Nikitina-Zake, Liene; Nisenbaum, Laura; Nordin, Annelie; O'Callaghan, Eadbhard; O'Dushlaine, Colm; O'Neill, F. Anthony; Oh, Sang-Yun; Olincy, Ann; Olsen, Line; Van Os, Jim; Pantelis, Christos; Papadimitriou, George N.; Papiol, Sergi; Parkhomenko, Elena; Pato, Michele T.; Paunio, Tiina; Pejovic-Milovancevic, Milica; Perkins, Diana O.; Pietilainen, Olli; Pimm, Jonathan; Pocklington, Andrew J.; Powell, John; Price, Alkes; Pulver, Ann E.; Purcell, Shaun M.; Quested, Digby; Rasmussen, Henrik B.; Reichenberg, Abraham; Reimers, Mark A.; Richards, Alexander L.; Roffman, Joshua L.; Roussos, Panos; Ruderfer, Douglas M.; Salomaa, Veikko; Sanders, Alan R.; Schall, Ulrich; Schubert, Christian R.; Schulze, Thomas G.; Schwab, Sibylle G.; Scolnick, Edward M.; Scott, Rodney J.; Seidman, Larry J.; Shi, Jianxin; Sigurdsson, Engilbert; Silagadze, Teimuraz; Silverman, Jeremy M.; Sim, Kang; Slominsky, Petr; Smoller, Jordan W.; So, Hon-Cheong; Spencer, Chris C. A.; Stahl, Eli A.; Stefansson, Hreinn; Steinberg, Stacy; Stogmann, Elisabeth; Straub, Richard E.; Strengman, Eric; Strohmaier, Jana; Stroup, T. Scott; Subramaniam, Mythily; Suvisaari, Jaana; Svrakic, Dragan M.; Szatkiewicz, Jin P.; Soderman, Erik; Thirumalai, Srinivas; Toncheva, Draga; Tosato, Sarah; Veijola, Juha; Waddington, John; Walsh, Dermot; Wang, Dai; Wang, Qiang; Webb, Bradley T.; Weiser, Mark; Wildenauer, Dieter B.; Williams, Nigel M.; Williams, Stephanie; Witt, Stephanie H.; Wolen, Aaron R.; Wong, Emily H. M.; Wormley, Brandon K.; Xi, Hualin Simon; Zai, Clement C.; Zheng, Xuebin; Zimprich, Fritz; Wray, Naomi R.; Stefansson, Kari; Visscher, Peter M.; Adolfsson, Rolf; Andreassen, Ole A.; Blackwood, Douglas H. R.; Bramon, Elvira; Buxbaum, Joseph D.; Borglum, Anders D.; Cichon, Sven; Darvasi, Ariel; Domenici, Enrico; Ehrenreich, Hannelore; Esko, Tonu; Gejman, Pablo V.; Gill, Michael; Gurling, Hugh; Hultman, Christina M.; Iwata, Nakao; Jablensky, Assen V.; Jonsson, Erik G.; Kendler, Kenneth S.; Kirov, George; Knight, Jo; Lencz, Todd; Levinson, Douglas F.; Li, Qingqin S.; Liu, Jianjun; Malhotra, Anil K.; McCarroll, Steven A.; McQuillin, Andrew; Moran, Jennifer L.; Mortensen, Preben B.; Mowry, Bryan J.; Noethen, Markus M.; Ophoff, Roel A.; Owen, Michael J.; Palotie, Aarno; Pato, Carlos N.; Petryshen, Tracey L.; Posthuma, Danielle; Rietschel, Marcella; Riley, Brien P.; Rujescu, Dan; Sham, Pak C.; Sklar, Pamela; St Clair, David; Weinberger, Daniel R.; Wendland, Jens R.; Werge, Thomas; Daly, Mark J.; Sullivan, Patrick F.; O'Donovan, Michael C.

    2014-01-01

    Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and

  14. Biological insights from 108 schizophrenia-associated genetic loci

    NARCIS (Netherlands)

    Ripke, Stephan; Neale, Benjamin M.; Corvin, Aiden; Walters, James T. R.; Farh, Kai-How; Holmans, Peter A.; Lee, Phil; Bulik-Sullivan, Brendan; Collier, David A.; Huang, Hailiang; Pers, Tune H.; Agartz, Ingrid; Agerbo, Esben; Albus, Margot; Alexander, Madeline; Amin, Farooq; Bacanu, Silviu A.; Begemann, Martin; Belliveau, Richard A.; Bene, Judit; Bergen, Sarah E.; Bevilacqua, Elizabeth; Bigdeli, Tim B.; Black, Donald W.; Bruggeman, Richard; Buccola, Nancy G.; Buckner, Randy L.; Byerley, William; Cahn, Wiepke; Cai, Guiqing; Campion, Dominique; Cantor, Rita M.; Carr, Vaughan J.; Carrera, Noa; Catts, Stanley V.; Chambert, Kimberly D.; Chan, Raymond C. K.; Chen, Ronald Y. L.; Chen, Eric Y. H.; Cheng, Wei; Cheung, Eric F. C.; Chong, Siow Ann; Cloninger, C. Robert; Cohen, David; Cohen, Nadine; Cormican, Paul; Craddock, Nick; Crowley, James J.; Curtis, David; Davidson, Michael; Davis, Kenneth L.; Degenhardt, Franziska; Del Favero, Jurgen; Demontis, Ditte; Dikeos, Dimitris; Dinan, Timothy; Djurovic, Srdjan; Donohoe, Gary; Drapeau, Elodie; Duan, Jubao; Dudbridge, Frank; Durmishi, Naser; Eichhammer, Peter; Eriksson, Johan; Escott-Price, Valentina; Essioux, Laurent; Fanous, Ayman H.; Farrell, Martilias S.; Frank, Josef; Franke, Lude; Freedman, Robert; Freimer, Nelson B.; Friedl, Marion; Friedman, Joseph I.; Fromer, Menachem; Genovese, Giulio; Georgieva, Lyudmila; Giegling, Ina; Giusti-Rodriguez, Paola; Godard, Stephanie; Goldstein, Jacqueline I.; Golimbet, Vera; Gopal, Srihari; Gratten, Jacob; de Haan, Lieuwe; Hammer, Christian; Hamshere, Marian L.; Hansen, Mark; Hansen, Thomas; Haroutunian, Vahram; Hartmann, Annette M.; Henskens, Frans A.; Herms, Stefan; Hirschhorn, Joel N.; Hoffmann, Per; Hofman, Andrea; Hollegaard, Mads V.; Hougaard, David M.; Ikeda, Masashi; Joa, Inge; Julia, Antonio; Kahn, Rene S.; Kalaydjieva, Luba; Karachanak-Yankova, Sena; Karjalainen, Juha; Kavanagh, David; Keller, Matthew C.; Kennedy, James L.; Khrunin, Andrey; Kim, Yunjung; Klovins, Janis; Knowles, James A.; Konte, Bettina; Kucinskas, Vaidutis; Kucinskiene, Zita Ausrele; Kuzelova-Ptackova, Hana; Kahler, Anna K.; Laurent, Claudine; Keong, Jimmy Lee Chee; Lee, S. Hong; Legge, Sophie E.; Lerer, Bernard; Li, Miaoxin; Li, Tao; Liang, Kung-Yee; Lieberman, Jeffrey; Limborska, Svetlana; Loughland, Carmel M.; Lubinski, Jan; Lonnqvist, Jouko; Macek, Milan; Magnusson, Patrik K. E.; Maher, Brion S.; Maier, Wolfgang; Mallet, Jacques; Marsal, Sara; Mattheisen, Manuel; Mattingsdal, Morten; McCarley, Robert W.; McDonald, Colm; McIntosh, Andrew M.; Meier, Sandra; Meijer, Carin J.; Melegh, Bela; Melle, Ingrid; Mesholam-Gately, Raquelle I.; Metspalu, Andres; Michie, Patricia T.; Milani, Lili; Milanova, Vihra; Mokrab, Younes; Morris, Derek W.; Mors, Ole; Murphy, Kieran C.; Murray, Robin M.; Myin-Germeys, Inez; Mueller-Myhsok, Bertram; Nelis, Mari; Nenadic, Igor; Nertney, Deborah A.; Nestadt, Gerald; Nicodemus, Kristin K.; Nikitina-Zake, Liene; Nisenbaum, Laura; Nordin, Annelie; O'Callaghan, Eadbhard; O'Dushlaine, Colm; O'Neill, F. Anthony; Oh, Sang-Yun; Olincy, Ann; Olsen, Line; Van Os, Jim; Pantelis, Christos; Papadimitriou, George N.; Papiol, Sergi; Parkhomenko, Elena; Pato, Michele T.; Paunio, Tiina; Pejovic-Milovancevic, Milica; Perkins, Diana O.; Pietilainen, Olli; Pimm, Jonathan; Pocklington, Andrew J.; Powell, John; Price, Alkes; Pulver, Ann E.; Purcell, Shaun M.; Quested, Digby; Rasmussen, Henrik B.; Reichenberg, Abraham; Reimers, Mark A.; Richards, Alexander L.; Roffman, Joshua L.; Roussos, Panos; Ruderfer, Douglas M.; Salomaa, Veikko; Sanders, Alan R.; Schall, Ulrich; Schubert, Christian R.; Schulze, Thomas G.; Schwab, Sibylle G.; Scolnick, Edward M.; Scott, Rodney J.; Seidman, Larry J.; Shi, Jianxin; Sigurdsson, Engilbert; Silagadze, Teimuraz; Silverman, Jeremy M.; Sim, Kang; Slominsky, Petr; Smoller, Jordan W.; So, Hon-Cheong; Spencer, Chris C. A.; Stahl, Eli A.; Stefansson, Hreinn; Steinberg, Stacy; Stogmann, Elisabeth; Straub, Richard E.; Strengman, Eric; Strohmaier, Jana; Stroup, T. Scott; Subramaniam, Mythily; Suvisaari, Jaana; Svrakic, Dragan M.; Szatkiewicz, Jin P.; Soderman, Erik; Thirumalai, Srinivas; Toncheva, Draga; Tosato, Sarah; Veijola, Juha; Waddington, John; Walsh, Dermot; Wang, Dai; Wang, Qiang; Webb, Bradley T.; Weiser, Mark; Wildenauer, Dieter B.; Williams, Nigel M.; Williams, Stephanie; Witt, Stephanie H.; Wolen, Aaron R.; Wong, Emily H. M.; Wormley, Brandon K.; Xi, Hualin Simon; Zai, Clement C.; Zheng, Xuebin; Zimprich, Fritz; Wray, Naomi R.; Stefansson, Kari; Visscher, Peter M.; Adolfsson, Rolf; Andreassen, Ole A.

    2014-01-01

    Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and

  15. Haplotype Analysis Discriminates Genetic Risk for DR3-Associated Endocrine Autoimmunity and Helps Define Extreme Risk for Addison’s Disease

    Science.gov (United States)

    Baker, Peter R.; Baschal, Erin E.; Fain, Pam R.; Triolo, Taylor M.; Nanduri, Priyaanka; Siebert, Janet C.; Armstrong, Taylor K.; Babu, Sunanda R.; Rewers, Marian J.; Gottlieb, Peter A.; Barker, Jennifer M.; Eisenbarth, George S.

    2010-01-01

    Context: Multiple autoimmune disorders (e.g. Addison’s disease, type 1 diabetes, celiac disease) are associated with HLA-DR3, but it is likely that alleles of additional genes in linkage disequilibrium with HLA-DRB1 contribute to disease. Objective: The objective of the study was to characterize major histocompatability complex (MHC) haplotypes conferring extreme risk for autoimmune Addison’s disease (AD). Design, Setting, and Participants: Eighty-six 21-hydroxylase autoantibody-positive, nonautoimmune polyendocrine syndrome type 1, Caucasian individuals collected from 1992 to 2009 with clinical AD from 68 families (12 multiplex and 56 simplex) were genotyped for HLA-DRB1, HLA-DQB1, MICA, HLA-B, and HLA-A as well as high density MHC single-nucleotide polymorphism (SNP) analysis for 34. Main Outcome Measures: AD and genotype were measured. Result: Ninety-seven percent of the multiplex individuals had both HLA-DR3 and HLA-B8 vs. 60% of simplex AD patients (P = 9.72 × 10−4) and 13% of general population controls (P = 3.00 × 10−19). The genotype DR3/DR4 with B8 was present in 85% of AD multiplex patients, 24% of simplex patients, and 1.5% of control individuals (P = 4.92 × 10−191). The DR3-B8 haplotype of AD patients had HLA-A1 less often (47%) than controls (81%, P = 7.00 × 10−5) and type 1 diabetes patients (73%, P = 1.93 × 10−3). Analysis of 1228 SNPs across the MHC for individuals with AD revealed a shorter conserved haplotype (3.8) with the loss of the extended conserved 3.8.1 haplotype approximately halfway between HLA-B and HLA-A. Conclusion: Extreme risk for AD, especially in multiplex families, is associated with haplotypic DR3 variants, in particular a portion (3.8) but not all of the conserved 3.8.1 haplotype. PMID:20631027

  16. A mixed model reduces spurious genetic associations produced by population stratification in genome-wide association studies.

    Science.gov (United States)

    Shin, Jimin; Lee, Chaeyoung

    2015-04-01

    Population stratification can produce spurious genetic associations in genome-wide association studies (GWASs). Mixed model methodology has been regarded useful for correcting population stratification. This study explored statistical power and false discovery rate (FDR) with the data simulated for dichotomous traits. Empirical FDRs and powers were estimated using fixed models with and without genomic control and using mixed models with and without reflecting loci linked to the candidate marker in genetic relationships. Population stratification with admixture degree ranged from 1% to 10% resulted in inflated FDRs from the fixed model analysis without genomic control and decreased power from the fixed model analysis with genomic control (Ppopulation stratification could not change FDR and power estimates from the mixed model analyses (P>0.05). We suggest that the mixed model methodology was useful to reduce spurious genetic associations produced by population stratification in GWAS, even with a high degree of admixture (10%). Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Sequence imputation of HPV16 genomes for genetic association studies.

    Directory of Open Access Journals (Sweden)

    Benjamin Smith

    Full Text Available BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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

  18. 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 (PCSPG4). In particular, the genetic associations with CDC42BPA and LARGE were confirmed using an independent data set of Korean cattle. The results implied that allele frequencies of functional variants and their proximity variants have been augmented by directional 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.

  19. Genetic Overlap Between Affective Disorders: An Association Analysis of M18 and M23 SNPs of DAOA/G72 Gene With Schizophrenia and Bipolar Disorder

    OpenAIRE

    Leila Ahmadi; Seyyed Reza Kazeminezhad; Niloufar Khajehdin; Mehdi Pourmehdi-Boroujeni; Parisima Behbahani

    2015-01-01

    Background: Schizophrenia and bipolar disorder are common and often destructive brain disorders. It has generally been assumed that dozens of genes, along with environmental factors, contribute to the development of these diseases. Schizophrenia and bipolar mood disorder affect many families simultaneously. This theme suggests that these disorders have a shared genetic etiology at least to some extent. The DAOA/G72 gene is one of the common loci shared both by schizophrenia and bipolar disord...

  20. Further evidence for association between genetic variants in the cannabinoid receptor 1 (CNR1) gene and cocaine dependence: Confirmation in an independent sample and meta-analysis

    OpenAIRE

    Clarke, Toni-Kim; Bloch, Paul J.; Ambrose-Lanci, Lisa M; Doyle, Glenn A.; Ferraro, Thomas N; Berrettini, Wade H; Kampman, Kyle M.; Dackis, Charles A.; Pettinati, Helen M.; O’Brien, Charles P.; OSLIN, DAVID W.; Lohoff, Falk W.

    2011-01-01

    Genetic research on cocaine dependence may help clarify our understanding of the disorder as well as provide insights for effective treatment. Since endocannabinoid signaling and dopamine neurotransmission have been shown to be involved with drug reward, genes related to these systems are plausible candidates for susceptibility to cocaine dependence. The cannabinoid receptor 1 (CB1) protein regulates both the endocannabinoid and dopaminergic neurobiological systems, and polymorphisms in the c...

  1. Haplotype sharing analysis with SNPs in candidate genes : The genetic analysis workshop 12 example

    NARCIS (Netherlands)

    Fischer, C; Beckmann, L; Majoram, P; Meerman, GT; Chang-Claude, J

    2003-01-01

    Haplotype sharing analysis was used to investigate the association of affection status with single nucleotide polymorphism (SNP) haplotypes within candidate gene 1 in one sample each from the isolated and the general population of Genetic Analysis Workshop (GAW) 12 simulated data. Gene 1 has direct

  2. Survival analysis with incomplete genetic data.

    Science.gov (United States)

    Lin, D Y

    2014-01-01

    Genetic data are now collected frequently in clinical studies and epidemiological cohort studies. For a large study, it may be prohibitively expensive to genotype all study subjects, especially with the next-generation sequencing technology. Two-phase sampling, such as case-cohort and nested case-control sampling, is cost-effective in such settings but entails considerable analysis challenges, especially if efficient estimators are desired. Another type of missing data arises when the investigators are interested in the haplotypes or the genetic markers that are not on the genotyping platform used for the current study. Valid and efficient analysis of such missing data is also interesting and challenging. This article provides an overview of these issues and outlines some directions for future research.

  3. Genetic Analysis of Nitroaromatic Degradation by Clostridium

    Science.gov (United States)

    2013-07-30

    REPORT Final Report on Genetic Analysis of Nitroaromatic Degradation by Clostridium 14. ABSTRACT 16. SECURITY CLASSIFICATION OF: 2,4,6-trinitrotoluene...Among different microorganisms that act in TNT biodegradation, clostridium species were distinguished for their rapid degradation rate. Here we compared...TERMS clostridium , TNT, genes, electron carriers, metabolism George N. Bennett William Marsh Rice University Office of Sponsored Research 6100 Main St

  4. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): A meta-analysis of genome-wide association studies

    NARCIS (Netherlands)

    M. Traylor (Matthew); M. Farrall (Martin); E.G. Holliday (Elizabeth); C. Sudlow (Cathie); J. Hopewell; Y.-C. Cheng (Yu-Ching); M. Fornage (Myriam); M.A. Ikram (Arfan); R. Malik (Rainer); S. Bevan (Steve); U. Thorsteinsdottir (Unnur); M.A. Nalls (Michael); W.T. Longstreth Jr; K.L. Wiggins (Kerri); S. Yadav (Sunaina); E.A. Parati (Eugenio); A.L. DeStefano (Anita); B.B. Worrall (Bradford B.); T. Kittner (Thomas); M.I. Khan (Muhammad); A. Reiner (Alexander); H.T. Helgadottir (Hafdis); S. Achterberg (Sefanja); I. Fernandez-Cadenas (Israel); S. Abboud (Shimon); R. Schmidt (Reinhold); M. Walters; W-M. Chen; E.B. Ringelstein (E. Bernd); M. O'Donnell (Martin); W.K. Ho (Weang Kee); M.F. Pera (Martin ); R. Lemmens (Robin); B. Norrving (Bo); P. Higgins (Peter); M. Benn (Marianne); P. Sale (Patrizio); G. Kuhlenbäumer (Gregor); A.S.F. Doney (Alex); A.M. Vicente (Astrid M); H. Delavaran (Hossein); A. Algra (Ale); G. Davies (Gail); S.A. Oliveira (Sofia); C.N.A. Palmer (Colin); I.J. Deary (Ian); R. Schmidt (Reinhold); M. Pandolfo (Massimo); J. Montaner (Joan); C. Carty (Cara); P.I.W. de Bakker (Paul); K. Kostulas (Konstantinos); M.T. Ferro (María); N.R. van Zuydam (Natalie); E. Valdimarsson (Einar); B.G. Nordestgaard (Børge); A. Lindgren (Arne); V. Thijs (Vincent); A. Slowik (Agnieszka); D. Saleheen; G. Paré (Guillaume); K. Berger (Klaus); G. Thorleifsson (Gudmar); A. Hofman (Albert); T.H. Mosley (Thomas); B.D. Mitchell (Braxton); K.L. Furie (Karen); R. Clarke (Robert); C. Levi (Christopher); S. Seshadri (Sudha); A. Gschwendtner (Andreas); G. Boncoraglio (Giorgio Battista); P. Sharma (Pankaj); J.C. Bis (Joshua); S. Gretarsdottir (Solveig); B.M. Psaty (Bruce); P.M. Rothwell (Peter); J. Rosand (Jonathan); J.F. Meschia (James F.); J-A. Zwart (John-Anker); C. Kubisch (Christian); H.S. Markus (Hugh)

    2012-01-01

    textabstractBackground: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previ

  5. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): A meta-analysis of genome-wide association studies

    NARCIS (Netherlands)

    M. Traylor (Matthew); M. Farrall (Martin); E.G. Holliday (Elizabeth); C. Sudlow (Cathie); J. Hopewell; Y.-C. Cheng (Yu-Ching); M. Fornage (Myriam); M.A. Ikram (Arfan); R. Malik (Rainer); S. Bevan (Steve); U. Thorsteinsdottir (Unnur); M.A. Nalls (Michael); W.T. Longstreth Jr; K.L. Wiggins (Kerri); S. Yadav (Sunaina); E.A. Parati (Eugenio); A.L. DeStefano (Anita); B.B. Worrall (Bradford B.); T. Kittner (Thomas); M.I. Khan (Muhammad); A. Reiner (Alexander); H.T. Helgadottir (Hafdis); S. Achterberg (Sefanja); I. Fernandez-Cadenas (Israel); S. Abboud (Shimon); R. Schmidt (Reinhold); M. Walters; W-M. Chen; E.B. Ringelstein (E. Bernd); M. O'Donnell (Martin); W.K. Ho (Weang Kee); M.F. Pera (Martin ); R. Lemmens (Robin); B. Norrving (Bo); P. Higgins (Peter); M. Benn (Marianne); P. Sale (Patrizio); G. Kuhlenbäumer (Gregor); A.S.F. Doney (Alex); A.M. Vicente (Astrid M); H. Delavaran (Hossein); A. Algra (Ale); G. Davies (Gail); S.A. Oliveira (Sofia); C.N.A. Palmer (Colin); I.J. Deary (Ian); R. Schmidt (Reinhold); M. Pandolfo (Massimo); J. Montaner (Joan); C. Carty (Cara); P.I.W. de Bakker (Paul); K. Kostulas (Konstantinos); M.T. Ferro (María); N.R. van Zuydam (Natalie); E. Valdimarsson (Einar); B.G. Nordestgaard (Børge); A. Lindgren (Arne); V. Thijs (Vincent); A. Slowik (Agnieszka); D. Saleheen; G. Paré (Guillaume); K. Berger (Klaus); G. Thorleifsson (Gudmar); A. Hofman (Albert); T.H. Mosley (Thomas); B.D. Mitchell (Braxton); K.L. Furie (Karen); R. Clarke (Robert); C. Levi (Christopher); S. Seshadri (Sudha); A. Gschwendtner (Andreas); G. Boncoraglio (Giorgio Battista); P. Sharma (Pankaj); J.C. Bis (Joshua); S. Gretarsdottir (Solveig); B.M. Psaty (Bruce); P.M. Rothwell (Peter); J. Rosand (Jonathan); J.F. Meschia (James F.); J-A. Zwart (John-Anker); C. Kubisch (Christian); H.S. Markus (Hugh)

    2012-01-01

    textabstractBackground: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previ

  6. A comprehensive haplotype analysis of the XPC genomic sequence reveals a cluster of genetic variants associated with sensitivity to tobacco-smoke mutagens.

    Science.gov (United States)

    Rondelli, Catherine M; El-Zein, Randa A; Wickliffe, Jeffrey K; Etzel, Carol J; Abdel-Rahman, Sherif Z

    2010-05-01

    The impact of single-nucleotide polymorphisms (SNPs) of the DNA repair gene XPC on DNA repair capacity (DRC) and genotoxicity has not been comprehensively determined. We constructed a comprehensive haplotype map encompassing all common XPC SNPs and evaluated the effect of Bayesian-inferred haplotypes on DNA damage associated with tobacco smoking, using chromosome aberrations (CA) as a biomarker. We also used the mutagen-sensitivity assay, in which mutagen-induced CA in cultured lymphocytes are determined, to evaluate the haplotype effects on DRC. We hypothesized that if certain XPC haplotypes have functional effects, a correlation between these haplotypes and baseline and/or mutagen-induced CA would exist. Using HapMap and single nucleotide polymorphism (dbSNP) databases, we identified 92 SNPs, of which 35 had minor allele frequencies >or= 0.05. Bayesian inference and subsequent phylogenetic analysis identified 21 unique haplotypes, which segregated into six distinct phylogenetically grouped haplotypes (PGHs A-F). A SNP tagging approach used identified 11 tagSNPs representing these 35 SNPs (r(2) = 0.80). We utilized these tagSNPs to genotype a population of smokers matched to nonsmokers (n = 123). Haplotypes for each individual were reconstituted and PGH designations were assigned. Relationships between XPC haplotypes and baseline and/or mutagen-induced CA were then evaluated. We observed significant interaction among smoking and PGH-C (p = 0.046) for baseline CA where baseline CA was 3.5 times higher in smokers compared to nonsmokers. Significant interactions among smoking and PGH-D (p = 0.023) and PGH-F (p = 0.007) for mutagen-induced CA frequencies were also observed. These data indicate that certain XPC haplotypes significantly alter CA and DRC in smokers and, thus, can contribute to cancer risk.

  7. Contribution of large region joint associations to complex traits genetics.

    Science.gov (United States)

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

    2015-04-01

    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.

  8. Genetic Features of Aflatoxin-Associated Hepatocellular Carcinoma.

    Science.gov (United States)

    Zhang, Weilong; He, Huan; Zang, Mengya; Wu, Qifeng; Zhao, Hong; Lu, Ling-Ling; Ma, Peiqing; Zheng, Hongwei; Wang, Nengjin; Zhang, Ying; He, Siyuan; Chen, Xiaoyan; Wu, Zhiyuan; Wang, Xiaoyue; Cai, Jianqiang; Liu, Zhihua; Sun, Zongtang; Zeng, Yi-Xin; Qu, Chunfeng; Jiao, Yuchen

    2017-07-01

    Dietary exposure to aflatoxin is an important risk factor for hepatocellular carcinoma (HCC). However, little is known about the genomic features and mutations of aflatoxin-associated HCCs compared with HCCs not associated with aflatoxin exposure. We investigated the genetic features of aflatoxin-associated HCC that can be used to differentiate them from HCCs not associated with this carcinogen. We obtained HCC tumor tissues and matched non-tumor liver tissues from 49 patients, collected from 1990 through 2016, at the Qidong Liver Cancer Hospital Institute in China-a high-risk region for aflatoxin exposure (38.2% of food samples test positive for aflatoxin contamination). Somatic variants were identified using GATK Best Practices Pipeline. We validated part of the mutations from whole-genome sequencing and whole-exome sequencing by Sanger sequencing. We also analyzed genomes of 1072 HCCs, obtained from 5 datasets from China, the United States, France, and Japan. Mutations in 49 aflatoxin-associated HCCs and 1072 HCCs from other regions were analyzed using the Wellcome Trust Sanger Institute mutational signatures framework with non-negative matrix factorization. The mutation landscape and mutational signatures from the aflatoxin-associated HCC and HCC samples from general population were compared. We identified genetic features of aflatoxin-associated HCC, and used these to identify aflatoxin-associated HCCs in datasets from other regions. Tumor samples were analyzed by immunohistochemistry to determine microvessel density and levels of CD34 and CD274 (PD-L1). Aflatoxin-associated HCCs frequently contained C>A transversions, the sequence motif GCN, and strand bias. In addition to previously reported mutations in TP53, we found frequent mutations in the adhesion G protein-coupled receptor B1 gene (ADGRB1), which were associated with increased capillary density of tumor tissue. Aflatoxin-associated HCC tissues contained high-level potential mutation-associated

  9. Genetic variant in DNA repair gene GTF2H4 is associated with lung cancer risk: a large-scale analysis of six published GWAS datasets in the TRICL consortium.

    Science.gov (United States)

    Wang, Meilin; Liu, Hongliang; Liu, Zhensheng; Yi, Xiaohua; Bickeboller, Heike; Hung, Rayjean J; Brennan, Paul; Landi, Maria Teresa; Caporaso, Neil; Christiani, David C; Doherty, Jennifer Anne; Amos, Christopher I; Wei, Qingyi

    2016-09-01

    DNA repair pathways maintain genomic integrity and stability, and dysfunction of DNA repair leads to cancer. We hypothesize that functional genetic variants in DNA repair genes are associated with risk of lung cancer. We performed a large-scale meta-analysis of 123,371 single nucleotide polymorphisms (SNPs) in 169 DNA repair genes obtained from six previously published genome-wide association studies (GWASs) of 12160 lung cancer cases and 16838 controls. We calculated odds ratios (ORs) with 95% confidence intervals (CIs) using the logistic regression model and used the false discovery rate (FDR) method for correction of multiple testing. As a result, 14 SNPs had a significant odds ratio (OR) for lung cancer risk with P FDR < 0.05, of which rs3115672 in MSH5 (OR = 1.20, 95% CI = 1.14-1.27) and rs114596632 in GTF2H4 (OR = 1.19, 95% CI = 1.12-1.25) at 6q21.33 were the most statistically significant (P combined = 3.99×10(-11) and P combined = 5.40×10(-10), respectively). The MSH5 rs3115672, but not GTF2H4 rs114596632, was strongly correlated with MSH5 rs3131379 in that region (r (2) = 1.000 and r (2) = 0.539, respectively) as reported in a previous GWAS. Importantly, however, the GTF2H4 rs114596632 T, but not MSH5 rs3115672 T, allele was significantly associated with both decreased DNA repair capacity phenotype and decreased mRNA expression levels. These provided evidence that functional genetic variants of GTF2H4 confer susceptibility to lung cancer.

  10. Genetic association of multiple sclerosis with the marker rs391745 near the endogenous retroviral locus HERV-Fc1: analysis of disease subtypes

    DEFF Research Database (Denmark)

    Hansen, Bettina; Oturai, Annette Bang; Harbo, Hanne F;

    2011-01-01

    We have previously described the occurrence of multiple sclerosis (MS) to be associated with human endogenous retroviruses, specifically the X-linked viral locus HERV-Fc1. The aim of this study was to investigate a possible association of the HERV-Fc1 locus with subtypes of MS. MS patients are ge...

  11. The association between intelligence and lifespan is mostly genetic

    DEFF Research Database (Denmark)

    Arden, Rosalind; Luciano, Michelle; Deary, Ian J

    2016-01-01

    differed between the samples. We used three methods of genetic analysis to examine the relationship between intelligence and lifespan: we calculated the proportion of the more intelligent twins who outlived their co-twin; we regressed within-twin-pair lifespan differences on within-twin-pair intelligence......BACKGROUND: Several studies in the new field of cognitive epidemiology have shown that higher intelligence predicts longer lifespan. This positive correlation might arise from socioeconomic status influencing both intelligence and health; intelligence leading to better health behaviours; and....../or some shared genetic factors influencing both intelligence and health. Distinguishing among these hypotheses is crucial for medicine and public health, but can only be accomplished by studying a genetically informative sample. METHODS: We analysed data from three genetically informative samples...

  12. Working-memory endophenotype and dyslexia-associated genetic variant predict dyslexia phenotype.

    Science.gov (United States)

    Männel, Claudia; Meyer, Lars; Wilcke, Arndt; Boltze, Johannes; Kirsten, Holger; Friederici, Angela D

    2015-10-01

    Developmental dyslexia, a severe impairment of literacy acquisition, is known to have a neurological basis and a strong genetic background. However, effects of individual genetic variations on dyslexia-associated deficits are only moderate and call for the assessment of the genotype's impact on mediating neuro-endophenotypes by the imaging genetics approach. Using voxel-based morphometry (VBM) in German participants with and without dyslexia, we investigated gray matter changes and their association with impaired phonological processing, such as reduced verbal working memory. These endophenotypical alterations were, together with dyslexia-associated genetic variations, examined on their suitability as potential predictors of dyslexia. We identified two gray matter clusters in the left posterior temporal cortex related to verbal working memory capacity. Regional cluster differences correlated with genetic risk variants in TNFRSF1B. High-genetic-risk participants exhibit a structural predominance of auditory-association areas relative to auditory-sensory areas, which may partly compensate for deficient early auditory-sensory processing stages of verbal working memory. The reverse regional predominance observed in low-genetic-risk participants may in turn reflect reliance on these early auditory-sensory processing stages. Logistic regression analysis further supported that regional gray matter differences and genetic risk interact in the prediction of individuals' diagnostic status: With increasing genetic risk, the working-memory related structural predominance of auditory-association areas relative to auditory-sensory areas classifies participants with dyslexia versus control participants. Focusing on phonological deficits in dyslexia, our findings suggest endophenotypical changes in the left posterior temporal cortex could comprise novel pathomechanisms for verbal working memory-related processes translating TNFRSF1B genotype into the dyslexia phenotype.

  13. GENETIC ANALYSIS OF BLACK SLAVONIAN PIG

    Directory of Open Access Journals (Sweden)

    Vladimir Margeta

    2012-12-01

    Full Text Available Pairs (18 of microsatelite primers were used in this study to detect the genetic relationship within Black Slavonian Pig and between Turopolje Pig, Mangalitsa breed and Croatian Wild Pigs. The second goal of this study was to determine phylogenetic relationships among these breeds and some Asian and European pigs using the mtDNA D-loop sequence polymorphism. The third goal was to determine the MC1R genotype of Black Slavonian pigs and to find an efficient and simple PCR-RFLP method, based on differences in MC1R genotype, to distinguish between purebred Black Slavonian pigs and their crossings with commercial pig breeds and Wild Boars. Aiming to conduct microsatellite analysis each animal was genotyped for 18 microsatelite markers, chosen based on their quality, size, polymorphism and location on the porcine genome as proposed by the FAO. Two pairs of primers amplified a 511-bp fragment of control region between sites 15 390 and 15 900 (Mit1.F and Mit1.R and a 810-bp fragment between sites 15 825 and 16 634 (Mit2.F and Mi2.R were genotyped for mtDNA. Two primer pairs were used to amplify the majority of the single exon of MC1R gene aiming to determinate MC1R genotype of Black Slavonian pig. The first pair of primers, MERL1 and EPIG2, was used to amplify a 428-bp product from the 5’ half of the exon, whereas EPIG1 and EPIG3 amplified a 405-bp product from the 3’ half. Our results showed that the 18 microsatellites used in this study were useful markers to study genetic diversity among Croatian autochthonous pig breeds. This set of microsatellites may be used for identifying individuals and for genetic diversity studies for selection and conservation of the Black Slavonian pig, Turopolje pig and Mangalitsa breed. Genetic distances between populations made with Principal Component Analysis (PCA method noticed that studied populations are mostly clearly geneticaly defined. mtDNA analysis suggested that Black Slavonian and Turopolje pig showed

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

    Science.gov (United States)

    Tan, Qihua; Zhao, Jing Hua; Li, Shuxia; Kruse, Torben A; Christensen, Kaare

    2010-07-01

    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 association approach that compares genotype frequency between centenarians and young controls, the power has been of concern. This paper reports a power study performed on the indirect approach using computer simulation. We perform our simulation study by introducing the current Danish population life table 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 for each setting of the specified allele risk and frequency parameters under different modes of inheritance and for different sample sizes. The indirect genetic association analysis is a valid approach for studying gene-longevity association, but the sample size requirement is about 3-4 time larger than 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 choice for studying longevity in comparison with other alternatives, when relatively large sample size is available.

  15. Genetic association signal near NTN4 in Tourette syndrome

    NARCIS (Netherlands)

    Paschou, Peristera; Yu, Dongmei; Gerber, Gloria; Evans, Patrick; Tsetsos, Fotis; Davis, Lea K; Karagiannidis, Iordanis; Chaponis, Jonathan; Gamazon, Eric; Mueller-Vahl, Kirsten; Stuhrmann, Manfred; Schloegelhofer, Monika; Stamenkovic, Mara; Hebebrand, Johannes; Noethen, Markus; Nagy, Peter; Barta, Csaba; Tarnok, Zsanett; Rizzo, Renata; Depienne, Christel; Worbe, Yulia; Hartmann, Andreas; Cath, Danielle C; Budman, Cathy L; Sandor, Paul; Barr, Cathy; Wolanczyk, Thomas; Singer, Harvey; Chou, I-Ching; Grados, Marco; Posthuma, Danielle; Rouleau, Guy A; Aschauer, Harald; Freimer, Nelson B; Pauls, David L; Cox, Nancy J; Mathews, Carol A; Scharf, Jeremiah M

    2014-01-01

    Tourette syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (p < 10(-3) ) from the recent TS genomewide association study (GWAS) in 609 independent cases and 610 ancestry-matched cont

  16. 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.

  17. Genetic association signal near NTN4 in Tourette syndrome

    NARCIS (Netherlands)

    Paschou, Peristera; Yu, Dongmei; Gerber, Gloria; Evans, Patrick; Tsetsos, Fotis; Davis, Lea K; Karagiannidis, Iordanis; Chaponis, Jonathan; Gamazon, Eric; Mueller-Vahl, Kirsten; Stuhrmann, Manfred; Schloegelhofer, Monika; Stamenkovic, Mara; Hebebrand, Johannes; Noethen, Markus; Nagy, Peter; Barta, Csaba; Tarnok, Zsanett; Rizzo, Renata; Depienne, Christel; Worbe, Yulia; Hartmann, Andreas; Cath, Danielle C; Budman, Cathy L; Sandor, Paul; Barr, Cathy; Wolanczyk, Thomas; Singer, Harvey; Chou, I-Ching; Grados, Marco; Posthuma, Danielle; Rouleau, Guy A; Aschauer, Harald; Freimer, Nelson B; Pauls, David L; Cox, Nancy J; Mathews, Carol A; Scharf, Jeremiah M

    2014-01-01

    Tourette syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (p < 10(-3) ) from the recent TS genomewide association study (GWAS) in 609 independent cases and 610 ancestry-matched cont

  18. Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium.

    Science.gov (United States)

    Lei, Jieping; Rudolph, Anja; Moysich, Kirsten B; Behrens, Sabine; Goode, Ellen L; Bolla, Manjeet K; Dennis, Joe; Dunning, Alison M; Easton, Douglas F; Wang, Qin; Benitez, Javier; Hopper, John L; Southey, Melissa C; Schmidt, Marjanka K; Broeks, Annegien; Fasching, Peter A; Haeberle, Lothar; Peto, Julian; Dos-Santos-Silva, Isabel; Sawyer, Elinor J; Tomlinson, Ian; Burwinkel, Barbara; Marmé, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Flyger, Henrik; Nielsen, Sune F; Nordestgaard, Børge G; González-Neira, Anna; Menéndez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan L; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Hamann, Ute; Nevanlinna, Heli; Fagerholm, Rainer; Dörk, Thilo; Bogdanova, Natalia V; Mannermaa, Arto; Hartikainen, Jaana M; Van Dijck, Laurien; Smeets, Ann; Flesch-Janys, Dieter; Eilber, Ursula; Radice, Paolo; Peterlongo, Paolo; Couch, Fergus J; Hallberg, Emily; Giles, Graham G; Milne, Roger L; Haiman, Christopher A; Schumacher, Fredrick; Simard, Jacques; Goldberg, Mark S; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Zheng, Wei; Beeghly-Fadiel, Alicia; Winqvist, Robert; Grip, Mervi; Andrulis, Irene L; Glendon, Gord; García-Closas, Montserrat; Figueroa, Jonine; Czene, Kamila; Brand, Judith S; Darabi, Hatef; Eriksson, Mikael; Hall, Per; Li, Jingmei; Cox, Angela; Cross, Simon S; Pharoah, Paul D P; Shah, Mitul; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Ademuyiwa, Foluso; Ambrosone, Christine B; Swerdlow, Anthony; Jones, Michael; Chang-Claude, Jenny

    2016-01-01

    Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03-1.08; p value = 1.4 × 10(-6)). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10(-3) and 7.0 × 10(-3), respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10(-3), 4.5 × 10(-4) and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3, IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.

  19. Genetic diversity analysis of some exotic, Indian and mutant ...

    African Journals Online (AJOL)

    USER

    2010-06-28

    Jun 28, 2010 ... Genetic make-up of Brassica crops has been playing a major contributory role towards its enhanced ... morphological and biochemical characteristics. The .... The genetic associations between genotypes were evaluated by.

  20. Comprehensive assessment and network analysis of the emerging genetic susceptibility landscape of prostate cancer.

    Science.gov (United States)

    Hicks, Chindo; Miele, Lucio; Koganti, Tejaswi; Vijayakumar, Srinivasan

    2013-01-01

    Recent advances in high-throughput genotyping have made possible identification of genetic variants associated with increased risk of developing prostate cancer using genome-wide associations studies (GWAS). However, the broader context in which the identified genetic variants operate is poorly understood. Here we present a comprehensive assessment, network, and pathway analysis of the emerging genetic susceptibility landscape of prostate cancer. We created a comprehensive catalog of genetic variants and associated genes by mining published reports and accompanying websites hosting supplementary data on GWAS. We then performed network and pathway analysis using single nucleotide polymorphism (SNP)-containing genes to identify gene regulatory networks and pathways enriched for genetic variants. We identified multiple gene networks and pathways enriched for genetic variants including IGF-1, androgen biosynthesis and androgen signaling pathways, and the molecular mechanisms of cancer. The results provide putative functional bridges between GWAS findings and gene regulatory networks and biological pathways.

  1. Born to Lead? A Twin Design and Genetic Association Study of Leadership Role Occupancy.

    Science.gov (United States)

    De Neve, Jan-Emmanuel; Mikhaylov, Slava; Dawes, Christopher T; Christakis, Nicholas A; Fowler, James H

    2013-02-01

    We address leadership emergence and the possibility that there is a partially innate predisposition to occupy a leadership role. Employing twin design methods on data from the National Longitudinal Study of Adolescent Health, we estimate the heritability of leadership role occupancy at 24%. Twin studies do not point to specific genes or neurological processes that might be involved. We therefore also conduct association analysis on the available genetic markers. The results show that leadership role occupancy is associated with rs4950, a single nucleotide polymorphism (SNP) residing on a neuronal acetylcholine receptor gene (CHRNB3). We replicate this family-based genetic association result on an independent sample in the Framingham Heart Study. This is the first study to identify a specific genotype associated with the tendency to occupy a leadership position. The results suggest that what determines whether an individual occupies a leadership position is the complex product of genetic and environmental influences; with a particular role for rs4950.

  2. Genetic analysis of CRHRA1 and CRHRA2 microsatellites and their association with rheumatoid arthritis in South Asian and Caucasian populations of the East Midlands, UK.

    Directory of Open Access Journals (Sweden)

    Anant Ghelani

    2012-06-01

    Full Text Available Two microsatellites from corticotropin releasing hormone (CRH gene locus (CRHRA1 and CRHRA2 were reported to be associated with rheumatoid arthritis (RA in Caucasians. This study aims to replicate the association in a South Asian (SA and Caucasian RA sample from the East Midlands, UK. DNA from 281 South Asians (111 patients, 43 siblings, 127 controls and 287 Caucasians (116 patients, 64 siblings, 107 controls were genotyped. The Odds Ratio for carrying at least one copy of the CRHRA1*10 risk allele was 1.32 (Confidence Interval, CI=0.77-2.28 in Caucasians and 1.55 (CI=0.92-2.63 in South Asians, indicative of a trend for association. The risk allele CRHRA2*14 was lower in South Asians compared to Caucasians (5.5%-8.6% vs. 17.7-18.2 %; P<0.005. Significant linkage disequilibrium was observed between CRHRA1 and CRHRA2 in both cohorts. CRHRA1*10 was the frequently transmitted allele in SA patients. A non-significant association was observed with CRHRA1*10 allele in both RA populations.

  3. A Quantitative Genetic Analysis of the Associations among Language Skills, Peer Interactions, and Behavioral Problems in Childhood: Results from a Sample of Twins

    Science.gov (United States)

    Beaver, Kevin M.; Boutwell, Brian B.; Barnes, J. C.; Schwartz, Joseph A.; Connolly, Eric J.

    2014-01-01

    A body of empirical research has revealed that there are associations among language skills, peer interactions, and behavioral problems in childhood. At the same time, however, there has been comparatively less research devoted to exploring the mutual unfolding of these factors over the first few years of life. The current study is designed to…

  4. A Quantitative Genetic Analysis of the Associations among Language Skills, Peer Interactions, and Behavioral Problems in Childhood: Results from a Sample of Twins

    Science.gov (United States)

    Beaver, Kevin M.; Boutwell, Brian B.; Barnes, J. C.; Schwartz, Joseph A.; Connolly, Eric J.

    2014-01-01

    A body of empirical research has revealed that there are associations among language skills, peer interactions, and behavioral problems in childhood. At the same time, however, there has been comparatively less research devoted to exploring the mutual unfolding of these factors over the first few years of life. The current study is designed to…

  5. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk : a meta-analysis of genetic studies and randomised trials

    NARCIS (Netherlands)

    Holmes, Michael V.; Newcombe, Paul; Hubacek, Jaroslav A.; Sofat, Reecha; Ricketts, Sally L.; Cooper, Jackie; Breteler, Monique M. B.; Bautista, Leonelo E.; Sharma, Pankaj; Whittaker, John C.; Smeeth, Liam; Fowkes, F. Gerald R.; Algra, Ale; Shmeleva, Veronika; Szolnoki, Zoltan; Roest, Mark; Linnebank, Michael; Zacho, Jeppe; Nalls, Michael A.; Singleton, Andrew B.; Ferrucci, Luigi; Hardy, John; Worrall, Bradford B.; Rich, Stephen S.; Matarin, Mar; Norman, Paul E.; Flicker, Leon; Almeida, Osvaldo P.; van Bockxmeer, Frank M.; Shimokata, Hiroshi; Khaw, Kay-Tee; Wareham, Nicholas J.; Bobak, Martin; Sterne, Jonathan A. C.; Smith, George Davey; Talmud, Philippa J.; van Duijn, Cornelia; Humphries, Steve E.; Price, Jackie F.; Ebrahim, Shah; Lawlor, Debbie A.; Hankey, Graeme J.; Meschia, James F.; Sandhu, Manjinder S.; Hingorani, Aroon D.; Casas, Juan P.

    2011-01-01

    Background The MTHFR 677C -> T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and

  6. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk : a meta-analysis of genetic studies and randomised trials

    NARCIS (Netherlands)

    Holmes, Michael V.; Newcombe, Paul; Hubacek, Jaroslav A.; Sofat, Reecha; Ricketts, Sally L.; Cooper, Jackie; Breteler, Monique M. B.; Bautista, Leonelo E.; Sharma, Pankaj; Whittaker, John C.; Smeeth, Liam; Fowkes, F. Gerald R.; Algra, Ale; Shmeleva, Veronika; Szolnoki, Zoltan; Roest, Mark; Linnebank, Michael; Zacho, Jeppe; Nalls, Michael A.; Singleton, Andrew B.; Ferrucci, Luigi; Hardy, John; Worrall, Bradford B.; Rich, Stephen S.; Matarin, Mar; Norman, Paul E.; Flicker, Leon; Almeida, Osvaldo P.; van Bockxmeer, Frank M.; Shimokata, Hiroshi; Khaw, Kay-Tee; Wareham, Nicholas J.; Bobak, Martin; Sterne, Jonathan A. C.; Smith, George Davey; Talmud, Philippa J.; van Duijn, Cornelia; Humphries, Steve E.; Price, Jackie F.; Ebrahim, Shah; Lawlor, Debbie A.; Hankey, Graeme J.; Meschia, James F.; Sandhu, Manjinder S.; Hingorani, Aroon D.; Casas, Juan P.

    2011-01-01

    Background The MTHFR 677C -> T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-st

  7. Genetic analysis of complement C1s deficiency associated with systemic lupus erythematosus highlights alternative splicing of normal C1s gene

    DEFF Research Database (Denmark)

    Armano, MT; Ferriani, VP; Florido, MP

    2008-01-01

    Deficiencies of complement proteins of the classical pathway are strongly associated with the development of autoimmune diseases. Deficiency of C1r has been observed to occur concomitantly with deficiency in C1s and 9 out of 15 reported cases presented systemic lupus erythematosus (SLE). Here, we...

  8. The Association between Pediatric NAFLD and Common Genetic Variants

    Directory of Open Access Journals (Sweden)

    Giuseppina Rosaria Umano

    2017-06-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD is one of the most common complications of obesity. Several studies have shown that genetic predisposition probably plays an important role in its pathogenesis. In fact, in the last few years a large number of genetic studies have provided compelling evidence that some gene variants, especially those in genes encoding proteins regulating lipid metabolism, are associated with intra-hepatic fat accumulation. Here we provide a comprehensive review of the gene variants that have affected the natural history of the disease.

  9. Methods for Analyzing Multivariate Phenotypes in Genetic Association Studies.

    Science.gov (United States)

    Yang, Qiong; Wang, Yuanjia

    2012-05-01

    This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Multivariate phenotypes are frequently encountered in genetic association studies. The purpose of analyzing multivariate phenotypes usually includes discovery of novel genetic variants of pleiotropy effects, that is, affecting multiple phenotypes, and the ultimate goal of uncovering the underlying genetic mechanism. In recent years, there have been new method development and application of existing statistical methods to such phenotypes. In this paper, we provide a review of the available methods for analyzing association between a single marker and a multivariate phenotype consisting of the same type of components (e.g., all continuous or all categorical) or different types of components (e.g., some are continuous and others are categorical). We also reviewed causal inference methods designed to test whether the detected association with the multivariate phenotype is truly pleiotropy or the genetic marker exerts its effects on some phenotypes through affecting the others.

  10. Identification of Genetic Loci Associated with Quality Traits in Almond via Association Mapping.

    Directory of Open Access Journals (Sweden)

    Carolina Font i Forcada

    Full Text Available To design an appropriate association study, we need to understand population structure and the structure of linkage disequilibrium within and among populations as well as in different regions of the genome in an organism. In this study, we have used a total of 98 almond accessions, from five continents located and maintained at the Centro de Investigación y Tecnología Agroalimentaria de Aragón (CITA; Spain, and 40 microsatellite markers. Population structure analysis performed in 'Structure' grouped the accessions into two principal groups; the Mediterranean (Western-Europe and the non-Mediterranean, with K = 3, being the best fit for our data. There was a strong subpopulation structure with linkage disequilibrium decaying with increasing genetic distance resulting in lower levels of linkage disequilibrium between more distant markers. A significant impact of population structure on linkage disequilibrium in the almond cultivar groups was observed. The mean r2 value for all intra-chromosomal loci pairs was 0.040, whereas, the r2 for the inter-chromosomal loci pairs was 0.036. For analysis of association between the markers and phenotypic traits, five models comprising both general linear models and mixed linear models were selected to test the marker trait associations. The mixed linear model (MLM approach using co-ancestry values from population structure and kinship estimates (K model as covariates identified a maximum of 16 significant associations for chemical traits and 12 for physical traits. This study reports for the first time the use of association mapping for determining marker-locus trait associations in a world-wide almond germplasm collection. It is likely that association mapping will have the most immediate and largest impact on the tier of crops such as almond with the greatest economic value.

  11. A genetic epidemiological mega analysis of smoking initiation in adolescents

    NARCIS (Netherlands)

    Maes, H.H.; Prom-Wormley, E.; Eaves, L.J.; Rhee, S.H.; Hewitt, J.K.; Young, S.; Corley, R.; McGue, M.K.; Iacono, W.G.; Legrand, L.; Samek, D.; Murrelle, E.L.; Silberg, J.L.; Miles, D.; Schieken, R.M.; Beunen, G.P.; Thomis, M.; Rose, R.J.; Dick, D.M.; Boomsma, D.I.; Bartels, M.; Vink, J.M.; Lichtenstein, P.; White, V.; Kaprio, J.; Neale, M.C.

    2017-01-01

    Introduction. Previous studies in adolescents were not adequately powered to accurately disentangle genetic and environmental influences on smoking initiation across adolescence. Methods. Mega-analysis of pooled genetically informative data on smoking initiation was performed, with structural

  12. Association of Genetic Loci With Glucose Levels in Childhood and Adolescence A Meta-Analysis of Over 6,000 Children

    DEFF Research Database (Denmark)

    Barker, A.; Sharp, S. J.; Timpson, N. J.;

    2011-01-01

    glucose loci. Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced p-cell function, as indicated by homeostasis model assessment of beta-cell function. Analysis using a weighted risk score showed an increase [beta (95% CI)] in fasting glucose level...

  13. 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.

  14. Gender-Specific Associations between CHGB Genetic Variants and Schizophrenia in a Korean Population.

    Science.gov (United States)

    Shin, Joong Gon; Kim, Jeong Hyun; Park, Chul Soo; Kim, Bong Jo; Kim, Jae Won; Choi, Ihn Geun; Hwang, Jaeuk; Shin, Hyoung Doo; Woo, Sung Il

    2017-05-01

    Schizophrenia is a devastating mental disorder and is known to be affected by genetic factors. The chromogranin B (CHGB), a member of the chromogranin gene family, has been proposed as a candidate gene associated with the risk of schizophrenia. The secretory pathway for peptide hormones and neuropeptides in the brain is regulated by chromogranin proteins. The aim of this study was to investigate the potential associations between genetic variants of CHGB and schizophrenia susceptibility. In the current study, 15 single nucleotide polymorphisms of CHGB were genotyped in 310 schizophrenia patients and 604 healthy controls. Statistical analysis revealed that two genetic variants (non-synonymous rs910122; rs2821 in 3'-untranslated region) were associated with schizophrenia [minimum p=0.002; odds ratio (OR)=0.72], even after correction for multiple testing (p(corr)=0.02). Since schizophrenia is known to be differentially expressed between sexes, additional analysis for sex was performed. As a result, these two genetic variants (rs910122 and rs2821) and a haplotype (ht3) showed significant associations with schizophrenia in male subjects (p(corr)=0.02; OR=0.64), whereas the significance disappeared in female subjects (p>0.05). Although this study has limitations including a small number of samples and lack of functional study, our results suggest that genetic variants of CHGB may have sex-specific effects on the risk of schizophrenia and provide useful preliminary information for further study.

  15. Marburg hemorrhagic fever associated with multiple genetic lineages of virus

    DEFF Research Database (Denmark)

    Bausch, D G; Nichol, S T; Muyembe-Tamfum, J J

    2006-01-01

    chains of human-to-human transmission continued to occur until September 2000. Suspected cases were identified on the basis of a case definition; cases were confirmed by the detection of virus antigen and nucleic acid in blood, cell culture, antibody responses, and immunohistochemical analysis. Results...... genetically distinct lineages of virus in circulation during the outbreak. Conclusions Marburg hemorrhagic fever can have a very high case fatality rate. Since multiple genetic variants of virus were identified, ongoing introduction of virus into the population helped perpetuate this outbreak. The findings...

  16. Functional analysis of variance for association studies.

    Directory of Open Access Journals (Sweden)

    Olga A Vsevolozhskaya

    Full Text Available While progress has been made in identifying common genetic variants associated with human diseases, for most of common complex diseases, the identified genetic variants only account for a small proportion of heritability. Challenges remain in finding additional unknown genetic variants predisposing to complex diseases. With the advance in next-generation sequencing technologies, sequencing studies have become commonplace in genetic research. The ongoing exome-sequencing and whole-genome-sequencing studies generate a massive amount of sequencing variants and allow researchers to comprehensively investigate their role in human diseases. The discovery of new disease-associated variants can be enhanced by utilizing powerful and computationally efficient statistical methods. In this paper, we propose a functional analysis of variance (FANOVA method for testing an association of sequence variants in a genomic region with a qualitative trait. The FANOVA has a number of advantages: (1 it tests for a joint effect of gene variants, including both common and rare; (2 it fully utilizes linkage disequilibrium and genetic position information; and (3 allows for either protective or risk-increasing causal variants. Through simulations, we show that FANOVA outperform two popularly used methods - SKAT and a previously proposed method based on functional linear models (FLM, - especially if a sample size of a study is small and/or sequence variants have low to moderate effects. We conduct an empirical study by applying three methods (FANOVA, SKAT and FLM to sequencing data from Dallas Heart Study. While SKAT and FLM respectively detected ANGPTL 4 and ANGPTL 3 associated with obesity, FANOVA was able to identify both genes associated with obesity.

  17. Genetic risks and familial associations of small bowel carcinoma

    Institute of Scientific and Technical Information of China (English)

    Santosh Shenoy

    2016-01-01

    Adenocarcinoma of small intestines(SBA) is a relatively rare malignancy with poor outcomes due to delayed diagnosis.Fifty percent of patients have metastases on presentation and therefore early detection and treatment offers the best long term outcomes.Certain genetic polyposis syndromes and familial diseases are associatedwith increased risks for SBA.These include familial adenomatous polyposis(FAP),Lynch syndromes(LS),Juvenile polyposis syndrome,Peutz-Jeghers syndrome,Crohn’s disease(CD) and celiac disease.Mutations in APC gene,Mismatch repair genes,STK11 gene,and SMAD4 gene have been implicated for the genetic diseases respectively.While there are no specific inherited genetic mutations for CD,genome-wide association studies have established over 140 loci associated with CD.CpG island mutations with defects in mismatch repair genes have been identified in celiac disease.Significant diagnostic advances have occurred in the past decade and intuitively,it would seem beneficial to use these advanced modalities for surveillance of these patients.At present it is debatable and no clear data exists to support this approach except for established guidelines to diagnose duodenal polyps in FAP,and LS.Here we discuss the genetic alterations,cancer risks,signaling mechanisms and briefly touch the surveillance modalities available for these genetic and clinical syndromes.English language articles from Pub Med/Medline and Embase was searched were collected using the phrases "small-bowel adenocarcinoma,genetics,surveillance,familial adenomatous polyposis,lynch syndromes,Peutz-Jeghers syndrome,juvenile polyposis syndrome,CD and celiac disease".Figures,tables and schematic diagram to illustrate pathways are included in the review.

  18. 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

    Obesity is a complex condition with world-wide exponentially rising prevalence rates, linked with severe diseases like Type 2 Diabetes. Economic and welfare consequences have led to a raised interest in a better understanding of the biological and genetic background. To date, whole genome...... 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...

  19. 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

    Obesity is a complex condition with world-wide exponentially rising prevalence rates, linked with severe diseases like Type 2 Diabetes. Economic and welfare consequences have led to a raised interest in a better understanding of the biological and genetic background. To date, whole genome...... 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...

  20. Genetic factors associated with cancer male breast: a literature review

    Directory of Open Access Journals (Sweden)

    Nathalia Maria Tomaz Silveira

    2016-10-01

    Full Text Available The male breast cancer is a rare neoplastic framework, covers 1% of cases of breast cancer worldwide, 1% of malignant tumors in men and has an annual incidence of 1 per 100,000 men. Information was gathered about the current studies related to genetic character in addressed condition, in which the goal was to analyze aspects of predisposition and association, using 16 original articles indexed in the period between January 2011 to February 2016, written in English and Spanish, with experimental design or observational, using male breast cancer descriptors, breast cancer and genetic factor for breast cancer, as well as their English translations male breast cancer, cancer treatment, breast cancer and genetic factors. It was mainly discussed the genetic influence on the occurrence of male breast cancer, such as changes in suppressors BRCA genes, relationships with CHECK2 checkpoint, family history and links with Klinefelter syndrome, among other factors. Environmental aspects are also suggested by the literature on the clinical neoplasic manifestation, but with less conclusive emphases. Although the literature on the subject still need growth and deepening, we observe scientific reassurances about the importance of genetic influence, especially the BRCA 1, about the Multifactorial etiology of the neoplasia.

  1. Genetic Loci Associated with Allergic Sensitization in Lithuanians.

    Directory of Open Access Journals (Sweden)

    Ingrida Šaulienė

    Full Text Available Allergic rhinitis (AR is a common and complex disease. It is associated with environmental as well as genetic factors. Three recent genome-wide association studies (GWAS reported altogether 47 single nucleotide polymorphisms (SNPs associated with AR or allergic sensitization (AS in Europeans and North Americans. Two follow up studies in Swedish and Chinese replicated 15 associations. In these studies individuals were selected based on the self-reported AR, or AR/AS diagnosed using blood IgE test or skin prick test (SPT, which were performed often without restriction to specific allergens. Here we performed third replication study in Lithuanians. We used SPT and carefully selected set of allergens prevalent in Lithuania, as well as Illumina Core Exome chip for SNP detection. We genotyped 270 SPT-positive individuals (137 Betulaceae -, 174 Poaceae-, 199 Artemisia-, 70 Helianthus-, 22 Alternaria-, 22 Cladosporium-, 140 mites-, 95 cat- and 97 dog dander-sensitive cases and 162 SPT-negative controls. We found altogether 13 known SNPs associated with AS (p ≤0.05. Three SNPs were found in Lithuanians sensitive to several allergens, and 10 SNPs were found in Lithuanians sensitive to a certain allergen. For the first time, SNP rs7775228:C was associated with patient sensitivity to dog allergens (F_A=0,269, F_U=0.180, P=0.008. Thus, careful assessment of AS allowed us to detect known genetic variants associated with AS/AR in relatively small cohort of Lithuanians.

  2. Genetic Loci Associated with Allergic Sensitization in Lithuanians.

    Science.gov (United States)

    Šaulienė, Ingrida; Greičiuvienė, Jūratė; Šukienė, Laura; Juškevičiūtė, Neringa; Benner, Christian; Zinkevičienė, Auksė; Ripatti, Samuli; Donner, Kati; Kainov, Denis

    2015-01-01

    Allergic rhinitis (AR) is a common and complex disease. It is associated with environmental as well as genetic factors. Three recent genome-wide association studies (GWAS) reported altogether 47 single nucleotide polymorphisms (SNPs) associated with AR or allergic sensitization (AS) in Europeans and North Americans. Two follow up studies in Swedish and Chinese replicated 15 associations. In these studies individuals were selected based on the self-reported AR, or AR/AS diagnosed using blood IgE test or skin prick test (SPT), which were performed often without restriction to specific allergens. Here we performed third replication study in Lithuanians. We used SPT and carefully selected set of allergens prevalent in Lithuania, as well as Illumina Core Exome chip for SNP detection. We genotyped 270 SPT-positive individuals (137 Betulaceae -, 174 Poaceae-, 199 Artemisia-, 70 Helianthus-, 22 Alternaria-, 22 Cladosporium-, 140 mites-, 95 cat- and 97 dog dander-sensitive cases) and 162 SPT-negative controls. We found altogether 13 known SNPs associated with AS (p ≤0.05). Three SNPs were found in Lithuanians sensitive to several allergens, and 10 SNPs were found in Lithuanians sensitive to a certain allergen. For the first time, SNP rs7775228:C was associated with patient sensitivity to dog allergens (F_A=0,269, F_U=0.180, P=0.008). Thus, careful assessment of AS allowed us to detect known genetic variants associated with AS/AR in relatively small cohort of Lithuanians.

  3. Genetic diversity, population structure and marker trait associations for seed quality traits in cotton (Gossypium hirsutum)

    Indian Academy of Sciences (India)

    Ashok Badigannavar; Gerald O. Myers

    2015-03-01

    Cottonseed contains 16% seed oil and 23% seed protein by weight. High levels of palmitic acid provides a degree of stability to the oil, while the presence of bound gossypol in proteins considerably changes their properties, including their biological value. This study uses genetic principles to identify genomic regions associated with seed oil, protein and fibre content in upland cotton cultivars. Cotton association mapping panel representing the US germplasm were genotyped using amplified fragment length polymorphism markers, yielding 234 polymorphic DNA fragments. Phenotypic analysis showed high genetic variability for the seed traits, seed oil range from 6.47–25.16%, protein from 1.85–28.45% and fibre content from 15.88–37.12%. There were negative correlations between seed oil and protein content. With reference to genetic diversity, the average estimate of ST was 8.852 indicating a low level of genetic differentiation among subpopulations. The AMOVA test revealed that variation was 94% within and 6% among subpopulations. Bayesian population structure identified five subpopulations and was in agreement with their geographical distribution. Among the mixed models analysed, mixed linear model (MLM) identified 21 quantitative trait loci for lint percentage and seed quality traits, such as seed protein and oil. Establishing genetic diversity, population structure and marker trait associations for the seed quality traits could be valuable in understanding the genetic relationships and their utilization in breeding programmes.

  4. Genetic Analysis and Species Specific Amplification of the Artemisinin Resistance-Associated Kelch Propeller Domain in P. falciparum and P. vivax.

    Directory of Open Access Journals (Sweden)

    Eldin Talundzic

    Full Text Available Plasmodium falciparum resistance to artemisinin has emerged in the Greater Mekong Subregion and now poses a threat to malaria control and prevention. Recent work has identified mutations in the kelch propeller domain of the P. falciparum K13 gene to be associated artemisinin resistance as defined by delayed parasite clearance and ex vivo ring stage survival assays. Species specific primers for the two most prevalent human malaria species, P. falciparum and P. vivax, were designed and tested on multiple parasite isolates including human, rodent, and non- humans primate Plasmodium species. The new protocol described here using the species specific primers only amplified their respective species, P. falciparum and P. vivax, and did not cross react with any of the other human malaria Plasmodium species. We provide an improved species specific PCR and sequencing protocol that could be effectively used in areas where both P. falciparum and P. vivax are circulating. To design this improved protocol, the kelch gene was analyzed and compared among different species of Plasmodium. The kelch propeller domain was found to be highly conserved across the mammalian Plasmodium species.

  5. 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...

  6. Genetic variants associated with warfarin dosage in Kuwaiti population.

    Science.gov (United States)

    John, Sumi Elsa; Antony, Dinu; Eaaswarkhanth, Muthukrishnan; Hebbar, Prashantha; Alkayal, Fadi; Tuomilehto, Jaakko; Alsmadi, Osama; Thanaraj, Thangavel Alphonse

    2017-06-01

    Assessing the distinct prevalence or absence of genetic variants associated with differential response to the anticoagulant medication of warfarin in different population groups is actively pursued by pharmacogenomics community. Populations from Arabian Peninsula are underrepresented in such studies. By way of examining exome- and genome-wide genotype data from 1395 Arab individuals in Kuwait, we report distinct occurrence of warfarin response-related variants rs12460590_A/CYP2A7, rs2108622_T/CYP4F2, rs2884737_C/VKORC1 and distinct absence of rs11150606_C/PRSS53 in Kuwaiti population. The presented results in conjunction with similar literature reports on Qatari population enhance the worldwide understanding on population-specific distributions of genetic variants associated with warfarin drug dosage.

  7. Identification of genomic loci associated with resting heart rate and shared genetic predictors with all-cause mortality

    NARCIS (Netherlands)

    Eppinga, Ruben N.; Hagemeijer, Yanick; Burgess, Stephen; Hinds, David A.; Stefansson, Kari; Gudbjartsson, Daniel F.; van Veldhuisen, Dirk J.; Munroe, Patricia B.; Verweij, Niek; van der Harst, Pim

    2016-01-01

    Resting heart rate is a heritable trait correlated with life span. Little is known about the genetic contribution to resting heart rate and its relationship with mortality. We performed a genome-wide association discovery and replication analysis starting with 19.9 million genetic variants and study

  8. Genetic analysis of haemophilia A in Bulgaria

    Directory of Open Access Journals (Sweden)

    Kremensky Ivo

    2004-03-01

    Full Text Available Abstract Background Haemophilias are the most common hereditary severe disorders of blood clotting. In families afflicted with heamophilia, genetic analysis provides opportunities to prevent recurrence of the disease. This study establishes a diagnostical strategy for carriership determination and prenatal diagnostics of haemophilia A in Bulgarian haemophilic population. Methods A diagnostical strategy consisting of screening for most common mutations in the factor VIII gene and analysis of a panel of eight linked to the factor VIII gene locus polymorphisms was established. Results Polymorphic analysis for carrier status determination of haemophilia A was successful in 30 families out of 32 (94%. Carrier status was determined in 25 of a total of 28 women at risk (89%. Fourteen prenatal diagnoses in women at high risk of having a haemophilia A – affected child were performed, resulting in 6 healthy boys and 5 girls. Conclusion The compound approach proves to be a highly informative and cost-effective strategy for prevention of recurrence of haemophilia A in Bulgaria. DNA analysis facilitates carriership determination and subsequent prenatal diagnosis in the majority of Bulgarian families affected by haemophilia A.

  9. Genetic association studies in drug-induced liver injury.

    Science.gov (United States)

    Daly, Ann K; Day, Chris P

    2009-11-01

    Genetic studies on drug-induced liver injury (DILI) have proved challenging, both because of their rarity and their difficulty in replicating observed effects. However, significant progress has now been achieved by both candidate-gene and genome-wide association studies. These two approaches are considered in detail, together with examples of DILI due to specific drugs where consistent associations have been reported. Particular consideration is given to associations between antituberculosis drug-related liver injury and the "slow acetylator" genotype for N-acetyltransferase 2, amoxicillin/clavulanate-related liver injury, and the human leukocyte antigen (HLA) class II DRB1*1501 allele and flucloxacillin-related injury and the HLA class I B*5701 allele. Although these associations are drug-specific, the possibility that additional, more general susceptibility genes for DILI exist requires further investigation, ideally by genome-wide association studies involving international collaboration. The possibility of interethnic variation in susceptibility to DILI also requires further study.

  10. Describing the genetic architecture of epilepsy through heritability analysis.

    Science.gov (United States)

    Speed, Doug; O'Brien, Terence J; Palotie, Aarno; Shkura, Kirill; Marson, Anthony G; Balding, David J; Johnson, Michael R

    2014-10-01

    Epilepsy is a disease with substantial missing heritability; despite its high genetic component, genetic association studies have had limited success detecting common variants which influence susceptibility. In this paper, we reassess the role of common variants on epilepsy using extensions of heritability analysis. Our data set consists of 1258 UK patients with epilepsy, of which 958 have focal epilepsy, and 5129 population control subjects, with genotypes recorded for over 4 million common single nucleotide polymorphisms. Firstly, we show that on the liability scale, common variants collectively explain at least 26% (standard deviation 5%) of phenotypic variation for all epilepsy and 27% (standard deviation 5%) for focal epilepsy. Secondly we provide a new method for estimating the number of causal variants for complex traits; when applied to epilepsy, our most optimistic estimate suggests that at least 400 variants influence disease susceptibility, with potentially many thousands. Thirdly, we use bivariate analysis to assess how similar the genetic architecture of focal epilepsy is to that of non-focal epilepsy; we demonstrate both significant differences (P = 0.004) and significant similarities (P = 0.01) between the two subtypes, indicating that although the clinical definition of focal epilepsy does identify a genetically distinct epilepsy subtype, there is also scope to improve the classification of epilepsy by incorporating genotypic information. Lastly, we investigate the potential value in using genetic data to diagnose epilepsy following a single epileptic seizure; we find that a prediction model explaining 10% of phenotypic variation could have clinical utility for deciding which single-seizure individuals are likely to benefit from immediate anti-epileptic drug therapy.

  11. A Multi-Marker Genetic Association Test Based on the Rasch Model Applied to Alzheimer's Disease.

    Directory of Open Access Journals (Sweden)

    Wenjia Wang

    Full Text Available Results from Genome-Wide Association Studies (GWAS have shown that the genetic basis of complex traits often include many genetic variants with small to moderate effects whose identification remains a challenging problem. In this context multi-marker analysis at the gene and pathway level can complement traditional point-wise approaches that treat the genetic markers individually. In this paper we propose a novel statistical approach for multi-marker analysis based on the Rasch model. The method summarizes the categorical genotypes of SNPs by a generalized logistic function into a genetic score that can be used for association analysis. Through different sets of simulations, the false-positive rate and power of the proposed approach are compared to a set of existing methods, and shows good performances. The application of the Rasch model on Alzheimer's Disease (AD ADNI GWAS dataset also allows a coherent interpretation of the results. Our analysis supports the idea that APOE is a major susceptibility gene for AD. In the top genes selected by proposed method, several could be functionally linked to AD. In particular, a pathway analysis of these genes also highlights the metabolism of cholesterol, that is known to play a key role in AD pathogenesis. Interestingly, many of these top genes can be integrated in a hypothetic signalling network.

  12. Inbreeding and genetic diversity in dogs: results from DNA analysis.

    Science.gov (United States)

    Wade, Claire M

    2011-08-01

    This review assesses evidence from DNA analysis to determine whether there is sufficient genetic diversity within breeds to ensure that populations are sustainable in the absence of cross breeding and to determine whether genetic diversity is declining. On average, dog breeds currently retain approximately 87% of the available domestic canine genetic diversity. Requirements that breeding stock must be 'clear' for all genetic disorders may firstly place undue genetic pressure on animals tested as being 'clear' of known genetic disorders, secondly may contribute to loss of diversity and thirdly may result in the dissemination of new recessive disorders for which no genetic tests are available. Global exchange of genetic material may hasten the loss of alleles and this practice should be discussed in relation to the current effective population size of a breed and its expected future popularity. Genomic data do not always support the results from pedigree analysis and possible reasons for this are discussed.

  13. 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.

  14. Multiethnic genetic association studies improve power for locus discovery.

    Directory of Open Access Journals (Sweden)

    Sara L Pulit

    Full Text Available To date, genome-wide association studies have focused almost exclusively on populations of European ancestry. These studies continue with the advent of next-generation sequencing, designed to systematically catalog and test low-frequency variation for a role in disease. A complementary approach would be to focus further efforts on cohorts of multiple ethnicities. This leverages the idea that population genetic drift may have elevated some variants to higher allele frequency in different populations, boosting statistical power to detect an association. Based on empirical allele frequency distributions from eleven populations represented in HapMap Phase 3 and the 1000 Genomes Project, we simulate a range of genetic models to quantify the power of association studies in multiple ethnicities relative to studies that exclusively focus on samples of European ancestry. In each of these simulations, a first phase of GWAS in exclusively European samples is followed by a second GWAS phase in any of the other populations (including a multiethnic design. We find that nontrivial power gains can be achieved by conducting future whole-genome studies in worldwide populations, where, in particular, African populations contribute the largest relative power gains for low-frequency alleles (<5% of moderate effect that suffer from low power in samples of European descent. Our results emphasize the importance of broadening genetic studies to worldwide populations to ensure efficient discovery of genetic loci contributing to phenotypic trait variability, especially for those traits for which large numbers of samples of European ancestry have already been collected and tested.

  15. Replication of genetic associations as pseudoreplication due to shared genealogy.

    Science.gov (United States)

    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.

  16. Systematic review genetic biomarkers associated with anti-TNF treatment response in inflammatory bowel diseases

    DEFF Research Database (Denmark)

    Sørensen, Signe Bek; Nielsen, J V; Bo Bojesen, Anders

    2016-01-01

    : To identify polymorphisms and candidate genes from the literature that are associated with anti-tumour necrosis factor (TNF) treatment response in patients with inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis. METHODS: We performed a PubMed literature search and retrieved...... studies reporting original data on association between polymorphisms and anti-TNF treatment response and conducted a meta-analysis. RESULTS: A functional polymorphism in FCGR3A was significantly associated with anti-TNF treatment response among CD patients using biological response criterion (decrease...... in an explorative analysis. CONCLUSIONS: There are no genetic markers currently available which are adequately predictive of anti-TNF response for use in the clinic. Genetic markers bear the advantage that they do not change over time. Therefore, hypothesis-free approaches, testing a large number of polymorphisms...

  17. GENETIC ANALYSIS OF ABSCISIC ACID BIOSYNTHESIS

    Energy Technology Data Exchange (ETDEWEB)

    MCCARTY D R

    2012-01-10

    The carotenoid cleavage dioxygenases (CCD) catalyze synthesis of a variety of apo-carotenoid secondary metabolites in plants, animals and bacteria. In plants, the reaction catalyzed by the 11, 12, 9-cis-epoxy carotenoid dioxygenase (NCED) is the first committed and key regulated step in synthesis of the plant hormone, abscisic acid (ABA). ABA is a key regulator of plant stress responses and has critical functions in normal root and seed development. The molecular mechanisms responsible for developmental control of ABA synthesis in plant tissues are poorly understood. Five of the nine CCD genes present in the Arabidopsis genome encode NCED's involved in control of ABA synthesis in the plant. This project is focused on functional analysis of these five AtNCED genes as a key to understanding developmental regulation of ABA synthesis and dissecting the role of ABA in plant development. For this purpose, the project developed a comprehensive set of gene knockouts in the AtNCED genes that facilitate genetic dissection of ABA synthesis. These mutants were used in combination with key molecular tools to address the following specific objectives: (1) the role of ABA synthesis in root development; (2) developmental control of ABA synthesis in seeds; (3) analysis of ATNCED over-expressers; (4) preliminary crystallography of the maize VP14 protein.

  18. Methods for genetic linkage analysis using trisomies

    Energy Technology Data Exchange (ETDEWEB)

    Feingold, E. [Emory Univ. School of Public Health, Atlanta, GA (United States); Lamb, N.E.; Sherman, S.L. [Emory Univ., Atlanta, GA (United States)

    1995-02-01

    Certain genetic disorders are rare in the general population, but more common in individuals with specific trisomies. Examples of this include leukemia and duodenal atresia in trisomy 21. This paper presents a linkage analysis method for using trisomic individuals to map genes for such traits. It is based on a very general gene-specific dosage model that posits that the trait is caused by specific effects of different alleles at one or a few loci and that duplicate copies of {open_quotes}susceptibility{close_quotes} alleles inherited from the nondisjoining parent give increased likelihood of having the trait. Our mapping method is similar to identity-by-descent-based mapping methods using affected relative pairs and also to methods for mapping recessive traits using inbred individuals by looking for markers with greater than expected homozygosity by descent. In the trisomy case, one would take trisomic individuals and look for markers with greater than expected homozygosity in the chromosomes inherited from the nondisjoining parent. We present statistical methods for performing such a linkage analysis, including a test for linkage to a marker, a method for estimating the distance from the marker to the trait gene, a confidence interval for that distance, and methods for computing power and sample sizes. We also resolve some practical issues involved in implementing the methods, including how to use partially informative markers and how to test candidate genes. 20 refs., 5 figs., 1 tab.

  19. Effect of genetic variants associated with plasma homocysteine levels on stroke risk.

    Science.gov (United States)

    Cotlarciuc, Ioana; Malik, Rainer; Holliday, Elizabeth G; Ahmadi, Kourosh R; Paré, Guillaume; Psaty, Bruce M; Fornage, Myriam; Hasan, Nazeeha; Rinne, Paul E; Ikram, M Arfan; Markus, Hugh S; Rosand, Jonathan; Mitchell, Braxton D; Kittner, Steven J; Meschia, James F; van Meurs, Joyce B J; Uitterlinden, Andre G; Worrall, Bradford B; Dichgans, Martin; Sharma, Pankaj

    2014-07-01

    Elevated total plasma homocysteine (tHcy) levels are known to be associated with increased risk of ischemic stroke (IS). Given that both tHcy and IS are heritable traits, we investigated a potential genetic relationship between homocysteine levels and stroke risk by assessing 18 polymorphisms previously associated with tHcy levels for their association with IS and its subtypes. Previous meta-analysis results from an international stroke collaborative network, METASTROKE, were used to assess association of the 18 tHcy-associated single-nucleotide polymorphisms (SNPs) in 12 389 IS cases and 62 004 controls. We also investigated the associations in regions located within 50 kb from the 18 tHcy-related SNPs and the association of a genetic risk score, including the 18 SNPs. One SNP located in the RASIP1 gene and a cluster of 3 SNPs located at and near SLC17A3 were significantly associated with IS (Pstroke subtypes, the sentinel SNP located upstream of MUT was significantly associated with small-vessel disease (P=0.0022), whereas 1 SNP located in MTHFR was significantly associated with large-vessel disease (P=0.00019). A genetic risk score, including the 18 SNPs, did not show significant association with IS or its subtypes. This study found several potential associations with IS and its subtypes: an association of an MUT variant with small-vessel disease, an MTHFR variant with large-vessel disease, and associations of RASIP1 and SLC17A3 variants with overall IS. © 2014 American Heart Association, Inc.

  20. Are there common genetic and environmental factors behind the endophenotypes associated with the metabolic syndrome?

    DEFF Research Database (Denmark)

    Benyamin, B; Sørensen, T I A; Schousboe, K

    2007-01-01

    AIMS/HYPOTHESIS: The cluster of obesity, insulin resistance, dyslipidaemia and hypertension, called the metabolic syndrome, has been suggested as a risk factor for cardiovascular disease and type 2 diabetes. The aim of the present study was to evaluate whether there are common genetic...... and environmental factors influencing this cluster in a general population of twin pairs. MATERIALS AND METHODS: A multivariate genetic analysis was performed on nine endophenotypes associated with the metabolic syndrome from 625 adult twin pairs of the GEMINAKAR study of the Danish Twin Registry. RESULTS: All...

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

    Directory of Open Access Journals (Sweden)

    Christine E McLaren

    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.

  2. 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 gard

  3. 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 gard

  4. An ICA with reference approach in identification of genetic variation and associated brain networks

    Directory of Open Access Journals (Sweden)

    Jingyu eLiu

    2012-02-01

    Full Text Available To address the statistical challenges associated with genome-wide association studies, we present an independent component analysis (ICA with reference approach to target a specific genetic variation and associated brain networks. First, a small set of single nucleotide polymorphisms (SNPs are empirically chosen to reflect a feature of interest and these SNPs are used as a reference when applying ICA to a full genomic SNP array. After extracting the genetic component maximally representing the characteristics of the reference, we test its association with brain networks in functional magnetic resonance imaging (fMRI data. The method was evaluated on both real and simulated datasets. Simulation demonstrates that ICA with reference can extract a specific genetic factor, even when the variance accounted for by such a factor is so small that a regular ICA fails. Our real data application from 48 schizophrenia patients and 40 healthy controls include 300K SNPs and fMRI images in an auditory oddball task. Using SNPs with allelic frequency difference in two groups as a reference, we extracted a genetic component that maximally differentiates patients from controls (p<4×10-17, and discovered a brain functional network that was significantly associated with this genetic component (p<1×10-4. The regions in the functional network mainly locate in the thalamus, anterior and posterior cingulate gyri. The contributing SNPs in the genetic factor mainly fall into two clusters centered at chromosome 7q21 and chromosome 5q35. The findings from the schizophrenia application are in concordance with previous knowledge about brain regions and gene function. All together, the results suggest that the ICA with reference can be particularly useful to explore the whole genome to find a specific factor of interest and further study its effect on brain.

  5. Modeling the cumulative genetic risk for multiple sclerosis from genome-wide association data.

    Science.gov (United States)

    Wang, Joanne H; Pappas, Derek; De Jager, Philip L; Pelletier, Daniel; de Bakker, Paul Iw; Kappos, Ludwig; Polman, Chris H; Chibnik, Lori B; Hafler, David A; Matthews, Paul M; Hauser, Stephen L; Baranzini, Sergio E; Oksenberg, Jorge R

    2011-01-18

    Multiple sclerosis (MS) is the most common cause of chronic neurologic disability beginning in early to middle adult life. Results from recent genome-wide association studies (GWAS) have substantially lengthened the list of disease loci and provide convincing evidence supporting a multifactorial and polygenic model of inheritance. Nevertheless, the knowledge of MS genetics remains incomplete, with many risk alleles still to be revealed. We used a discovery GWAS dataset (8,844 samples, 2,124 cases and 6,720 controls) and a multi-step logistic regression protocol to identify novel genetic associations. The emerging genetic profile included 350 independent markers and was used to calculate and estimate the cumulative genetic risk in an independent validation dataset (3,606 samples). Analysis of covariance (ANCOVA) was implemented to compare clinical characteristics of individuals with various degrees of genetic risk. Gene ontology and pathway enrichment analysis was done using the DAVID functional annotation tool, the GO Tree Machine, and the Pathway-Express profiling tool. In the discovery dataset, the median cumulative genetic risk (P-Hat) was 0.903 and 0.007 in the case and control groups, respectively, together with 79.9% classification sensitivity and 95.8% specificity. The identified profile shows a significant enrichment of genes involved in the immune response, cell adhesion, cell communication/signaling, nervous system development, and neuronal signaling, including ionotropic glutamate receptors, which have been implicated in the pathological mechanism driving neurodegeneration. In the validation dataset, the median cumulative genetic risk was 0.59 and 0.32 in the case and control groups, respectively, with classification sensitivity 62.3% and specificity 75.9%. No differences in disease progression or T2-lesion volumes were observed among four levels of predicted genetic risk groups (high, medium, low, misclassified). On the other hand, a significant

  6. Bayesian LASSO, scale space and decision making in association genetics.

    Science.gov (United States)

    Pasanen, Leena; Holmström, Lasse; Sillanpää, Mikko J

    2015-01-01

    LASSO is a penalized regression method that facilitates model fitting in situations where there are as many, or even more explanatory variables than observations, and only a few variables are relevant in explaining the data. We focus on the Bayesian version of LASSO and consider four problems that need special attention: (i) controlling false positives, (ii) multiple comparisons, (iii) collinearity among explanatory variables, and (iv) the choice of the tuning parameter that controls the amount of shrinkage and the sparsity of the estimates. The particular application considered is association genetics, where LASSO regression can be used to find links between chromosome locations and phenotypic traits in a biological organism. However, the proposed techniques are relevant also in other contexts where LASSO is used for variable selection. We separate the true associations from false positives using the posterior distribution of the effects (regression coefficients) provided by Bayesian LASSO. We propose to solve the multiple comparisons problem by using simultaneous inference based on the joint posterior distribution of the effects. Bayesian LASSO also tends to distribute an effect among collinear variables, making detection of an association difficult. We propose to solve this problem by considering not only individual effects but also their functionals (i.e. sums and differences). Finally, whereas in Bayesian LASSO the tuning parameter is often regarded as a random variable, we adopt a scale space view and consider a whole range of fixed tuning parameters, instead. The effect estimates and the associated inference are considered for all tuning parameters in the selected range and the results are visualized with color maps that provide useful insights into data and the association problem considered. The methods are illustrated using two sets of artificial data and one real data set, all representing typical settings in association genetics.

  7. Bayesian LASSO, scale space and decision making in association genetics.

    Directory of Open Access Journals (Sweden)

    Leena Pasanen

    Full Text Available LASSO is a penalized regression method that facilitates model fitting in situations where there are as many, or even more explanatory variables than observations, and only a few variables are relevant in explaining the data. We focus on the Bayesian version of LASSO and consider four problems that need special attention: (i controlling false positives, (ii multiple comparisons, (iii collinearity among explanatory variables, and (iv the choice of the tuning parameter that controls the amount of shrinkage and the sparsity of the estimates. The particular application considered is association genetics, where LASSO regression can be used to find links between chromosome locations and phenotypic traits in a biological organism. However, the proposed techniques are relevant also in other contexts where LASSO is used for variable selection.We separate the true associations from false positives using the posterior distribution of the effects (regression coefficients provided by Bayesian LASSO. We propose to solve the multiple comparisons problem by using simultaneous inference based on the joint posterior distribution of the effects. Bayesian LASSO also tends to distribute an effect among collinear variables, making detection of an association difficult. We propose to solve this problem by considering not only individual effects but also their functionals (i.e. sums and differences. Finally, whereas in Bayesian LASSO the tuning parameter is often regarded as a random variable, we adopt a scale space view and consider a whole range of fixed tuning parameters, instead. The effect estimates and the associated inference are considered for all tuning parameters in the selected range and the results are visualized with color maps that provide useful insights into data and the association problem considered. The methods are illustrated using two sets of artificial data and one real data set, all representing typical settings in association genetics.

  8. Genetic analysis of captive proboscis monkeys.

    Science.gov (United States)

    Ogata, Mitsuaki; Seino, Satoru

    2015-01-01

    Information on the genetic relationships of captive founders is important for captive population management. In this study, we investigated DNA polymorphisms of four microsatellite loci and the mitochondrial control region sequence of five proboscis monkeys residing in a Japanese zoo as captive founders, to clarify their genetic relationship. We found that two of the five monkeys appeared to be genetically related. Furthermore, the haplotypes of the mitochondrial control region of the five monkeys were well differentiated from the haplotypes previously reported from wild populations from the northern area of Borneo, indicating a greater amount of genetic diversity in proboscis monkeys than previously reported. © 2014 Wiley Periodicals, Inc.

  9. WWW portal usage analysis using genetic algorithms

    Directory of Open Access Journals (Sweden)

    Ondřej Popelka

    2009-01-01

    Full Text Available The article proposes a new method suitable for advanced analysis of web portal visits. This is part of retrieving information and knowledge from web usage data (web usage mining. Such information is necessary in order to gain better insight into visitor’s needs and generally consumer behaviour. By le­ve­ra­ging this information a company can optimize the organization of its internet presentations and offer a better end-user experience. The proposed approach is using Grammatical evolution which is computational method based on genetic algorithms. Grammatical evolution is using a context-free grammar in order to generate the solution in arbitrary reusable form. This allows us to describe visitors’ behaviour in different manners depending on desired further processing. In this article we use description with a procedural programming language. Web server access log files are used as source data.The extraction of behaviour patterns can currently be solved using statistical analysis – specifically sequential analysis based methods. Our objective is to develop an alternative algorithm.The article further describes the basic algorithms of two-level grammatical evolution; this involves basic Grammatical Evolution and Differential Evolution, which forms the second phase of the computation. Grammatical evolution is used to generate the basic structure of the solution – in form of a part of application code. Differential evolution is used to find optimal parameters for this solution – the specific pages visited by a random visitor. The grammar used to conduct experiments is described along with explanations of the links to the actual implementation of the algorithm. Furthermore the fitness function is described and reasons which yield to its’ current shape. Finally the process of analyzing and filtering the raw input data is described as it is vital part in obtaining reasonable results.

  10. Association of susceptible genetic markers and autoantibodies in rheumatoid arthritis

    Indian Academy of Sciences (India)

    Vasanth Konda Mohan; Nalini Ganesan; Rajasekhar Gopalakrishnan

    2014-08-01

    Rheumatoid arthritis (RA) is a chronic autoimmune disorder of unknown aetiology resulting in inflammation of the synovium, cartilage and bone. The disease has a heterogeneous character, consisting of clinical subsets of anti-citrullinated protein antibody (ACPA)-positive and APCA-negative disease. Although, the pathogenesis of RA is incompletely understood, genetic factors play a vital role in susceptibility to RA as the heritability of RA is between 50 and 60%, with the human leukocyte antigen (HLA) locus accounting for at least 30% of overall genetic risk. Non-HLA genes, i.e. tumour necrosis factor- (TNF-) within the MHC (major histocompatibility complex) have also been investigated for association with RA. Although, some contradictory results have originated from several studies on TNF- gene, the data published so far indicate the possible existence of TNF- gene promoter variants that act as markers for disease severity and response to treatment in RA. The correlation of HLA and non-HLA genes within MHC region is apparently interpreted. A considerable number of confirmed associations with RA and other autoimmune disease susceptibility loci including peptidylarginine deiminase type 4 (PADI4), protein tyrosine phosphatase non-receptor type 22 (PTPN22), signal transducer and activator of transcription (STAT4), cluster of differentiation 244 (CD244) and cytotoxic T lymphocyte-associated antigen 4 (CTLA4), located outside the MHC have been reported recently. In this review, we aim to give an update on recent progress in RA genetics, the importance of the combination of HLA-DRB1 alleles, non-HLA gene polymorphism, its detection and autoantibodies as susceptibility markers for early RA disease.

  11. 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....

  12. Genetic variants associated with neurodegenerative Alzheimer disease in natural models.

    Science.gov (United States)

    Salazar, Claudia; Valdivia, Gonzalo; Ardiles, Álvaro O; Ewer, John; Palacios, Adrián G

    2016-02-26

    The use of transgenic models for the study of neurodegenerative diseases has made valuable contributions to the field. However, some important limitations, including protein overexpression and general systemic compensation for the missing genes, has caused researchers to seek natural models that show the main biomarkers of neurodegenerative diseases during aging. Here we review some of these models-most of them rodents, focusing especially on the genetic variations in biomarkers for Alzheimer diseases, in order to explain their relationships with variants associated with the occurrence of the disease in humans.

  13. DNA degradation and genetic analysis of empty puparia: genetic identification limits in forensic entomology.

    Science.gov (United States)

    Mazzanti, Morena; Alessandrini, Federica; Tagliabracci, Adriano; Wells, Jeffrey D; Campobasso, Carlo P

    2010-02-25

    Puparial cases are common remnants of necrophagous flies in crime investigations. They usually represent the longest developmental time and, therefore, they can be very useful for the estimation of the post-mortem interval (PMI). However, before any PMI estimate, it is crucial to identify the species of fly eclosed from each puparium associated with the corpse. Morphological characteristics of the puparium are often distinctive enough to permit a species identification. But, even an accurate morphological analysis of empty puparia cannot discriminate among different species of closely related flies. Furthermore, morphological identification may be impossible if the fly puparia are poorly preserved or in fragments. This study explores the applicability of biomolecular techniques on empty puparia and their fragments for identification purposes. A total of 63 empty puparia of necrophagous Diptera resulting from forensic casework were examined. Samples were divided into three groups according to size, type and time of eclosion in order to verify whether the physical characteristics and puparia weathering can influence the amount of DNA extraction. The results suggest that a reliable genetic identification of forensically important flies may also be performed from empty puparia and/or their fragments. However, DNA degradation can deeply compromise the genetic analysis since the older the fly puparia, the smaller are the amplified fragments.

  14. Developments in statistical analysis in quantitative genetics

    DEFF Research Database (Denmark)

    Sorensen, Daniel

    2009-01-01

    A remarkable research impetus has taken place in statistical genetics since the last World Conference. This has been stimulated by breakthroughs in molecular genetics, automated data-recording devices and computer-intensive statistical methods. The latter were revolutionized by the bootstrap and ...

  15. COMPARITIVE GENETIC DIVERSITY ANALYSIS OF OAT (Avena ...

    African Journals Online (AJOL)

    knsccf

    Equivalence was appraised between phenotypic and molecular markers (ISSR) to analyze the genetic diversity of 20 ... Country of origin. Pedigree ... explain between and within geographical variation and granting ..... JM (2008). Development of PCR-based SCAR and ... Genetic. Resources and Crop Evolution, 56:465–480.

  16. Biological Insights From 108 Schizophrenia-Associated Genetic Loci

    Science.gov (United States)

    Ripke, Stephan; Neale, Benjamin M; Corvin, Aiden; Walters, James TR; Farh, Kai-How; Holmans, Peter A; Lee, Phil; Bulik-Sullivan, Brendan; Collier, David A; Huang, Hailiang; Pers, Tune H; Agartz, Ingrid; Agerbo, Esben; Albus, Margot; Alexander, Madeline; Amin, Farooq; Bacanu, Silviu A; Begemann, Martin; Belliveau, Richard A; Bene, Judit; Bergen, Sarah E; Bevilacqua, Elizabeth; Bigdeli, Tim B; Black, Donald W; Bruggeman, Richard; Buccola, Nancy G; Buckner, Randy L; Byerley, William; Cahn, Wiepke; Cai, Guiqing; Campion, Dominique; Cantor, Rita M; Carr, Vaughan J; Carrera, Noa; Catts, Stanley V; Chambert, Kimberley D; Chan, Raymond CK; Chan, Ronald YL; Chen, Eric YH; Cheng, Wei; Cheung, Eric FC; Chong, Siow Ann; Cloninger, C Robert; Cohen, David; Cohen, Nadine; Cormican, Paul; Craddock, Nick; Crowley, James J; Curtis, David; Davidson, Michael; Davis, Kenneth L; Degenhardt, Franziska; Del Favero, Jurgen; Demontis, Ditte; Dikeos, Dimitris; Dinan, Timothy; Djurovic, Srdjan; Donohoe, Gary; Drapeau, Elodie; Duan, Jubao; Dudbridge, Frank; Durmishi, Naser; Eichhammer, Peter; Eriksson, Johan; Escott-Price, Valentina; Essioux, Laurent; Fanous, Ayman H; Farrell, Martilias S; Frank, Josef; Franke, Lude; Freedman, Robert; Freimer, Nelson B; Friedl, Marion; Friedman, Joseph I; Fromer, Menachem; Genovese, Giulio; Georgieva, Lyudmila; Giegling, Ina; Giusti-Rodríguez, Paola; Godard, Stephanie; Goldstein, Jacqueline I; Golimbet, Vera; Gopal, Srihari; Gratten, Jacob; de Haan, Lieuwe; Hammer, Christian; Hamshere, Marian L; Hansen, Mark; Hansen, Thomas; Haroutunian, Vahram; Hartmann, Annette M; Henskens, Frans A; Herms, Stefan; Hirschhorn, Joel N; Hoffmann, Per; Hofman, Andrea; Hollegaard, Mads V; Hougaard, David M; Ikeda, Masashi; Joa, Inge; Julià, Antonio; Kahn, René S; Kalaydjieva, Luba; Karachanak-Yankova, Sena; Karjalainen, Juha; Kavanagh, David; Keller, Matthew C; Kennedy, James L; Khrunin, Andrey; Kim, Yunjung; Klovins, Janis; Knowles, James A; Konte, Bettina; Kucinskas, Vaidutis; Kucinskiene, Zita Ausrele; Kuzelova-Ptackova, Hana; Kähler, Anna K; Laurent, Claudine; Lee, Jimmy; Lee, S Hong; Legge, Sophie E; Lerer, Bernard; Li, Miaoxin; Li, Tao; Liang, Kung-Yee; Lieberman, Jeffrey; Limborska, Svetlana; Loughland, Carmel M; Lubinski, Jan; Lönnqvist, Jouko; Macek, Milan; Magnusson, Patrik KE; Maher, Brion S; Maier, Wolfgang; Mallet, Jacques; Marsal, Sara; Mattheisen, Manuel; Mattingsdal, Morten; McCarley, Robert W; McDonald, Colm; McIntosh, Andrew M; Meier, Sandra; Meijer, Carin J; Melegh, Bela; Melle, Ingrid; Mesholam-Gately, Raquelle I; Metspalu, Andres; Michie, Patricia T; Milani, Lili; Milanova, Vihra; Mokrab, Younes; Morris, Derek W; Mors, Ole; Murphy, Kieran C; Murray, Robin M; Myin-Germeys, Inez; Müller-Myhsok, Bertram; Nelis, Mari; Nenadic, Igor; Nertney, Deborah A; Nestadt, Gerald; Nicodemus, Kristin K; Nikitina-Zake, Liene; Nisenbaum, Laura; Nordin, Annelie; O’Callaghan, Eadbhard; O’Dushlaine, Colm; O’Neill, F Anthony; Oh, Sang-Yun; Olincy, Ann; Olsen, Line; Van Os, Jim; Pantelis, Christos; Papadimitriou, George N; Papiol, Sergi; Parkhomenko, Elena; Pato, Michele T; Paunio, Tiina; Pejovic-Milovancevic, Milica; Perkins, Diana O; Pietiläinen, Olli; Pimm, Jonathan; Pocklington, Andrew J; Powell, John; Price, Alkes; Pulver, Ann E; Purcell, Shaun M; Quested, Digby; Rasmussen, Henrik B; Reichenberg, Abraham; Reimers, Mark A; Richards, Alexander L; Roffman, Joshua L; Roussos, Panos; Ruderfer, Douglas M; Salomaa, Veikko; Sanders, Alan R; Schall, Ulrich; Schubert, Christian R; Schulze, Thomas G; Schwab, Sibylle G; Scolnick, Edward M; Scott, Rodney J; Seidman, Larry J; Shi, Jianxin; Sigurdsson, Engilbert; Silagadze, Teimuraz; Silverman, Jeremy M; Sim, Kang; Slominsky, Petr; Smoller, Jordan W; So, Hon-Cheong; Spencer, Chris C A; Stahl, Eli A; Stefansson, Hreinn; Steinberg, Stacy; Stogmann, Elisabeth; Straub, Richard E; Strengman, Eric; Strohmaier, Jana; Stroup, T Scott; Subramaniam, Mythily; Suvisaari, Jaana; Svrakic, Dragan M; Szatkiewicz, Jin P; Söderman, Erik; Thirumalai, Srinivas; Toncheva, Draga; Tosato, Sarah; Veijola, Juha; Waddington, John; Walsh, Dermot; Wang, Dai; Wang, Qiang; Webb, Bradley T; Weiser, Mark; Wildenauer, Dieter B; Williams, Nigel M; Williams, Stephanie; Witt, Stephanie H; Wolen, Aaron R; Wong, Emily HM; Wormley, Brandon K; Xi, Hualin Simon; Zai, Clement C; Zheng, Xuebin; Zimprich, Fritz; Wray, Naomi R; Stefansson, Kari; Visscher, Peter M; Adolfsson, Rolf; Andreassen, Ole A; Blackwood, Douglas HR; Bramon, Elvira; Buxbaum, Joseph D; Børglum, Anders D; Cichon, Sven; Darvasi, Ariel; Domenici, Enrico; Ehrenreich, Hannelore; Esko, Tõnu; Gejman, Pablo V; Gill, Michael; Gurling, Hugh; Hultman, Christina M; Iwata, Nakao; Jablensky, Assen V; Jönsson, Erik G; Kendler, Kenneth S; Kirov, George; Knight, Jo; Lencz, Todd; Levinson, Douglas F; Li, Qingqin S; Liu, Jianjun; Malhotra, Anil K; McCarroll, Steven A; McQuillin, Andrew; Moran, Jennifer L; Mortensen, Preben B; Mowry, Bryan J; Nöthen, Markus M; Ophoff, Roel A; Owen, Michael J; Palotie, Aarno; Pato, Carlos N; Petryshen, Tracey L; Posthuma, Danielle; Rietschel, Marcella; Riley, Brien P; Rujescu, Dan; Sham, Pak C; Sklar, Pamela; St Clair, David; Weinberger, Daniel R; Wendland, Jens R; Werge, Thomas; Daly, Mark J; Sullivan, Patrick F; O’Donovan, Michael C

    2014-01-01

    Summary Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain providing biological plausibility for the findings. Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that play important roles in immunity, providing support for the hypothesized link between the immune system and schizophrenia. PMID:25056061

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

    Directory of Open Access Journals (Sweden)

    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.

  18. 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.

  19. STrengthening the REporting of Genetic Association Studies (STREGA: an extension of the STROBE statement.

    Directory of Open Access Journals (Sweden)

    Julian Little

    2009-02-01

    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.

  20. Overview of genetic analysis of human opioid receptors.

    Science.gov (United States)

    Spampinato, Santi M

    2015-01-01

    The human μ-opioid receptor gene (OPRM1), due to its genetic and structural variation, has been a target of interest in several pharmacogenetic studies. The μ-opioid receptor (MOR), encoded by OPRM1, contributes to regulate the analgesic response to pain and also controls the rewarding effects of many drugs of abuse, including opioids, nicotine, and alcohol. Genetic polymorphisms of opioid receptors are candidates for the variability of clinical opioid effects. The non-synonymous polymorphism A118G of the OPRM1 has been repeatedly associated with the efficacy of opioid treatments for pain and various types of dependence. Genetic analysis of human opioid receptors has evidenced the presence of numerous polymorphisms either in exonic or in intronic sequences as well as the presence of synonymous coding variants that may have important effects on transcription, mRNA stability, and splicing, thus affecting gene function despite not directly disrupting any specific residue. Genotyping of opioid receptors is still in its infancy and a relevant progress in this field can be achieved by using advanced gene sequencing techniques described in this review that allow the researchers to obtain vast quantities of data on human genomes and transcriptomes in a brief period of time and with affordable costs.

  1. Non-genetic variance in pigs: genetic analysis of reproduction and production traits

    NARCIS (Netherlands)

    Sell-Kubiak, E.B.

    2015-01-01

    Abstract Sell-Kubiak, E. (2015). Non-genetic variance in pigs: genetic analysis of reproduction and production traits. PhD thesis, Wageningen University, The Netherlands The main objective of this thesis was to study the origin of random variance in reproduction and production trait

  2. Novel genetic loci associated with prostate cancer in the Japanese population

    Institute of Scientific and Technical Information of China (English)

    Yin Sun; Jiaoti Huang

    2011-01-01

    @@ Takata et al.1 recently reported in Nature Genetics that they have identified five nove associated with prostate cancer in the Japanese population.Using most updated Illumina Quad BeadChip to genotype 3001 prostate cancer patients and 5415 control subjects,they identified263 single-nucleotide polymorphisms(SNPs)showing significant association with prostate cancer in Japan.Further analysis indicated that 80 SNPs reside in the previously known regions,and five of them are novel susceptibility loci associated with the prostate cancer.

  3. A cluster analysis on road traffic accidents using genetic algorithms

    Science.gov (United States)

    Saharan, Sabariah; Baragona, Roberto

    2017-04-01

    The analysis of traffic road accidents is increasingly important because of the accidents cost and public road safety. The availability or large data sets makes the study of factors that affect the frequency and severity accidents are viable. However, the data are often highly unbalanced and overlapped. We deal with the data set of the road traffic accidents recorded in Christchurch, New Zealand, from 2000-2009 with a total of 26440 accidents. The data is in a binary set and there are 50 factors road traffic accidents with four level of severity. We used genetic algorithm for the analysis because we are in the presence of a large unbalanced data set and standard clustering like k-means algorithm may not be suitable for the task. The genetic algorithm based on clustering for unknown K, (GCUK) has been used to identify the factors associated with accidents of different levels of severity. The results provided us with an interesting insight into the relationship between factors and accidents severity level and suggest that the two main factors that contributes to fatal accidents are "Speed greater than 60 km h" and "Did not see other people until it was too late". A comparison with the k-means algorithm and the independent component analysis is performed to validate the results.

  4. Genetic factors associated with patient-specific warfarin dose in ethnic Indonesians

    Directory of Open Access Journals (Sweden)

    Utama Andi

    2011-06-01

    Full Text Available Abstract Background CYP2C9 and VKORC1 are two major genetic factors associated with inter-individual variability in warfarin dose. Additionally, genes in the warfarin metabolism pathway have also been associated with dose variance. We analyzed Single Nucleotide Polymorphisms (SNPs in these genes to identify genetic factors that might confer warfarin sensitivity in Indonesian patients. Methods Direct sequencing method was used to identify SNPs in CYP2C9, VKORC1, CYP4F2, EPHX1, PROC and GGCX genes in warfarin-treated patients. Multiple linear regressions were performed to model the relationship warfarin daily dose requirement with genetic and non-genetic variables measured and used to develop a novel algorithm for warfarin dosing. Results From the 40 SNPs analyzed, CYP2C9 rs17847036 and VKORC1 rs9923231 showed significant association with warfarin sensitivity. In our study population, no significant correlation could be detected between CYP2C9*3, CYP2C9C-65 (rs9332127, CYP4F2 rs2108622, GGCX rs12714145, EPHX1 rs4653436 and PROC rs1799809 with warfarin sensitivity. Conclusions VKORC1 rs9923231 AA and CYP2C9 rs17847036 GG genotypes were associated with low dosage requirements of most patients (2.05 ± 0.77 mg/day and 2.09 ± 0.70 mg/day, respectively. CYP2C9 and VKORC1 genetic variants as well as non-genetic factors such as age, body weight and body height account for 15.4% of variance in warfarin dose among our study population. Additional analysis of this combination could allow for personalized warfarin treatment in ethnic Indonesians.

  5. Dissection of genetic factors associated with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Leblond, Claire S; Kaneb, Hannah M; Dion, Patrick A; Rouleau, Guy A

    2014-12-01

    Amyotrophic lateral sclerosis (ALS) is a fatal late onset neurological disorder characterized by motor neuron degeneration in the primary motor cortex, brainstem and spinal cord. The majority of cases are sporadic (SALS) and only 5-10% have a family history (FALS). FALS cases show a high heritability and this has enabled the identification of several genetic triggers, of which mutations in SOD1, FUS, TARDBP and C9ORF72 are the most frequent. While such advances have contributed to our current understanding of the causes of most cases of FALS and their underlying pathophysiological consequences, they only explain a small fraction of SALS with the etiology of most SALS cases remaining unexplained. Here, we review past and current methods used for the identification of FALS and SALS associated genes and propose a risk-based classification for these. We also discuss how the growing number of whole exome/genome sequencing datasets prepared from SALS cases, and control individuals, may reveal novel insights into the genetic etiology of SALS; for instance through revealing increased mutation burden rates across genes or genomic regions that were not previously associated with ALS or through allowing the examination of a potential "oligogenic" mechanism of the disease. Finally we summarize the three most recently discovered 'high risk' genes in ALS.

  6. 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.

  7. Genetic variation in the epidermal transglutaminase genes is not associated with atopic dermatitis.

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    Agne Liedén

    Full Text Available BACKGROUND: Atopic dermatitis (AD is a common chronic inflammatory skin disorder where epidermal barrier dysfunction is a major factor in the pathogenesis. The identification of AD susceptibility genes related to barrier dysfunction is therefore of importance. The epidermal transglutaminases (TGM1, TGM3 and TGM5 encodes essential cross-linking enzymes in the epidermis. OBJECTIVE: To determine whether genetic variability in the epidermal transglutaminases contributes to AD susceptibility. METHODS: Forty-seven single nucleotide polymorphisms (SNPs in the TGM1, TGM3 and TGM5 gene region were tested for genetic association with AD, independently and in relation to FLG genotype, using a pedigree disequilibrium test (PDT in a Swedish material consisting of 1753 individuals from 539 families. In addition, a German case-control material, consisting of 533 AD cases and 1996 controls, was used for in silico analysis of the epidermal TGM regions. Gene expression of the TGM1, TGM3 and TGM5 gene was investigated by relative quantification with Real Time PCR (qRT-PCR. Immunohistochemical (IHC analysis was performed to detect TG1, TG3 and TG5 protein expression in the skin of patients and healthy controls. RESULTS: PDT analysis identified a significant association between the TGM1 SNP rs941505 and AD with allergen-specific IgE in the Swedish AD family material. However, the association was not replicated in the German case-control material. No significant association was detected for analyzed SNPs in relation to FLG genotype. TG1, TG3 and TG5 protein expression was detected in AD skin and a significantly increased TGM3 mRNA expression was observed in lesional skin by qRT-PCR. CONCLUSION: Although TGM1 and TGM3 may be differentially expressed in AD skin, the results from the genetic analysis suggest that genetic variation in the epidermal transglutaminases is not an important factor in AD susceptibility.

  8. Common Genetic Variant in VIT Is Associated with Human Brain Asymmetry

    OpenAIRE

    Tadayon, Sayed H.; Vaziri-Pashkam, Maryam; Kahali, Pegah; Ansari Dezfouli, Mitra; Abbassian, Abdolhossein

    2016-01-01

    Brain asymmetry varies across individuals. However, genetic factors contributing to this normal variation are largely unknown. Here we studied variation of cortical surface area asymmetry in a large sample of subjects. We performed principal component analysis (PCA) to capture correlated asymmetry variation across cortical regions. We found that caudal and rostral anterior cingulate together account for a substantial part of asymmetry variation among individuals. To find SNPs associated with ...

  9. Discovery of novel genetic networks associated with 19 economically important traits in beef cattle

    Directory of Open Access Journals (Sweden)

    Zhihua Jiang, Jennifer J. Michal, Jie Chen, Tyler F. Daniels, Tanja Kunej, Matthew D. Garcia, Charles T. Gaskins, Jan R. Busboom, Leeson J. Alexander, Raymond W. Wright Jr., Michael D. MacNeil

    2009-01-01

    Full Text Available Quantitative or complex traits are determined by the combined effects of many loci, and are affected by genetic networks or molecular pathways. In the present study, we genotyped a total of 138 mutations, mainly single nucleotide polymorphisms derived from 71 functional genes on a Wagyu x Limousin reference population. Two hundred forty six F2 animals were measured for 5 carcass, 6 eating quality and 8 fatty acid composition traits. A total of 2,280 single marker-trait association runs with 120 tagged mutations selected based on the HAPLOVIEW analysis revealed 144 significant associations (P < 0.05, but 50 of them were removed from the analysis due to the small number of animals (≤ 9 in one genotype group or absence of one genotype among three genotypes. The remaining 94 single-trait associations were then placed into three groups of quantitative trait modes (QTMs with additive, dominant and overdominant effects. All significant markers and their QTMs associated with each of these 19 traits were involved in a linear regression model analysis, which confirmed single-gene associations for 4 traits, but revealed two-gene networks for 8 traits and three-gene networks for 5 traits. Such genetic networks involving both genotypes and QTMs resulted in high correlations between predicted and actual values of performance, thus providing evidence that the classical Mendelian principles of inheritance can be applied in understanding genetic complexity of complex phenotypes. Our present study also indicated that carcass, eating quality and fatty acid composition traits rarely share genetic networks. Therefore, marker-assisted selection for improvement of one category of these traits would not interfere with improvement of another.

  10. Association between Common Genetic Variants and Polycystic Ovary Syndrome Risk in a Chinese Han Population

    Science.gov (United States)

    Sun, Ying; Yuan, Yi; Yang, Hua; Li, Jingjie; Feng, Tian; Ouyang, Yongri; Jin, Tianbo; Liu, Ming

    2016-01-01

    Objective: Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting 5-7% of reproductive age women worldwide. The aim of our study was to explore the PCOS-related single nucleotide polymorphism (SNP) associations between common genetic variants and PCOS risk in a Han Chinese women population. Methods: In this case-control study, 285 Chinese Han women aged 28.50±6.858 years with PCOS and 299 controls of a mean age of 32.66±7.018 years were compared. We selected recently published genome-wide association studies (GWAS) which identified several genetic loci in PCOS. All the SNPs were genotyped by Sequenom Mass-ARRAY technology. Associations between the gene and the risk of PCOS were tested using various genetic models by Statistical Package for the Social Sciences and Plink. Results: We found that rs705702 in the RAB5B/SUOX was associated with PCOS (odds ratio=1.42; 95% confidence interval=1.08-1.87, p=0.011) and increased the PCOS risk. The genotypic model analysis also showed that rs705702 was associated with PCOS risk. Conclusion: Our results suggest that SNPs rs705702 in gene RAB5B/SUOX was associated with PCOS in Han Chinese women. PMID:27217259

  11. Replication of genetic association studies in aortic stenosis in adults.

    Science.gov (United States)

    Gaudreault, Nathalie; Ducharme, Valérie; Lamontagne, Maxime; Guauque-Olarte, Sandra; Mathieu, Patrick; Pibarot, Philippe; Bossé, Yohan

    2011-11-01

    Only a handful of studies have attempted to unravel the genetic architecture of calcific aortic valve stenosis (AS). The goal of this study was to validate genes previously associated with AS. Seven genes were assessed: APOB, APOE, CTGF, IL10, PTH, TGFB1, and VDR. Each gene was tested for a comprehensive set of single-nucleotide polymorphisms (SNPs). SNPs were genotyped in 457 patients who underwent surgical aortic valve replacement, and allele frequencies were compared to 3,294 controls. A missense mutation in the APOB gene was significantly associated with AS (rs1042031, E4181K, p = 0.00001). A second SNP located 5.6 kilobases downstream of the APOB stop codon was also associated with the disease (rs6725189, p = 0.000013). Six SNPs surrounding the IL10 locus were strongly associated with AS (0.02 > p > 6.2 × 10⁻¹¹). The most compelling association for IL10 was found with a promoter polymorphism (rs1800872) well known to regulate the production of the encoded anti-inflammatory cytokine. The frequency of the low-producing allele was greater in cases compared to controls (30% vs 20%, p = 6.2 × 10⁻¹¹). SNPs in PTH, TGFB1, and VDR had nominal p values <0.05 but did not resist Bonferroni correction. In conclusion, this study suggests that subjects carrying specific polymorphisms in the IL10 and APOB genes are at higher risk for developing AS.

  12. 一个46,XY"女性"不育症家系的遗传学分析%Genetic Analysis of a Family with 46, XY "Female" Associated with Infertility

    Institute of Scientific and Technical Information of China (English)

    王旭; 王晓然; 刘木根; 王擎; 刘静宇

    2006-01-01

    运用常规的染色体G带分析和基因分析技术对一46,XY男性女性化家系进行遗传学分析,发现:先证者及其妹妹的染色体核型为46,XY,其母亲和父亲的核型正常;对睾丸决定基因(SRY)和雄激素受体基因(AR)进行突变检测,在SRY基因的整个编码区中没有发现突变,而AR基因的第7个外显子的第840个密码子由CGT(编码精氨酸)变为CAT(编码组氨酸),这一改变可能是导致核型为46,XY女性化而发生不育.%Genetic analysis of a family with 46,XY "female" associated with infertility was performed using the conventional G-banding and gene mutation screening. The karyotypes of the two female patients were 46,XY and those of their parents were normal. The mutation screenings in sex-determining region Y (SRY) gene and androgen receptor (AR) gene were carried out. No mutation has been found in the whole coding sequence of SRY gene. The mutation of codon 840 CGT (arginine) to CAT (histidine)of AR gene led to the infertility in the patients. The patients showed androgen insensitivity. The clinical phenotype of theirs presented more deleteriously than and different from the one reported before, though they had the same mutation of codon 840 CGT (arginine) to CAT (histidine) of AR gene, which was very different from the mutation of 840 CGT (arginine) to TGT (cysteine) at the same codon.

  13. Genetic analysis of the Venezuelan Criollo horse.

    Science.gov (United States)

    Cothran, E G; Canelon, J L; Luis, C; Conant, E; Juras, R

    2011-10-07

    Various horse populations in the Americas have an origin in Spain; they are remnants of the first livestock introduced to the continent early in the colonial period (16th and 17th centuries). We evaluated genetic variability within the Venezuelan Criollo horse and its relationship with other horse breeds. We observed high levels of genetic diversity within the Criollo breed. Significant population differentiation was observed between all South American breeds. The Venezuelan Criollo horse showed high levels of genetic diversity, and from a conservation standpoint, there is no immediate danger of losing variation unless there is a large drop in population size.

  14. Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma.

    Science.gov (United States)

    Machiela, Mitchell J; Hofmann, Jonathan N; Carreras-Torres, Robert; Brown, Kevin M; Johansson, Mattias; Wang, Zhaoming; Foll, Matthieu; Li, Peng; Rothman, Nathaniel; Savage, Sharon A; Gaborieau, Valerie; McKay, James D; Ye, Yuanqing; Henrion, Marc; Bruinsma, Fiona; Jordan, Susan; Severi, Gianluca; Hveem, Kristian; Vatten, Lars J; Fletcher, Tony; Koppova, Kvetoslava; Larsson, Susanna C; Wolk, Alicja; Banks, Rosamonde E; Selby, Peter J; Easton, Douglas F; Pharoah, Paul; Andreotti, Gabriella; Freeman, Laura E Beane; Koutros, Stella; Albanes, Demetrius; Mannisto, Satu; Weinstein, Stephanie; Clark, Peter E; Edwards, Todd E; Lipworth, Loren; Gapstur, Susan M; Stevens, Victoria L; Carol, Hallie; Freedman, Matthew L; Pomerantz, Mark M; Cho, Eunyoung; Kraft, Peter; Preston, Mark A; Wilson, Kathryn M; Gaziano, J Michael; Sesso, Howard S; Black, Amanda; Freedman, Neal D; Huang, Wen-Yi; Anema, John G; Kahnoski, Richard J; Lane, Brian R; Noyes, Sabrina L; Petillo, David; Colli, Leandro M; Sampson, Joshua N; Besse, Celine; Blanche, Helene; Boland, Anne; Burdette, Laurie; Prokhortchouk, Egor; Skryabin, Konstantin G; Yeager, Meredith; Mijuskovic, Mirjana; Ognjanovic, Miodrag; Foretova, Lenka; Holcatova, Ivana; Janout, Vladimir; Mates, Dana; Mukeriya, Anush; Rascu, Stefan; Zaridze, David; Bencko, Vladimir; Cybulski, Cezary; Fabianova, Eleonora; Jinga, Viorel; Lissowska, Jolanta; Lubinski, Jan; Navratilova, Marie; Rudnai, Peter; Szeszenia-Dabrowska, Neonila; Benhamou, Simone; Cancel-Tassin, Geraldine; Cussenot, Olivier; Bueno-de-Mesquita, H Bas; Canzian, Federico; Duell, Eric J; Ljungberg, Börje; Sitaram, Raviprakash T; Peters, Ulrike; White, Emily; Anderson, Garnet L; Johnson, Lisa; Luo, Juhua; Buring, Julie; Lee, I-Min; Chow, Wong-Ho; Moore, Lee E; Wood, Christopher; Eisen, Timothy; Larkin, James; Choueiri, Toni K; Lathrop, G Mark; Teh, Bin Tean; Deleuze, Jean-Francois; Wu, Xifeng; Houlston, Richard S; Brennan, Paul; Chanock, Stephen J; Scelo, Ghislaine; Purdue, Mark P

    2017-08-07

    Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings. We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length. Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis. Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, pbody of evidence indicating some aspect of longer telomere length is important for RCC risk. Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma. Published by Elsevier B.V.

  15. Using volcano plots and regularized-chi statistics in genetic association studies.

    Science.gov (United States)

    Li, Wentian; Freudenberg, Jan; Suh, Young Ju; Yang, Yaning

    2014-02-01

    Labor intensive experiments are typically required to identify the causal disease variants from a list of disease associated variants in the genome. For designing such experiments, candidate variants are ranked by their strength of genetic association with the disease. However, the two commonly used measures of genetic association, the odds-ratio (OR) and p-value may rank variants in different order. To integrate these two measures into a single analysis, here we transfer the volcano plot methodology from gene expression analysis to genetic association studies. In its original setting, volcano plots are scatter plots of fold-change and t-test statistic (or -log of the p-value), with the latter being more sensitive to sample size. In genetic association studies, the OR and Pearson's chi-square statistic (or equivalently its square root, chi; or the standardized log(OR)) can be analogously used in a volcano plot, allowing for their visual inspection. Moreover, the geometric interpretation of these plots leads to an intuitive method for filtering results by a combination of both OR and chi-square statistic, which we term "regularized-chi". This method selects associated markers by a smooth curve in the volcano plot instead of the right-angled lines which corresponds to independent cutoffs for OR and chi-square statistic. The regularized-chi incorporates relatively more signals from variants with lower minor-allele-frequencies than chi-square test statistic. As rare variants tend to have stronger functional effects, regularized-chi is better suited to the task of prioritization of candidate genes.

  16. Kernel Approach for Modeling Interaction Effects in Genetic Association Studies of Complex Quantitative Traits.

    Science.gov (United States)

    Broadaway, K Alaine; Duncan, Richard; Conneely, Karen N; Almli, Lynn M; Bradley, Bekh; Ressler, Kerry J; Epstein, Michael P

    2015-07-01

    The etiology of complex traits likely involves the effects of genetic and environmental factors, along with complicated interaction effects between them. Consequently, there has been interest in applying genetic association tests of complex traits that account for potential modification of the genetic effect in the presence of an environmental factor. One can perform such an analysis using a joint test of gene and gene-environment interaction. An optimal joint test would be one that remains powerful under a variety of models ranging from those of strong gene-environment interaction effect to those of little or no gene-environment interaction effect. To fill this demand, we have extended a kernel machine based approach for association mapping of multiple SNPs to consider joint tests of gene and gene-environment interaction. The kernel-based approach for joint testing is promising, because it incorporates linkage disequilibrium information from multiple SNPs simultaneously in analysis and permits flexible modeling of interaction effects. Using simulated data, we show that our kernel machine approach typically outperforms the traditional joint test under strong gene-environment interaction models and further outperforms the traditional main-effect association test under models of weak or no gene-environment interaction effects. We illustrate our test using genome-wide association data from the Grady Trauma Project, a cohort of highly traumatized, at-risk individuals, which has previously been investigated for interaction effects. © 2015 WILEY PERIODICALS, INC.

  17. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study

    Science.gov (United States)

    Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke; Schumm, L Philip; Zeissig, Sebastian; Ahmad, Tariq; Andersen, Vibeke; Andrews, Jane M; Annese, Vito; Brand, Stephan; Brant, Steven R; Cho, Judy H; Daly, Mark J; Dubinsky, Marla; Duerr, Richard H; Ferguson, Lynnette R; Franke, Andre; Gearry, Richard B; Goyette, Philippe; Hakonarson, Hakon; Halfvarson, Jonas; Hov, Johannes R; Huang, Hailang; Kennedy, Nicholas A; Kupcinskas, Limas; Lawrance, Ian C; Lee, James C; Satsangi, Jack; Schreiber, Stephan; Théâtre, Emilie; van der Meulen-de Jong, Andrea E; Weersma, Rinse K; Wilson, David C; Parkes, Miles; Vermeire, Severine; Rioux, John D; Mansfield, John; Silverberg, Mark S; Radford-Smith, Graham; McGovern, Dermot P B; Barrett, Jeffrey C; Lees, Charlie W

    2016-01-01

    Summary Background Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. Methods This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohn's disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype–phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. Findings After quality control, the primary analysis included 29 838 patients (16 902 with Crohn's disease, 12 597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for

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

    Science.gov (United States)

    Adams, Hieab HH; Hibar, Derrek P; Chouraki, Vincent; Stein, Jason L; Nyquist, Paul A; Rentería, Miguel E; Trompet, Stella; Arias-Vasquez, Alejandro; Seshadri, Sudha; Desrivières, Sylvane; Beecham, Ashley H; Jahanshad, Neda; Wittfeld, Katharina; Van der Lee, Sven J; Abramovic, Lucija; Alhusaini, Saud; Amin, Najaf; Andersson, Micael; Arfanakis, Konstantinos; Aribisala, Benjamin S; Armstrong, Nicola J; Athanasiu, Lavinia; Axelsson, Tomas; Beiser, Alexa; Bernard, Manon; Bis, Joshua C; Blanken, Laura ME; Blanton, Susan H; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brickman, Adam M; Carmichael, Owen; Chakravarty, M Mallar; Chauhan, Ganesh; Chen, Qiang; Ching, Christopher RK; Cuellar-Partida, Gabriel; Den Braber, Anouk; Doan, Nhat Trung; Ehrlich, Stefan; Filippi, Irina; Ge, Tian; Giddaluru, Sudheer; Goldman, Aaron L; Gottesman, Rebecca F; Greven, Corina U; Grimm, Oliver; Griswold, Michael E; Guadalupe, Tulio; Hass, Johanna; Haukvik, Unn K; Hilal, Saima; Hofer, Edith; Hoehn, David; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kasperaviciute, Dalia; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Liao, Jiemin; Liewald, David CM; Lopez, Lorna M; Luciano, Michelle; Macare, Christine; Marquand, Andre; Matarin, Mar; Mather, Karen A; Mattheisen, Manuel; Mazoyer, Bernard; McKay, David R; McWhirter, Rebekah; Milaneschi, Yuri; Mirza-Schreiber, Nazanin; Muetzel, Ryan L; Maniega, Susana Muñoz; Nho, Kwangsik; Nugent, Allison C; Olde Loohuis, Loes M; Oosterlaan, Jaap; Papmeyer, Martina; Pappa, Irene; Pirpamer, Lukas; Pudas, Sara; Pütz, Benno; Rajan, Kumar B; Ramasamy, Adaikalavan; Richards, Jennifer S; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rommelse, Nanda; Rose, Emma J; Royle, Natalie A; Rundek, Tatjana; Sämann, Philipp G; Satizabal, Claudia L; Schmaal, Lianne; Schork, Andrew J; Shen, Li; Shin, Jean; Shumskaya, Elena; Smith, Albert V; Sprooten, Emma; Strike, Lachlan T; Teumer, Alexander; Thomson, Russell; Tordesillas-Gutierrez, Diana; Toro, Roberto; Trabzuni, Daniah; Vaidya, Dhananjay; Van der Grond, Jeroen; Van der Meer, Dennis; Van Donkelaar, Marjolein MJ; Van Eijk, Kristel R; Van Erp, Theo GM; Van Rooij, Daan; Walton, Esther; Westlye, Lars T; Whelan, Christopher D; Windham, Beverly G; Winkler, Anderson M; Woldehawariat, Girma; Wolf, Christiane; Wolfers, Thomas; Xu, Bing; Yanek, Lisa R; Yang, Jingyun; Zijdenbos, Alex; Zwiers, Marcel P; Agartz, Ingrid; Aggarwal, Neelum T; Almasy, Laura; Ames, David; Amouyel, Philippe; Andreassen, Ole A; Arepalli, Sampath; Assareh, Amelia A; Barral, Sandra; Bastin, Mark E; Becker, Diane M; Becker, James T; Bennett, David A; Blangero, John; van Bokhoven, Hans; Boomsma, Dorret I; Brodaty, Henry; Brouwer, Rachel M; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Bulayeva, Kazima B; Cahn, Wiepke; Calhoun, Vince D; Cannon, Dara M; Cavalleri, Gianpiero L; Chen, Christopher; Cheng, Ching-Yu; Cichon, Sven; Cookson, Mark R; Corvin, Aiden; Crespo-Facorro, Benedicto; Curran, Joanne E; Czisch, Michael; Dale, Anders M; Davies, Gareth E; De Geus, Eco JC; De Jager, Philip L; de Zubicaray, Greig I; Delanty, Norman; Depondt, Chantal; DeStefano, Anita L; Dillman, Allissa; Djurovic, Srdjan; Donohoe, Gary; Drevets, Wayne C; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Espeseth, Thomas; Evans, Denis A; Fedko, Iryna O; Fernández, Guillén; Ferrucci, Luigi; Fisher, Simon E; Fleischman, Debra A; Ford, Ian; Foroud, Tatiana M; Fox, Peter T; Francks, Clyde; Fukunaga, Masaki; Gibbs, J Raphael; Glahn, David C; Gollub, Randy L; Göring, Harald HH; Grabe, Hans J; Green, Robert C; Gruber, Oliver; Gudnason, Vilmundur; Guelfi, Sebastian; Hansell, Narelle K; Hardy, John; Hartman, Catharina A; Hashimoto, Ryota; Hegenscheid, Katrin; Heinz, Andreas; Le Hellard, Stephanie; Hernandez, Dena G; Heslenfeld, Dirk J; Ho, Beng-Choon; Hoekstra, Pieter J; Hoffmann, Wolfgang; Hofman, Albert; Holsboer, Florian; Homuth, Georg; Hosten, Norbert; Hottenga, Jouke-Jan; Hulshoff Pol, Hilleke E; Ikeda, Masashi; Ikram, M Kamran; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Jönsson, Erik G; Jukema, J Wouter; Kahn, René S; Kanai, Ryota; Kloszewska, Iwona; Knopman, David S; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Lemaître, Hervé; Liu, Xinmin; Longo, Dan L; Longstreth, WT; Lopez, Oscar L; Lovestone, Simon; Martinez, Oliver; Martinot, Jean-Luc; Mattay, Venkata S; McDonald, Colm; McIntosh, Andrew M; McMahon, Katie L; McMahon, Francis J; Mecocci, Patrizia; Melle, Ingrid; Meyer-Lindenberg, Andreas; Mohnke, Sebastian; Montgomery, Grant W; Morris, Derek W; Mosley, Thomas H; Mühleisen, Thomas W; Müller-Myhsok, Bertram; Nalls, Michael A; Nauck, Matthias; Nichols, Thomas E; Niessen, Wiro J; Nöthen, Markus M; Nyberg, Lars; Ohi, Kazutaka; Olvera, Rene L; Ophoff, Roel A; Pandolfo, Massimo; Paus, Tomas; Pausova, Zdenka; Penninx, Brenda WJH; Pike, G Bruce; Potkin, Steven G; Psaty, Bruce M; Reppermund, Simone; Rietschel, Marcella; Roffman, Joshua L; Romanczuk-Seiferth, Nina; Rotter, Jerome I; Ryten, Mina; Sacco, Ralph L; Sachdev, Perminder S; Saykin, Andrew J; 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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

  19. Genetic susceptibility variants associated with colorectal cancer prognosis.

    Science.gov (United States)

    Abulí, Anna; Lozano, Juan José; Rodríguez-Soler, María; Jover, Rodrigo; Bessa, Xavier; Muñoz, Jenifer; Esteban-Jurado, Clara; Fernández-Rozadilla, Ceres; Carracedo, Angel; Ruiz-Ponte, Clara; Cubiella, Joaquín; Balaguer, Francesc; Bujanda, Luis; Reñé, Josep M; Clofent, Juan; Morillas, Juan Diego; Nicolás-Pérez, David; Xicola, Rosa M; Llor, Xavier; Piqué, Josep M; Andreu, Montserrat; Castells, Antoni; Castellví-Bel, Sergi

    2013-10-01

    Colorectal cancer (CRC) is the second leading cause of cancer-related death among men and women in Western countries. Once a tumour develops, a differentiated prognosis could be determined by lifestyle habits or inherited and somatic genetic factors. Finding such prognostic factors will be helpful in order to identify cases with a shorter survival or at a higher risk of recurrence that may benefit from more intensive treatment and follow-up surveillance. Sixteen CRC genetic susceptibility variants were directly genotyped in a cohort of 1235 CRC patients recruited by the EPICOLON Spanish consortium. Univariate Cox and multivariate regression analyses were performed taking as primary outcomes overall survival (OS), disease-free survival and recurrence-free interval. Genetic variants rs9929218 at 16q22.1 and rs10795668 at 10p14 may have an effect on OS. The G allele of rs9929218 was linked with a better OS [GG genotype, genotypic model: hazard ratio (HR) = 0.65, 95% confidence interval (CI) 0.45-0.93, P = 0.0179; GG/GA genotypes, dominant model: HR = 0.66, 95% CI 0.47-0.94, P = 0.0202]. Likewise, the G allele of rs10795668 was associated with better clinical outcome (GG genotype, genotypic model: HR = 0.73, 95% CI 0.53-1.01, P = 0.0570; GA genotype, genotypic model: HR = 0.66, 95% CI 0.47-0.92, P = 0.0137; GG/GA genotypes, dominant model: HR = 0.68, 95% CI 0.50-0.94, P = 0.0194). In conclusion, CRC susceptibility variants rs9929218 and rs10795668 may exert some influence in modulating patient's survival and they deserve to be further tested in additional CRC cohorts in order to confirm their potential as prognosis or predictive biomarkers.

  20. Association between LDL-cholesterol lowering genetic variants and risk of type 2 diabetes

    Science.gov (United States)

    Lotta, Luca A.; Sharp, Stephen. J; Burgess, Stephen; Perry, John R. B.; Stewart, Isobel. D; Willems, Sara M.; Luan, Jian’an; Ardanaz, Eva; Arriola, Larraitz; Balkau, Beverley; Boeing, Heiner; Deloukas, Panos; Forouhi, Nita G; Franks, Paul W; Grioni, Sara; Kaaks, Rudolf; Key, Timothy J; Navarro, Carmen; Nilsson, Peter M; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Quirós, Jose-Ramón; Riboli, Elio; Rolandsson, Olov; Sacerdote, Carlotta; Salamanca, Elena C; Slimani, Nadia; Spijkerman, Annemieke MW; Tjonneland, Anne; Tumino, Rosario; van der A, Daphne L; van der Schouw, Yvonne T; McCarthy, Mark I.; Barroso, Inês; O’Rahilly, Stephen; Savage, David. B; Sattar, Naveed; Langenberg, Claudia

    2017-01-01

    Importance Low-density lipoprotein (LDL) cholesterol-lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, mimicking the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are also associated with the risk of type 2 diabetes. Objective To investigate whether LDL-lowering alleles in or near NPC1L1 and other genes encoding current or prospective molecular targets of lipid-lowering therapy (i.e. HMGCR, PCSK9, ABCG5/G8, LDLR) are associated with the risk of type 2 diabetes. Design, Setting and Participants The associations with type 2 diabetes and coronary artery disease of LDL-lowering genetic variants were investigated in meta-analyses of genetic association studies. Meta-analyses included 50,775 individuals with type 2 diabetes and 270,269 controls including three studies and 60,801 individuals with coronary artery disease and 123,504 controls from a published meta-analysis. Data collection took place in Europe and the United States between 1991 and 2016. Exposure LDL-lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, LDLR. Main Outcomes and Measures Odds ratio of type 2 diabetes and coronary artery disease. Results LDL-lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease (odds ratio for a genetically-predicted reduction of 1 mmol/L in LDL cholesterol, 0.61; 95% confidence interval, 0.42-0.88; p=0.008) and directly associated with type 2 diabetes (2.42, 1.70-3.43; p<0.001). The odds ratio of type 2 diabetes for PCSK9 genetic variants was 1.19 (95% confidence interval, 1.02-1.38, p=0.03). For a given reduction in LDL cholesterol, genetic variants were associated with a similar reduction in coronary artery

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

    NARCIS (Netherlands)

    van Rheenen, Wouter; Shatunov, Aleksey; Dekker, Annelot M.; McLaughlin, Russell L.; Diekstra, Frank P.; Pulit, Sara L.; van der Spek, Rick A. A.; Vosa, Urmo; de Jong, Simone; Robinson, Matthew R.; Yang, Jian; Fogh, Isabella; van Doormaal, Perry T. C.; Tazelaar, Gijs H. P.; Koppers, Max; Blokhuis, Anna M.; Sproviero, William; Jones, Ashley R.; Kenna, Kevin P.; van Eijk, Kristel R.; Harschnitz, Oliver; Schellevis, Raymond D.; Brands, William J.; Medic, Jelena; Menelaou, Androniki; Vajda, Alice; Ticozzi, Nicola; Lin, Kuang; Rogelj, Boris; Vrabec, Katarina; Ravnik-Glavac, Metka; Koritnik, Blazi; Zidar, Janez; Leonardis, Lea; Groselj, Leja Dolenc; Millecamps, Stephanie; Salachas, Francois; Meininger, Vincent; de Carvalho, Mamede; Pinto, Susana; Mora, Jesus S.; Rojas-Garcia, Ricardo; Polak, Meraida; Chandran, Siddharthan; Colville, Shuna; Swingler, Robert; Morrison, Karen E.; Shaw, Pamela J.; Hardy, John; Orrell, Richard W.; Pittman, Alan; Sidle, Katie; Fratta, Pietro; Malaspina, Andrea; Topp, Simon; Petri, Susanne; Abdulla, Susanne; Drepper, Carsten; Sendtner, Michael; Meyer, Thomas; Ophoff, Roel A.; Staats, Kim A.; Wiedau-Pazos, Martina; Lomen-Hoerth, Catherine; Van Deerlin, Vivianna M.; Trojanowski, John Q.; Elman, Lauren; McCluskey, Leo; Basak, A. Nazli; Tunca, Ceren; Hamzeiy, Hamid; Parman, Yesim; Meitinger, Thomas; Lichtner, Peter; Radivojkov-Blagojevic, Milena; Andres, Christian R.; Maurel, Cindy; Bensimon, Gilbert; Landwehrmeyer, Bernhard; Brice, Alexis; Payan, Christine A. M.; Saker-Delye, Safaa; Duerr, Alexandra; Wood, Nicholas W.; Tittmann, Lukas; Lieb, Wolfgang; Franke, Andre; Rietschel, Marcella; Cichon, Sven; Noethen, Markus M.; Amouyel, Philippe; Tzourio, Christophe; Dartigues, Jean-Francois; Uitterlinden, Andre G.; Rivadeneira, Fernando; Estrada, Karol; Hofman, Albert; Curtis, Charles; Blauw, Hylke M.; van der Kooi, Anneke J.; de Visser, Marianne; Goris, An; Weber, Markus; Shaw, Christopher E.; Smith, Bradley N.; Pansarasa, Orietta; Cereda, Cristina; Del Bo, Roberto; Comi, Giacomo P.; D'Alf