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Sample records for genetic association analysis

  1. Multivariate Methods for Meta-Analysis of Genetic Association Studies.

    Science.gov (United States)

    Dimou, Niki L; Pantavou, Katerina G; Braliou, Georgia G; Bagos, Pantelis G

    2018-01-01

    Multivariate meta-analysis of genetic association studies and genome-wide association studies has received a remarkable attention as it improves the precision of the analysis. Here, we review, summarize and present in a unified framework methods for multivariate meta-analysis of genetic association studies and genome-wide association studies. Starting with the statistical methods used for robust analysis and genetic model selection, we present in brief univariate methods for meta-analysis and we then scrutinize multivariate methodologies. Multivariate models of meta-analysis for a single gene-disease association studies, including models for haplotype association studies, multiple linked polymorphisms and multiple outcomes are discussed. The popular Mendelian randomization approach and special cases of meta-analysis addressing issues such as the assumption of the mode of inheritance, deviation from Hardy-Weinberg Equilibrium and gene-environment interactions are also presented. All available methods are enriched with practical applications and methodologies that could be developed in the future are discussed. Links for all available software implementing multivariate meta-analysis methods are also provided.

  2. 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.

  3. 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

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

    NARCIS (Netherlands)

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

    2017-01-01

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

  5. Genetic analysis and QTL mapping of maize yield and associate ...

    African Journals Online (AJOL)

    STORAGESEVER

    2008-06-17

    Jun 17, 2008 ... strongly influenced by both genotype and environment, and the interaction of ... associated with yield components as well as secondary ... QTLs that control grain yield under drought ... statistical analysis (ANOVA etc) of phenotypic traits was carried out .... which means that the loci had stable heredity.

  6. A functional data analysis approach for genetic association studies

    OpenAIRE

    Reimherr, Matthew; Nicolae, Dan

    2014-01-01

    We present a new method based on Functional Data Analysis (FDA) for detecting associations between one or more scalar covariates and a longitudinal response, while correcting for other variables. Our methods exploit the temporal structure of longitudinal data in ways that are otherwise difficult with a multivariate approach. Our procedure, from an FDA perspective, is a departure from more established methods in two key aspects. First, the raw longitudinal phenotypes are assembled into functio...

  7. Bayesian analysis of genetic association across tree-structured routine healthcare data in the UK Biobank.

    Science.gov (United States)

    Cortes, Adrian; Dendrou, Calliope A; Motyer, Allan; Jostins, Luke; Vukcevic, Damjan; Dilthey, Alexander; Donnelly, Peter; Leslie, Stephen; Fugger, Lars; McVean, Gil

    2017-09-01

    Genetic discovery from the multitude of phenotypes extractable from routine healthcare data can transform understanding of the human phenome and accelerate progress toward precision medicine. However, a critical question when analyzing high-dimensional and heterogeneous data is how best to interrogate increasingly specific subphenotypes while retaining statistical power to detect genetic associations. Here we develop and employ a new Bayesian analysis framework that exploits the hierarchical structure of diagnosis classifications to analyze genetic variants against UK Biobank disease phenotypes derived from self-reporting and hospital episode statistics. Our method displays a more than 20% increase in power to detect genetic effects over other approaches and identifies new associations between classical human leukocyte antigen (HLA) alleles and common immune-mediated diseases (IMDs). By applying the approach to genetic risk scores (GRSs), we show the extent of genetic sharing among IMDs and expose differences in disease perception or diagnosis with potential clinical implications.

  8. 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.

  9. 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.

  10. MetaGenyo: a web tool for meta-analysis of genetic association studies.

    Science.gov (United States)

    Martorell-Marugan, Jordi; Toro-Dominguez, Daniel; Alarcon-Riquelme, Marta E; Carmona-Saez, Pedro

    2017-12-16

    Genetic association studies (GAS) aims to evaluate the association between genetic variants and phenotypes. In the last few years, the number of this type of study has increased exponentially, but the results are not always reproducible due to experimental designs, low sample sizes and other methodological errors. In this field, meta-analysis techniques are becoming very popular tools to combine results across studies to increase statistical power and to resolve discrepancies in genetic association studies. A meta-analysis summarizes research findings, increases statistical power and enables the identification of genuine associations between genotypes and phenotypes. Meta-analysis techniques are increasingly used in GAS, but it is also increasing the amount of published meta-analysis containing different errors. Although there are several software packages that implement meta-analysis, none of them are specifically designed for genetic association studies and in most cases their use requires advanced programming or scripting expertise. We have developed MetaGenyo, a web tool for meta-analysis in GAS. MetaGenyo implements a complete and comprehensive workflow that can be executed in an easy-to-use environment without programming knowledge. MetaGenyo has been developed to guide users through the main steps of a GAS meta-analysis, covering Hardy-Weinberg test, statistical association for different genetic models, analysis of heterogeneity, testing for publication bias, subgroup analysis and robustness testing of the results. MetaGenyo is a useful tool to conduct comprehensive genetic association meta-analysis. The application is freely available at http://bioinfo.genyo.es/metagenyo/ .

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

    Science.gov (United States)

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

    2008-12-25

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

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

    DEFF Research Database (Denmark)

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

    2014-01-01

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

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

    DEFF Research Database (Denmark)

    Tan, Q.

    2013-01-01

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

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

    Science.gov (United States)

    Chintalapudi, Sumana R; Jablonski, Monica M

    2017-01-01

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

  15. 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

    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...... of sequence variants in LARS2 in type 2 diabetes susceptibility, we found no evidence to support previous data indicating a role in type 2 diabetes susceptibility....

  16. Genetic analysis

    NARCIS (Netherlands)

    Koornneef, M.; Alonso-Blanco, C.; Stam, P.

    2006-01-01

    The Mendelian analysis of genetic variation, available as induced mutants or as natural variation, requires a number of steps that are described in this chapter. These include the determination of the number of genes involved in the observed trait's variation, the determination of dominance

  17. Association Between Coronary Artery Disease Genetic Variants and Subclinical Atherosclerosis: An Association Study and Meta-analysis.

    Science.gov (United States)

    Zabalza, Michel; Subirana, Isaac; Lluis-Ganella, Carla; Sayols-Baixeras, Sergi; de Groot, Eric; Arnold, Roman; Cenarro, Ana; Ramos, Rafel; Marrugat, Jaume; Elosua, Roberto

    2015-10-01

    Recent studies have identified several genetic variants associated with coronary artery disease. Some of these genetic variants are not associated with classical cardiovascular risk factors and the mechanism of such associations is unclear. The aim of the study was to determine whether these genetic variants are related to subclinical atherosclerosis measured by carotid intima media thickness, carotid stiffness, and ankle brachial index. A cross-sectional study nested in the follow-up of the REGICOR cohort was undertaken. The study included 2667 individuals. Subclinical atherosclerosis measurements were performed with standardized methods. Nine genetic variants were genotyped to assess associations with subclinical atherosclerosis, individually and in a weighted genetic risk score. A systematic review and meta-analysis of previous studies that analyzed these associations was undertaken. Neither the selected genetic variants nor the genetic risk score were significantly associated with subclinical atherosclerosis. In the meta-analysis, the rs1746048 (CXCL12; n = 10581) risk allele was directly associated with carotid intima-media thickness (β = 0.008; 95% confidence interval, 0.001-0.015), whereas the rs6725887 (WDR12; n = 7801) risk allele was inversely associated with this thickness (β = -0.013; 95% confidence interval, -0.024 to -0.003). The analyzed genetic variants seem to mediate their association with coronary artery disease through different mechanisms. Our results generate the hypothesis that the CXCL12 variant appears to influence coronary artery disease risk through arterial remodeling and thickening, whereas the WDR12 risk variant could be related to higher plaque vulnerability. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  18. 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

  19. Genetic analysis of a Drosophila microtubule-associated protein

    OpenAIRE

    1992-01-01

    The 205-kD microtubule-associated protein (205K MAP) is one of the principal MAPs in Drosophila. 205K MAP is similar to the HeLa 210K/MAP4 family of MAPs since it shares the following biochemical properties: it is present in several isoforms, has a molecular mass of approximately 200 kD, and is thermostable. Furthermore, immuno-crossreactivity has been observed between mouse MAP4, HeLa 210K, and Drosophila 205K MAP. Currently, there is little information concerning the biological function of ...

  20. Bayesian analysis of genetic association across tree-structured routine healthcare data in the UK Biobank

    DEFF Research Database (Denmark)

    Cortes, Adrian; Dendrou, Calliope A; Motyer, Allan

    2017-01-01

    Genetic discovery from the multitude of phenotypes extractable from routine healthcare data can transform understanding of the human phenome and accelerate progress toward precision medicine. However, a critical question when analyzing high-dimensional and heterogeneous data is how best...... to interrogate increasingly specific subphenotypes while retaining statistical power to detect genetic associations. Here we develop and employ a new Bayesian analysis framework that exploits the hierarchical structure of diagnosis classifications to analyze genetic variants against UK Biobank disease phenotypes...... derived from self-reporting and hospital episode statistics. Our method displays a more than 20% increase in power to detect genetic effects over other approaches and identifies new associations between classical human leukocyte antigen (HLA) alleles and common immune-mediated diseases (IMDs). By applying...

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

    Directory of Open Access Journals (Sweden)

    Arunabha Majumdar

    2018-02-01

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

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

    Directory of Open Access Journals (Sweden)

    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

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

    DEFF Research Database (Denmark)

    Wu, Yili; Duan, Haiping; Tian, Xiaocao

    2018-01-01

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

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

    Science.gov (United States)

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

    2017-10-01

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

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

    Science.gov (United States)

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

    2014-12-01

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

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

    Directory of Open Access Journals (Sweden)

    Binod Neupane

    Full Text Available 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

  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. Association genetics and transcriptome analysis reveal a gibberellin-responsive pathway involved in regulating photosynthesis.

    Science.gov (United States)

    Xie, Jianbo; Tian, Jiaxing; Du, Qingzhang; Chen, Jinhui; Li, Ying; Yang, Xiaohui; Li, Bailian; Zhang, Deqiang

    2016-05-01

    Gibberellins (GAs) regulate a wide range of important processes in plant growth and development, including photosynthesis. However, the mechanism by which GAs regulate photosynthesis remains to be understood. Here, we used multi-gene association to investigate the effect of genes in the GA-responsive pathway, as constructed by RNA sequencing, on photosynthesis, growth, and wood property traits, in a population of 435 Populus tomentosa By analyzing changes in the transcriptome following GA treatment, we identified many key photosynthetic genes, in agreement with the observed increase in measurements of photosynthesis. Regulatory motif enrichment analysis revealed that 37 differentially expressed genes related to photosynthesis shared two essential GA-related cis-regulatory elements, the GA response element and the pyrimidine box. Thus, we constructed a GA-responsive pathway consisting of 47 genes involved in regulating photosynthesis, including GID1, RGA, GID2, MYBGa, and 37 photosynthetic differentially expressed genes. Single nucleotide polymorphism (SNP)-based association analysis showed that 142 SNPs, representing 40 candidate genes in this pathway, were significantly associated with photosynthesis, growth, and wood property traits. Epistasis analysis uncovered interactions between 310 SNP-SNP pairs from 37 genes in this pathway, revealing possible genetic interactions. Moreover, a structural gene-gene matrix based on a time-course of transcript abundances provided a better understanding of the multi-gene pathway affecting photosynthesis. The results imply a functional role for these genes in mediating photosynthesis, growth, and wood properties, demonstrating the potential of combining transcriptome-based regulatory pathway construction and genetic association approaches to detect the complex genetic networks underlying quantitative traits. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights

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

    NARCIS (Netherlands)

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

    2017-01-01

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

  11. Genetic association analysis of vitamin D receptor gene polymorphisms and obesity-related phenotypes.

    Science.gov (United States)

    Correa-Rodríguez, M; Carrillo-Ávila, J A; Schmidt-RioValle, J; González-Jiménez, E; Vargas, S; Martín, J; Rueda-Medina, B

    2018-01-15

    Vitamin D has been established as a key factor in the development of obesity through the vitamin D receptor (VDR). The aim of this study was to investigate the contribution of the VDR gene to obesity-related phenotypes in a population of Caucasian young adults. The study population consisted of 701 healthy Spanish young adults (mean age 20.41±2.48). Three single-nucleotide polymorphisms (SNPs) of VDR (TaqI, BsmI and FokI) were selected as genetic markers. Body composition measurements including weight, body mass index (BMI), fat mass (FM), percentage of fat mass (PFM), fat-free mass (FFM) and visceral fat level (VFL) were analysed. Differences in obesity traits across the genotypes were determined using analysis of covariance (ANCOVA). The FokI polymorphism showed a significant association with PFM across the whole population after adjusting for age and sex (p=0.022). Age-adjusted analysis revealed an association between body weight and the TaqI and BsmI SNPs in males (p=0.033 and p=0.028, respectively). However, these positive findings did not remain significant after applying the Bonferroni correction for multiple testing. Our findings suggest that VDR genetic variants are unlikely to play a major role in obesity-related phenotypes in a population of Caucasian young adults. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Methodological issues of genetic association studies.

    Science.gov (United States)

    Simundic, Ana-Maria

    2010-12-01

    Genetic association studies explore the association between genetic polymorphisms and a certain trait, disease or predisposition to disease. It has long been acknowledged that many genetic association studies fail to replicate their initial positive findings. This raises concern about the methodological quality of these reports. Case-control genetic association studies often suffer from various methodological flaws in study design and data analysis, and are often reported poorly. Flawed methodology and poor reporting leads to distorted results and incorrect conclusions. Many journals have adopted guidelines for reporting genetic association studies. In this review, some major methodological determinants of genetic association studies will be discussed.

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

    Science.gov (United States)

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

    2018-01-15

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

  14. 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.

  15. COMPUTER METHODS OF GENETIC ANALYSIS.

    Directory of Open Access Journals (Sweden)

    A. L. Osipov

    2017-02-01

    Full Text Available The basic statistical methods used in conducting the genetic analysis of human traits. We studied by segregation analysis, linkage analysis and allelic associations. Developed software for the implementation of these methods support.

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

    Science.gov (United States)

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

    2009-09-01

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

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

    Science.gov (United States)

    Demissie, Serkalem; Cupples, L Adrienne

    2011-11-01

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

  18. Multivariate genetic divergence among sugarcane clones by multivariate analysis associated with mixed models

    Directory of Open Access Journals (Sweden)

    Valéria Rosa Lopes

    2014-02-01

    Full Text Available This work had the aim to evaluate the genetic divergence in sugarcane clones using the methodology of graphic dispersion by principal components analysis associated to linear mixed models, indentifying the more divergent and productive genotypes with more precision, for a subsequent combination. 138 sugarcane clones of the RB97 series of the Sugarcane Breeding Program of the Universidade Federal do Parana, more two standard cultivars were evaluated in three environments, with two replications. The two first components explained 96% of the total variation, sufficiently for explaining the divergence found. The variable that contributed the most to de divergence was kilogram of brix per plot (BKP followed by brix, mass of 10 stalks and number of stalks per plot. The more divergent sugarcane clones were RB975008, RB975112, RB975019, RB975153 and RB975067 and the more productive clones were RB975269, RB977533, RB975102, RB975317 and RB975038.

  19. 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.

  20. Association analysis of PON2 genetic variants with serum paraoxonase activity and systemic lupus erythematosus

    Directory of Open Access Journals (Sweden)

    Manzi Susan

    2011-01-01

    Full Text Available Abstract Background Low serum paraoxonase (PON activity is associated with the risk of coronary artery disease, diabetes and systemic lupus erythematosus (SLE. Our prior studies have shown that the PON1/rs662 (p.Gln192Arg, PON1/rs854560 (p.Leu55Met, PON3/rs17884563 and PON3/rs740264 SNPs (single nucleotide polymorphisms significantly affect serum PON activity. Since PON1, PON2 and PON3 share high degree of structural and functional properties, in this study, we examined the role of PON2 genetic variation on serum PON activity, risk of SLE and SLE-related clinical manifestations in a Caucasian case-control sample. Methods PON2 SNPs were selected from HapMap and SeattleSNPs databases by including at least one tagSNP from each bin defined in these resources. A total of nineteen PON2 SNPs were successfully genotyped in 411 SLE cases and 511 healthy controls using pyrosequencing, restriction fragment length polymorphism (RFLP or TaqMan allelic discrimination methods. Results Our pair-wise linkage disequilibrium (LD analysis, using an r2 cutoff of 0.7, identified 14 PON2 tagSNPs that captured all 19 PON2 variants in our sample, 12 of which were not in high LD with known PON1 and PON3 SNP modifiers of PON activity. Stepwise regression analysis of PON activity, including the known modifiers, identified five PON2 SNPs [rs6954345 (p.Ser311Cys, rs13306702, rs987539, rs11982486, and rs4729189; P = 0.005 to 2.1 × 10-6] that were significantly associated with PON activity. We found no association of PON2 SNPs with SLE risk but modest associations were observed with lupus nephritis (rs11981433, rs17876205, rs17876183 and immunologic disorder (rs11981433 in SLE patients (P = 0.013 to 0.042. Conclusions Our data indicate that PON2 genetic variants significantly affect variation in serum PON activity and have modest effects on risk of lupus nephritis and SLE-related immunologic disorder.

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

    Science.gov (United States)

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

    2018-01-01

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

  2. 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.

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

    African Journals Online (AJOL)

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

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

    Directory of Open Access Journals (Sweden)

    Iris Broce

    2018-01-01

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

  5. 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

    Autophagy is one of the major intracellular catabolic pathways, but little is known about the composition of autophagosomes. To study the associated proteins, we isolated autophagosomes from human breast cancer cells using two different biochemical methods and three stimulus types: amino acid dep...... regulators of autophagy, including subunits of the retromer complex. The combined spatiotemporal proteomic and genetic data sets presented here provide a basis for further characterization of autophagosome biogenesis and cargo selection....

  6. Whole genome population genetics analysis of Sudanese goats identifies regions harboring genes associated with major traits.

    Science.gov (United States)

    Rahmatalla, Siham A; Arends, Danny; Reissmann, Monika; Said Ahmed, Ammar; Wimmers, Klaus; Reyer, Henry; Brockmann, Gudrun A

    2017-10-23

    Sudan is endowed with a variety of indigenous goat breeds which are used for meat and milk production and which are well adapted to the local environment. The aim of the present study was to determine the genetic diversity and relationship within and between the four main Sudanese breeds of Nubian, Desert, Taggar and Nilotic goats. Using the 50 K SNP chip, 24 animals of each breed were genotyped. More than 96% of high quality SNPs were polymorphic with an average minor allele frequency of 0.3. In all breeds, no significant difference between observed (0.4) and expected (0.4) heterozygosity was found and the inbreeding coefficients (F IS ) did not differ from zero. F st coefficients for the genetic distance between breeds also did not significantly deviate from zero. In addition, the analysis of molecular variance revealed that 93% of the total variance in the examined population can be explained by differences among individuals, while only 7% result from differences between the breeds. These findings provide evidence for high genetic diversity and little inbreeding within breeds on one hand, and low diversity between breeds on the other hand. Further examinations using Nei's genetic distance and STRUCTURE analysis clustered Taggar goats distinct from the other breeds. In a principal component (PC) analysis, PC1 could separate Taggar, Nilotic and a mix of Nubian and Desert goats into three groups. The SNPs that contributed strongly to PC1 showed high F st values in Taggar goat versus the other goat breeds. PCA allowed us to identify target genomic regions which contain genes known to influence growth, development, bone formation and the immune system. The information on the genetic variability and diversity in this study confirmed that Taggar goat is genetically different from the other goat breeds in Sudan. The SNPs identified by the first principal components show high F st values in Taggar goat and allowed to identify candidate genes which can be used in the

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

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    Haihua Bai

    2015-01-01

    Full Text Available 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 T2D and diabetes related quantitative traits. We replicated T2D association of 11 SNPs, namely, rs7578326 (IRS1, rs1531343 (HMGA2, rs8042680 (PRC1, rs7578597 (THADA, rs1333051 (CDKN2, rs6723108 (TMEM163, rs163182 and rs2237897 (KCNQ1, rs1387153 (MTNR1B, rs243021 (BCL11A, and rs10229583 (PAX4 in our sample. Further, we showed that risk allele of the strongest T2D associated SNP in our sample, rs757832 (IRS1, is associated with increased level of TG. We observed substantial difference of T2D risk allele frequency between the Mongolian sample and the 1000G Caucasian sample for a few SNPs, including rs6723108 (TMEM163 whose risk allele reaches near fixation in the Mongolian sample. Further study of genetic architecture of these variants in susceptibility of T2D is needed to understand the role of these variants in heterogeneous populations.

  8. MTLRP genetic polymorphism (214C>A) was associated with Type 2 diabetes in Caucasian population: a meta-analysis

    OpenAIRE

    Chen, Li-Li; Han, Song-Mei; Tang, Fei-Fei; Li, Qiang

    2014-01-01

    Background Previous studies reported the relation between MTLRP genetic polymorphism and type 2 diabetes, however, the conclusion were conflicting. In the present study, we performed a meta-analysis to reveal this association. Methods Literature retrieval, selection and assessment, data extraction, and meta-analyses were performed according to the RevMan 5.0 guidelines. In the meta-analysis, we utilized random-effect model or fixed-effect model to pool the Odds ratio (OR) according to the tes...

  9. Genetic variability, heritability, character association and path analysis in F/sub 1/ hybrids of tomato

    International Nuclear Information System (INIS)

    Saleem, M.Y.; Iqbal, Q.; Asghar, M.

    2013-01-01

    Twenty-five F/sub 1/ hybrids generated from 5*5 diallel crosses were evaluated to study the quantitative genetics of yield and some yield related traits during 2009-10. Worth of room was realized for improvement due to highly significant genetic variations among all traits studied. The highest estimates of genotypic and phenotypic coefficients of variability were recorded for number of fruits per plant while fruit width was the most heritable trait. Plant height, number of fruits per plant and fruit weight revealed significant positive genotypic and phenotypic association along with direct positive effect on fruit yield per plant. It is therefore, recommended that fruit weight, number of fruits per plant and plant height should be given due importance in selection of promising crosses to develop commercial hybrid variety in tomato. (author)

  10. 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.

  11. Association analysis of the genetic polymorphisms with leprosy subtypes in Chinese Han population from Northern China.

    Science.gov (United States)

    Wang, Chuan; Wang, Zhenzhen; Wang, Honglei; Pan, Qing; Fu, Xi'an; Liu, Tingting; Yu, Gongqi; Liu, Hong; Zhang, Furen

    2018-03-24

    Leprosy is characterized by a broad spectrum of clinical manifestations that extend from paucibacillary (PB) to multibacillary (MB) depending upon the different immunologic response to the invading of M. leprae 3,4 . It has been widely accepted that genetic predisposition plays the crucial role in the different clinical manifestations. Host susceptibility to leprosy is modified by number of genes via two stages. In the first stage, a group of genes confers susceptibility to leprosy per se; A second group of genes are associated to the type of host immune response and leprosy subtype 5 . This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  12. The genetic structure of fermentative vineyard-associated Saccharomyces cerevisiae populations revealed by microsatellite analysis.

    Science.gov (United States)

    Schuller, Dorit; Casal, Margarida

    2007-02-01

    From the analysis of six polymorphic microsatellite loci performed in 361 Saccharomyces cerevisiae isolates, 93 alleles were identified, 52 of them being described for the first time. All these isolates have a distinct mtDNA RFLP pattern. They are derived from a pool of 1620 isolates obtained from spontaneous fermentations of grapes collected in three vineyards of the Vinho Verde Region in Portugal, during the 2001-2003 harvest seasons. For all loci analyzed, observed heterozygosity was 3-4 times lower than the expected value supposing a Hardy-Weinberg equilibrium (random mating and no evolutionary mechanisms acting), indicating a clonal structure and strong populational substructuring. Genetic differences among S. cerevisiae populations were apparent mainly from gradations in allele frequencies rather than from distinctive "diagnostic" genotypes, and the accumulation of small allele-frequency differences across six loci allowed the identification of population structures. Genetic differentiation in the same vineyard in consecutive years was of the same order of magnitude as the differences verified among the different vineyards. Correlation of genetic differentiation with the distance between sampling points within a vineyard suggested a pattern of isolation-by-distance, where genetic divergence in a vineyard increased with size. The continuous use of commercial yeasts has a limited influence on the autochthonous fermentative yeast population collected from grapes and may just slightly change populational structures of strains isolated from sites very close to the winery where they have been used. The present work is the first large-scale approach using microsatellite typing allowing a very fine resolution of indigenous S. cerevisiae populations isolated from vineyards.

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

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    Xiaoquan Wen

    2017-03-01

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

  14. 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.

  15. Population Structure, Genetic Diversity and Molecular Marker-Trait Association Analysis for High Temperature Stress Tolerance in Rice.

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    Sharat Kumar Pradhan

    Full Text Available Rice exhibits enormous genetic diversity, population structure and molecular marker-traits associated with abiotic stress tolerance to high temperature stress. A set of breeding lines and landraces representing 240 germplasm lines were studied. Based on spikelet fertility percent under high temperature, tolerant genotypes were broadly classified into four classes. Genetic diversity indicated a moderate level of genetic base of the population for the trait studied. Wright's F statistic estimates showed a deviation of Hardy-Weinberg expectation in the population. The analysis of molecular variance revealed 25 percent variation between population, 61 percent among individuals and 14 percent within individuals in the set. The STRUCTURE analysis categorized the entire population into three sub-populations and suggested that most of the landraces in each sub-population had a common primary ancestor with few admix individuals. The composition of materials in the panel showed the presence of many QTLs representing the entire genome for the expression of tolerance. The strongly associated marker RM547 tagged with spikelet fertility under stress and the markers like RM228, RM205, RM247, RM242, INDEL3 and RM314 indirectly controlling the high temperature stress tolerance were detected through both mixed linear model and general linear model TASSEL analysis. These markers can be deployed as a resource for marker-assisted breeding program of high temperature stress tolerance.

  16. Population Structure, Genetic Diversity and Molecular Marker-Trait Association Analysis for High Temperature Stress Tolerance in Rice.

    Science.gov (United States)

    Pradhan, Sharat Kumar; Barik, Saumya Ranjan; Sahoo, Ambika; Mohapatra, Sudipti; Nayak, Deepak Kumar; Mahender, Anumalla; Meher, Jitandriya; Anandan, Annamalai; Pandit, Elssa

    2016-01-01

    Rice exhibits enormous genetic diversity, population structure and molecular marker-traits associated with abiotic stress tolerance to high temperature stress. A set of breeding lines and landraces representing 240 germplasm lines were studied. Based on spikelet fertility percent under high temperature, tolerant genotypes were broadly classified into four classes. Genetic diversity indicated a moderate level of genetic base of the population for the trait studied. Wright's F statistic estimates showed a deviation of Hardy-Weinberg expectation in the population. The analysis of molecular variance revealed 25 percent variation between population, 61 percent among individuals and 14 percent within individuals in the set. The STRUCTURE analysis categorized the entire population into three sub-populations and suggested that most of the landraces in each sub-population had a common primary ancestor with few admix individuals. The composition of materials in the panel showed the presence of many QTLs representing the entire genome for the expression of tolerance. The strongly associated marker RM547 tagged with spikelet fertility under stress and the markers like RM228, RM205, RM247, RM242, INDEL3 and RM314 indirectly controlling the high temperature stress tolerance were detected through both mixed linear model and general linear model TASSEL analysis. These markers can be deployed as a resource for marker-assisted breeding program of high temperature stress tolerance.

  17. 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.

  18. 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…

  19. 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.

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

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    Wang Kai

    2011-05-01

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

  1. Analysis of cryopyrin-associated periodic syndromes (CAPS) in German children: epidemiological, clinical and genetic characteristics.

    Science.gov (United States)

    Lainka, E; Neudorf, U; Lohse, P; Timmann, C; Bielak, M; Stojanov, S; Huss, K; von Kries, R; Niehues, T

    2010-11-01

    Cryopyrin-associated periodic syndromes (CAPS) are rare disorders belonging to the group of hereditary periodic fever (HPF)syndromes. These auto-inflammatory diseases(AID) are characterized by recurrent episodes of inflammation with attacks of fever variably associated with serosal, synovial and / or cutaneous inflammation, usually in a self-limiting manner, and with a mostly monogenic origin. The aims were to determine the incidence of CAPS and the spectrum of mutations in the NLRP3 (formerly= CIAS1) gene and to describe the clinical manifestations. A prospective surveillance of children with CAPS was conducted in Germany during a time period of 3 years(2003-2006). Monthly inquiries were sent to 370 children's hospitals by the German Paediatric Surveillance Unit (Clinic-ESPED, n1) and to 2 laboratories (Laboratory-ESPED, n2). Inclusion criteria were children ≤ 16 years of age, disease-associated NLRP3 mutation, more than 3 self-limiting episodes of fever > 38.5 ° C, and increased inflammation markers. Clinical, epidemiological and genetic data were evaluated via questionnaires. 6 out of 14 patients were identified in Clinic-ESPED (n1) and 13 / 14 in Laboratory-ESPED(n2). Clinical and laboratory surveys overlapped in 5 of 14 cases. The incidence of CAPS in German children was estimated to be 3.43 per 10⁷ person-years. The patients carried 11 different NLRP3 mutations and were classified as MWS(n = 6), CINCA (n = 4), FCAS (n = 1) and undefined CAPS (n = 3). The incidence of CAPS in Germany is very low and corresponds to 2-7 newly diagnosed patients ≤ 16 years per year. © Georg Thieme Verlag KG Stuttgart · New York.

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

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    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

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

    Directory of Open Access Journals (Sweden)

    Qiuhong Sun

    2014-04-01

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

  4. 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

  5. Integrated genetic analysis microsystems

    International Nuclear Information System (INIS)

    Lagally, Eric T; Mathies, Richard A

    2004-01-01

    With the completion of the Human Genome Project and the ongoing DNA sequencing of the genomes of other animals, bacteria, plants and others, a wealth of new information about the genetic composition of organisms has become available. However, as the demand for sequence information grows, so does the workload required both to generate this sequence and to use it for targeted genetic analysis. Microfabricated genetic analysis systems are well poised to assist in the collection and use of these data through increased analysis speed, lower analysis cost and higher parallelism leading to increased assay throughput. In addition, such integrated microsystems may point the way to targeted genetic experiments on single cells and in other areas that are otherwise very difficult. Concomitant with these advantages, such systems, when fully integrated, should be capable of forming portable systems for high-speed in situ analyses, enabling a new standard in disciplines such as clinical chemistry, forensics, biowarfare detection and epidemiology. This review will discuss the various technologies available for genetic analysis on the microscale, and efforts to integrate them to form fully functional robust analysis devices. (topical review)

  6. Argonaute 2 and nasopharyngeal carcinoma: a genetic association study and functional analysis

    International Nuclear Information System (INIS)

    Li, Peiyao; Meng, Jinfeng; Zhai, Yun; Zhang, Hongxing; Yu, Lixia; Wang, Zhifu; Zhang, Xiaoai; Cao, Pengbo; Chen, Xi; Han, Yuqing; Zhang, Yang; Chen, Huipeng; Ling, Yan; Li, Yuxia; Cui, Ying; Bei, Jin-Xin; Zeng, Yi-Xin; He, Fuchu; Zhou, Gangqiao

    2015-01-01

    Argonaute 2 (AGO2), a central component of RNA-induced silencing complex, plays critical roles in cancer. We examined whether the single nucleotide polymorphisms (SNPs) of AGO2 were related to the risk of nasopharyngeal carcinoma (NPC). Twenty-five tag SNPs within AGO2 were genotyped in Guangxi population consisting of 855 NPC patients and 1036 controls. The SNPs significantly associated with NPC were further replicated in Guangdong population consisting of 996 NPC patients and 972 controls. Functional experiments were conducted to examine the biologic roles of AGO2 in NPC. A significantly increased risk of advanced lymph node metastasis of NPC was identified for the AGO2 rs3928672 GA + AA genotype compared with GG genotype in both the Guangxi and Guangdong populations (combined odd ratio = 2.08, 95 % confidence interval = 1.44-3.01, P = 8.60 × 10 −5 ). Moreover, the AGO2 protein expression levels of rs3928672 GA + AA genotype carriers were higher than the GG genotype carriers in the NPC tissues (P = 0.041), and AGO2 was significantly over-expressed in NPC tissues compared with non-cancerous nasopharyngeal tissues (P = 0.011). In addition, AGO2 knockdown reduced cell proliferation, induced apoptosis, and inhibited migration of NPC cells. Furthermore, gene expression microarray showed that genes altered following AGO2 knockdown were clustered in tumorigenesis and metastasis relevant pathways. Our findings suggest that the genetic polymorphism in AGO2 may be a risk factor for the advanced lymph node metastasis of NPC in Chinese populations, and AGO2 acts as an oncogene in the development of NPC. The online version of this article (doi:10.1186/s12885-015-1895-4) contains supplementary material, which is available to authorized users

  7. Genetic Analysis of Seed Yield Components and its Association with Forage Production in Wild and Cultivated Species of Sainfoin

    Directory of Open Access Journals (Sweden)

    A. Najafipoor

    2017-02-01

    Full Text Available Little is known about genetic variation of seed related traits and their association with forage characters in sainfoin. In order to investigate the variation and relationship among seed yield and its components, 93 genotypes from 21 wild and cultivated species of genus Onobrychis were evaluated using a randomized complete block design with four replications at Isfahan University of Technology Research Farm, Isfahan, Iran. Analysis of variance showed that there was significant difference among genotypes, indicating existence of considerable genetic variation in this germplasm. Panicle fertility and panicle length had the most variation in cultivated and the wild genotypes, respectively. Results of correlation analysis showed that seed yield was positively correlated with number of stems per plant and number of seeds per panicle and negatively correlated with panicle length and days to 50% flowering. Seed yield had positive correlation with forage yield in wild species while this correlation was not significant in cultivated one. Cluster analysis classified the genotypes into three groups which separate wild and cultivated species. Based on principal component analysis the first component was related to seed yield and the second one was related to components of forage yield which can be used for selection of high forage and seed yielding genotypes.

  8. Analysis of malaria associated genetic traits in Cabo Verde, a melting pot of European and sub Saharan settlers.

    Science.gov (United States)

    Alves, Joana; Machado, Patrícia; Silva, João; Gonçalves, Nilza; Ribeiro, Letícia; Faustino, Paula; do Rosário, Virgílio Estólio; Manco, Licínio; Gusmão, Leonor; Amorim, António; Arez, Ana Paula

    2010-01-15

    Malaria has occurred in the Cabo Verde archipelago with epidemic characteristics since its colonization. Nowadays, it occurs in Santiago Island alone and though prophylaxis is not recommended by the World Health Organization, studies have highlight the prospect of malaria becoming a serious public health problem as a result of the presence of antimalarial drug resistance associated with mutations in the parasite populations and underscore the need for tighter surveillance. Despite the presumptive weak immune status of the population, severe symptoms of malaria are not observed and many people present a subclinical course of the disease. No data on the prevalence of sickle-cell trait and red cell glucose-6-phosphate dehydrogenase deficiency (two classical genetic factors associated with resistance to severe malaria) were available for the Cabo Verde archipelago and, therefore, we studied the low morbidity from malaria in relation to the particular genetic characteristics of the human host population. We also included the analysis of the pyruvate kinase deficiency associated gene, reported as putatively associated with resistance to the disease. Allelic frequencies of the polymorphisms examined are closer to European than to African populations and no malaria selection signatures were found. No association was found between the analyzed human factors and infection but one result is of high interest: a linkage disequilibrium test revealed an association of distant loci in the PKLR gene and adjacent regions, only in non-infected individuals. This could mean a more conserved gene region selected in association to protection against the infection and/or the disease. Copyright 2009 Elsevier Inc. All rights reserved.

  9. 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

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

    NARCIS (Netherlands)

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

    2008-01-01

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

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

    NARCIS (Netherlands)

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

    2013-01-01

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

  12. Genetic Architecture of Aluminum Tolerance in Rice (Oryza sativa) Determined through Genome-Wide Association Analysis and QTL Mapping

    Science.gov (United States)

    Famoso, Adam N.; Zhao, Keyan; Clark, Randy T.; Tung, Chih-Wei; Wright, Mark H.; Bustamante, Carlos; Kochian, Leon V.; McCouch, Susan R.

    2011-01-01

    Aluminum (Al) toxicity is a primary limitation to crop productivity on acid soils, and rice has been demonstrated to be significantly more Al tolerant than other cereal crops. However, the mechanisms of rice Al tolerance are largely unknown, and no genes underlying natural variation have been reported. We screened 383 diverse rice accessions, conducted a genome-wide association (GWA) study, and conducted QTL mapping in two bi-parental populations using three estimates of Al tolerance based on root growth. Subpopulation structure explained 57% of the phenotypic variation, and the mean Al tolerance in Japonica was twice that of Indica. Forty-eight regions associated with Al tolerance were identified by GWA analysis, most of which were subpopulation-specific. Four of these regions co-localized with a priori candidate genes, and two highly significant regions co-localized with previously identified QTLs. Three regions corresponding to induced Al-sensitive rice mutants (ART1, STAR2, Nrat1) were identified through bi-parental QTL mapping or GWA to be involved in natural variation for Al tolerance. Haplotype analysis around the Nrat1 gene identified susceptible and tolerant haplotypes explaining 40% of the Al tolerance variation within the aus subpopulation, and sequence analysis of Nrat1 identified a trio of non-synonymous mutations predictive of Al sensitivity in our diversity panel. GWA analysis discovered more phenotype–genotype associations and provided higher resolution, but QTL mapping identified critical rare and/or subpopulation-specific alleles not detected by GWA analysis. Mapping using Indica/Japonica populations identified QTLs associated with transgressive variation where alleles from a susceptible aus or indica parent enhanced Al tolerance in a tolerant Japonica background. This work supports the hypothesis that selectively introgressing alleles across subpopulations is an efficient approach for trait enhancement in plant breeding programs and

  13. Discovery of new candidate genes for rheumatoid arthritis through integration of genetic association data with expression pathway analysis.

    Science.gov (United States)

    Shchetynsky, Klementy; Diaz-Gallo, Lina-Marcella; Folkersen, Lasse; Hensvold, Aase Haj; Catrina, Anca Irinel; Berg, Louise; Klareskog, Lars; Padyukov, Leonid

    2017-02-02

    Here we integrate verified signals from previous genetic association studies with gene expression and pathway analysis for discovery of new candidate genes and signaling networks, relevant for rheumatoid arthritis (RA). RNA-sequencing-(RNA-seq)-based expression analysis of 377 genes from previously verified RA-associated loci was performed in blood cells from 5 newly diagnosed, non-treated patients with RA, 7 patients with treated RA and 12 healthy controls. Differentially expressed genes sharing a similar expression pattern in treated and untreated RA sub-groups were selected for pathway analysis. A set of "connector" genes derived from pathway analysis was tested for differential expression in the initial discovery cohort and validated in blood cells from 73 patients with RA and in 35 healthy controls. There were 11 qualifying genes selected for pathway analysis and these were grouped into two evidence-based functional networks, containing 29 and 27 additional connector molecules. The expression of genes, corresponding to connector molecules was then tested in the initial RNA-seq data. Differences in the expression of ERBB2, TP53 and THOP1 were similar in both treated and non-treated patients with RA and an additional nine genes were differentially expressed in at least one group of patients compared to healthy controls. The ERBB2, TP53. THOP1 expression profile was successfully replicated in RNA-seq data from peripheral blood mononuclear cells from healthy controls and non-treated patients with RA, in an independent collection of samples. Integration of RNA-seq data with findings from association studies, and consequent pathway analysis implicate new candidate genes, ERBB2, TP53 and THOP1 in the pathogenesis of RA.

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

    DEFF Research Database (Denmark)

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

    2018-01-01

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

  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...

  16. Identification of genes associated with dissociation of cognitive performance and neuropathological burden: Multistep analysis of genetic, epigenetic, and transcriptional data.

    Directory of Open Access Journals (Sweden)

    Charles C White

    2017-04-01

    the previously documented effect of depression on cognitive decline, while UNC5C may alter the composition of presynaptic terminals. Of note, the TMEM106B allele identified in the first step as being associated with better residual cognition is in strong linkage disequilibrium with rs1990622A (r2 = 0.66, a previously identified protective allele for TDP-43 proteinopathy. Limitations include the small sample size for the genetic analysis, which was underpowered to detect genome-wide significance, the evaluation being limited to a single cortical region for epigenetic and transcriptomic data, and the use of categorical measures for certain non-amyloid-plaque, non-neurofibrillary-tangle neuropathologies.Through a multistep analysis of cognitive, neuropathological, genomic, epigenomic, and transcriptomic data, we identified ENC1 and UNC5C as genes with convergent genetic, epigenetic, and transcriptomic evidence supporting a potential role in the dissociation of cognition and neuropathology in an aging population, and we expanded our understanding of the TMEM106B haplotype that is protective against TDP-43 proteinopathy.

  17. Guidance for the utility of linear models in meta-analysis of genetic association studies of binary phenotypes.

    Science.gov (United States)

    Cook, James P; Mahajan, Anubha; Morris, Andrew P

    2017-02-01

    Linear mixed models are increasingly used for the analysis of genome-wide association studies (GWAS) of binary phenotypes because they can efficiently and robustly account for population stratification and relatedness through inclusion of random effects for a genetic relationship matrix. However, the utility of linear (mixed) models in the context of meta-analysis of GWAS of binary phenotypes has not been previously explored. In this investigation, we present simulations to compare the performance of linear and logistic regression models under alternative weighting schemes in a fixed-effects meta-analysis framework, considering designs that incorporate variable case-control imbalance, confounding factors and population stratification. Our results demonstrate that linear models can be used for meta-analysis of GWAS of binary phenotypes, without loss of power, even in the presence of extreme case-control imbalance, provided that one of the following schemes is used: (i) effective sample size weighting of Z-scores or (ii) inverse-variance weighting of allelic effect sizes after conversion onto the log-odds scale. Our conclusions thus provide essential recommendations for the development of robust protocols for meta-analysis of binary phenotypes with linear models.

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

    Science.gov (United States)

    McKay, James D; Hung, Rayjean J; Han, Younghun; Zong, Xuchen; Carreras-Torres, Robert; Christiani, David C; Caporaso, Neil E; Johansson, Mattias; Xiao, Xiangjun; Li, Yafang; Byun, Jinyoung; Dunning, Alison; Pooley, Karen A; Qian, David C; Ji, Xuemei; Liu, Geoffrey; Timofeeva, Maria N; Bojesen, Stig E; Wu, Xifeng; Le Marchand, Loic; Albanes, Demetrios; Bickeböller, Heike; Aldrich, Melinda C; Bush, William S; Tardon, Adonina; Rennert, Gad; Teare, M Dawn; Field, John K; Kiemeney, Lambertus A; Lazarus, Philip; Haugen, Aage; Lam, Stephen; Schabath, Matthew B; Andrew, Angeline S; Shen, Hongbing; Hong, Yun-Chul; Yuan, Jian-Min; Bertazzi, Pier Alberto; Pesatori, Angela C; Ye, Yuanqing; Diao, Nancy; Su, Li; Zhang, Ruyang; Brhane, Yonathan; Leighl, Natasha; Johansen, Jakob S; Mellemgaard, Anders; Saliba, Walid; Haiman, Christopher A; Wilkens, Lynne R; Fernandez-Somoano, Ana; Fernandez-Tardon, Guillermo; van der Heijden, Henricus F M; Kim, Jin Hee; Dai, Juncheng; Hu, Zhibin; Davies, Michael P A; Marcus, Michael W; Brunnström, Hans; Manjer, Jonas; Melander, Olle; Muller, David C; Overvad, Kim; Trichopoulou, Antonia; Tumino, Rosario; Doherty, Jennifer A; Barnett, Matt P; Chen, Chu; Goodman, Gary E; Cox, Angela; Taylor, Fiona; Woll, Penella; Brüske, Irene; Wichmann, H-Erich; Manz, Judith; Muley, Thomas R; Risch, Angela; Rosenberger, Albert; Grankvist, Kjell; Johansson, Mikael; Shepherd, Frances A; Tsao, Ming-Sound; Arnold, Susanne M; Haura, Eric B; Bolca, Ciprian; Holcatova, Ivana; Janout, Vladimir; Kontic, Milica; Lissowska, Jolanta; Mukeria, Anush; Ognjanovic, Simona; Orlowski, Tadeusz M; Scelo, Ghislaine; Swiatkowska, Beata; Zaridze, David; Bakke, Per; Skaug, Vidar; Zienolddiny, Shanbeh; Duell, Eric J; Butler, Lesley M; Koh, Woon-Puay; Gao, Yu-Tang; Houlston, Richard S; McLaughlin, John; Stevens, Victoria L; Joubert, Philippe; Lamontagne, Maxime; Nickle, David C; Obeidat, Ma'en; Timens, Wim; Zhu, Bin; Song, Lei; Kachuri, Linda; Artigas, María Soler; Tobin, Martin D; Wain, Louise V; Rafnar, Thorunn; Thorgeirsson, Thorgeir E; Reginsson, Gunnar W; Stefansson, Kari; Hancock, Dana B; Bierut, Laura J; Spitz, Margaret R; Gaddis, Nathan C; Lutz, Sharon M; Gu, Fangyi; Johnson, Eric O; Kamal, Ahsan; Pikielny, Claudio; Zhu, Dakai; Lindströem, Sara; Jiang, Xia; Tyndale, Rachel F; Chenevix-Trench, Georgia; Beesley, Jonathan; Bossé, Yohan; Chanock, Stephen; Brennan, Paul; Landi, Maria Teresa; Amos, Christopher I

    2017-07-01

    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 genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

  19. 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.

  20. 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...... processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis....

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

    OpenAIRE

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

    2014-01-01

    Motivation: Sharing genomic data is crucial to support scientific investigation such as genome-wide association studies. However, recent investigations suggest the privacy of the individual participants in these studies can be compromised, leading to serious concerns and consequences, such as overly restricted access to data.

  2. 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

    with that of the case-only model. RESULTS: Results from our simulation study indicate that our retrospective model exhibits high power in capturing even relatively small effect with reasonable sample sizes. Application of our method to data from an association study on the catalase -262C/T promoter polymorphism...

  3. Association analysis between genetic variants in interleukin genes among different populations with hyperuricemia in Xinjiang Autonomous Region

    Science.gov (United States)

    Zhang, Bei; Sun, Yuping; Li, Yuanyuan; Yu, Jiahui; Wang, Tingting; Xia, He; Li, Changgui; Liu, Shiguo; Yao, Hua

    2015-01-01

    To investigate whether functional variants of five interleukin genes (IL-1β, IL-10, IL-8, IL-18 and IL-18RAP) are associated with susceptibility to hyperuricemia among different nationalities (including Uygur, Kazak and Han populations) in the Xinjiang Autonomous Region of China. A total of 884 hyperuricemia patients and 1316 matched controls were recruited from the First Affiliated Hospital of Xinjiang Medical University in Urumqi. After genotyping of rs4073 in IL-8, rs16944 in IL-1, rs187238 in IL-18, rs1800871 in IL-10 and rs13015714 in IL-18RAP by TaqMan allele discrimination assays, an association analysis was performed using the χ2 test as well as a genotype-phenotype analysis. For the Uygur population, IL-8 rs4073, IL-18 rs187238 and IL-18RAP rs130154 polymorphisms were all associated with hyperuricemia (P<0.001 by genotype and P=0.008, OR 0.802 by allele for IL-8; P=0.01 by genotype and P=0.006, OR 1.332 by allele for IL-18 rs187238; P=0.007 by genotype and P=0.005, OR 1.27 by allele for IL-18RAP rs130154). For the Kazak population, only IL-18 rs187238 showed statistical significance with hyperuricemia (P=0.002 by genotype and P=0.007, OR 1.823 by allele). However, no differences were found between the five SNPs and hyperuricemia among the Han population. This study demonstrated genetic polymorphisms of different interleukin genes related to hyperuricemia vary in different nationalities in the Xinjiang Autonomous Region because of different geographical environments. IL-8, IL-1RL1 and IL-18 might be involved in the development of hyperuricemia in the Uygur population, whereas only IL-18 might be involved in the Kazak population. PMID:26722554

  4. Genetic Variation and Association Analysis of the SSR Markers Linked to the Major Drought-Yield QTLs of Rice.

    Science.gov (United States)

    Tabkhkar, Narjes; Rabiei, Babak; Samizadeh Lahiji, Habibollah; Hosseini Chaleshtori, Maryam

    2018-02-24

    Drought is one of the major abiotic stresses, which hampers the production of rice worldwide. Informative molecular markers are valuable tools for improving the drought tolerance in various varieties of rice. The present study was conducted to evaluate the informative simple sequence repeat (SSR) markers in a diverse set of rice genotypes. The genetic diversity analyses of the 83 studied rice genotypes were performed using 34 SSR markers closely linked to the major quantitative trait loci (QTLs) of grain yield under drought stress (qDTYs). In general, our results indicated high levels of polymorphism. In addition, we screened these rice genotypes at the reproductive stage under both drought stress and nonstressful conditions. The results of the regression analysis demonstrated a significant relationship between 11 SSR marker alleles and the plant paddy weight under stressful conditions. Under the nonstressful conditions, 16 SSR marker alleles showed a significant correlation with the plant paddy weight. Finally, four markers (RM279, RM231, RM166, and RM231) demonstrated a significant association with the plant paddy weight under both stressful and nonstressful conditions. These informative-associated alleles may be useful for improving the crop yield under both drought stress and nonstressful conditions in breeding programs.

  5. Microsatellite analysis of chloroquine resistance associated alleles and neutral loci reveal genetic structure of Indian Plasmodium falciparum

    Science.gov (United States)

    Mallick, Prashant K.; Sutton, Patrick L.; Singh, Ruchi; Singh, Om P.; Dash, Aditya P.; Singh, Ashok K.; Carlton, Jane M.; Bhasin, Virendra K.

    2013-01-01

    Efforts to control malignant malaria caused by Plasmodium falciparum are hampered by the parasite’s acquisition of resistance to antimalarial drugs, e.g., chloroquine. This necessitates evaluating the spread of chloroquine resistance in any malaria-endemic area. India displays highly variable malaria epidemiology and also shares porous international borders with malaria-endemic Southeast Asian countries having multi-drug resistant malaria. Malaria epidemiology in India is believed to be affected by two major factors: high genetic diversity and evolving drug resistance in P. falciparum. How transmission intensity of malaria can influence the genetic structure of chloroquine-resistant P. falciparum population in India is unknown. Here, genetic diversity within and among P. falciparum populations is analyzed with respect to their prevalence and chloroquine resistance observed in 13 different locations in India. Microsatellites developed for P. falciparum, including three putatively neutral and seven microsatellites thought to be under a hitchhiking effect due to chloroquine selection were used. Genetic hitchhiking is observed in five of seven microsatellites flanking the gene responsible for chloroquine resistance. Genetic admixture analysis and F-statistics detected genetically distinct groups in accordance with transmission intensity of different locations and the probable use of chloroquine. A large genetic break between the chloroquine-resistant parasite of the Northeast-East-Island group and Southwest group (FST = 0.253, P<0.001) suggests a long period of isolation or a possibility of different origin between them. A pattern of significant isolation by distance was observed in low transmission areas (r = 0.49, P=0.003, N = 83, Mantel test). An unanticipated pattern of spread of hitchhiking suggests genetic structure for Indian P. falciparum population. Overall, the study suggests that transmission intensity can be an efficient driver for genetic differentiation

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

    Science.gov (United States)

    McKay, James D.; Hung, Rayjean J.; Han, Younghun; Zong, Xuchen; Carreras-Torres, Robert; Christiani, David C.; Caporaso, Neil E.; Johansson, Mattias; Xiao, Xiangjun; Li, Yafang; Byun, Jinyoung; Dunning, Alison; Pooley, Karen A.; Qian, David C.; Ji, Xuemei; Liu, Geoffrey; Timofeeva, Maria N.; Bojesen, Stig E.; Wu, Xifeng; Le Marchand, Loic; Albanes, Demetrios; Bickeböller, Heike; Aldrich, Melinda C.; Bush, William S.; Tardon, Adonina; Rennert, Gad; Teare, M. Dawn; Field, John K.; Kiemeney, Lambertus A.; Lazarus, Philip; Haugen, Aage; Lam, Stephen; Schabath, Matthew B.; Andrew, Angeline S.; Shen, Hongbing; Hong, Yun-Chul; Yuan, Jian-Min; Bertazzi, Pier Alberto; Pesatori, Angela C.; Ye, Yuanqing; Diao, Nancy; Su, Li; Zhang, Ruyang; Brhane, Yonathan; Leighl, Natasha; Johansen, Jakob S.; Mellemgaard, Anders; Saliba, Walid; Haiman, Christopher A.; Wilkens, Lynne R.; Fernandez-Somoano, Ana; Fernandez-Tardon, Guillermo; van der Heijden, Henricus F.M.; Kim, Jin Hee; Dai, Juncheng; Hu, Zhibin; Davies, Michael PA; Marcus, Michael W.; Brunnström, Hans; Manjer, Jonas; Melander, Olle; Muller, David C.; Overvad, Kim; Trichopoulou, Antonia; Tumino, Rosario; Doherty, Jennifer A.; Barnett, Matt P.; Chen, Chu; Goodman, Gary E.; Cox, Angela; Taylor, Fiona; Woll, Penella; Brüske, Irene; Wichmann, H.-Erich; Manz, Judith; Muley, Thomas R.; Risch, Angela; Rosenberger, Albert; Grankvist, Kjell; Johansson, Mikael; Shepherd, Frances A.; Tsao, Ming-Sound; Arnold, Susanne M.; Haura, Eric B.; Bolca, Ciprian; Holcatova, Ivana; Janout, Vladimir; Kontic, Milica; Lissowska, Jolanta; Mukeria, Anush; Ognjanovic, Simona; Orlowski, Tadeusz M.; Scelo, Ghislaine; Swiatkowska, Beata; Zaridze, David; Bakke, Per; Skaug, Vidar; Zienolddiny, Shanbeh; Duell, Eric J.; Butler, Lesley M.; Koh, Woon-Puay; Gao, Yu-Tang; Houlston, Richard S.; McLaughlin, John; Stevens, Victoria L.; Joubert, Philippe; Lamontagne, Maxime; Nickle, David C.; Obeidat, Ma’en; Timens, Wim; Zhu, Bin; Song, Lei; Kachuri, Linda; Artigas, María Soler; Tobin, Martin D.; Wain, Louise V.; Rafnar, Thorunn; Thorgeirsson, Thorgeir E.; Reginsson, Gunnar W.; Stefansson, Kari; Hancock, Dana B.; Bierut, Laura J.; Spitz, Margaret R.; Gaddis, Nathan C.; Lutz, Sharon M.; Gu, Fangyi; Johnson, Eric O.; Kamal, Ahsan; Pikielny, Claudio; Zhu, Dakai; Lindströem, Sara; Jiang, Xia; Tyndale, Rachel F.; Chenevix-Trench, Georgia; Beesley, Jonathan; Bossé, Yohan; Chanock, Stephen; Brennan, Paul; Landi, Maria Teresa; Amos, Christopher I.

    2017-01-01

    Summary While several lung cancer susceptibility loci have been identified, much of lung cancer heritability 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 GWAS analysis of lung cancer on 29,266 patients and 56,450 controls. We identified 18 susceptibility loci achieving genome wide significance, including 10 novel loci. The novel loci highlighted the striking heterogeneity in genetic susceptibility across lung cancer histological subtypes, with four loci associated with lung cancer overall and six with lung adenocarcinoma. Gene expression quantitative trait analysis (eQTL) in 1,425 normal lung tissues highlighted RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes, OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer. PMID:28604730

  7. 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.

  8. Support of positive association in family-based genetic analysis between COL27A1 and Tourette syndrome.

    Science.gov (United States)

    Liu, Shiguo; Yu, Xiaoxia; Xu, Quanchen; Cui, Jiajia; Yi, Mingji; Zhang, Xinhua; Ge, Yinlin; Ma, Xu

    2015-08-03

    Recently, a genome-wide association study has indicated associations between single nucleotide polymorphisms in the Collagen Type XXVII Alpha 1 gene (COL27A1) and Tourette syndrome in several ethnic populations. To clarify the global relevance of the previously identified SNPs in the development of Tourette syndrome, the associations between polymorphisms in COL27A1 and Tourette syndrome were assessed in Chinese trios. PCR-directed sequencing was used to evaluate the genetic contributions of three SNPs in COL27A1(rs4979356, rs4979357 and rs7868992) using haplotype relative risk (HRR) and transmission disequilibrium tests (TDT) with a total of 260 Tourette syndrome trios. The family-based association was significant between Tourette syndrome and rs4979356 (TDT: χ2 = 4.804, P = 0.033; HRR = 1.75, P = 0.002; HHRR = 1.32, P = 0.027), and transmission disequilibrium was suspected for rs4979357 (TDT: χ2 = 3.969, P = 0.053; HRR = 1.84, P = 0.001; HHRR = 1.29, P = 0.044). No statistically significant allele transfer was found for rs7868992 (TDT: χ2 = 2.177, P = 0.158). Although the TDT results did not remain significant after applying the conservative Bonferroni correction (p = 0.005), the significant positive HRR analysis confirmed the possibility of showing transmission disequilibrium, which provides evidence for an involvement of COL27A1in the development of TS. However, these results need to be verified with larger datasets from different populations.

  9. Superoxide Dismutase 2 Polymorphisms and Osteoporosis in Asian Indians: A Genetic Association Analysis.

    Science.gov (United States)

    Botre, Chaitali; Shahu, Arjun; Adkar, Neeraj; Shouche, Yogesh; Ghaskadbi, Saroj; Ashma, Richa

    2015-12-01

    Oxidative stress plays an important role in the development of osteoporosis. The present cross-sectional study focuses on mapping single nucleotide polymorphisms (SNPs) in the mitochondrial manganese superoxide dismutase (SOD2) gene in Asian Indians. The bone mineral density (BMD) of study subjects was assessed by dual x-ray absorptiometry. Individuals were classified as normal (n = 82) or osteoporotic (n = 98). Biochemical parameters such as vitamin D, total oxidant status (TOS) and SOD2 enzyme activity were estimated from plasma samples. Semi-quantitative PCR was carried out using GAPDH as an endogenous control. Genomic DNA was isolated from whole blood and SNPs were evaluated by PCR sequencing. Thirteen SNPs are reported in the examined region of the SOD2 gene, out of which in our samples SNPs rs5746094 and rs4880 were found to be polymorphic. Allele G of rs5746094 (intronic) and allele C of rs4880 (exonic) are significantly higher in the osteoporotic individuals. Presence of allele C of rs4880 and increased level of TOS among osteoporotic individuals were found to be associated with disease risk.

  10. 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.

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

    Directory of Open Access Journals (Sweden)

    Y. Liu

    2013-08-01

    Full Text Available 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.

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

    International Nuclear Information System (INIS)

    Liu, Y.; Wang, F.; Yu, X.L.; Miao, Z.M.; Wang, Z.C.; Chen, Y.; Wang, Y.G.

    2013-01-01

    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

  13. Genetic correlation analysis suggests association between increased self reported sleep duration in adults and schizophrenia and type 2 diabetes

    NARCIS (Netherlands)

    E.M. Byrne (Enda); P.R. Gehrman (Philip); Trzaskowski, M. (Maciej); H.W. Tiemeier (Henning); Pack, A.I. (Allan I.)

    2016-01-01

    textabstractStudy Objectives: We sought to examine how much of the heritability of self-report sleep duration is tagged by common genetic variation in populations of European ancestry and to test if the common variants contributing to sleep duration are also associated with other diseases and

  14. 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

  15. Microsatellite analysis of chloroquine resistance associated alleles and neutral loci reveal genetic structure of Indian Plasmodium falciparum.

    Science.gov (United States)

    Mallick, Prashant K; Sutton, Patrick L; Singh, Ruchi; Singh, Om P; Dash, Aditya P; Singh, Ashok K; Carlton, Jane M; Bhasin, Virendra K

    2013-10-01

    Efforts to control malignant malaria caused by Plasmodium falciparum are hampered by the parasite's acquisition of resistance to antimalarial drugs, e.g., chloroquine. This necessitates evaluating the spread of chloroquine resistance in any malaria-endemic area. India displays highly variable malaria epidemiology and also shares porous international borders with malaria-endemic Southeast Asian countries having multi-drug resistant malaria. Malaria epidemiology in India is believed to be affected by two major factors: high genetic diversity and evolving drug resistance in P. falciparum. How transmission intensity of malaria can influence the genetic structure of chloroquine-resistant P. falciparum population in India is unknown. Here, genetic diversity within and among P. falciparum populations is analyzed with respect to their prevalence and chloroquine resistance observed in 13 different locations in India. Microsatellites developed for P. falciparum, including three putatively neutral and seven microsatellites thought to be under a hitchhiking effect due to chloroquine selection were used. Genetic hitchhiking is observed in five of seven microsatellites flanking the gene responsible for chloroquine resistance. Genetic admixture analysis and F-statistics detected genetically distinct groups in accordance with transmission intensity of different locations and the probable use of chloroquine. A large genetic break between the chloroquine-resistant parasite of the Northeast-East-Island group and Southwest group (FST=0.253, Pstructure for Indian P. falciparum population. Overall, the study suggests that transmission intensity can be an efficient driver for genetic differentiation at both neutral and adaptive loci across India. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. 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 (Jing Hua); 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.J. 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. de 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 (Cornelia); K. Stefansson (Kari); L.A. Cupples (Adrienne); R.J.F. Loos (Ruth); I.E. 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

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

    DEFF Research Database (Denmark)

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

    2017-01-01

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

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

    Science.gov (United States)

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

    2017-06-01

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

  19. 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

    2016-01-01

    DNA damage is an established mediator of carcinogenesis, although genome-wide association studies (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. We conducted a cross-cancer analysis of 60,297 single nucleotide polymorphisms, 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. We identified three susceptibility DNA repair genes, RAD51B (P cancer risk in the base excision repair, nucleotide excision repair, mismatch repair, and homologous recombination pathways. 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. 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. ©2015 American Association for Cancer Research.

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

    Science.gov (United States)

    Bonàs-Guarch, Sílvia; Guindo-Martínez, Marta; Miguel-Escalada, Irene; Grarup, Niels; Sebastian, David; Rodriguez-Fos, Elias; Sánchez, Friman; Planas-Fèlix, Mercè; Cortes-Sánchez, Paula; González, Santi; Timshel, Pascal; Pers, Tune H; Morgan, Claire C; Moran, Ignasi; Atla, Goutham; González, Juan R; Puiggros, Montserrat; Martí, Jonathan; Andersson, Ehm A; Díaz, Carlos; Badia, Rosa M; Udler, Miriam; Leong, Aaron; Kaur, Varindepal; Flannick, Jason; Jørgensen, Torben; Linneberg, Allan; Jørgensen, Marit E; Witte, Daniel R; Christensen, Cramer; Brandslund, Ivan; Appel, Emil V; Scott, Robert A; Luan, Jian'an; Langenberg, Claudia; Wareham, Nicholas J; Pedersen, Oluf; Zorzano, Antonio; Florez, Jose C; Hansen, Torben; Ferrer, Jorge; Mercader, Josep Maria; Torrents, David

    2018-01-22

    The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662057, associated with a twofold increased risk for T2D in males. rs146662057 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches.

  1. Genetic architecture of wood properties based on association analysis and co-expression networks in white spruce.

    Science.gov (United States)

    Lamara, Mebarek; Raherison, Elie; Lenz, Patrick; Beaulieu, Jean; Bousquet, Jean; MacKay, John

    2016-04-01

    Association studies are widely utilized to analyze complex traits but their ability to disclose genetic architectures is often limited by statistical constraints, and functional insights are usually minimal in nonmodel organisms like forest trees. We developed an approach to integrate association mapping results with co-expression networks. We tested single nucleotide polymorphisms (SNPs) in 2652 candidate genes for statistical associations with wood density, stiffness, microfibril angle and ring width in a population of 1694 white spruce trees (Picea glauca). Associations mapping identified 229-292 genes per wood trait using a statistical significance level of P wood associated genes and several known MYB and NAC regulators were identified as network hubs. The network revealed a link between the gene PgNAC8, wood stiffness and microfibril angle, as well as considerable within-season variation for both genetic control of wood traits and gene expression. Trait associations were distributed throughout the network suggesting complex interactions and pleiotropic effects. Our findings indicate that integration of association mapping and co-expression networks enhances our understanding of complex wood traits. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

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

    Science.gov (United States)

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

    2014-01-01

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

  3. Genetic variability, trait association and path analysis of yield and yield components in mungbean (vigna radiata (L.) wilczek)

    International Nuclear Information System (INIS)

    Tabasum, A.; Saleem, M.; Aziz, I.

    2010-01-01

    Genetic variability, heritability along with genetic advance of traits, their association and direct and indirect effects on yield are essential for crop improvement. Ten mungbean genotypes were studied to assess variability and degree to which various plant traits associate with seed yield. Primary and secondary branches, pods per cluster and pod length showed lesser variability while clusters per plant, 100 seed weight and harvest index exhibited intermediate range of variability. Sufficient genetic variability was observed for plant height, pods per plant, total plant weight and seed yield. Moderate to high heritability estimates were found for all traits. Primary and secondary branches per plant, pod length and 100-seed weight exhibited negative and non significant genotypic and phenotypic correlations with seed yield. Plant height showed positive non-significant and significant genotypic and phenotypic correlation. Pods per cluster correlated significantly negative with seed yield. Clusters per plant, pods per plant, total plant weight and harvest index showed positive significant genotypic and phenotypic correlations with seed yield. Positive direct effects were exerted through secondary branches, pods per plant, pod length, 100 seed weight, total plant weight and harvest index while primary branches, plant height, clusters per plant and pods per cluster had negative direct effects. The present findings could be useful for establishing selection criteria for high seed yield in the mungbean breeding. (author)

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

    OpenAIRE

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

    2014-01-01

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

  5. 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

  6. Novel genetic loci associated with hippocampal volume.

    Science.gov (United States)

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

    2017-01-18

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

  7. Genetic relatedness and recombination analysis of Allorhizobium vitis strains associated with grapevine crown gall outbreaks in Europe.

    Science.gov (United States)

    Kuzmanović, N; Biondi, E; Bertaccini, A; Obradović, A

    2015-09-01

    To analyse genetic diversity and epidemiological relationships among 54 strains of Allorhizobium vitis isolated in Europe during an 8-year period and to assess the relative contribution of mutation and recombination in shaping their diversity. By using random amplified polymorphic DNA (RAPD) PCR, strains studied were distributed into 12 genetic groups. Sequence analysis of dnaK, gyrB and recA housekeeping genes was employed to characterize a representative subcollection of 28 strains. A total of 15 different haplotypes were found. Nucleotide sequence analysis suggested the presence of recombination events in A. vitis, particularly affecting dnaK locus. Although prevalence of mutation over recombination was found, impact of recombination was about two times greater than mutation in the evolution of the housekeeping genes analysed. The RAPD analysis indicated high degree of genetic diversity among the strains. However, the most abundant RAPD group was composed of 35 strains, which could lead to the conclusion that they share a common origin and were distributed by the movement of infected grapevine planting material as a most common way of crossing long distances. Furthermore, it seems that recombination is acting as an important driving force in the evolution of A. vitis. As no substantial evidence of recombination was detected within recA gene fragment, this phylogenetic marker could be reliable to characterize phylogenetic relationships among A. vitis strains. We demonstrated clear epidemiological relationship between majority of strains studied, suggesting a need for more stringent phytosanitary measures in international trade. Moreover, this is the first study to report recombination in A. vitis. © 2015 The Society for Applied Microbiology.

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

    Directory of Open Access Journals (Sweden)

    István Monostori

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

  9. 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.

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

    Science.gov (United States)

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

    2015-01-01

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

  11. Genetic analysis of Enterobius vermicularis isolated from a chimpanzee with lethal hemorrhagic colitis and pathology of the associated lesions.

    Science.gov (United States)

    Yaguchi, Yuji; Okabayashi, Sachi; Abe, Niichiro; Masatou, Haruhisa; Iida, Shinya; Teramoto, Isao; Matsubayashi, Makoto; Shibahara, Tomoyuki

    2014-11-01

    Human pinworms, Enterobius vermicularis, are normally recognized as minor pathogens. However, a fatal case of human pinworm infection has been reported in a nonhuman primate, a zoo reared chimpanzee. Here, we histopathologically examined the lesions in tissues from the deceased chimpanzee and genetically characterized the isolated worms to investigate the pathogenicity and determine the phylogeny. We identified ulcers deep in the submucosa where many parasites were found to have invaded the lamina propria mucosa or submucous tissue. An inflammatory reaction consisting mainly of neutrophils and lymphocytes but not eosinophils was observed around the parasites, and intense hemorrhage in the lamina propria was confirmed. The parasites were morphologically similar to E. vermicularis based on the shape of the copulatory spicules. Mitochondrial cytochrome c oxidase subunit 1 gene products were amplified from worm DNA by PCR and were genetically identified as E. vermicularis based on >98.7% similarity of partial sequences. Phylogenetic analysis revealed that the sequences clustered together with other chimpanzee E. vermicularis isolates in a group which has been referred to as type C and which differs from human isolates (type A). The samples were negative for bacterial pathogens and Entamoeba histolytica indicating that E. vermicularis could be pathogenic in chimpanzees. Phylogenetic clustering of the isolates indicated that the parasite may be host specific.

  12. Evidence for genetic factors explaining the association between birth weight and low-density lipoprotein cholesterol and possible intrauterine factors influencing the association between birth weight and high-density lipoprotein cholesterol: Analysis in twins

    NARCIS (Netherlands)

    IJzerman, R.G.; Stehouwer, C.D.A.; van Weissenbruch, M.M.; de Geus, E.J.C.; Boomsma, D.I.

    2001-01-01

    Recent studies have demonstrated an association between low weight at birth and an atherogenic lipid profile in later life. To examine the influences of intrauterine and genetic factors, we investigated 53 dizygotic and 61 monozygotic adolescent twin pairs. Regression analysis demonstrated that low

  13. Evolving temporal association rules with genetic algorithms

    OpenAIRE

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

    2010-01-01

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

  14. Genetic Variations and their Association with Diseases among ...

    African Journals Online (AJOL)

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

  15. 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

    . 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...... for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies....

  16. Construction of the model for the Genetic Analysis Workshop 14 simulated data: genotype-phenotype relationships, gene interaction, linkage, association, disequilibrium, and ascertainment effects for a complex phenotype.

    Science.gov (United States)

    Greenberg, David A; Zhang, Junying; Shmulewitz, Dvora; Strug, Lisa J; Zimmerman, Regina; Singh, Veena; Marathe, Sudhir

    2005-12-30

    The Genetic Analysis Workshop 14 simulated dataset was designed 1) To test the ability to find genes related to a complex disease (such as alcoholism). Such a disease may be given a variety of definitions by different investigators, have associated endophenotypes that are common in the general population, and is likely to be not one disease but a heterogeneous collection of clinically similar, but genetically distinct, entities. 2) To observe the effect on genetic analysis and gene discovery of a complex set of gene x gene interactions. 3) To allow comparison of microsatellite vs. large-scale single-nucleotide polymorphism (SNP) data. 4) To allow testing of association to identify the disease gene and the effect of moderate marker x marker linkage disequilibrium. 5) To observe the effect of different ascertainment/disease definition schemes on the analysis. Data was distributed in two forms. Data distributed to participants contained about 1,000 SNPs and 400 microsatellite markers. Internet-obtainable data consisted of a finer 10,000 SNP map, which also contained data on controls. While disease characteristics and parameters were constant, four "studies" used varying ascertainment schemes based on differing beliefs about disease characteristics. One of the studies contained multiplex two- and three-generation pedigrees with at least four affected members. The simulated disease was a psychiatric condition with many associated behaviors (endophenotypes), almost all of which were genetic in origin. The underlying disease model contained four major genes and two modifier genes. The four major genes interacted with each other to produce three different phenotypes, which were themselves heterogeneous. The population parameters were calibrated so that the major genes could be discovered by linkage analysis in most datasets. The association evidence was more difficult to calibrate but was designed to find statistically significant association in 50% of datasets. We also

  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......Mitochondria play an important role in many processes, like glucose metabolism, fatty acid oxidation and ATP synthesis. In this study, we aimed to identify association of common polymorphisms in nuclear-encoded genes involved in mitochondrial protein synthesis and biogenesis with type II diabetes...

  18. Prenatal and Postnatal Survival of Fetal Tetralogy of Fallot: A Meta-analysis of Perinatal Outcomes and Associated Genetic Disorders.

    Science.gov (United States)

    Zhao, Yili; Abuhamad, Alfred; Fleenor, Jonathan; Guo, Yajun; Zhang, Wangshu; Cao, Danming; Zeng, Shi; Sinkovskaya, Elena; Zhou, Qichang

    2016-05-01

    The aim of this systematic review was to compare the postnatal outcomes, genetic testing results, and sonographic findings in 3 subtypes of tetralogy of Fallot. Thirty-six articles from the MEDLINE and EMBASE databases were selected for this review. The postnatal outcomes, karyotyping results, and sonographic findings of fetal tetralogy of Fallot with pulmonary stenosis, tetralogy of Fallot with pulmonary atresia, and tetralogy of Fallot with an absent pulmonary valve were collected and compared. The survival rates (termination of pregnancy was considered fetal death) for prenatally diagnosed tetralogy of Fallot with pulmonary atresia and tetralogy of Fallot with an absent pulmonary valve at the end of neonatal period were significantly lower than the rate for tetralogy of Fallot with pulmonary stenosis (P tetralogy of Fallot with pulmonary atresia was also lower at birth (P tetralogy of Fallot with pulmonary stenosis (Ptetralogy of Fallot with pulmonary atresia and tetralogy of Fallot with an absent pulmonary valve (P tetralogy of Fallot with pulmonary stenosis, a right aortic arch was more associated with tetralogy of Fallot with pulmonary atresia (32.6%; P tetralogy of Fallot with an absent pulmonary valve (87.5%; P tetralogy of Fallot. Documenting those details at diagnosis can help specialists better counsel their patients. © 2016 by the American Institute of Ultrasound in Medicine.

  19. 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

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

    Science.gov (United States)

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

    2013-10-01

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

  1. Large-scale genomic analysis shows association between homoplastic genetic variation in Mycobacterium tuberculosis genes and meningeal or pulmonary tuberculosis.

    NARCIS (Netherlands)

    Ruesen, Carolien; Chaidir, Lidya; van Laarhoven, Arjan; Dian, Sofiati; Ganiem, Ahmad Rizal; Nebenzahl-Guimaraes, Hanna; Huynen, Martijn A; Alisjahbana, Bachti; Dutilh, Bas E; van Crevel, Reinout

    2018-01-01

    Meningitis is the most severe manifestation of tuberculosis. It is largely unknown why some people develop pulmonary TB (PTB) and others TB meningitis (TBM); we examined if the genetic background of infecting M. tuberculosis strains may be relevant.

  2. Mitochondrial GWA Analysis of Lipid Profile Identifies Genetic Variants to Be Associated with HDL Cholesterol and Triglyceride Levels.

    Directory of Open Access Journals (Sweden)

    Antònia Flaquer

    Full Text Available It has been suggested that mitochondrial dysfunction has an influence on lipid metabolism. The fact that mitochondrial defects can be accumulated over time as a normal part of aging may explain why cholesterol levels often are altered with age. To test the hypothesis whether mitochondrial variants are associated with lipid profile (total cholesterol, LDL, HDL, and triglycerides we analyzed a total number of 978 mitochondrial single nucleotide polymorphisms (mtSNPs in a sample of 2,815 individuals participating in the population-based KORA F4 study. To assess mtSNP association while taking the presence of heteroplasmy into account we used the raw signal intensity values measured on the microarray and applied linear regression. Ten mtSNPs (mt3285, mt3336, mt5285, mt6591, mt6671, mt9163, mt13855, mt13958, mt14000, and mt14580 were significantly associated with HDL cholesterol and one mtSNP (mt15074 with triglycerides levels. These results highlight the importance of the mitochondrial genome among the factors that contribute to the regulation of lipid levels. Focusing on mitochondrial variants may lead to further insights regarding the underlying physiological mechanisms, or even to the development of innovative treatments. Since this is the first mitochondrial genome-wide association analysis (mtGWAS for lipid profile, further analyses are needed to follow up on the present findings.

  3. Rapid Genetic Analysis in Congenital Hyperinsulinism

    DEFF Research Database (Denmark)

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

    2007-01-01

    BACKGROUND: In severe, medically unresponsive congenital hyperinsulinism (CHI), the histological differentiation of focal versus diffuse disease is vital, since the surgical management is completely different. Genetic analysis may help in the differential diagnosis, as focal CHI is associated...... with a paternal germline ABCC8 or KCNJ11 mutation and a focal loss of maternal chromosome 11p15, whereas a maternal mutation, or homozygous/compound heterozygous ABCC8 and KCNJ11 mutations predict diffuse-type disease. However, genotyping usually takes too long to be helpful in the absence of a founder mutation....... 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...

  4. 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 o...... studies on attitudes towards genetic testing as well as in the health care context, e.g. in genetic counselling.......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...

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

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

    2011-11-01

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

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

    Directory of Open Access Journals (Sweden)

    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

  9. 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...

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

    Science.gov (United States)

    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. We evaluated i...

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

    NARCIS (Netherlands)

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

    2013-01-01

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

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

    NARCIS (Netherlands)

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

    2013-01-01

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

  13. 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.

  14. Genetic variants associated with lung function

    DEFF Research Database (Denmark)

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

    2014-01-01

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

  15. Genetic Basis of Variation in Rice Seed Storage Protein (Albumin, Globulin, Prolamin, and Glutelin) Content Revealed by Genome-Wide Association Analysis.

    Science.gov (United States)

    Chen, Pingli; Shen, Zhikang; Ming, Luchang; Li, Yibo; Dan, Wenhan; Lou, Guangming; Peng, Bo; Wu, Bian; Li, Yanhua; Zhao, Da; Gao, Guanjun; Zhang, Qinglu; Xiao, Jinghua; Li, Xianghua; Wang, Gongwei; He, Yuqing

    2018-01-01

    Rice seed storage protein (SSP) is an important source of nutrition and energy. Understanding the genetic basis of SSP content and mining favorable alleles that control it will be helpful for breeding new improved cultivars. An association analysis for SSP content was performed to identify underlying genes using 527 diverse Oryza sativa accessions grown in two environments. We identified more than 107 associations for five different traits, including the contents of albumin (Alb), globulin (Glo), prolamin (Pro), glutelin (Glu), and total SSP (Total). A total of 28 associations were located at previously reported QTLs or intervals. A lead SNP sf0709447538, associated for Glu content in the indica subpopulation in 2015, was further validated in near isogenic lines NIL(Zhenshan97) and NIL(Delong208), and the Glu phenotype had significantly difference between two NILs. The association region could be target for map-based cloning of the candidate genes. There were 13 associations in regions close to grain-quality-related genes; five lead single nucleotide polymorphisms (SNPs) were located less than 20 kb upstream from grain-quality-related genes ( PG5a , Wx , AGPS2a , RP6 , and, RM1 ). Several starch-metabolism-related genes ( AGPS2a , OsACS6 , PUL , GBSSII , and ISA2 ) were also associated with SSP content. We identified favorable alleles of functional candidate genes, such as RP6 , RM1 , Wx , and other four candidate genes by haplotype analysis and expression pattern. Genotypes of RP6 and RM1 with higher Pro were not identified in japonica and exhibited much higher expression levels in indica group. The lead SNP sf0601764762, repeatedly detected for Alb content in 2 years in the whole association population, was located in the Wx locus that controls the synthesis of amylose. And Alb content was significantly and negatively correlated with amylose content and the level of 2.3 kb Wx pre-mRNA examined in this study. The associations or candidate genes identified would

  16. Genetic Basis of Variation in Rice Seed Storage Protein (Albumin, Globulin, Prolamin, and Glutelin Content Revealed by Genome-Wide Association Analysis

    Directory of Open Access Journals (Sweden)

    Pingli Chen

    2018-05-01

    Full Text Available Rice seed storage protein (SSP is an important source of nutrition and energy. Understanding the genetic basis of SSP content and mining favorable alleles that control it will be helpful for breeding new improved cultivars. An association analysis for SSP content was performed to identify underlying genes using 527 diverse Oryza sativa accessions grown in two environments. We identified more than 107 associations for five different traits, including the contents of albumin (Alb, globulin (Glo, prolamin (Pro, glutelin (Glu, and total SSP (Total. A total of 28 associations were located at previously reported QTLs or intervals. A lead SNP sf0709447538, associated for Glu content in the indica subpopulation in 2015, was further validated in near isogenic lines NIL(Zhenshan97 and NIL(Delong208, and the Glu phenotype had significantly difference between two NILs. The association region could be target for map-based cloning of the candidate genes. There were 13 associations in regions close to grain-quality-related genes; five lead single nucleotide polymorphisms (SNPs were located less than 20 kb upstream from grain-quality-related genes (PG5a, Wx, AGPS2a, RP6, and, RM1. Several starch-metabolism-related genes (AGPS2a, OsACS6, PUL, GBSSII, and ISA2 were also associated with SSP content. We identified favorable alleles of functional candidate genes, such as RP6, RM1, Wx, and other four candidate genes by haplotype analysis and expression pattern. Genotypes of RP6 and RM1 with higher Pro were not identified in japonica and exhibited much higher expression levels in indica group. The lead SNP sf0601764762, repeatedly detected for Alb content in 2 years in the whole association population, was located in the Wx locus that controls the synthesis of amylose. And Alb content was significantly and negatively correlated with amylose content and the level of 2.3 kb Wx pre-mRNA examined in this study. The associations or candidate genes identified would provide

  17. Genetic Association Analysis of Fasting and 1- and 2-Hour Glucose Tolerance Test Data Using a Generalized Index of Dissimilarity Measure for the Korean Population

    Directory of Open Access Journals (Sweden)

    Jaeyong Yee

    2016-12-01

    Full Text Available Glucose tolerance tests have been devised to determine the speed of blood glucose clearance. Diabetes is often tested with the standard oral glucose tolerance test (OGTT, along with fasting glucose level. However, no single test may be sufficient for the diagnosis, and the World Health Organization (WHO/International Diabetes Federation (IDF has suggested composite criteria. Accordingly, a single multi-class trait was constructed with three of the fasting phenotypes and 1- and 2-hour OGTT phenotypes from the Korean Association Resource (KARE project, and the genetic association was investigated. All of the 18 possible combinations made out of the 3 sets of classification for the individual phenotypes were taken into our analysis. These were possible due to a method that was recently developed by us for estimating genomic associations using a generalized index of dissimilarity. Eight single-nucleotide polymorphisms (SNPs that were found to have the strongest main effect are reported with the corresponding genes. Four of them conform to previous reports, located in the CDKAL1 gene, while the other 4 SNPs are new findings. Two-order interacting SNP pairs of are also presented. One pair (rs2328549 and rs6486740 has a prominent association, where the two single-nucleotide polymorphism locations are CDKAL1 and GLT1D1. The latter has not been found to have a strong main effect. New findings may result from the proper construction and analysis of a composite trait.

  18. 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. Copyright © 2015 Elsevier Inc. All rights reserved.

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

    DEFF Research Database (Denmark)

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

    2016-01-01

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

  20. Human MTHFR-G1793A transition may be a protective mutation against male infertility: a genetic association study and in silico analysis.

    Science.gov (United States)

    Karimian, Mohammad; Hosseinzadeh Colagar, Abasalt

    2018-06-01

    In this paper, we evaluate the association of the human methylenetetrahydrofolate reductase (MTHFR)-G1793A transition with male infertility using a case-control study, a meta-analysis and an in silico analysis. In the case-control study, 308 blood samples (169 infertile and 139 fertile men) were collected. MTHFR-G1793A genotyping was performed by PCR-RFLP. The study revealed a significant protective association between the GA genotype (OR: 0.3737, 95%CI: 0.1874-0.7452, p = 0.0052) and A allele (OR: 0.4266, 95%CI: 0.2267-0.8030, p = 0.0083) with male infertility. Meta-analysis showed that the G1793A transition might be a protective mutation against male infertility in both A vs. G (OR: 0.608, 95%CI: 0.466-0.792, p silico-analysis revealed that although G1793A could not make fundamental changes in the function and structure of MTHFR, it could modify the structure of the mRNA (Distance =0.1809, p = 0.1095; p < 0.2 is significant). The results suggest that G1793A substitution might be a protective genetic factor against male infertility. However, further case-control studies are required to provide a more robust conclusion.

  1. Arthritis Genetics Analysis Aids Drug Discovery

    Science.gov (United States)

    ... NIH Research Matters January 13, 2014 Arthritis Genetics Analysis Aids Drug Discovery An international research team identified 42 new ... Edition Distracted Driving Raises Crash Risk Arthritis Genetics Analysis Aids Drug Discovery Oxytocin Affects Facial Recognition Connect with Us ...

  2. 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 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.

  3. 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 < 0.001) between ssrOeUA-DCA14 and stearic acid and between GAPU71B and oleic acid indicated that these markers could be used for marker-assisted selection in olive.

  4. Genetic analysis and identification of SSR markers associated with rice blast disease in a BC2F1 backcross population.

    Science.gov (United States)

    Hasan, N; Rafii, M Y; Abdul Rahim, H; Nusaibah, S A; Mazlan, N; Abdullah, S

    2017-01-23

    Rice (Oryza sativa L.) blast disease is one of the most destructive rice diseases in the world. The fungal pathogen, Magnaporthe oryzae, is the causal agent of rice blast disease. Development of resistant cultivars is the most preferred method to achieve sustainable rice production. However, the effectiveness of resistant cultivars is hindered by the genetic plasticity of the pathogen genome. Therefore, information on genetic resistance and virulence stability are vital to increase our understanding of the molecular basis of blast disease resistance. The present study set out to elucidate the resistance pattern and identify potential simple sequence repeat markers linked with rice blast disease. A backcross population (BC 2 F 1 ), derived from crossing MR264 and Pongsu Seribu 2 (PS2), was developed using marker-assisted backcross breeding. Twelve microsatellite markers carrying the blast resistance gene clearly demonstrated a polymorphic pattern between both parental lines. Among these, two markers, RM206 and RM5961, located on chromosome 11 exhibited the expected 1:1 testcross ratio in the BC 2 F 1 population. The 195 BC 2 F 1 plants inoculated against M. oryzae pathotype P7.2 showed a significantly different distribution in the backcrossed generation and followed Mendelian segregation based on a single-gene model. This indicates that blast resistance in PS2 is governed by a single dominant gene, which is linked to RM206 and RM5961 on chromosome 11. The findings presented in this study could be useful for future blast resistance studies in rice breeding programs.

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

    Directory of Open Access Journals (Sweden)

    Elizabeth G Holliday

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

  6. 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.

  7. 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

  8. 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. Copyright © 2016 John Wiley & Sons, Ltd.

  9. 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

  10. Biological annotation of genetic loci associated with intelligence in a meta-analysis of 87,740 individuals

    NARCIS (Netherlands)

    Coleman, Jonathan R.I.; Bryois, Julien; Gaspar, Héléna A.; Jansen, Philip R.; Savage, Jeanne E.; Skene, Nathan; Plomin, Robert; Muñoz-Manchado, Ana B.; Linnarsson, Sten; Crawford, Greg; Hjerling-Leffler, Jens; Sullivan, Patrick F.; Posthuma, Danielle; Breen, Gerome

    2018-01-01

    Variance in IQ is associated with a wide range of health outcomes, and 1% of the population are affected by intellectual disability. Despite a century of research, the fundamental neural underpinnings of intelligence remain unclear. We integrate results from genome-wide association studies (GWAS) of

  11. 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 ischemic 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 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. PMID:24619398

  12. 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

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

    Science.gov (United States)

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

    2014-01-01

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

  14. Novel genetic loci associated with hippocampal volume

    OpenAIRE

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

    2017-01-01

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

  15. Biological annotation of genetic loci associated with intelligence in a meta-analysis of 87,740 individuals.

    Science.gov (United States)

    Coleman, Jonathan R I; Bryois, Julien; Gaspar, Héléna A; Jansen, Philip R; Savage, Jeanne E; Skene, Nathan; Plomin, Robert; Muñoz-Manchado, Ana B; Linnarsson, Sten; Crawford, Greg; Hjerling-Leffler, Jens; Sullivan, Patrick F; Posthuma, Danielle; Breen, Gerome

    2018-03-08

    Variance in IQ is associated with a wide range of health outcomes, and 1% of the population are affected by intellectual disability. Despite a century of research, the fundamental neural underpinnings of intelligence remain unclear. We integrate results from genome-wide association studies (GWAS) of intelligence with brain tissue and single cell gene expression data to identify tissues and cell types associated with intelligence. GWAS data for IQ (N = 78,308) were meta-analyzed with a study comparing 1247 individuals with mean IQ ~170 to 8185 controls. Genes associated with intelligence implicate pyramidal neurons of the somatosensory cortex and CA1 region of the hippocampus, and midbrain embryonic GABAergic neurons. Tissue-specific analyses find the most significant enrichment for frontal cortex brain expressed genes. These results suggest specific neuronal cell types and genes may be involved in intelligence and provide new hypotheses for neuroscience experiments using model systems.

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

    NARCIS (Netherlands)

    Mckay, James D.; Hung, Rayjean J; Han, Younghun; Zong, Xuchen; Carreras-Torres, Robert; Christiani, David C.; Caporaso, Neil E.; Johansson, Mattias; Xiao, Xiangjun; Li, Yafang; Byun, Jinyoung; Dunning, Alison; Pooley, Karen A.; Qian, David C.; Ji, Xuemei; Liu, Geoffrey; Timofeeva, Maria N.; Bojesen, Stig E.; Wu, Xifeng; Le Marchand, Loic; Albanes, Demetrios; Bickeboeller, Heike; Aldrich, Melinda C.; Bush, William S.; Tardon, Adonina; Rennert, Gad; Teare, M. Dawn; Field, John K.; Kiemeney, Lambertus A.; Lazarus, Philip; Haugen, Aage; Lam, Stephen; Schabath, Matthew B.; Andrew, Angeline S.; Shen, Hongbing; Hong, Yun-Chul; Yuan, Jian-Min; Bertazzi, Pier Alberto; Pesatori, Angela C.; Ye, Yuanqing; Diao, Nancy; Su, Li; Zhang, Ruyang; Brhane, Yonathan; Leighl, Natasha; Johansen, Jakob S.; Mellemgaard, Anders; Saliba, Walid; Marcus, Michael W.; Timens, Wim

    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

  17. An analysis of the genetic diversity and genetic structure of ...

    African Journals Online (AJOL)

    Scientific approaches to conservation of threatened species depend on a good understanding of the genetic information of wild and artificial population. The genetic diversity and structure analysis of 10 Eucommia ulmoides population was analyzed using inter-simple sequence repeat (ISSR) markers in this paper.

  18. 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 genome-wide association ...... receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer....

  19. Preimplantation genetic diagnosis associated to Duchenne muscular dystrophy.

    Science.gov (United States)

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

    2017-01-01

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

  20. Statistically Derived Subtypes and Associations with Cerebrospinal Fluid and Genetic Biomarkers in Mild Cognitive Impairment: A Latent Profile Analysis.

    Science.gov (United States)

    Eppig, Joel S; Edmonds, Emily C; Campbell, Laura; Sanderson-Cimino, Mark; Delano-Wood, Lisa; Bondi, Mark W

    2017-08-01

    Research demonstrates heterogeneous neuropsychological profiles among individuals with mild cognitive impairment (MCI). However, few studies have included visuoconstructional ability or used latent mixture modeling to statistically identify MCI subtypes. Therefore, we examined whether unique neuropsychological MCI profiles could be ascertained using latent profile analysis (LPA), and subsequently investigated cerebrospinal fluid (CSF) biomarkers, genotype, and longitudinal clinical outcomes between the empirically derived classes. A total of 806 participants diagnosed by means of the Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI criteria received a comprehensive neuropsychological battery assessing visuoconstructional ability, language, attention/executive function, and episodic memory. Test scores were adjusted for demographic characteristics using standardized regression coefficients based on "robust" normal control performance (n=260). Calculated Z-scores were subsequently used in the LPA, and CSF-derived biomarkers, genotype, and longitudinal clinical outcome were evaluated between the LPA-derived MCI classes. Statistical fit indices suggested a 3-class model was the optimal LPA solution. The three-class LPA consisted of a mixed impairment MCI class (n=106), an amnestic MCI class (n=455), and an LPA-derived normal class (n=245). Additionally, the amnestic and mixed classes were more likely to be apolipoprotein e4+ and have worse Alzheimer's disease CSF biomarkers than LPA-derived normal subjects. Our study supports significant heterogeneity in MCI neuropsychological profiles using LPA and extends prior work (Edmonds et al., 2015) by demonstrating a lower rate of progression in the approximately one-third of ADNI MCI individuals who may represent "false-positive" diagnoses. Our results underscore the importance of using sensitive, actuarial methods for diagnosing MCI, as current diagnostic methods may be over-inclusive. (JINS, 2017, 23, 564-576).

  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, Anto 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...

  2. 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 ...

  3. The Analysis of Polyploid Genetic Data

    NARCIS (Netherlands)

    Meirmans, P.G.; Liu, S.; van Tienderen, P.H.

    2018-01-01

    Though polyploidy is an important aspect of the evolutionary genetics of both plants and animals, the development of population genetic theory of polyploids has seriously lagged behind that of diploids. This is unfortunate since the analysis of polyploid genetic data—and the interpretation of the

  4. SOX10 mutation causes Waardenburg syndrome associated with distinctive phenotypic features in an Iranian family: A clue for phenotype-directed genetic analysis.

    Science.gov (United States)

    Jalilian, Nazanin; Tabatabaiefar, Mohammad Amin; Alimadadi, Hossein; Noori-Daloii, Mohammad Reza

    2017-05-01

    Waardenburg syndrome (WS) is a neurocristopathy characterized by hearing impairment and pigmentary disturbances in hair, eyes, and skin. WS is clinically heterogeneous and can be subdivided into four major types (WS1-WS4) where WS4 or Shah-Waardenburg is diagnosed when WS2 is accompanied by Hirschsprung disease (HD). Mutations of SOX10, EDN3/EDNRB have been identified in association with WS4. This study was aimed to determine the pathogenic variant in an Iranian pedigree affected with WS4. A two-generation pedigree with three affected members and considerable phenotypic heterogeneity was recruited. The proband was a 15-year-old boy, with severe to profound sensorineural hearing impairment, heterochromia iridis, hypoplastic blue eyes and Hirschprung disease. The other two also presented characteristics of WS2 and complained of chronic constipation with normal anorectal reflex. Sequencing of all exons and exon-intron boundaries of SOX10, EDN3/EDNRB revealed a heterozygous variant c.422T > C in exon 3 of SOX10 confirmed by a series of evidence to be pathogenic. It resulted in p.L141P at the protein level. Leucin 141 is located in Nuclear Export signal, HMG box of the protein. This study is the first report of a WS4 family in the Iranian population. The mutation is associated with distinctive phenotypic profile (association of anosmia and chronic constipation with SOX10 mutations) and could further improve diagnosis and counseling of WS in the Iranian population and can contribute to phenotype-directed genetic analysis. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. 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.J. 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 (David); N. Amin (Najaf); P. Amouyel (Philippe); A.A. Assareh; R. Au; J.T. Becker (James); 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); 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); 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

  6. RESEARCH NOTE Molecular genetic analysis of consanguineous ...

    Indian Academy of Sciences (India)

    Navya

    Molecular genetic analysis of consanguineous families with primary microcephaly ... Translational Research Institute, Academic Health System, Hamad Medical ..... bridging the gap between homozygosity mapping and deep sequencing.

  7. 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.

  8. Genetic Variants Associated with Circulating Parathyroid Hormone.

    Science.gov (United States)

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

    2017-05-01

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

  9. Significant differences in gene expression and key genetic components associated with high growth vigor in populus section tacamahaca as revealed by comparative transcriptome analysis

    International Nuclear Information System (INIS)

    Cheng, S.; Chen, M.; Li, Y.; Wang, J.; Sun, X.; Wang, J.

    2017-01-01

    To identify genetic components involved in high growth vigor in F1 Populus section Tacamahaca hybrid plants, high and low vigor plants showing significant differences in apical dominance during a rapid growth period were selected. Apical bud transcriptomes of high and low-growth-vigor hybrids and their parents were analyzed using high-throughput RNA sequencing on an Illumina HiSeq 2000 platform. A total of 5,542 genes were differently expressed between high growth vigor hybrid and its parents, the genes were significantly enriched in pathways related to processes such as photosynthesis, pyrimidine ribonucleotide biosynthetic processes and nucleoside metabolic processes. There were 1410 differentially expressed genes between high and low growth vigor hybrid, the genes were mainly involved in photosynthesis, chlorophyll biosynthetic process, carbon fixation in photosynthetic organisms, porphyrin and chlorophyll metabolism and nitrogen metabolism. Moreover, a k-core of a gene co-expression network analysis was performed to identify the potential functions of genes related to high growth vigor. The functions of 8 selected candidate genes were associated mainly with circadian rhythm, water transport, cellulose catabolic processes, sucrose biosynthesis, pyrimidine ribonucleotide biosynthesis, purine nucleotide biosynthesis, meristem maintenance, and carbohydrate metabolism. Our results may contribute to a better understanding of the molecular basis of high growth vigor in hybrids and its regulation. (author)

  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. 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.

  12. Genetic analysis of oocyte and embryo production traits in Guzerá breed donors and their associations with age at first calving.

    Science.gov (United States)

    Perez, B C; Peixoto, M G C D; Bruneli, F T; Ramos, P V B; Balieiro, J C C

    2016-04-26

    The objective of this study was to estimate variance components for oocyte and embryo production traits in Guzerá breed female donors, and investigate their associations with age at first calving (AFC). The traits analyzed were the number of viable oocytes (NOV), the number of grade I oocytes (NGI), the number of cleaved embryos (NCLV), and viable embryos produced (NEMB), and the percentages of viable oocytes (POV), grade I oocytes (PGI), cleaved embryos (PCLV), and viable embryos (PEMB). Data were obtained from 5173 ovary puncture and in vitro fertilization (IVF) sessions using 1080 Guzerá female donors of different ages, occurred from March 2005 to July 2013. Variables were log-transformed (logeX+1) prior to analysis. (Co)variance components were estimated by restricted maximum likelihood (REML), using one- and two-trait animal models. Permanent environment and IVF sire (father of the embryos) random effects were included. Estimated heritabilities for NOV, NGI, NCLV, NEMB, POV, PGI, PCLV, and PEMB were 0.19, 0.08, 0.16, 0.14, 0.04, 0.03, 0.01, and 0.07, respectively. Repeatabilities for count traits (NOV, NGI, NCLV, and NEMB) varied from 0.14 and 0.32, higher than estimated for percentage traits (POV, PGI, PCLV, and PEMB), which varied from 0.01 to 0.08. Selection for NOV may be more appropriate in breeding programs than selection for NEMB, because of its strong genetic correlation (0.68) with NEMB and its greater time- and cost-effectiveness. AFC was only weakly associated with the oocyte and embryo production traits, which indicates that there would be no effect on AFC when selecting for these traits.

  13. 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.

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

    OpenAIRE

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

    2017-01-01

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

  15. Disease-Concordant Twins Empower Genetic Association Studies

    DEFF Research Database (Denmark)

    Tan, Qihua; Li, Weilong; Vandin, Fabio

    2017-01-01

    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...... 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...... 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...

  16. Signature of genetic associations in oral cancer.

    Science.gov (United States)

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

    2017-10-01

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

  17. 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......-Fc1 locus (p = 0.003), while primary progressive disease was not. The ability to see genetic differences between subtypes of MS near this gene speaks for the involvement of the virus HERV-Fc1 locus in modifying the disease course of MS....

  18. Genetic analysis of Schizosaccharomyces pombe

    DEFF Research Database (Denmark)

    Ekwall, Karl; Thon, Genevieve

    2017-01-01

    In this introduction we discuss some basic genetic tools and techniques that are used with the fission yeast Schizosaccharomyces pombe. Genes commonly used for selection or as reporters are discussed, with an emphasis on genes that permit counterselection, intragenic complementation, or colony......-color assays. S. pombe is most stable as a haploid organism. We describe its mating-type system, how to perform genetic crosses and methods for selecting and propagating diploids. We discuss the relative merits of tetrad dissection and random spore preparation in strain construction and genetic analyses...

  19. 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)

  20. 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.

  1. Analysis of genetic diversity inpigeonpeagermplasm using ...

    Indian Academy of Sciences (India)

    Navya

    2016-11-25

    Nov 25, 2016 ... accessions from Orissa (105) and AP (15) do not group with any Indian accessions. ... In the present work, comparison between SSAP and REMAP revealed ... (sequence-specific amplified polymorphism) for genetic analysis of sweet potato. ... Sharma,V.and Nandinemi, M.R. 2014 Assessment of genetic ...

  2. '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.

  3. Developments in statistical analysis in quantitative genetics

    DEFF Research Database (Denmark)

    Sorensen, Daniel

    2009-01-01

    of genetic means and variances, models for the analysis of categorical and count data, the statistical genetics of a model postulating that environmental variance is partly under genetic control, and a short discussion of models that incorporate massive genetic marker information. We provide an overview......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 by Markov chain Monte Carlo (McMC). In this overview a number of specific areas are chosen to illustrate the enormous flexibility that McMC has provided for fitting models and exploring features of data that were previously inaccessible. The selected areas are inferences of the trajectories over time...

  4. The Analysis of Polyploid Genetic Data.

    Science.gov (United States)

    Meirmans, Patrick G; Liu, Shenglin; van Tienderen, Peter H

    2018-03-16

    Though polyploidy is an important aspect of the evolutionary genetics of both plants and animals, the development of population genetic theory of polyploids has seriously lagged behind that of diploids. This is unfortunate since the analysis of polyploid genetic data-and the interpretation of the results-requires even more scrutiny than with diploid data. This is because of several polyploidy-specific complications in segregation and genotyping such as tetrasomy, double reduction, and missing dosage information. Here, we review the theoretical and statistical aspects of the population genetics of polyploids. We discuss several widely used types of inferences, including genetic diversity, Hardy-Weinberg equilibrium, population differentiation, genetic distance, and detecting population structure. For each, we point out how the statistical approach, expected result, and interpretation differ between different ploidy levels. We also discuss for each type of inference what biases may arise from the polyploid-specific complications and how these biases can be overcome. From our overview, it is clear that the statistical toolbox that is available for the analysis of genetic data is flexible and still expanding. Modern sequencing techniques will soon be able to overcome some of the current limitations to the analysis of polyploid data, though the techniques are lagging behind those available for diploids. Furthermore, the availability of more data may aggravate the biases that can arise, and increase the risk of false inferences. Therefore, simulations such as we used throughout this review are an important tool to verify the results of analyses of polyploid genetic data.

  5. Genetic analysis in Bartter syndrome from India.

    Science.gov (United States)

    Sharma, Pradeep Kumar; Saikia, Bhaskar; Sharma, Rachna; Ankur, Kumar; Khilnani, Praveen; Aggarwal, Vinay Kumar; Cheong, Hae

    2014-10-01

    Bartter syndrome is a group of inherited, salt-losing tubulopathies presenting as hypokalemic metabolic alkalosis with normotensive hyperreninemia and hyperaldosteronism. Around 150 cases have been reported in literature till now. Mutations leading to salt losing tubulopathies are not routinely tested in Indian population. The authors have done the genetic analysis for the first time in the Bartter syndrome on two cases from India. First case was antenatal Bartter syndrome presenting with massive polyuria and hyperkalemia. Mutational analysis revealed compound heterozygous mutations in KCNJ1(ROMK) gene [p(Leu220Phe), p(Thr191Pro)]. Second case had a phenotypic presentation of classical Bartter syndrome however, genetic analysis revealed only heterozygous novel mutation in SLC12A gene p(Ala232Thr). Bartter syndrome is a clinical diagnosis and genetic analysis is recommended for prognostication and genetic counseling.

  6. 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.

  7. Genome-wide analysis in UK Biobank identifies four loci associated with mood instability and genetic correlation with major depressive disorder, anxiety disorder and schizophrenia.

    Science.gov (United States)

    Ward, Joey; Strawbridge, Rona J; Bailey, Mark E S; Graham, Nicholas; Ferguson, Amy; Lyall, Donald M; Cullen, Breda; Pidgeon, Laura M; Cavanagh, Jonathan; Mackay, Daniel F; Pell, Jill P; O'Donovan, Michael; Escott-Price, Valentina; Smith, Daniel J

    2017-11-30

    Mood instability is a core clinical feature of affective and psychotic disorders. In keeping with the Research Domain Criteria approach, it may be a useful construct for identifying biology that cuts across psychiatric categories. We aimed to investigate the biological validity of a simple measure of mood instability and evaluate its genetic relationship with several psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD), schizophrenia, attention deficit hyperactivity disorder (ADHD), anxiety disorder and post-traumatic stress disorder (PTSD). We conducted a genome-wide association study (GWAS) of mood instability in 53,525 cases and 60,443 controls from UK Biobank, identifying four independently associated loci (on chromosomes 8, 9, 14 and 18), and a common single-nucleotide polymorphism (SNP)-based heritability estimate of ~8%. We found a strong genetic correlation between mood instability and MDD (r g  = 0.60, SE = 0.07, p = 8.95 × 10 -17 ) and a small but significant genetic correlation with both schizophrenia (r g  = 0.11, SE = 0.04, p = 0.01) and anxiety disorders (r g  = 0.28, SE = 0.14, p = 0.04), although no genetic correlation with BD, ADHD or PTSD was observed. Several genes at the associated loci may have a role in mood instability, including the DCC netrin 1 receptor (DCC) gene, eukaryotic translation initiation factor 2B subunit beta (eIF2B2), placental growth factor (PGF) and protein tyrosine phosphatase, receptor type D (PTPRD). Strengths of this study include the very large sample size, but our measure of mood instability may be limited by the use of a single question. Overall, this work suggests a polygenic basis for mood instability. This simple measure can be obtained in very large samples; our findings suggest that doing so may offer the opportunity to illuminate the fundamental biology of mood regulation.

  8. Genetic variants of SLC11A1 are associated with both autoimmune and infectious diseases: systematic review and meta-analysis.

    Science.gov (United States)

    Archer, N S; Nassif, N T; O'Brien, B A

    2015-06-01

    A systematic review and meta-analyses were undertaken to investigate the association of SLC11A1 genetic variants with disease occurrence. Literature searching indentified 109 publications to include in the meta-analyses assessing the association of 11 SLC11A1 variants with autoimmune and infectious disease. The (GT)n promoter alleles 2 and 3 (rs534448891), which alter SLC11A1 expression, were significantly associated with tuberculosis (OR=1.47 (1.30-1.66), OR=0.76 (0.65-0.89), respectively) and infectious disease (OR=1.25 (1.10-1.42), OR=0.83 (0.74-0.93), respectively). However, although no association was observed with autoimmune disease, a modest significant association was observed with type 1 diabetes (allele 2 OR=0.94 (0.89-0.98)). On the basis of a stronger association of (GT)n allele 2 with tuberculosis, compared with the protective effect of allele 3, we hypothesise that allele 2 is likely the disease-causing variant influencing disease susceptibility. Significant associations were observed between the 469+14G/C polymorphism (rs3731865) and autoimmune disease (OR=1.30 (1.04-1.64)) and rheumatoid arthritis (OR=1.60 (1.20-2.13)) and between the -237C/T polymorphism (rs7573065) and inflammatory bowel disease (OR=0.60 (0.43-0.84)). Further, significant associations were identified between the 469+14G/C, 1730G/A and 1729+55del4 polymorphisms (rs3731865, rs17235409 and rs17235416, respectively) and both infectious disease per se and tuberculosis. These findings show a clear association between variants in the SLC11A1 locus and autoimmune and infectious disease susceptibility.

  9. 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....... The Bayesian method is able to include prior information on both concordance rates and prevalence rates at the same time and is illustrated using twin data on cleft lip and rheumatoid arthritis....

  10. A roadmap for the genetic analysis of renal aging

    Science.gov (United States)

    Noordmans, Gerda A; Hillebrands, Jan-Luuk; van Goor, Harry; Korstanje, Ron

    2015-01-01

    Several studies show evidence for the genetic basis of renal disease, which renders some individuals more prone than others to accelerated renal aging. Studying the genetics of renal aging can help us to identify genes involved in this process and to unravel the underlying pathways. First, this opinion article will give an overview of the phenotypes that can be observed in age-related kidney disease. Accurate phenotyping is essential in performing genetic analysis. For kidney aging, this could include both functional and structural changes. Subsequently, this article reviews the studies that report on candidate genes associated with renal aging in humans and mice. Several loci or candidate genes have been found associated with kidney disease, but identification of the specific genetic variants involved has proven to be difficult. CUBN, UMOD, and SHROOM3 were identified by human GWAS as being associated with albuminuria, kidney function, and chronic kidney disease (CKD). These are promising examples of genes that could be involved in renal aging, and were further mechanistically evaluated in animal models. Eventually, we will provide approaches for performing genetic analysis. We should leverage the power of mouse models, as testing in humans is limited. Mouse and other animal models can be used to explain the underlying biological mechanisms of genes and loci identified by human GWAS. Furthermore, mouse models can be used to identify genetic variants associated with age-associated histological changes, of which Far2, Wisp2, and Esrrg are examples. A new outbred mouse population with high genetic diversity will facilitate the identification of genes associated with renal aging by enabling high-resolution genetic mapping while also allowing the control of environmental factors, and by enabling access to renal tissues at specific time points for histology, proteomics, and gene expression. PMID:26219736

  11. A roadmap for the genetic analysis of renal aging.

    Science.gov (United States)

    Noordmans, Gerda A; Hillebrands, Jan-Luuk; van Goor, Harry; Korstanje, Ron

    2015-10-01

    Several studies show evidence for the genetic basis of renal disease, which renders some individuals more prone than others to accelerated renal aging. Studying the genetics of renal aging can help us to identify genes involved in this process and to unravel the underlying pathways. First, this opinion article will give an overview of the phenotypes that can be observed in age-related kidney disease. Accurate phenotyping is essential in performing genetic analysis. For kidney aging, this could include both functional and structural changes. Subsequently, this article reviews the studies that report on candidate genes associated with renal aging in humans and mice. Several loci or candidate genes have been found associated with kidney disease, but identification of the specific genetic variants involved has proven to be difficult. CUBN, UMOD, and SHROOM3 were identified by human GWAS as being associated with albuminuria, kidney function, and chronic kidney disease (CKD). These are promising examples of genes that could be involved in renal aging, and were further mechanistically evaluated in animal models. Eventually, we will provide approaches for performing genetic analysis. We should leverage the power of mouse models, as testing in humans is limited. Mouse and other animal models can be used to explain the underlying biological mechanisms of genes and loci identified by human GWAS. Furthermore, mouse models can be used to identify genetic variants associated with age-associated histological changes, of which Far2, Wisp2, and Esrrg are examples. A new outbred mouse population with high genetic diversity will facilitate the identification of genes associated with renal aging by enabling high-resolution genetic mapping while also allowing the control of environmental factors, and by enabling access to renal tissues at specific time points for histology, proteomics, and gene expression. © 2015 The Authors. Aging Cell published by the Anatomical Society and John

  12. 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.

  13. Genetic analysis of Mexican Criollo cattle populations.

    Science.gov (United States)

    Ulloa-Arvizu, R; Gayosso-Vázquez, A; Ramos-Kuri, M; Estrada, F J; Montaño, M; Alonso, R A

    2008-10-01

    The objective of this study was to evaluate the genetic structure of Mexican Criollo cattle populations using microsatellite genetic markers. DNA samples were collected from 168 animals from four Mexican Criollo cattle populations, geographically isolated in remote areas of Sierra Madre Occidental (West Highlands). Also were included samples from two breeds with Iberian origin: the fighting bull (n = 24) and the milking central American Criollo (n = 24) and one Asiatic breed: Guzerat (n = 32). Genetic analysis consisted of the estimation of the genetic diversity in each population by the allele number and the average expected heterozygosity found in nine microsatellite loci. Furthermore, genetic relationships among the populations were defined by their genetic distances. Our data shows that Mexican cattle populations have a relatively high level of genetic diversity based either on the mean number of alleles (10.2-13.6) and on the expected heterozygosity (0.71-0.85). The degree of observed homozygosity within the Criollo populations was remarkable and probably caused by inbreeding (reduced effective population size) possibly due to reproductive structure within populations. Our data shows that considerable genetic differentiation has been occurred among the Criollo cattle populations in different regions of Mexico.

  14. A systematic review and meta-analysis of genetic association studies for the role of inflammation and the immune system in diabetic nephropathy

    Science.gov (United States)

    Tziastoudi, Maria; Hadjigeorgiou, Georgios M.; Stravodimos, Konstantinos; Zintzaras, Elias

    2017-01-01

    Abstract Background: Despite the certain contribution of metabolic and haemodynamic factors in diabetic nephropathy (DN), many lines of evidence highlight the role of immunologic and inflammatory mechanisms. To elucidate the contribution of the immune system in the development of DN, we explored the contribution of gene variants (polymorphisms) in relevant pathophysiologic pathways. Methods: We selected six major pathways related to immune response from the Kyoto Encyclopaedia of Genes and Genomes database and thereafter we traced all available genetic association studies (GASs) involving gene variants in these pathways from PubMed and HuGE Navigator. Finally, we used meta-analytic methods for synthesizing the results of the GASs. Results: One hundred three GASs were retrieved that included 443 variants from 75 genes. Of those variants, 138 were meta-analysed and 61 produced significant results; seven variants were investigated in single GASs and showed significant association. Variants in CCL2, CCR5, IL6, IL8, EPO, IL1A, IL1B, IL100, IL1RN, GHRL, MMP9, TGFB1, VEGFA, MMP3, MMP12, IL12RB1, PRKCE, TNF and TNFRSF19 genes were associated with an increased risk of DN. Conclusions: There is evidence that variants related with immunologic response affect the course of DN. However, the present results should be interpreted with caution since the current number of available GASs is limited. PMID:28616206

  15. Genetic divergence analysis in pumpkin

    International Nuclear Information System (INIS)

    Quamruzzaman, A.M.; Moniruzzaman, M.

    2013-01-01

    Genetic divergence among 18 punpkin genotypes was estimated using Mahalanohis's 1) statistic. Altogether lour clusters were formed where cluster I contained the highest number of genotypes (8) and cluster II contained the lowest (I). The highest intra-cluster distance was observed h.ir cluster I (0.83 I) and the lowest for clustcr IV (0.65 I). The highest inter-cluster distance was observed between cluster I and 11(24.346). Cluster II recorded the highest mean for fruit number/plant, TSS, fruit yield and niinitnuiii III cavity length and cavity diameter. Cluster III had the second highest mean for fruit diameter, fruit number/plant, individual unit weight, fruit yield and the fewest number of days to 1st Female flowering, earliness being a desirable trait. These crosses may produce new recombinants with desirable traits. (author)

  16. 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 (Lucija); 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); L.T. Strike (Lachlan); 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.J. 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.J. Ames (David); Amouyel, P. (Philippe); O.A. Andreassen (Ole); S. Arepalli (Sampath); A.A. Assareh; S. Barral (Sandra); M.E. Bastin (Mark); Becker, D.M. (Diane M.); J.T. Becker (James); 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 (René); 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 (Marcella); 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 (Cornelia); 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

  17. 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; 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, 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

  18. Celiac disease : moving from genetic associations to causal variants

    NARCIS (Netherlands)

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

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

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

    OpenAIRE

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

    2015-01-01

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

  20. 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

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

    DEFF Research Database (Denmark)

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

    2014-01-01

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

  2. 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.

  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; et al.,

    2011-01-01

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

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

    NARCIS (Netherlands)

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

    2011-01-01

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

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

    Science.gov (United States)

    Benson, Jacqueline M; Poland, Jesse A; Benson, Brent M; Stromberg, Erik L; Nelson, Rebecca J

    2015-03-01

    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 facilitate the

  6. 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

  7. 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.

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

    Science.gov (United States)

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

    2016-08-01

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

  9. Genetic diversity analysis of pearl millet ( Pennisetum glauccum [L ...

    African Journals Online (AJOL)

    between genotype PT 2835/1 and PT 5552 and lowest similarity index was observed between PT 5554 and PT 2835/1. Analysis of RAPD data appears to be helpful in determining the genetic relationship among 20 pearl millet genotypes. The associations among the 20 genotypes were also examined with Principle ...

  10. 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....

  11. 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 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.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.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 cumulative number of risk alleles was significantly

  12. 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

  13. 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.

  14. Genetic Variants of CD209 Associated with Kawasaki Disease Susceptibility

    Science.gov (United States)

    Kuo, Ho-Chang; Huang, Ying-Hsien; Chien, Shu-Chen; Yu, Hong-Ren; Hsieh, Kai-Sheng; Hsu, Yu-Wen; Chang, Wei-Chiao

    2014-01-01

    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. PMID:25148534

  15. 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...

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

    Indian Academy of Sciences (India)

    Molecular evaluation of genetic diversity and association studies in rice. (Oryza sativa L.) C. Vanniarajan, K. K. Vinod and Andy Pereira. J. Genet. 91, 9–19. Table 1. Chromosome-wise distribution of SSR alleles and their number (k), polymorphic information content (PIC) and allele discrimination index (Dm). Chromosome.

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

    Indian Academy of Sciences (India)

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

  18. 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...

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

    DEFF Research Database (Denmark)

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

    2016-01-01

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

  20. Genetic and cytokine changes associated with symptomatic stages of CLL.

    Science.gov (United States)

    Agarwal, Amit; Cooke, Lawrence; Riley, Christopher; Qi, Wenqing; Mount, David; Mahadevan, Daruka

    2014-09-01

    The pathogenesis and drug resistance of symptomatic CLL patients involves genetic changes associated with the CLL clone as well as changes within the microenvironment. To further understand these processes, we compared early stage CLL to symptomatic late stage using gene expression and serum cytokine profiling to gain insight of the genetic and microenvironment changes associated with the most severe form of the disease. Patients were classified into low stage (Rai stage 0/I/II) and high stage (Rai stage III/IV). Gene expression profiles were obtained on pretreatment samples using the HG-U133A 2.0 Affymetrix platform. A comparison of low versus high stage CLL revealed a set of 21 genes differentially expressed genes. 15 genes were up regulated in the high stage compared to low stage while 6 genes were down regulated. Analysis of GO molecular function revealed 9 of 21 genes were involved in transcription factor activity. Serum cytokine profiles showed six cytokines to be significantly different in high stage patients. Two chemokines, SDF-1/CXCL12 and uPAR known to be involved in stem cell mobilization and homing were increased in serum of high stage patients. This study has identified therapeutic targets for symptomatic CLL patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. 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

  2. Role of genetics in infection-associated arthritis.

    Science.gov (United States)

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

    2015-04-01

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

  3. 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.

  4. 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.

  5. Methods for genetic linkage analysis using trisomies.

    OpenAIRE

    Feingold, E; Lamb, N E; Sherman, S L

    1995-01-01

    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 "susceptibility" ...

  6. 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

    with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9-16 years. We performed meta-analyses to test associations of individual SNPs and a weighted risk score of the 16 loci with fasting glucose. RESULTS-Nine loci were...... 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....... In nondiabetic adults, fasting glucose changes little over time, and our results suggest that age-independent effects of fasting glucose loci contribute to long-term interindividual differences in glucose levels from childhood onwards. Diabetes 60:1805-1812, 2011...

  7. Genetic mapping of DArT markers in the Festuca-Lolium complex and their use in freezing tolerance association analysis

    Czech Academy of Sciences Publication Activity Database

    Bartoš, Jan; Sandve, S. R.; Kolliker, R.; Kopecký, David; Christelová, Pavla; Stočes, Štěpán; Ostrem, L.; Larsen, A.; Kilian, A.; Rognli, O. A.; Doležel, Jaroslav

    2011-01-01

    Roč. 122, č. 6 (2011), s. 1133-1147 ISSN 0040-5752 R&D Projects: GA MZe QH71267; GA MŠk ED0007/01/01 Institutional research plan: CEZ:AV0Z50380511 Keywords : PRATENSIS HUDS * TEMPERATE CEREALS * MULTIFLORUM LAM Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.297, year: 2011

  8. Genetic Linkage and Association Analysis for Loneliness in Dutch Twin and Sibling Pairs Points to a Region on Chromosome 12q23–24

    NARCIS (Netherlands)

    Boomsma, D.I.; Cacioppo, J.T.; Slagboom, P.E.; Posthuma, D.

    2006-01-01

    We obtained evidence from a large study in Dutch twins (N = 8387) and siblings (N = 2295) that variation in loneliness has a genetic component. The heritability estimate for loneliness, which was assessed as an ordinal trait, was 40% and did not differ between males and females. There were 682

  9. Genetic Polymorphisms of Osteopontin in Association with ...

    African Journals Online (AJOL)

    2323. ISSN: 1596-5996 (print); 1596-9827 (electronic) ... Revised accepted: 5 November 2015. Abstract. Purpose: To determine the association of ..... Brenner D, Labreuche J, Touboul PJ, Schmidt-Petersen. K, Poirier O, Perret C, Schonfelder J, ...

  10. Genetic variants associated with sleep disorders.

    Science.gov (United States)

    Kripke, Daniel F; Kline, Lawrence E; Nievergelt, Caroline M; Murray, Sarah S; Shadan, Farhad F; Dawson, Arthur; Poceta, J Steven; Cronin, John; Jamil, Shazia M; Tranah, Gregory J; Loving, Richard T; Grizas, Alexandra P; Hahn, Elizabeth K

    2015-02-01

    The diagnostic boundaries of sleep disorders are under considerable debate. The main sleep disorders are partly heritable; therefore, defining heritable pathophysiologic mechanisms could delineate diagnoses and suggest treatment. We collected clinical data and DNA from consenting patients scheduled to undergo clinical polysomnograms, to expand our understanding of the polymorphisms associated with the phenotypes of particular sleep disorders. Patients at least 21 years of age were recruited to contribute research questionnaires, and to provide access to their medical records, saliva for deoxyribonucleic acid (DNA), and polysomnographic data. From these complex data, 38 partly overlapping phenotypes were derived indicating complaints, subjective and objective sleep timing, and polysomnographic disturbances. A custom chip was used to genotype 768 single-nucleotide polymorphisms (SNPs). Additional assays derived ancestry-informative markers (eg, 751 participants of European ancestry). Linear regressions controlling for age, gender, and ancestry were used to assess the associations of each phenotype with each of the SNPs, highlighting those with Bonferroni-corrected significance. In peroxisome proliferator-activated receptor gamma, coactivator 1 beta (PPARGC1B), rs6888451 was associated with several markers of obstructive sleep apnea. In aryl hydrocarbon receptor nuclear translocator-like (ARNTL), rs10766071 was associated with decreased polysomnographic sleep duration. The association of rs3923809 in BTBD9 with periodic limb movements in sleep was confirmed. SNPs in casein kinase 1 delta (CSNK1D rs11552085), cryptochrome 1 (CRY1 rs4964515), and retinoic acid receptor-related orphan receptor A (RORA rs11071547) were less persuasively associated with sleep latency and time of falling asleep. SNPs associated with several sleep phenotypes were suggested, but due to risks of false discovery, independent replications are needed before the importance of these associations

  11. Analysis of genetic polymorphism and genetic distance among four ...

    African Journals Online (AJOL)

    use

    2011-11-21

    Nov 21, 2011 ... The genomes of 4 sheep populations {Yuanqu white Tan sheep (YWT), Baozhongchang white Tan sheep. (BWT), black Tan sheep (BT) and small-tailed Han sheep (Han)} were screened using 10 microsatellite. DNA markers to estimate the genetic diversities and genetic distances among these ...

  12. 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

  13. Association analysis of multiple traits by an approach of combining ...

    Indian Academy of Sciences (India)

    Lili Chen

    diseases. Joint analysis of multiple traits can increase statistical power of association analysis and uncover the underlying genetic ... genthaler and Thilly 2007), the combined multivariate and ... Because of using reverse regression model, our.

  14. The role of TLR4 896 A>G and 1196 C>T in susceptibility to infections: a review and meta-analysis of genetic association studies.

    Directory of Open Access Journals (Sweden)

    Panayiotis D Ziakas

    Full Text Available BACKGROUND: Toll-like receptor 4 plays a role in pathogen recognition, and common polymorphisms may alter host susceptibility to infectious diseases. PURPOSE: To review the association of two common polymorphisms (TLR4 896A>G and TLR4 1196C>T with infectious diseases. DATA SOURCES: We searched PubMed and EMBASE up to March 2013 for pertinent literature in English, and complemented search with references lists of eligible studies. STUDY SELECTION: We included all studies that: reported an infectious outcome; had a case-control design and reported the TLR4 896A>G and/or TLR4 1196C>T genotype frequencies; 59 studies fulfilled these criteria and were analyzed. DATA EXTRACTION: Two authors independently extracted study data. DATA SYNTHESIS: The generalized odds ratio metric (ORG was used to quantify the impact of TLR4 variants on disease susceptibility. A meta-analysis was undertaken for outcomes reported in >1 study. Eleven of 37 distinct outcomes were significant. TLR4 896 A>G increased risk for all parasitic infections (ORG 1.59; 95%CI 1.05-2.42, malaria (1.31; 95%CI 1.04-1.66, brucellosis (2.66; 95%CI 1.66-4.27, cutaneous leishmaniasis (7.22; 95%CI 1.91-27.29, neurocysticercosis (4.39; 95%CI 2.53-7.61, Streptococcus pyogenes tonsillar disease (2.93; 95%CI 1.24-6.93 , typhoid fever (2.51; 95%CI 1.18-5.34 and adult urinary tract infections (1.98; 95%CI 1.04-3.98, but was protective for leprosy (0.36; 95%CI 0.22-0.60. TLR4 1196 C>T effects were similar to TLR4 896 A>G for brucellosis, cutaneous leishmaniasis, leprosy, typhoid fever and S. pyogenes tonsillar disease, and was protective for bacterial vaginosis in pregnancy (0.55; 95%CI 0.31-0.98 and Haemophilus influenzae tonsillar disease (0.42; 95%CI 0.17-1.00. The majority of significant associations were among predominantly Asian populations and significant associations were rare among European populations. CONCLUSIONS: Depending on the type of infection and population, TLR4 polymorphisms are

  15. 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.

  16. Evaluating Genetic Association between Fusarium and Pythium ...

    African Journals Online (AJOL)

    Resistance to Fusarium root rot (Fusarium solani f.s.p phaseoli) has been reported in common bean (Phaseolus vulgaris L.) sources and is usually associated with Pythium root rot resistance. Pythium root rot (Pythium ultimum var ultimum) resistance is controlled by a single dominant gene, marked by a SCAR marker ...

  17. 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

  18. A Genetic Analysis of Mortality in Pigs

    DEFF Research Database (Denmark)

    Varona, Luis; Sorensen, Daniel

    2010-01-01

    to investigate whether there is support for genetic variation for mortality and to study the quality of fit and predictive properties of the various models. In both breeds, the model that provided the best fit to the data was the standard binomial hierarchical model. The model that performed best in terms......An analysis of mortality is undertaken in two breeds of pigs: Danish Landrace and Yorkshire. Zero-inflated and standard versions of hierarchical Poisson, binomial, and negative binomial Bayesian models were fitted using Markov chain Monte Carlo (MCMC). The objectives of the study were...... of the ability to predict the distribution of stillbirths was the hierarchical zero-inflated negative binomial model. The best fit of the binomial hierarchical model and of the zero-inflated hierarchical negative binomial model was obtained when genetic variation was included as a parameter. For the hierarchical...

  19. 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

  20. Investigation of genetic diversity and epidemiological characteristics of Pasteurella multocida isolates from poultry in southwest China by population structure, multi-locus sequence typing and virulence-associated gene profile analysis.

    Science.gov (United States)

    Li, Zhangcheng; Cheng, Fangjun; Lan, Shimei; Guo, Jianhua; Liu, Wei; Li, Xiaoyan; Luo, Zeli; Zhang, Manli; Wu, Juan; Shi, Yang

    2018-04-25

    Fowl cholera caused by Pasteurella multocida has always been a disease of global importance for poultry production. The aim of this study was to obtain more information about the epidemiology of avian P. multocida infection in southwest China and the genetic characteristics of clinical isolates. P. multocida isolates were characterized by biochemical and molecular-biological methods. The distributions of the capsular serogroups, the phenotypic antimicrobial resistance profiles, lipopolysaccharide (LPS) genotyping and the presence of 19 virulence genes were investigated in 45 isolates of P. multocida that were associated with clinical disease in poultry. The genetic diversity of P. multocida strains was performed by 16S rRNA and rpoB gene sequence analysis as well as multilocus sequence typing (MLST). The results showed that most (80.0%) of the P. multocida isolates in this study represented special P. multocida subspecies, and 71.1% of the isolates showed multiple-drug resistance. 45 isolates belonged to capsular types: A (100%) and two LPS genotypes: L1 (95.6%) and L3 (4.4%). MLST revealed two new alleles (pmi77 and gdh57) and one new sequence type (ST342). ST129 types dominated in 45 P. multocida isolates. Isolates belonging to ST129 were with the genes ompH+plpB+ptfA+tonB, whereas ST342 included isolates with fur+hgbA+tonB genes. Population genetic analysis and the MLST results revealed that at least one new ST genotype was present in the avian P. multocida in China. These findings provide novel insights into the epidemiological characteristics of avian P. multocida isolates in southwest China.

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

    Science.gov (United States)

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

    2014-01-01

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

  2. Genetic variants associated with sleep disorders

    OpenAIRE

    Kripke, Daniel F.; Kline, Lawrence E.; Nievergelt, Caroline M.; Murray, Sarah S.; Shadan, Farhad F.; Dawson, Arthur; Poceta, J. Steven; Cronin, John; Jamil, Shazia M.; Tranah, Gregory J.; Loving, Richard T.; Grizas, Alexandra P.; Hahn, Elizabeth K.

    2015-01-01

    © 2014 The Authors. Objective: The diagnostic boundaries of sleep disorders are under considerable debate. The main sleep disorders are partly heritable therefore, defining heritable pathophysiologic mechanisms could delineate diagnoses and suggest treatment. We collected clinical data and DNA from consenting patients scheduled to undergo clinical polysomnograms, to expand our understanding of the polymorphisms associated with the phenotypes of particular sleep disorders. Methods: Patients at...

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

    Directory of Open Access Journals (Sweden)

    Benjamin Smith

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

  4. An analysis of the genetic diversity and genetic structure of ...

    African Journals Online (AJOL)

    ajl yemi

    2011-12-26

    Dec 26, 2011 ... relief, diuresis, blood pressure and lipid metabolism. (Kawasaki et al., 2000). ... Habitat. Longitude(N),. Latitude(E). Population size. Sample size. LY. Luoyang, Henan ..... Compared with the high genetic diversity at the species.

  5. Replication analysis of genetic association of the NCAN-CILP2 region with plasma lipid levels and non-alcoholic fatty liver disease in Asian and Pacific ethnic groups.

    Science.gov (United States)

    Boonvisut, Supichaya; Nakayama, Kazuhiro; Makishima, Saho; Watanabe, Kazuhisa; Miyashita, Hiroshi; Lkhagvasuren, Munkhtulga; Kagawa, Yasuo; Iwamoto, Sadahiko

    2016-01-13

    The Neurocan-cartilage intermediate layer protein 2 (NCAN-CILP2) region forms a tight linkage disequilibrium (LD) block and is associated with plasma lipid levels and non-alcoholic fatty liver disease (NAFLD) in individuals of European descent but not in the Malay and Japanese ethnic groups. Recent genome-wide resequence studies identified a missense single-nucleotide polymorphism (SNP) (rs58542926) of the transmembrane 6 superfamily member 2 (TM6SF2) gene in the NCAN-CILP2 region related to hepatic triglyceride content. This study aims to analyze the influences of SNPs in this region on NAFLD and plasma lipid levels in the Asian and Pacific ethnic groups and to reveal the reasons behind positive and negative genetic associations dependent on ethnicity. Samples and characteristic data were collected from 3,013 Japanese, 119 Palauan, 947 Mongolian, 212 Thai and 401 Chinese people. Hepatic sonography data was obtained from the Japanese individuals. Genotyping data of five SNPs, rs58542926, rs735273, rs1009136, rs1858999, and rs16996148, were used to verify the effect on serum lipid levels by multiple linear regression, and the association with NAFLD in the Japanese population was examined by logistic regression analysis. rs58542926 showed significant association with the plasma triglyceride (TG) level in Japanese (P = 0.0009, effect size = 9.5 (± 3.25) mg/dl/allele) and Thai (P = 0.0008, effect size = 31.6 (± 11.7) mg/dl/allele) study subjects. In Mongolian individuals, there was a significant association of rs58542926 with total cholesterol level (P = 0.0003, 11.7 (± 3.2) mg/dl/allele) but not with TG level. In multiple comparisons in Chinese individuals, rs58542926 was weakly (P = 0.022) associated with TG levels, although the threshold for statistical significance was not reached. In Palauan individuals, there was no significant association with the studied SNPs. rs58542926 also showed significant association with Japanese NAFLD. The minor allele (t) increased

  6. 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

  7. Population genetic analysis of ascertained SNP data

    Directory of Open Access Journals (Sweden)

    Nielsen Rasmus

    2004-03-01

    Full Text Available Abstract The large single nucleotide polymorphism (SNP typing projects have provided an invaluable data resource for human population geneticists. Almost all of the available SNP loci, however, have been identified through a SNP discovery protocol that will influence the allelic distributions in the sampled loci. Standard methods for population genetic analysis based on the available SNP data will, therefore, be biased. This paper discusses the effect of this ascertainment bias on allelic distributions and on methods for quantifying linkage disequilibrium and estimating demographic parameters. Several recently developed methods for correcting for the ascertainment bias will also be discussed.

  8. Convergence analysis of canonical genetic algorithms.

    Science.gov (United States)

    Rudolph, G

    1994-01-01

    This paper analyzes the convergence properties of the canonical genetic algorithm (CGA) with mutation, crossover and proportional reproduction applied to static optimization problems. It is proved by means of homogeneous finite Markov chain analysis that a CGA will never converge to the global optimum regardless of the initialization, crossover, operator and objective function. But variants of CGA's that always maintain the best solution in the population, either before or after selection, are shown to converge to the global optimum due to the irreducibility property of the underlying original nonconvergent CGA. These results are discussed with respect to the schema theorem.

  9. A hybrid correlation analysis with application to imaging genetics

    Science.gov (United States)

    Hu, Wenxing; Fang, Jian; Calhoun, Vince D.; Wang, Yu-Ping

    2018-03-01

    Investigating the association between brain regions and genes continues to be a challenging topic in imaging genetics. Current brain region of interest (ROI)-gene association studies normally reduce data dimension by averaging the value of voxels in each ROI. This averaging may lead to a loss of information due to the existence of functional sub-regions. Pearson correlation is widely used for association analysis. However, it only detects linear correlation whereas nonlinear correlation may exist among ROIs. In this work, we introduced distance correlation to ROI-gene association analysis, which can detect both linear and nonlinear correlations and overcome the limitation of averaging operations by taking advantage of the information at each voxel. Nevertheless, distance correlation usually has a much lower value than Pearson correlation. To address this problem, we proposed a hybrid correlation analysis approach, by applying canonical correlation analysis (CCA) to the distance covariance matrix instead of directly computing distance correlation. Incorporating CCA into distance correlation approach may be more suitable for complex disease study because it can detect highly associated pairs of ROI and gene groups, and may improve the distance correlation level and statistical power. In addition, we developed a novel nonlinear CCA, called distance kernel CCA, which seeks the optimal combination of features with the most significant dependence. This approach was applied to imaging genetic data from the Philadelphia Neurodevelopmental Cohort (PNC). Experiments showed that our hybrid approach produced more consistent results than conventional CCA across resampling and both the correlation and statistical significance were increased compared to distance correlation analysis. Further gene enrichment analysis and region of interest (ROI) analysis confirmed the associations of the identified genes with brain ROIs. Therefore, our approach provides a powerful tool for finding

  10. Genome-Wide SNP Discovery and Analysis of Genetic Diversity in Farmed Sika Deer (Cervus nippon in Northeast China Using Double-Digest Restriction Site-Associated DNA Sequencing

    Directory of Open Access Journals (Sweden)

    Hengxing Ba

    2017-09-01

    Full Text Available Sika deer are an economically valuable species owing to their use in traditional Chinese medicine, particularly their velvet antlers. Sika deer in northeast China are mostly farmed in enclosure. Therefore, genetic management of farmed sika deer would benefit from detailed knowledge of their genetic diversity. In this study, we generated over 1.45 billion high-quality paired-end reads (288 Gbp across 42 unrelated individuals using double-digest restriction site-associated DNA sequencing (ddRAD-seq. A total of 96,188 (29.63% putative biallelic SNP loci were identified with an average sequencing depth of 23×. Based on the analysis, we found that the majority of the loci had a deficit of heterozygotes (FIS >0 and low values of Hobs, which could be due to inbreeding and Wahlund effects. We also developed a collection of high-quality SNP probes that will likely be useful in a variety of applications in genotyping for cervid species in the future.

  11. Genome-Wide SNP Discovery and Analysis of Genetic Diversity in Farmed Sika Deer (Cervus nippon) in Northeast China Using Double-Digest Restriction Site-Associated DNA Sequencing.

    Science.gov (United States)

    Ba, Hengxing; Jia, Boyin; Wang, Guiwu; Yang, Yifeng; Kedem, Gilead; Li, Chunyi

    2017-09-07

    Sika deer are an economically valuable species owing to their use in traditional Chinese medicine, particularly their velvet antlers. Sika deer in northeast China are mostly farmed in enclosure. Therefore, genetic management of farmed sika deer would benefit from detailed knowledge of their genetic diversity. In this study, we generated over 1.45 billion high-quality paired-end reads (288 Gbp) across 42 unrelated individuals using double-digest restriction site-associated DNA sequencing (ddRAD-seq). A total of 96,188 (29.63%) putative biallelic SNP loci were identified with an average sequencing depth of 23×. Based on the analysis, we found that the majority of the loci had a deficit of heterozygotes (F IS >0) and low values of H obs , which could be due to inbreeding and Wahlund effects. We also developed a collection of high-quality SNP probes that will likely be useful in a variety of applications in genotyping for cervid species in the future. Copyright © 2017 Ba et al.

  12. Analysis of genetic structure and relationship among nine ...

    Indian Academy of Sciences (India)

    These results indicated that the clustering analysis using the Structure program might provide an ..... of the current genetic relations among the breeds, and con- tribute to ... sis of the genetic structure of the Canary goat populations using.

  13. Genetic analysis of Myanmar Vigna species in responses to salt ...

    African Journals Online (AJOL)

    Genetic analysis of Myanmar Vigna species in responses to salt stress at the ... of reduction was highly dependent on different genotypes and salinity levels. ... the mechanism of salt tolerance and for the provision of genetic resources for ...

  14. Analysis of genetic relationships of mulberry (Morus L.) germplasm ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-06-03

    Jun 3, 2009 ... Full Length Research Paper. Analysis of genetic ... Key words: Mulberry, molecular marker, genetic diversity, SRAP. ... Europe, North and South America, and Africa, and it is cultivated ... Xingjiang autonomous region, China.

  15. 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

  16. Contribution of Large Region Joint Associations to Complex Traits Genetics

    Science.gov (United States)

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

    2015-01-01

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

  17. [Wolfram syndrome: clinical and genetic analysis in two sisters].

    Science.gov (United States)

    Conart, J-B; Maalouf, T; Jonveaux, P; Guerci, B; Angioi, K

    2011-10-01

    Wolfram syndrome is a severe genetic disorder defined by the association of diabetes mellitus, optic atrophy, deafness, and diabetes insipidus. Two sisters complained of progressive visual loss. Fundus examination evidenced optic atrophy. Their past medical history revealed diabetes mellitus and deafness since childhood. The association of these symptoms made the diagnosis of Wolfram syndrome possible. It was confirmed by molecular analysis, which evidenced composite WFS1 heterozygous mutations inherited from both their mother and father. Ophthalmologists should be aware of the possibility of Wolfram syndrome when diagnosing optic atrophy in diabetic children. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  18. 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

    BACKGROUND: Personalised medicine, including biomarkers for treatment selection, may provide new algorithms for more effective treatment of patients. Genetic variation may impact drug response and genetic markers could help selecting the best treatment strategy for the individual patient. AIM......2430561) [OR = 1.66 (1.05-2.63)], IL6 (rs10499563) [OR = 1.65 (1.04-2.63)] and IL1B (rs4848306) [OR = 1.88 (1.05-3.35)] were significantly associated with response among IBD patients using clinical response criteria. A positive predictive value of 0.96 was achieved by combining five genetic markers...... 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...

  19. Provenance research: investigation of genetic diversity associated with geography

    Science.gov (United States)

    Robert Z. Callaham

    1963-01-01

    Provenance in forestry refers to the population of trees growing at n particular place of origin. Provenance research defines the genetic and environmental components of phenotypic variation associated with geographic source. Information on provenance is important in assuring sources of seed to give well-adapted, productive trees and in directing breeding of...

  20. 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.

  1. Genetic diversity of disease-associated loci in Turkish population.

    Science.gov (United States)

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

    2015-04-01

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

  2. 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.

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

    Science.gov (United States)

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

    2015-06-18

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

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

    NARCIS (Netherlands)

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

    2000-01-01

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

  5. 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.

    2013-01-01

    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. PMID:23459689

  6. Pitfalls in genetic analysis of pheochromocytomas/paragangliomas-case report.

    Science.gov (United States)

    Canu, Letizia; Rapizzi, Elena; Zampetti, Benedetta; Fucci, Rossella; Nesi, Gabriella; Richter, Susan; Qin, Nan; Giachè, Valentino; Bergamini, Carlo; Parenti, Gabriele; Valeri, Andrea; Ercolino, Tonino; Eisenhofer, Graeme; Mannelli, Massimo

    2014-07-01

    About 35% of patients with pheochromocytoma/paraganglioma carry a germline mutation in one of the 10 main susceptibility genes. The recent introduction of next-generation sequencing will allow the analysis of all these genes in one run. When positive, the analysis is generally unequivocal due to the association between a germline mutation and a concordant clinical presentation or positive family history. When genetic analysis reveals a novel mutation with no clinical correlates, particularly in the presence of a missense variant, the question arises whether the mutation is pathogenic or a rare polymorphism. We report the case of a 35-year-old patient operated for a pheochromocytoma who turned out to be a carrier of a novel SDHD (succinate dehydrogenase subunit D) missense mutation. With no positive family history or clinical correlates, we decided to perform additional analyses to test the clinical significance of the mutation. We performed in silico analysis, tissue loss of heterozygosity analysis, immunohistochemistry, Western blot analysis, SDH enzymatic assay, and measurement of the succinate/fumarate concentration ratio in the tumor tissue by tandem mass spectrometry. Although the in silico analysis gave contradictory results according to the different methods, all the other tests demonstrated that the SDH complex was conserved and normally active. We therefore came to the conclusion that the variant was a nonpathogenic polymorphism. Advancements in technology facilitate genetic analysis of patients with pheochromocytoma but also offer new challenges to the clinician who, in some cases, needs clinical correlates and/or functional tests to give significance to the results of the genetic assay.

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

    Science.gov (United States)

    Ryu, J; Lee, C

    2016-04-01

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

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

    Science.gov (United States)

    Reis, Linda M; Semina, Elena V

    2015-06-01

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

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

    Science.gov (United States)

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

    2017-07-25

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

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

    DEFF Research Database (Denmark)

    Amano, Mariane T; Ferriani, Virgínia P L; Florido, Marlene P C

    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...... describe a family in which all four children are deficient in C1s but only two of them developed SLE. Hemolytic activity mediated by the alternative and the lectin pathways were normal, but classical pathway activation was absent in all children's sera. C1s was undetectable, while in the parents' sera...

  11. Diagnostic and therapeutic implications of genetic heterogeneity in myeloid neoplasms uncovered by comprehensive mutational analysis

    Directory of Open Access Journals (Sweden)

    Sarah M. Choi

    2017-01-01

    Full Text Available While growing use of comprehensive mutational analysis has led to the discovery of innumerable genetic alterations associated with various myeloid neoplasms, the under-recognized phenomenon of genetic heterogeneity within such neoplasms creates a potential for diagnostic confusion. Here, we describe two cases where expanded mutational testing led to amendment of an initial diagnosis of chronic myelogenous leukemia with subsequent altered treatment of each patient. We demonstrate the power of comprehensive testing in ensuring appropriate classification of genetically heterogeneous neoplasms, and emphasize thoughtful analysis of molecular and genetic data as an essential component of diagnosis and management.

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

    DEFF Research Database (Denmark)

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

    2016-01-01

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

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

    African Journals Online (AJOL)

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

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

    NARCIS (Netherlands)

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

    2012-01-01

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

  15. Quantitative genetic analysis of total glucosinolate, oil and protein ...

    African Journals Online (AJOL)

    Quantitative genetic analysis of total glucosinolate, oil and protein contents in Ethiopian mustard ( Brassica carinata A. Braun) ... Seeds were analyzed using HPLC (glucosinolates), NMR (oil) and NIRS (protein). Analyses of variance, Hayman's method of diallel analysis and a mixed linear model of genetic analysis were ...

  16. Genetic diversity and environmental associations of sacsaoul ( Haloxylon ammodendron)

    Science.gov (United States)

    Zhang, Linjing; Zhao, Guifang; Yue, Ming; Pan, Xiaoling

    2003-07-01

    Random amplified polymorphic DNA (RAPD) markers were used to assess levels and patterns of genetic diversity in H. ammodendron (Chenopodiaceae). A total of 117 plants from 6 subpopulations on oasis-desert ecotone was analyzed by 16 arbitrarily chosen primers resulting in highly reproducible RAPD bands. The analysis of molecular variance (AMOVA) with distances among individuals showed that most of the variation (74%) occurred among individuals within subpopulations, which is expected for a crossing organism, and 26% of variation among subpopulations. Estimates of Shannon index and Nei"s index from allele frequencies corroborated AMOVA partitioning in H. ammodendron. UPGMA cluster analyses, based on genetic distance, do not revealed grouping of some geographically proximate populations. This is the first report of the partitioning of genetic variability within and between subpopulations of H. ammodendron and provides important baseline data for optimizing sampling strategies and for conserving the genetic resources of this species. The Percentage of polymorphic loci was as high as 96%, presumably being response to oasis-desert ecotone. There were gene flows (Nm=5.38 individuals/generation), based on gene differentiation coefficient (GST was 0.1567) between subpopulations, and strong habitat selection override the gene flow to maintain the subpopulation differentiation. Correlation analyses showed that there was significant relationship between genetic diversity and soil CL ion.

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

    Directory of Open Access Journals (Sweden)

    Wang Tao

    2011-09-01

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

  18. Common genetic variants on 6q24 associated with exceptional episodic memory performance in the elderly

    DEFF Research Database (Denmark)

    Barral, Sandra; Cosentino, Stephanie; Christensen, Kaare

    2014-01-01

    IMPORTANCE: There are genetic influences on memory ability as we age, but no specific genes have been identified. OBJECTIVE: To use a cognitive endophenotype, exceptional episodic memory (EEM) performance, derived from nondemented offspring from the Long Life Family Study (LLFS) to identify genetic...... individuals. Results of the individual replication cohorts were combined by meta-analysis. MAIN OUTCOME MEASURE: Episodic memory scores computed as the mean of the 2 standardized measures of Logical Memory IA and IIA. RESULTS: Heritability estimates indicated a significant genetic component for EEM (h2 = 0...... peak. Replication in one cohort identified a set of 26 SNPs associated with episodic memory (P ≤ .05). Meta-analysis of the 26 SNPs using the 4 independent replication cohorts found SNPs rs9321334 and rs6902875 to be nominally significantly associated with episodic memory (P = .009 and P = .013...

  19. 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.

  20. Targeted association mapping demonstrating the complex molecular genetics of fatty acid formation in soybean.

    Science.gov (United States)

    Li, Ying-hui; Reif, Jochen C; Ma, Yan-song; Hong, Hui-long; Liu, Zhang-xiong; Chang, Ru-zhen; Qiu, Li-juan

    2015-10-23

    The relative abundance of five dominant fatty acids (FAs) (palmitic, stearic, oleic, linoleic and linolenic acids) is a major factor determining seed quality in soybean. To clarify the currently poorly understood genetic architecture of FAs in soybean, targeted association analysis was conducted in 421 diverse accessions phenotyped in three environments and genotyped using 1536 pre-selected SNPs. The population of 421 soybean accessions displayed significant genetic variation for each FA. Analysis of the molecular data revealed three subpopulations, which reflected a trend depending on latitude of cultivation. A total of 37 significant (p seed quality of soybean with benefits for human health and for food processing.

  1. Identifying Associations Between Brain Imaging Phenotypes and Genetic Factors via A Novel Structured SCCA Approach.

    Science.gov (United States)

    Du, Lei; Zhang, Tuo; Liu, Kefei; Yan, Jingwen; Yao, Xiaohui; Risacher, Shannon L; Saykin, Andrew J; Han, Junwei; Guo, Lei; Shen, Li

    2017-06-01

    Brain imaging genetics attracts more and more attention since it can reveal associations between genetic factors and the structures or functions of human brain. Sparse canonical correlation analysis (SCCA) is a powerful bi-multivariate association identification technique in imaging genetics. There have been many SCCA methods which could capture different types of structured imaging genetic relationships. These methods either use the group lasso to recover the group structure, or employ the graph/network guided fused lasso to find out the network structure. However, the group lasso methods have limitation in generalization because of the incomplete or unavailable prior knowledge in real world. The graph/network guided methods are sensitive to the sign of the sample correlation which may be incorrectly estimated. We introduce a new SCCA model using a novel graph guided pairwise group lasso penalty, and propose an efficient optimization algorithm. The proposed method has a strong upper bound for the grouping effect for both positively and negatively correlated variables. We show that our method performs better than or equally to two state-of-the-art SCCA methods on both synthetic and real neuroimaging genetics data. In particular, our method identifies stronger canonical correlations and captures better canonical loading profiles, showing its promise for revealing biologically meaningful imaging genetic associations.

  2. 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...

  3. 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.

  4. Multiple Genetic Associations with Irish Wolfhound Dilated Cardiomyopathy.

    Science.gov (United States)

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

    2016-01-01

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

  5. Multiple Genetic Associations with Irish Wolfhound Dilated Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Siobhan Simpson

    2016-01-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

  7. 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.

  8. 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.

  9. 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.

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

    Science.gov (United States)

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

    2015-06-01

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

  11. 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. 2009 Elsevier Ireland Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    M. A. Malek

    2014-01-01

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

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

    African Journals Online (AJOL)

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

  14. 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.

  15. 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

  16. 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.

  17. 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

    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......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...... endophenotypes showed moderate to high heritability (0.31-0.69) and small cial environmental background...

  18. Personality and divorce: a genetic analysis.

    Science.gov (United States)

    Jocklin, V; McGue, M; Lykken, D T

    1996-08-01

    M. McGue and D.T. Lykken (1992) found that divorce risk was, to a substantial degree, genetically mediated; prior research has identified numerous social and psychological factors that affect divorce risk (G.C. Kitson, K.B. Barbi, & M.J. Roach, 1985). The present study attempted to link these domains by examining the extent to which genetic influences on one such psychological factor, personality, explain divorce risk heritability. A sample of adult twins from the Minnesota Twin Registry completed a marital history questionnaire and the Multidimensional Personality Questionnaire (A. Tellegen, 1982). Positive Emotionality and Negative Emotionality factors were positively related to divorce risk, whereas Constraint was negatively related. In women and men, respectively, 30% and 42% of the heritability of divorce risk consisted of genetic factors affecting personality and divorce risk correlated largely as a result of these common genetic influences.

  19. Genetic algorithms and supernovae type Ia analysis

    International Nuclear Information System (INIS)

    Bogdanos, Charalampos; Nesseris, Savvas

    2009-01-01

    We introduce genetic algorithms as a means to analyze supernovae type Ia data and extract model-independent constraints on the evolution of the Dark Energy equation of state w(z) ≡ P DE /ρ DE . Specifically, we will give a brief introduction to the genetic algorithms along with some simple examples to illustrate their advantages and finally we will apply them to the supernovae type Ia data. We find that genetic algorithms can lead to results in line with already established parametric and non-parametric reconstruction methods and could be used as a complementary way of treating SNIa data. As a non-parametric method, genetic algorithms provide a model-independent way to analyze data and can minimize bias due to premature choice of a dark energy model

  20. Combinations of genetic variants associated with bipolar disorder

    DEFF Research Database (Denmark)

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

    2017-01-01

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

  1. Introns Protect Eukaryotic Genomes from Transcription-Associated Genetic Instability.

    Science.gov (United States)

    Bonnet, Amandine; Grosso, Ana R; Elkaoutari, Abdessamad; Coleno, Emeline; Presle, Adrien; Sridhara, Sreerama C; Janbon, Guilhem; Géli, Vincent; de Almeida, Sérgio F; Palancade, Benoit

    2017-08-17

    Transcription is a source of genetic instability that can notably result from the formation of genotoxic DNA:RNA hybrids, or R-loops, between the nascent mRNA and its template. Here we report an unexpected function for introns in counteracting R-loop accumulation in eukaryotic genomes. Deletion of endogenous introns increases R-loop formation, while insertion of an intron into an intronless gene suppresses R-loop accumulation and its deleterious impact on transcription and recombination in yeast. Recruitment of the spliceosome onto the mRNA, but not splicing per se, is shown to be critical to attenuate R-loop formation and transcription-associated genetic instability. Genome-wide analyses in a number of distant species differing in their intron content, including human, further revealed that intron-containing genes and the intron-richest genomes are best protected against R-loop accumulation and subsequent genetic instability. Our results thereby provide a possible rationale for the conservation of introns throughout the eukaryotic lineage. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Genetic analysis of bulimia nervosa: methods and sample description.

    Science.gov (United States)

    Kaye, Walter H; Devlin, Bernie; Barbarich, Nicole; Bulik, Cynthia M; Thornton, Laura; Bacanu, Silviu-Alin; Fichter, Manfred M; Halmi, Katherine A; Kaplan, Allan S; Strober, Michael; Woodside, D Blake; Bergen, Andrew W; Crow, Scott; Mitchell, James; Rotondo, Alessandro; Mauri, Mauro; Cassano, Giovanni; Keel, Pamela; Plotnicov, Katherine; Pollice, Christine; Klump, Kelly L; Lilenfeld, Lisa R; Ganjei, J Kelly; Quadflieg, Norbert; Berrettini, Wade H

    2004-05-01

    Twin and family studies suggest that genetic variants contribute to the pathogenesis of bulimia nervosa (BN) and anorexia nervosa (AN). The Price Foundation has supported an international, multisite study of families with these disorders to identify these genetic variations. The current study presents the clinical characteristics of this sample as well as a description of the study methodology. All probands met modified criteria for BN or bulimia nervosa with a history of AN (BAN) as defined in the 4th ed. of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 1994). All affected relatives met DSM-IV criteria for BN, AN, BAN, or eating disorders not otherwise specified (EDNOS). Probands and affected relatives were assessed diagnostically using both trained-rater and self-report assessments. DNA samples were collected from probands, affected relatives, and available biologic parents. Assessments were obtained from 163 BN probands and 165 BAN probands. Overall, there were 365 relative pairs available for linkage analysis. Of the affected relatives of BN probands, 62 were diagnosed as BN (34.8%), 49 as BAN (27.5%), 35 as AN (19.7%), and 32 as EDNOS (18.0%). For the relatives of BAN probands, 42 were diagnosed as BN (22.5%), 67 as BAN (35.8%), 48 as AN (25.7%), and 30 as EDNOS (16.0%). This study represents the largest genetic study of eating disorders to date. Clinical data indicate that although there are a large number of individuals with BN disorders, a range of eating pathology is represented in the sample, allowing for the examination of several different phenotypes in molecular genetic analyses. Copyright 2004 by Wiley Periodicals, Inc. Int J Eat Disord 35: 556-570, 2004.

  3. Population genetic analysis of Enterocytozoon bieneusi in humans.

    Science.gov (United States)

    Li, Wei; Cama, Vitaliano; Feng, Yaoyu; Gilman, Robert H; Bern, Caryn; Zhang, Xichen; Xiao, Lihua

    2012-01-01

    Genotyping based on sequence analysis of the ribosomal internal transcribed spacer has revealed significant genetic diversity in Enterocytozoonbieneusi. Thus far, the population genetics of E. bieneusi and its significance in the epidemiology of microsporidiosis have not been examined. In this study, a multilocus sequence typing of E. bieneusi in AIDS patients in Lima, Peru was conducted, using 72 specimens previously genotyped as A, D, IV, EbpC, WL11, Peru7, Peru8, Peru10 and Peru11 at the internal transcribed spacer locus. Altogether, 39 multilocus genotypes were identified among the 72 specimens. The observation of strong intragenic linkage disequilibria and limited genetic recombination among markers were indicative of an overall clonal population structure of E. bieneusi. Measures of pair-wise intergenic linkage disequilibria and a standardised index of association (IAS) based on allelic profile data further supported this conclusion. Both sequence-based and allelic profile-based phylogenetic analyses showed the presence of two genetically isolated groups in the study population, one (group 1) containing isolates of the anthroponotic internal transcribed spacer genotype A, and the other (group 2) containing isolates of multiple internal transcribed spacer genotypes (mainly genotypes D and IV) with zoonotic potential. The measurement of linkage disequilibria and recombination indicated group 2 had a clonal population structure, whereas group 1 had an epidemic population structure. The formation of the two sub-populations was confirmed by STRUCTURE and Wright's fixation index (FST) analyses. The data highlight the power of MLST in understanding the epidemiology of E. bieneusi. Published by Elsevier Ltd.

  4. 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.

  5. Genetic association between human chitinases and lung function in COPD.

    Science.gov (United States)

    Aminuddin, F; Akhabir, L; Stefanowicz, D; Paré, P D; Connett, J E; Anthonisen, N R; Fahy, J V; Seibold, M A; Burchard, E G; Eng, C; Gulsvik, A; Bakke, P; Cho, M H; Litonjua, A; Lomas, D A; Anderson, W H; Beaty, T H; Crapo, J D; Silverman, E K; Sandford, A J

    2012-07-01

    Two primary chitinases have been identified in humans--acid mammalian chitinase (AMCase) and chitotriosidase (CHIT1). Mammalian chitinases have been observed to affect the host's immune response. The aim of this study was to test for association between genetic variation in the chitinases and phenotypes related to chronic obstructive pulmonary disease (COPD). Polymorphisms in the chitinase genes were selected based on previous associations with respiratory diseases. Polymorphisms that were associated with lung function level or rate of decline in the Lung Health Study (LHS) cohort were analyzed for association with COPD affection status in four other COPD case-control populations. Chitinase activity and protein levels were also related to genotypes. In the caucasian LHS population, the baseline forced expiratory volume in one second (FEV(1)) was significantly different between the AA and GG genotypic groups of the AMCase rs3818822 polymorphism. Subjects with the GG genotype had higher AMCase protein and chitinase activity compared with AA homozygotes. For CHIT1 rs2494303, a significant association was observed between rate of decline in FEV(1) and the different genotypes. In the African American LHS population, CHIT1 rs2494303 and AMCase G339T genotypes were associated with rate of decline in FEV(1). Although a significant effect of chitinase gene alleles was found on lung function level and decline in the LHS, we were unable to replicate the associations with COPD affection status in the other COPD study groups.

  6. Association of genetic and phenotypic variability with geography and climate in three southern California oaks.

    Science.gov (United States)

    Riordan, Erin C; Gugger, Paul F; Ortego, Joaquín; Smith, Carrie; Gaddis, Keith; Thompson, Pam; Sork, Victoria L

    2016-01-01

    Geography and climate shape the distribution of organisms, their genotypes, and their phenotypes. To understand historical and future evolutionary and ecological responses to climate, we compared the association of geography and climate of three oak species (Quercus engelmannii, Quercus berberidifolia, and Quercus cornelius-mulleri) in an environmentally heterogeneous region of southern California at three organizational levels: regional species distributions, genetic variation, and phenotypic variation. We identified climatic variables influencing regional distribution patterns using species distribution models (SDMs), and then tested whether those individual variables are important in shaping genetic (microsatellite) and phenotypic (leaf morphology) variation. We estimated the relative contributions of geography and climate using multivariate redundancy analyses (RDA) with variance partitioning. The modeled distribution of each species was influenced by climate differently. Our analysis of genetic variation using RDA identified small but significant associations between genetic variation with climate and geography in Q. engelmannii and Q. cornelius-mulleri, but not in Q. berberidifolia, and climate explained more of the variation. Our analysis of phenotypic variation in Q. engelmannii indicated that climate had more impact than geography, but not in Q. berberidifolia. Throughout our analyses, we did not find a consistent pattern in effects of individual climatic variables. Our comparative analysis illustrates that climate influences tree response at all organizational levels, but the important climate factors vary depending on the level and on the species. Because of these species-specific and level-specific responses, today's sympatric species are unlikely to have similar distributions in the future. © 2016 Botanical Society of America.

  7. Genetic analysis of milk β-hydroxybutyrate and its association with fat-to-protein ratio, body condition score, clinical ketosis, and displaced abomasum in early first lactation of Canadian Holsteins.

    Science.gov (United States)

    Koeck, A; Jamrozik, J; Schenkel, F S; Moore, R K; Lefebvre, D M; Kelton, D F; Miglior, F

    2014-11-01

    The aim of this study was to estimate genetic parameters for milk β-hydroxybutyrate (BHBA) in early first lactation of Canadian Holstein cows and to examine its genetic association with indicators of energy balance (fat-to-protein ratio and body condition score) and metabolic diseases (clinical ketosis and displaced abomasum). Data for milk BHBA recorded between 5 and 100 d in milk was obtained from Valacta (Sainte-Anne-de-Bellevue, Québec, Canada), the Canadian Dairy Herd Improvement organization responsible for Québec and Atlantic provinces. Test-day milk samples were analyzed by mid-infrared spectrometry using previously developed calibration equations for milk BHBA. Test-day records of fat-to-protein ratio were obtained from the routine milk recording scheme. Body condition score records were available from the routine type classification system. Data on clinical ketosis and displaced abomasum recorded by producers were available from the national dairy cattle health system in Canada. Data were analyzed using linear animal models. Heritability estimates for milk BHBA at different stages of early lactation were between 0.14 and 0.29. Genetic correlations between milk BHBA were higher between adjacent lactation intervals and decreased as intervals were further apart. Correlations between breeding values for milk BHBA and routinely evaluated traits revealed that selection for lower milk BHBA in early lactation would lead to an improvement of several health and fertility traits, including SCS, calving to first service, number of services, first service to conception, and days open. Also, lower milk BHBA was associated with a longer herd life, better conformation, and better feet and legs. A higher genetic merit for milk yield was associated with higher milk BHBA, and, therefore, a greater susceptibility to hyperketonemia. Milk BHBA at the first test-day was moderately genetically correlated with fat-to-protein ratio (0.49), body condition score (-0.35), and

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

    Directory of Open Access Journals (Sweden)

    Christine E McLaren

    2011-03-01

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

  9. 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.

  10. 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.

  11. Analysis of genetic structure in Melia volkensii (Gurke.) populations ...

    African Journals Online (AJOL)

    Administrator

    2Farm Forestry Programme, Kenya Forestry Research Institute, P. O. Box 20412, Nairobi, Kenya. Accepted 5 ... were used to estimate genetic distances between populations and for construction of neighbour-joining phenograms. Analysis of Molecular Variance (AMOVA) indicated significant genetic differentiation between ...

  12. An analysis of food irradiation : genetic effects

    International Nuclear Information System (INIS)

    MacPhee, D.; Hall, W.

    1988-01-01

    A series of studies undertaken at the National Institute of Nutrition (NIN) in India in the 1970s reported the occurrence of polyploidy in bone-marrow or peripheral lymphocytes in a number of species, including children, fed on freshly irradiated wheat. Opponents of food irradiation use these studies as evidence that genetic damage is caused by the consumption of irradiated food. This review of those NIN studies and of the attempts to replicate them and of two other relevant studies concludes that the claim that consumption of irradiated food causes genetic damage has not been substantiated. Other researchers have been unable to replicate the NIN studies. Polyploidy appears to be a poor indicator of genetic damage and the NIN results are biologically implausible

  13. Genetic diversity analysis in the Hypericum perforatum populations ...

    African Journals Online (AJOL)

    user

    2014-01-01

    Jan 1, 2014 ... 2Cancer Genetics Lab, Department of Biochemistry, Maulana Azad Medical College and Associated ... sciatica and depression (Ghasemi et al., 2013; Barnes et .... environmental factors for each sampling site were also.

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

    Directory of Open Access Journals (Sweden)

    Fei-Yan Deng

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

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

    Science.gov (United States)

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

    2017-03-15

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

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

    Science.gov (United States)

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

    2014-06-16

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

  17. 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.

  18. Genetic association between leg conformation in young pigs and sow reproduction

    DEFF Research Database (Denmark)

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

    2015-01-01

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

  19. 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

    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......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...... endophenotypes showed moderate to high heritability (0.31-0.69) and small common environmental variance (0.05-0.21). In general, genetic and phenotypic correlations between the endophenotypes were strong only within sets of physiologically similar endophenotypes, but weak to moderate for other pairs...

  20. 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....

  1. A Genetic Analysis of Crystal Growth

    DEFF Research Database (Denmark)

    Brown, Stanley; Sarikaya, Mehmet; Johnson, E.

    2000-01-01

    The regulation of crystal morphology by proteins is often observed in biology. It is a central feature in the formation of hard tissues such as bones, teeth and mollusc shells. We have developed a genetic system in the bacterium Escherichia coli to study the protein-mediated control of crystal...

  2. 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

    2016-01-09

    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. 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. 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 inflammatory bowel disease showed strong association with

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

    Science.gov (United States)

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

    2017-09-01

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

  4. Identification of genetic variants associated with Huntington's disease progression

    DEFF Research Database (Denmark)

    Hensman Moss, Davina J; Pardiñas, Antonio F; Langbehn, Douglas

    2017-01-01

    indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008-11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers...... in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression......BACKGROUND: Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate...

  5. Analysis of the genetic diversity of four rabbit genotypes using ...

    African Journals Online (AJOL)

    Dr.Ola

    2013-05-15

    May 15, 2013 ... consumption and low cost, it has been widely utilized in genetics analysis in ... isozyme variation among the selected individuals within each rabbit genotype. ... with different embryo survival (Bolet and Theau-Clement, 1994).

  6. Genetic analysis of a consanguineous Pakistani family with Leber ...

    Indian Academy of Sciences (India)

    2014-08-01

    Aug 1, 2014 ... RESEARCH NOTE. Genetic analysis of a consanguineous Pakistani family with Leber .... representation of the deleterious mutation at genomic and protein level. ... In the last couple of years, numerous mutations in. GUCY2D ...

  7. A genetic analysis of segregation distortion revealed by molecular ...

    Indian Academy of Sciences (India)

    Journal of Genetics, Vol. 90, No. ... Segregation analysis was based on 64 molecular markers, including 26 .... FHB of RIL populations was controlled by quantitative trait ... The authors acknowledge financial support by the National Basic.

  8. Analysis of genetic diversity in mango ( Mangifera indica L.) using ...

    African Journals Online (AJOL)

    Analysis of genetic diversity in mango ( Mangifera indica L.) using isozymetic polymorphism. ... All the isozymes, used in the present study showed polymorphism for mango. A total of 25 different electrophoretic ... HOW TO USE AJOL.

  9. Phenotypic and molecular genetic analysis of Pyruvate Kinase ...

    African Journals Online (AJOL)

    Phenotypic and molecular genetic analysis of Pyruvate Kinase deficiency in a Tunisian family. Jaouani Mouna, Hamdi Nadia, Chaouch Leila, Kalai Miniar, Mellouli Fethi, Darragi Imen, Boudriga Imen, Chaouachi Dorra, Bejaoui Mohamed, Abbes Salem ...

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

    Science.gov (United States)

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

    2016-01-01

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

  11. Fatty Acid Diversity is Not Associated with Neutral Genetic Diversity in Native Populations of the Biodiesel Plant Jatropha curcas L.

    Science.gov (United States)

    Martínez-Díaz, Yesenia; González-Rodríguez, Antonio; Rico-Ponce, Héctor Rómulo; Rocha-Ramírez, Víctor; Ovando-Medina, Isidro; Espinosa-García, Francisco J

    2017-01-01

    Jatropha curcas L. (Euphorbiaceae) is a shrub native to Mexico and Central America, which produces seeds with a high oil content that can be converted to biodiesel. The genetic diversity of this plant has been widely studied, but it is not known whether the diversity of the seed oil chemical composition correlates with neutral genetic diversity. The total seed oil content, the diversity of profiles of fatty acids and phorbol esters were quantified, also, the genetic diversity obtained from simple sequence repeats was analyzed in native populations of J. curcas in Mexico. Using the fatty acids profiles, a discriminant analysis recognized three groups of individuals according to geographical origin. Bayesian assignment analysis revealed two genetic groups, while the genetic structure of the populations could not be explained by isolation-by-distance. Genetic and fatty acid profile data were not correlated based on Mantel test. Also, phorbol ester content and genetic diversity were not associated. Multiple linear regression analysis showed that total oil content was associated with altitude and seasonality of temperature. The content of unsaturated fatty acids was associated with altitude. Therefore, the cultivation planning of J. curcas should take into account chemical variation related to environmental factors. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

  12. FGWAS: Functional genome wide association analysis.

    Science.gov (United States)

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

    2017-10-01

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

  13. Genetic Variants Associated with Hyperandrogenemia in PCOS Pathophysiology

    Science.gov (United States)

    2018-01-01

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

  14. Genetic Variants Associated with Hyperandrogenemia in PCOS Pathophysiology

    Directory of Open Access Journals (Sweden)

    Roshan Dadachanji

    2018-01-01

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

  15. Genetic analysis of sunflower chlorophyll mutants

    International Nuclear Information System (INIS)

    Mashkina, E.V.; Guskov, E.P.

    2001-01-01

    The method of getting the chlorophyll mutations in sunflower was developed by Y.D. Beletskii in 1969 with the use of N-nitroso-N-methylurea (NMH). Certain concentrations of NMH are known to induce plastid mutations in growing seeds, and their yield depends on the duration of the exposure. The given work presented studies on the influence of rifampicin (R) and 2,4-dinitrophenol (DNP) on the genetic activity NMH, as an inductor of plastid and nuclear mutations

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

    Science.gov (United States)

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

    2018-01-01

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

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

    DEFF Research Database (Denmark)

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

    2017-01-01

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

  18. Genetic analysis of superovulatory response of Holstein cows in Canada.

    Science.gov (United States)

    Jaton, C; Koeck, A; Sargolzaei, M; Malchiodi, F; Price, C A; Schenkel, F S; Miglior, F

    2016-05-01

    Superovulation of dairy cattle is frequently used in Canada. The cost of this protocol is high, and so is the variability of the outcome. Knowing the superovulatory potential of a donor cow could influence the breeder's decision to superovulate it or not. The main objective of this study was to perform a genetic analysis for superovulatory response of Holstein cows in Canada using data recorded by Holstein Canada, and to investigate if these data could be used for genetic evaluation. Data contained the total number of embryos and the number of viable embryos from every successful flushing performed across Canada. After editing, 137,446 records of superovulation performed between 1992 and 2014 were analyzed. A univariate repeatability animal model analysis was performed for both total number of embryos and number of viable embryos. Because both data and residuals did not follow a normal distribution, records were subject to either logarithmic or Anscombe transformation. Using logarithmic transformation, heritability estimates (SE) of 0.15 (0.01) and 0.14 (0.01) were found for total number of embryos and number of viable embryos, respectively. Using Anscombe transformation, heritability estimates (SE) of 0.17 (0.01) and 0.14 (0.01) were found for total number of embryos and number of viable embryos, respectively. The genetic correlation between the 2 traits was estimated at 0.97 using logarithmic transformation and 0.95 using Anscombe transformation. Breeding values were estimated for 54,463 cows, and 3,513 sires. Only estimated breeding values of sires having a reliability higher than 40% were considered for estimated breeding values correlations with other routinely evaluated traits. The results showed that selection for a higher response to superovulation would lead to a slight decrease in milk production, but an improvement for functional traits, including all reproduction traits. In all cases, the estimated correlations are either low or modest. We conclude that

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

    Directory of Open Access Journals (Sweden)

    Umaima Al-Alem

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

  20. Evidence for genetic association of RORB with bipolar disorder

    Directory of Open Access Journals (Sweden)

    Mick Eric

    2009-11-01

    Full Text Available Abstract Background Bipolar disorder, particularly in children, is characterized by rapid cycling and switching, making circadian clock genes plausible molecular underpinnings for bipolar disorder. We previously reported work establishing mice lacking the clock gene D-box binding protein (DBP as a stress-reactive genetic animal model of bipolar disorder. Microarray studies revealed that expression of two closely related clock genes, RAR-related orphan receptors alpha (RORA and beta (RORB, was altered in these mice. These retinoid-related receptors are involved in a number of pathways including neurogenesis, stress response, and modulation of circadian rhythms. Here we report association studies between bipolar disorder and single-nucleotide polymorphisms (SNPs in RORA and RORB. Methods We genotyped 355 RORA and RORB SNPs in a pediatric cohort consisting of a family-based sample of 153 trios and an independent, non-overlapping case-control sample of 152 cases and 140 controls. Bipolar disorder in children and adolescents is characterized by increased stress reactivity and frequent episodes of shorter duration; thus our cohort provides a potentially enriched sample for identifying genes involved in cycling and switching. Results We report that four intronic RORB SNPs showed positive associations with the pediatric bipolar phenotype that survived Bonferroni correction for multiple comparisons in the case-control sample. Three RORB haplotype blocks implicating an additional 11 SNPs were also associated with the disease in the case-control sample. However, these significant associations were not replicated in the sample of trios. There was no evidence for association between pediatric bipolar disorder and any RORA SNPs or haplotype blocks after multiple-test correction. In addition, we found no strong evidence for association between the age-at-onset of bipolar disorder with any RORA or RORB SNPs. Conclusion Our findings suggest that clock genes in

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

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

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

    NARCIS (Netherlands)

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

    2016-01-01

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

  3. Genetic associations with valvular calcification and aortic stenosis

    DEFF Research Database (Denmark)

    Thanassoulis, George; Campbell, Catherine Y; Owens, David S

    2013-01-01

    Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease.......Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease....

  4. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits.

    Directory of Open Access Journals (Sweden)

    Angelo Scuteri

    2007-07-01

    Full Text Available The obesity epidemic is responsible for a substantial economic burden in developed countries and is a major risk factor for type 2 diabetes and cardiovascular disease. The disease is the result not only of several environmental risk factors, but also of genetic predisposition. To take advantage of recent advances in gene-mapping technology, we executed a genome-wide association scan to identify genetic variants associated with obesity-related quantitative traits in the genetically isolated population of Sardinia. Initial analysis suggested that several SNPs in the FTO and PFKP genes were associated with increased BMI, hip circumference, and weight. Within the FTO gene, rs9930506 showed the strongest association with BMI (p = 8.6 x10(-7, hip circumference (p = 3.4 x 10(-8, and weight (p = 9.1 x 10(-7. In Sardinia, homozygotes for the rare "G" allele of this SNP (minor allele frequency = 0.46 were 1.3 BMI units heavier than homozygotes for the common "A" allele. Within the PFKP gene, rs6602024 showed very strong association with BMI (p = 4.9 x 10(-6. Homozygotes for the rare "A" allele of this SNP (minor allele frequency = 0.12 were 1.8 BMI units heavier than homozygotes for the common "G" allele. To replicate our findings, we genotyped these two SNPs in the GenNet study. In European Americans (N = 1,496 and in Hispanic Americans (N = 839, we replicated significant association between rs9930506 in the FTO gene and BMI (p-value for meta-analysis of European American and Hispanic American follow-up samples, p = 0.001, weight (p = 0.001, and hip circumference (p = 0.0005. We did not replicate association between rs6602024 and obesity-related traits in the GenNet sample, although we found that in European Americans, Hispanic Americans, and African Americans, homozygotes for the rare "A" allele were, on average, 1.0-3.0 BMI units heavier than homozygotes for the more common "G" allele. In summary, we have completed a whole genome-association scan for

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

    Directory of Open Access Journals (Sweden)

    Allen-Brady Kristina

    2007-11-01

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

  6. Reconciling genetic evolution and the associative learning account of mirror neurons through data-acquisition mechanisms.

    Science.gov (United States)

    Lotem, Arnon; Kolodny, Oren

    2014-04-01

    An associative learning account of mirror neurons should not preclude genetic evolution of its underlying mechanisms. On the contrary, an associative learning framework for cognitive development should seek heritable variation in the learning rules and in the data-acquisition mechanisms that construct associative networks, demonstrating how small genetic modifications of associative elements can give rise to the evolution of complex cognition.

  7. Multivariate Survival Mixed Models for Genetic Analysis of Longevity Traits

    DEFF Research Database (Denmark)

    Pimentel Maia, Rafael; Madsen, Per; Labouriau, Rodrigo

    2014-01-01

    A class of multivariate mixed survival models for continuous and discrete time with a complex covariance structure is introduced in a context of quantitative genetic applications. The methods introduced can be used in many applications in quantitative genetics although the discussion presented co...... applications. The methods presented are implemented in such a way that large and complex quantitative genetic data can be analyzed......A class of multivariate mixed survival models for continuous and discrete time with a complex covariance structure is introduced in a context of quantitative genetic applications. The methods introduced can be used in many applications in quantitative genetics although the discussion presented...... concentrates on longevity studies. The framework presented allows to combine models based on continuous time with models based on discrete time in a joint analysis. The continuous time models are approximations of the frailty model in which the hazard function will be assumed to be piece-wise constant...

  8. Multivariate Survival Mixed Models for Genetic Analysis of Longevity Traits

    DEFF Research Database (Denmark)

    Pimentel Maia, Rafael; Madsen, Per; Labouriau, Rodrigo

    2013-01-01

    A class of multivariate mixed survival models for continuous and discrete time with a complex covariance structure is introduced in a context of quantitative genetic applications. The methods introduced can be used in many applications in quantitative genetics although the discussion presented co...... applications. The methods presented are implemented in such a way that large and complex quantitative genetic data can be analyzed......A class of multivariate mixed survival models for continuous and discrete time with a complex covariance structure is introduced in a context of quantitative genetic applications. The methods introduced can be used in many applications in quantitative genetics although the discussion presented...... concentrates on longevity studies. The framework presented allows to combine models based on continuous time with models based on discrete time in a joint analysis. The continuous time models are approximations of the frailty model in which the hazard function will be assumed to be piece-wise constant...

  9. Schizophrenia genetic variants are not associated with intelligence

    DEFF Research Database (Denmark)

    Van Scheltinga, A.F.T.; Bakker, S.C.; Van Haren, N.E.M.

    2013-01-01

    BACKGROUND: Schizophrenia is associated with lower pre-morbid intelligence (IQ) in addition to (pre-morbid) cognitive decline. Both schizophrenia and IQ are highly heritable traits. Therefore, we hypothesized that genetic variants associated with schizophrenia, including copy number variants (CNVs......) and a polygenic schizophrenia (risk) score (PSS), may influence intelligence. Method IQ was estimated with the Wechsler Adult Intelligence Scale (WAIS). CNVs were determined from single nucleotide polymorphism (SNP) data using the QuantiSNP and PennCNV algorithms. For the PSS, odds ratios for genome-wide SNP data...... significantly more genes were disrupted by deletions in schizophrenia patients compared to controls (p = 0.009), there was no effect of CNV measures on IQ. The PSS was associated with disease status (R 2 = 0.055, p = 2.1 × 10-7) and with IQ in the entire sample (R 2 = 0.018, p = 0.0008) but the effect on IQ...

  10. Genetic Analysis of Micro-environmental Plasticity in Drosophila melanogaster

    DEFF Research Database (Denmark)

    Morgante, Fabio; Sorensen, Daniel A; Sørensen, Peter

    Quantitative genetic models recognize the potential for genotype by environment interaction, whereby different genotypes have different plastic responses to changes in macro-environmental conditions. Recently, it has been recognized that micro-environmental plasticity (‘residual’ variance) may also...... be genetically variable. This study utilized the Drosophila Genetic Reference Panel (DGRP) to accurately estimate the genetic variance of micro-environmental plasticity for chill coma recovery time and startle response. Estimates of broad sense heritabilities for both traits are substantial (from 0.51 to 0.......77), of the same order as the heritability at the level of the trait mean for startle response and even larger for chill coma recovery. Genome wide association analyses identified molecular variants (from 15 to 31 depending on the sex and the trait) associated with micro-environmental plasticity. These findings...

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

    Science.gov (United States)

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

    2017-01-01

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

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

    Science.gov (United States)

    Langlais, David; Fodil, Nassima; Gros, Philippe

    2017-04-26

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

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

    Science.gov (United States)

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

    2018-01-01

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

  14. Association of a body mass index genetic risk score with growth throughout childhood and adolescence.

    Directory of Open Access Journals (Sweden)

    Nicole M Warrington

    Full Text Available While the number of established genetic variants associated with adult body mass index (BMI is growing, the relationships between these variants and growth during childhood are yet to be fully characterised. We examined the association between validated adult BMI associated single nucleotide polymorphisms (SNPs and growth trajectories across childhood. We investigated the timing of onset of the genetic effect and whether it was sex specific.Children from the ALSPAC and Raine birth cohorts were used for analysis (n = 9,328. Genotype data from 32 adult BMI associated SNPs were investigated individually and as an allelic score. Linear mixed effects models with smoothing splines were used for longitudinal modelling of the growth parameters and measures of adiposity peak and rebound were derived.The allelic score was associated with BMI growth throughout childhood, explaining 0.58% of the total variance in BMI in females and 0.44% in males. The allelic score was associated with higher BMI at the adiposity peak (females  =  0.0163 kg/m(2 per allele, males  =  0.0123 kg/m(2 per allele and earlier age (-0.0362 years per allele in males and females and higher BMI (0.0332 kg/m(2 per allele in females and 0.0364 kg/m(2 per allele in males at the adiposity rebound. No gene:sex interactions were detected for BMI growth.This study suggests that known adult genetic determinants of BMI have observable effects on growth from early childhood, and is consistent with the hypothesis that genetic determinants of adult susceptibility to obesity act from early childhood and develop over the life course.

  15. Lack of Association of CD55 Receptor Genetic Variants and Severe Malaria in Ghanaian Children

    Directory of Open Access Journals (Sweden)

    Kathrin Schuldt

    2017-03-01

    Full Text Available In a recent report, the cellular receptor CD55 was identified as a molecule essential for the invasion of human erythrocytes by Plasmodium falciparum, the causal agent of the most severe form of malaria. As this invasion process represents a critical step during infection with the parasite, it was hypothesized that genetic variants in the gene could affect severe malaria (SM susceptibility. We performed high-resolution variant discovery of rare and common genetic variants in the human CD55 gene. Association testing of these variants in over 1700 SM cases and unaffected control individuals from the malaria-endemic Ashanti Region in Ghana, West Africa, were performed on the basis of single variants, combined rare variant analyses, and reconstructed haplotypes. A total of 26 genetic variants were detected in coding and regulatory regions of CD55. Five variants were previously unknown. None of the single variants, rare variants, or haplotypes showed evidence for association with SM or P. falciparum density. Here, we present the first comprehensive analysis of variation in the CD55 gene in the context of SM and show that genetic variants present in a Ghanaian study group appear not to influence susceptibility to the disease.

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

    Science.gov (United States)

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

    2014-01-01

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

  17. First Analysis of the Association Between CYP3A4/5, ABCB1 Genetic Polymorphisms and Oxcarbazepine Metabolism and Transport in Chinese Epileptic Patients with Oxcarbazepine Monotherapy and Bitherapy.

    Science.gov (United States)

    Wang, Ping; Yin, Tao; Ma, Hong-ying; Liu, Dan-Qi; Sheng, Yangh-ao; Zhou, Bo-Ting

    2015-01-01

    Oxcarbazepine (OXC) is widely used in anti-epileptic treatment. Cytochrome P450 3A4 (CYP3A4), cytochrome P450 3A5(CYP3A5), and ATP-binding cassette sub-family B member 1 (ABCB1) are potential genes involved in OXC metabolisms and transport in vivo. This study aims to examine the genetic effects of CYP3A4, CYP3A5, and ABCB1 on OXC metabolism and transport in Chinese epileptic patients using OXC as monotherapy and bitherapy with lamotrigine (LTG), levetiracetam (LEV), or valproic acid (VPA). Sixty-six Chinese epileptic patients were recruited from Xiangya Hospital Central South University, of whom 40 patients were receiving OXC monotherapy, 11 patients were placed in the OXC bitherapy group combined with one enzyme-inducing anti-epileptic drugs (LTG or LEV), and 15 patients were placed in the OXC bitherapy group combined with VPA. Oxcarbazepine and its main metabolite 10-hydrocarbazepine (MHD) plasma concentrations were measured using high performance liquid chromatography (HPLC)-UV method. In addition, eight single nucleotide polymorphisms (SNPs) in CYP3A4, CYP3A5, ABCB1 gene were genotyped by polymerase chain reaction-improved multiple ligase detection reaction (PCR-iMLDR). In the OXC+VPA group, ABCB1 rs2032582 and rs2032582-rs10234411-rs1045642 TAG haplotype were associated with MHD and MHD+OXC plasma concentration before permutation test. In OXC monotherapy and OXC+ LTG/LEV groups, no significant association between genetic polymorphisms in CYP3A4/5, ABCB1 gene and OXC plasma concentration parameters were observed. CYP3A4/5 and ABCB1 genetic variants might not take part in the metabolism and transport of MHD and OXC among epileptic patients using OXC monotherapy and bitherapy in combination with LEV, LTG or VPA.

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

  20. Integrative genomic analysis identifies ancestry-related expression quantitative trait loci on DNA polymerase β and supports the association of genetic ancestry with survival disparities in head and neck squamous cell carcinoma.

    Science.gov (United States)

    Ramakodi, Meganathan P; Devarajan, Karthik; Blackman, Elizabeth; Gibbs, Denise; Luce, Danièle; Deloumeaux, Jacqueline; Duflo, Suzy; Liu, Jeffrey C; Mehra, Ranee; Kulathinal, Rob J; Ragin, Camille C

    2017-03-01

    African Americans with head and neck squamous cell carcinoma (HNSCC) have a lower survival rate than whites. This study investigated the functional importance of ancestry-informative single-nucleotide polymorphisms (SNPs) in HNSCC and also examined the effect of functionally important genetic elements on racial disparities in HNSCC survival. Ancestry-informative SNPs, RNA sequencing, methylation, and copy number variation data for 316 oral cavity and laryngeal cancer patients were analyzed across 178 DNA repair genes. The results of expression quantitative trait locus (eQTL) analyses were also replicated with a Gene Expression Omnibus (GEO) data set. The effects of eQTLs on overall survival (OS) and disease-free survival (DFS) were evaluated. Five ancestry-related SNPs were identified as cis-eQTLs in the DNA polymerase β (POLB) gene (false discovery rate [FDR] ancestry (P = .002). An association was observed between these eQTLs and OS (P ancestry-related alleles could act as eQTLs in HNSCC and support the association of ancestry-related genetic factors with survival disparities in patients diagnosed with oral cavity and laryngeal cancer. Cancer 2017;123:849-60. © 2016 American Cancer Society. © 2016 American Cancer Society.

  1. Polyglot programming in applications used for genetic data analysis.

    Science.gov (United States)

    Nowak, Robert M

    2014-01-01

    Applications used for the analysis of genetic data process large volumes of data with complex algorithms. High performance, flexibility, and a user interface with a web browser are required by these solutions, which can be achieved by using multiple programming languages. In this study, I developed a freely available framework for building software to analyze genetic data, which uses C++, Python, JavaScript, and several libraries. This system was used to build a number of genetic data processing applications and it reduced the time and costs of development.

  2. COMPARITIVE GENETIC DIVERSITY ANALYSIS OF OAT (Avena ...

    African Journals Online (AJOL)

    knsccf

    protein and 30 to 35% dry matter. ... environment interaction, hence not much dependable but ... Principal coordinate (3D) analysis was .... Relationships among 20 genotypes of oat visualized by principal component analysis (PCoA) of rainfed ...

  3. Identifying genetic marker sets associated with phenotypes via an efficient adaptive score test

    KAUST Repository

    Cai, T.

    2012-06-25

    In recent years, genome-wide association studies (GWAS) and gene-expression profiling have generated a large number of valuable datasets for assessing how genetic variations are related to disease outcomes. With such datasets, it is often of interest to assess the overall effect of a set of genetic markers, assembled based on biological knowledge. Genetic marker-set analyses have been advocated as more reliable and powerful approaches compared with the traditional marginal approaches (Curtis and others, 2005. Pathways to the analysis of microarray data. TRENDS in Biotechnology 23, 429-435; Efroni and others, 2007. Identification of key processes underlying cancer phenotypes using biologic pathway analysis. PLoS One 2, 425). Procedures for testing the overall effect of a marker-set have been actively studied in recent years. For example, score tests derived under an Empirical Bayes (EB) framework (Liu and others, 2007. Semiparametric regression of multidimensional genetic pathway data: least-squares kernel machines and linear mixed models. Biometrics 63, 1079-1088; Liu and others, 2008. Estimation and testing for the effect of a genetic pathway on a disease outcome using logistic kernel machine regression via logistic mixed models. BMC bioinformatics 9, 292-2; Wu and others, 2010. Powerful SNP-set analysis for case-control genome-wide association studies. American Journal of Human Genetics 86, 929) have been proposed as powerful alternatives to the standard Rao score test (Rao, 1948. Large sample tests of statistical hypotheses concerning several parameters with applications to problems of estimation. Mathematical Proceedings of the Cambridge Philosophical Society, 44, 50-57). The advantages of these EB-based tests are most apparent when the markers are correlated, due to the reduction in the degrees of freedom. In this paper, we propose an adaptive score test which up- or down-weights the contributions from each member of the marker-set based on the Z-scores of

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

    Science.gov (United States)

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

    2016-01-01

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

  5. Parameter determination for quantitative PIXE analysis using genetic algorithms

    International Nuclear Information System (INIS)

    Aspiazu, J.; Belmont-Moreno, E.

    1996-01-01

    For biological and environmental samples, PIXE technique is in particular advantage for elemental analysis, but the quantitative analysis implies accomplishing complex calculations that require the knowledge of more than a dozen parameters. Using a genetic algorithm, the authors give here an account of the procedure to obtain the best values for the parameters necessary to fit the efficiency for a X-ray detector. The values for some variables involved in quantitative PIXE analysis, were manipulated in a similar way as the genetic information is treated in a biological process. The authors carried out the algorithm until they reproduce, within the confidence interval, the elemental concentrations corresponding to a reference material

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

    Directory of Open Access Journals (Sweden)

    Wing Kam Fung

    2010-02-01

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

  7. Genetic Variants Associated with Gestational Hypertriglyceridemia and Pancreatitis.

    Directory of Open Access Journals (Sweden)

    Sai-Li Xie

    Full Text Available Severe hypertriglyceridemia is a well-known cause of pancreatitis. Usually, there is a moderate increase in plasma triglyceride level during pregnancy. Additionally, certain pre-existing genetic traits may render a pregnant woman susceptible to development of severe hypertriglyceridemia and pancreatitis, especially in the third trimester. To elucidate the underlying mechanism of gestational hypertriglyceridemic pancreatitis, we undertook DNA mutation analysis of the lipoprotein lipase (LPL, apolipoprotein C2 (APOC2, apolipoprotein A5 (APOA5, lipase maturation factor 1 (LMF1, and glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1 genes in five unrelated pregnant Chinese women with severe hypertriglyceridemia and pancreatitis. DNA sequencing showed that three out of five patients had the same homozygous variation, p.G185C, in APOA5 gene. One patient had a compound heterozygous mutation, p.A98T and p.L279V, in LPL gene. Another patient had a compound heterozygous mutation, p.A98T & p.C14F in LPL and GPIHBP1 gene, respectively. No mutations were seen in APOC2 or LMF1 genes. All patients were diagnosed with partial LPL deficiency in non-pregnant state. As revealed in our study, genetic variants appear to play an important role in the development of severe gestational hypertriglyceridemia, and, p.G185C mutation in APOA5 gene appears to be the most common variant implicated in the Chinese population. Antenatal screening for mutations in susceptible women, combined with subsequent interventions may be invaluable in the prevention of potentially life threatening gestational hypertriglyceridemia-induced pancreatitis.

  8. Genetic Variants Associated with Gestational Hypertriglyceridemia and Pancreatitis

    Science.gov (United States)

    Huang, Xie-Lin; Chen, Chao; Jin, Rong; Huang, Zhi-Ming; Zhou, Meng-Tao

    2015-01-01

    Severe hypertriglyceridemia is a well-known cause of pancreatitis. Usually, there is a moderate increase in plasma triglyceride level during pregnancy. Additionally, certain pre-existing genetic traits may render a pregnant woman susceptible to development of severe hypertriglyceridemia and pancreatitis, especially in the third trimester. To elucidate the underlying mechanism of gestational hypertriglyceridemic pancreatitis, we undertook DNA mutation analysis of the lipoprotein lipase (LPL), apolipoprotein C2 (APOC2), apolipoprotein A5 (APOA5), lipase maturation factor 1 (LMF1), and glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) genes in five unrelated pregnant Chinese women with severe hypertriglyceridemia and pancreatitis. DNA sequencing showed that three out of five patients had the same homozygous variation, p.G185C, in APOA5 gene. One patient had a compound heterozygous mutation, p.A98T and p.L279V, in LPL gene. Another patient had a compound heterozygous mutation, p.A98T & p.C14F in LPL and GPIHBP1 gene, respectively. No mutations were seen in APOC2 or LMF1 genes. All patients were diagnosed with partial LPL deficiency in non-pregnant state. As revealed in our study, genetic variants appear to play an important role in the development of severe gestational hypertriglyceridemia, and, p.G185C mutation in APOA5 gene appears to be the most common variant implicated in the Chinese population. Antenatal screening for mutations in susceptible women, combined with subsequent interventions may be invaluable in the prevention of potentially life threatening gestational hypertriglyceridemia-induced pancreatitis. PMID:26079787

  9. Prevotella as a Hub for Vaginal Microbiota under the Influence of Host Genetics and Their Association with Obesity.

    Science.gov (United States)

    Si, Jiyeon; You, Hyun Ju; Yu, Junsun; Sung, Joohon; Ko, GwangPyo

    2017-01-11

    While the vaginal ecosystem is maintained through mutualistic relationships between the host and the vaginal bacteria, the effect of host genetics on the vaginal microbiota has not been well characterized. We examined the heritability of vaginal microbiota and its association with obesity in 542 Korean females, including 222 monozygotic and 56 dizygotic twins. The vaginal microbiota significantly varied depending on host menopausal status and bacterial vaginosis. Lactobacillus and Prevotella, whose relative abundances are strongly associated with bacterial vaginosis, were the most heritable bacteria among the beneficial and potentially pathogenic vaginal microbiota, respectively. Candidate gene analysis revealed an association between genetic variants of interleukin-5 and the abundance of Prevotella sp. Furthermore, host obesity significantly increased the diversity of the vaginal microbiota in association with Prevotella. Our results provide insight into the effect of host genetics on the vaginal microbiota and their association with both vaginal and non-vaginal health. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. 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 Studies1234

    Science.gov (United States)

    Hruby, Adela; Ngwa, Julius S.; Renström, Frida; Wojczynski, Mary K.; Ganna, Andrea; Hallmans, Göran; Houston, Denise K.; Jacques, Paul F.; Kanoni, Stavroula; Lehtimäki, Terho; Lemaitre, Rozenn N.; Manichaikul, Ani; North, Kari E.; Ntalla, Ioanna; Sonestedt, Emily; Tanaka, Toshiko; van Rooij, Frank J. A.; Bandinelli, Stefania; Djoussé, Luc; Grigoriou, Efi; Johansson, Ingegerd; Lohman, Kurt K.; Pankow, James S.; Raitakari, Olli T.; Riserus, Ulf; Yannakoulia, Mary; Zillikens, M. Carola; Hassanali, Neelam; Liu, Yongmei; Mozaffarian, Dariush; Papoutsakis, Constantina; Syvänen, Ann-Christine; Uitterlinden, André G.; Viikari, Jorma; Groves, Christopher J.; Hofman, Albert; Lind, Lars; McCarthy, Mark I.; Mikkilä, Vera; Mukamal, Kenneth; Franco, Oscar H.; Borecki, Ingrid B.; Cupples, L. Adrienne; Dedoussis, George V.; Ferrucci, Luigi; Hu, Frank B.; Ingelsson, Erik; Kähönen, Mika; Kao, W. H. Linda; Kritchevsky, Stephen B.; Orho-Melander, Marju; Prokopenko, Inga; Rotter, Jerome I.; Siscovick, David S.; Witteman, Jacqueline C. M.; Franks, Paul W.; Meigs, James B.; McKeown, Nicola M.; Nettleton, Jennifer A.

    2013-01-01

    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) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (ln-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [β = −0.009 mmol/L (95% CI: −0.013, −0.005), P magnesium-related SNP or interaction between any SNP and magnesium reached significance after correction for multiple testing. However, rs2274924 in magnesium transporter-encoding TRPM6 showed a nominal association (uncorrected P = 0.03) with glucose, and rs11558471 in SLC30A8 and rs3740393 near CNNM2 showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with other studies, a higher magnesium intake was associated with lower fasting glucose and insulin. Nominal evidence of TRPM6 influence and magnesium interaction with select loci suggests that further investigation is warranted. PMID:23343670

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

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

    2016-05-01

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

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

    Directory of Open Access Journals (Sweden)

    Robert Michael Cronin

    2014-08-01

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

  14. The Genetic Association Between Neocortical Volume and General Cognitive Ability Is Driven by Global Surface Area Rather Than Thickness.

    Science.gov (United States)

    Vuoksimaa, Eero; Panizzon, Matthew S; Chen, Chi-Hua; Fiecas, Mark; Eyler, Lisa T; Fennema-Notestine, Christine; Hagler, Donald J; Fischl, Bruce; Franz, Carol E; Jak, Amy; Lyons, Michael J; Neale, Michael C; Rinker, Daniel A; Thompson, Wesley K; Tsuang, Ming T; Dale, Anders M; Kremen, William S

    2015-08-01

    Total gray matter volume is associated with general cognitive ability (GCA), an association mediated by genetic factors. It is expectable that total neocortical volume should be similarly associated with GCA. Neocortical volume is the product of thickness and surface area, but global thickness and surface area are unrelated phenotypically and genetically in humans. The nature of the genetic association between GCA and either of these 2 cortical dimensions has not been examined. Humans possess greater cognitive capacity than other species, and surface area increases appear to be the primary driver of the increased size of the human cortex. Thus, we expected neocortical surface area to be more strongly associated with cognition than thickness. Using multivariate genetic analysis in 515 middle-aged twins, we demonstrated that both the phenotypic and genetic associations between neocortical volume and GCA are driven primarily by surface area rather than thickness. Results were generally similar for each of 4 specific cognitive abilities that comprised the GCA measure. Our results suggest that emphasis on neocortical surface area, rather than thickness, could be more fruitful for elucidating neocortical-GCA associations and identifying specific genes underlying those associations. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  15. Genetic Diversity of Rose germplasm based on RAPD analysis

    African Journals Online (AJOL)

    AHSAN IQBAL

    2012-06-12

    Jun 12, 2012 ... identification and analysis of genetic variation within a collection of 4 species and 30 accessions of rose using RAPD analysis technique. The results showed the molecular distinctions among the ... that range in colour from white and yellow to many shades of pink and red have been developed. Since.

  16. Genetic data analysis for plant and animal breeding

    Science.gov (United States)

    This book is an advanced textbook covering the application of quantitative genetics theory to analysis of actual data (both trait and DNA marker information) for breeding populations of crops, trees, and animals. Chapter 1 is an introduction to basic software used for trait data analysis. Chapter 2 ...

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

    Directory of Open Access Journals (Sweden)

    Amanda A Fox

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

  18. Genetic Associations with Gestational Duration and Spontaneous Preterm Birth

    DEFF Research Database (Denmark)

    Zhang, G.; Feenstra, B.; Bacelis, J.

    2017-01-01

    . 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 (... of 8643 women) to test for replication of genomic loci that had significant genomewide association (Pdiscovery set. RESULTS: In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were...... significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence...

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

    NARCIS (Netherlands)

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

    2011-01-01

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

  20. Feto-maternal haemorrhage associated with genetic amniocentesis

    DEFF Research Database (Denmark)

    Tabor, A; Bang, J; Nørgaard-Pedersen, B

    1987-01-01

    Maternal serum alpha-fetoprotein (AFP) levels were determined before and after genetic amniocentesis (n = 283) or ultrasound scan (n = 268) in a group of women participating in a randomized trial of genetic amniocentesis. Increases in AFP levels were seen significantly more often after amniocente......Maternal serum alpha-fetoprotein (AFP) levels were determined before and after genetic amniocentesis (n = 283) or ultrasound scan (n = 268) in a group of women participating in a randomized trial of genetic amniocentesis. Increases in AFP levels were seen significantly more often after...

  1. Genetics Home Reference: PDGFRA-associated chronic eosinophilic leukemia

    Science.gov (United States)

    ... link) Genetic Testing Registry: Idiopathic hypereosinophilic syndrome Other Diagnosis and Management Resources (3 links) Cancer.Net: Leukemia - Eosinophilic: Treatment MedlinePlus Encyclopedia: Eosinophil Count - Absolute Seattle ...

  2. Association of systemic lupus erythematosus clinical features with European population genetic substructure.

    Directory of Open Access Journals (Sweden)

    Elisa Alonso-Perez

    Full Text Available Systemic Lupus Erythematosus (SLE is an autoimmune disease with a very varied spectrum of clinical manifestations that could be partly determined by genetic factors. We aimed to determine the relationship between prevalence of 11 clinical features and age of disease onset with European population genetic substructure. Data from 1413 patients of European ancestry recruited in nine countries was tested for association with genotypes of top ancestry informative markers. This analysis was done with logistic regression between phenotypes and genotypes or principal components extracted from them. We used a genetic additive model and adjusted for gender and disease duration. Three clinical features showed association with ancestry informative markers: autoantibody production defined as immunologic disorder (P = 6.8×10(-4, oral ulcers (P = 6.9×10(-4 and photosensitivity (P = 0.002. Immunologic disorder was associated with genotypes more common in Southern European ancestries, whereas the opposite trend was observed for photosensitivity. Oral ulcers were specifically more common in patients of Spanish and Portuguese self-reported ancestry. These results should be taken into account in future research and suggest new hypotheses and possible underlying mechanisms to be investigated. A first hypothesis linking photosensitivity with variation in skin pigmentation is suggested.

  3. Association of Systemic Lupus Erythematosus Clinical Features with European Population Genetic Substructure

    Science.gov (United States)

    Calaza, Manuel; Witte, Torsten; Papasteriades, Chryssa; Marchini, Maurizio; Migliaresi, Sergio; Kovacs, Attila; Ordi-Ros, Josep; Bijl, Marc; Santos, Maria Jose; Ruzickova, Sarka; Pullmann, Rudolf; Carreira, Patricia; Skopouli, Fotini N.; D'Alfonso, Sandra; Sebastiani, Gian Domenico; Suarez, Ana; Blanco, Francisco J.; Gomez-Reino, Juan J.; Gonzalez, Antonio

    2011-01-01

    Systemic Lupus Erythematosus (SLE) is an autoimmune disease with a very varied spectrum of clinical manifestations that could be partly determined by genetic factors. We aimed to determine the relationship between prevalence of 11 clinical features and age of disease onset with European population genetic substructure. Data from 1413 patients of European ancestry recruited in nine countries was tested for association with genotypes of top ancestry informative markers. This analysis was done with logistic regression between phenotypes and genotypes or principal components extracted from them. We used a genetic additive model and adjusted for gender and disease duration. Three clinical features showed association with ancestry informative markers: autoantibody production defined as immunologic disorder (P = 6.8×10−4), oral ulcers (P = 6.9×10−4) and photosensitivity (P = 0.002). Immunologic disorder was associated with genotypes more common in Southern European ancestries, whereas the opposite trend was observed for photosensitivity. Oral ulcers were specifically more common in patients of Spanish and Portuguese self-reported ancestry. These results should be taken into account in future research and suggest new hypotheses and possible underlying mechanisms to be investigated. A first hypothesis linking photosensitivity with variation in skin pigmentation is suggested. PMID:22194982

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

    Science.gov (United States)

    2014-01-01

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

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

    Science.gov (United States)

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

    2018-04-01

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

  6. Timing Analysis of Genetic Logic Circuits using D-VASim

    DEFF Research Database (Denmark)

    Baig, Hasan; Madsen, Jan

    and propagation delay analysis of single as well as cascaded geneticlogic circuits can be performed. D-VASim allows user to change the circuit parameters during runtime simulation to observe its effectson circuit’s timing behavior. The results obtained from D-VASim can be used not only to characterize the timing...... delay analysis may play a very significant role in the designing of genetic logic circuits. In thisdemonstration, we present the capability of D-VASim (Dynamic Virtual Analyzer and Simulator) to perform the timing and propagationdelay analysis of genetic logic circuits. Using D-VASim, the timing...... behavior of geneticlogic circuits but also to analyze the timing constraints of cascaded genetic logic circuits....

  7. Identification of genetic factors associated with susceptibility to angiotensin-converting enzyme inhibitors-induced cough.

    Science.gov (United States)

    Grilo, Antonio; Sáez-Rosas, María P; Santos-Morano, Juan; Sánchez, Elena; Moreno-Rey, Concha; Real, Luis M; Ramírez-Lorca, Reposo; Sáez, María E

    2011-01-01

    Angiotensin-converting enzyme inhibitors (ACEi) are the first selected drugs for hypertensive patients because of its protective properties against heart and kidney diseases. Persistent cough is a common adverse reaction associated with ACEi, which can bind to the treatment cessation, but its etiology remains an unresolved issue. The most accepted mechanism is that the inhibition of ACEi increases kinins levels, resulting in the activation of proinflammatory mechanisms and nitric oxide generation. However, relatively little is known about the genetic susceptibility to ACEi-induced cough in hypertensive patients. We carried out a monogenic association analysis of 39 polymorphisms and haplotypes in genes encoding key proteins related to ACEi activity with the occurrence of ACEi-induced cough. We also carried out a digenic association analysis and investigated the existence of epistatic interactions between the analyzed polymorphisms using a logistic regression procedure. Finally, we investigated the predictive value of the identified associations for ACEi-induced cough. We found that genetic polymorphisms in MME [rs2016848, P=0.002, odds ratio (OR)=1.795], BDKRB2 (rs8012552, P=0.012, OR=1.609), PTGER3 (rs11209716, P=0.002, OR=0.565), and ACE (rs4344) genes are associated with ACEi-related cough. For the latter, the effect is sex specific, having a protective effect in males (P=0.027, OR=0.560) and increasing the risk in females (P=0.031, OR=1.847). In addition, genetic interactions between peptidases involved in kinins levels (CPN1 and XPNPEP1) and proteins related to prostaglandin metabolism (PTGIS and PTGIR) strongly modify the risk of ACEi-induced cough presentation (0.102≤OR≤0.384 for protective combinations and 2.732≤OR≤7.216 for risk combinations). These results are consistent with the hypothesis that the mechanism of cough is related to the accumulation of bradykinin, substance P, and prostaglandins.

  8. Genetic recombination is associated with intrinsic disorder in plant proteomes.

    Science.gov (United States)

    Yruela, Inmaculada; Contreras-Moreira, Bruno

    2013-11-09

    Intrinsically disordered proteins, found in all living organisms, are essential for basic cellular functions and complement the function of ordered proteins. It has been shown that protein disorder is linked to the G + C content of the genome. Furthermore, recent investigations have suggested that the evolutionary dynamics of the plant nucleus adds disordered segments to open reading frames alike, and these segments are not necessarily conserved among orthologous genes. In the present work the distribution of intrinsically disordered proteins along the chromosomes of several representative plants was analyzed. The reported results support a non-random distribution of disordered proteins along the chromosomes of Arabidopsis thaliana and Oryza sativa, two model eudicot and monocot plant species, respectively. In fact, for most chromosomes positive correlations between the frequency of disordered segments of 30+ amino acids and both recombination rates and G + C content were observed. These analyses demonstrate that the presence of disordered segments among plant proteins is associated with the rates of genetic recombination of their encoding genes. Altogether, these findings suggest that high recombination rates, as well as chromosomal rearrangements, could induce disordered segments in proteins during evolution.

  9. Statin-associated myopathy: from genetic predisposition to clinical management.

    Science.gov (United States)

    Vrablik, M; Zlatohlavek, L; Stulc, T; Adamkova, V; Prusikova, M; Schwarzova, L; Hubacek, J A; Ceska, R

    2014-01-01

    Statin-associated myopathy (SAM) represents a broad spectrum of disorders from insignificant myalgia to fatal rhabdomyolysis. Its frequency ranges from 1-5 % in clinical trials to 15-20 % in everyday clinical practice. To a large extent, these variations can be explained by the definition used. Thus, we propose a scoring system to classify statin-induced myopathy according to clinical and biochemical criteria as 1) possible, 2) probable or 3) definite. The etiology of this disorder remains poorly understood. Most probably, an underlying genetic cause is necessary for overt SAM to develop. Variants in a few gene groups that encode proteins involved in: i) statin metabolism and distribution (e.g. membrane transporters and enzymes; OATP1B1, ABCA1, MRP, CYP3A4), ii) coenzyme Q10 production (e.g. COQ10A and B), iii) energy metabolism of muscle tissue (e.g. PYGM, GAA, CPT2) and several others have been proposed as candidates which can predispose to SAM. Pharmacological properties of individual statin molecules (e.g. lipophilicity, excretion pathways) and patients´ characteristics influence the likelihood of SAM development. This review summarizes current data as well as our own results.

  10. Genetic variability and inter-character associations in the mutants of Indian mustard

    International Nuclear Information System (INIS)

    Labana, K.S.; Chaurasia, B.D.; Singh, Balwant

    1980-01-01

    To study the genetic variability and the inter-character associations in Indian mustard [Brassica juncea (Linn.)Czern. and Coss. subsp. juncea Linn.], 104 radiation-induced mutants (including 'RLM 198') and 'RL 18' were grown during winter season of 1976-77 at the experimental farm of the Punjab Agricultural University. Analysis of variance revealed significant differences between the mutant genotypes for all the characters under study except for the primary branch number and siliqua number of main shoot, which were non-significant. High estimates of phenotypic coefficients of variation (pcv) and genetic coefficients of variation (gcv) were observed for secondary branch number, seed yield/plant, main shoot length and seed number/siliqua. In general, pcv estimates were higher than gcv estimates. The high estimates of both heritability and genetic advance were recorded in similar order for the plant height, seed number/siliqua, main shoot length and seed yield, in which the genetic progress could be achieved through mass selection. Seed yield was positively correlated with the primary branch number, the secondary branch number and the siliqua number of main shoot and negatively with the plant height. Shorter plant height w;.th more number of primary and secondary branches and more siliquae on main shoot were found to be good selection criteria for isolating high-yielding strains. (auth.)

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

    Directory of Open Access Journals (Sweden)

    Martín J

    2005-08-01

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

  12. Genetic diversity patterns of arbuscular mycorrhizal fungi associated with the mycoheterotroph Arachnitis uniflora Phil. (Corsiaceae).

    Science.gov (United States)

    Renny, Mauricio; Acosta, M Cristina; Cofré, Noelia; Domínguez, Laura S; Bidartondo, Martin I; Sérsic, Alicia N

    2017-06-01

    Arachnitis uniflora is a mycoheterotrophic plant that exploits arbuscular mycorrhizal fungi of neighbouring plants. We tested A. uniflora 's specificity towards fungi across its large latitudinal range, as well as the role of historical events and current environmental, geographical and altitudinal variables on fungal genetic diversity. Arachnitis uniflora mycorrhizas were sampled at 25 sites. Fungal phylogenetic relationships were reconstructed, genetic diversity was calculated and the main divergent lineages were dated. Phylogeographical analysis was performed with the main fungal clade. Fungal diversity correlations with environmental factors were investigated. Glomeraceae fungi dominated, with a main clade that likely originated in the Upper Cretaceous and diversified in the Miocene. Two other arbuscular mycorrhizal fungal families not previously known to be targeted by A. uniflora were detected rarely and appear to be facultative associations. High genetic diversity, found in Bolivia and both northern and southern Patagonia, was correlated with temperature, rainfall and soil features. Fungal genetic diversity and its distribution can be explained by the ancient evolutionary history of the target fungi and by micro-scale environmental conditions with a geographical mosaic pattern. © The Author 2017. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For Permissions, please email: journals.permissions@oup.com

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

    Science.gov (United States)

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

    2014-12-01

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

  14. Genetic diversity analysis of common beans based on molecular markers

    Directory of Open Access Journals (Sweden)

    Homar R. Gill-Langarica

    Full Text Available A core collection of the common bean (Phaseolus vulgaris L., representing genetic diversity in the entire Mexican holding, is kept at the INIFAP (Instituto Nacional de Investigaciones Forestales, Agricolas y Pecuarias, Mexico Germplasm Bank. After evaluation, the genetic structure of this collection (200 accessions was compared with that of landraces from the states of Oaxaca, Chiapas and Veracruz (10 genotypes from each, as well as a further 10 cultivars, by means of four amplified fragment length polymorphisms (AFLP +3/+3 primer combinations and seven simple sequence repeats (SSR loci, in order to define genetic diversity, variability and mutual relationships. Data underwent cluster (UPGMA and molecular variance (AMOVA analyses. AFLP analysis produced 530 bands (88.5% polymorphic while SSR primers amplified 174 alleles, all polymorphic (8.2 alleles per locus. AFLP indicated that the highest genetic diversity was to be found in ten commercial-seed classes from two major groups of accessions from Central Mexico and Chiapas, which seems to be an important center of diversity in the south. A third group included genotypes from Nueva Granada, Mesoamerica, Jalisco and Durango races. Here, SSR analysis indicated a reduced number of shared haplotypes among accessions, whereas the highest genetic components of AMOVA variation were found within accessions. Genetic diversity observed in the common-bean core collection represents an important sample of the total Phaseolus genetic variability at the main Germplasm Bank of INIFAP. Molecular marker strategies could contribute to a better understanding of the genetic structure of the core collection as well as to its improvement and validation.

  15. Genetic diversity analysis of common beans based on molecular markers

    Directory of Open Access Journals (Sweden)

    Homar R. Gill-Langarica

    2011-01-01

    Full Text Available A core collection of the common bean (Phaseolus vulgaris L., representing genetic diversity in the entire Mexican holding, is kept at the INIFAP (Instituto Nacional de Investigaciones Forestales, Agricolas y Pecuarias, Mexico Germplasm Bank. After evaluation, the genetic structure of this collection (200 accessions was compared with that of landraces from the states of Oaxaca, Chiapas and Veracruz (10 genotypes from each, as well as a further 10 cultivars, by means of four amplified fragment length polymorphisms (AFLP +3/+3 primer combinations and seven simple sequence repeats (SSR loci, in order to define genetic diversity, variability and mutual relationships. Data underwent cluster (UPGMA and molecular variance (AMOVA analyses. AFLP analysis produced 530 bands (88.5% polymorphic while SSR primers amplified 174 alleles, all polymorphic (8.2 alleles per locus. AFLP indicated that the highest genetic diversity was to be found in ten commercial-seed classes from two major groups of accessions from Central Mexico and Chiapas, which seems to be an important center of diversity in the south. A third group included genotypes from Nueva Granada, Mesoamerica, Jalisco and Durango races. Here, SSR analysis indicated a reduced number of shared haplotypes among accessions, whereas the highest genetic components of AMOVA variation were found within accessions. Genetic diversity observed in the common-bean core collection represents an important sample of the total Phaseolus genetic variability at the main Germplasm Bank of INIFAP. Molecular marker strategies could contribute to a better understanding of the genetic structure of the core collection as well as to its improvement and validation.

  16. Genetic diversity analysis of common beans based on molecular markers.

    Science.gov (United States)

    Gill-Langarica, Homar R; Muruaga-Martínez, José S; Vargas-Vázquez, M L Patricia; Rosales-Serna, Rigoberto; Mayek-Pérez, Netzahualcoyotl

    2011-10-01

    A core collection of the common bean (Phaseolus vulgaris L.), representing genetic diversity in the entire Mexican holding, is kept at the INIFAP (Instituto Nacional de Investigaciones Forestales, Agricolas y Pecuarias, Mexico) Germplasm Bank. After evaluation, the genetic structure of this collection (200 accessions) was compared with that of landraces from the states of Oaxaca, Chiapas and Veracruz (10 genotypes from each), as well as a further 10 cultivars, by means of four amplified fragment length polymorphisms (AFLP) +3/+3 primer combinations and seven simple sequence repeats (SSR) loci, in order to define genetic diversity, variability and mutual relationships. Data underwent cluster (UPGMA) and molecular variance (AMOVA) analyses. AFLP analysis produced 530 bands (88.5% polymorphic) while SSR primers amplified 174 alleles, all polymorphic (8.2 alleles per locus). AFLP indicated that the highest genetic diversity was to be found in ten commercial-seed classes from two major groups of accessions from Central Mexico and Chiapas, which seems to be an important center of diversity in the south. A third group included genotypes from Nueva Granada, Mesoamerica, Jalisco and Durango races. Here, SSR analysis indicated a reduced number of shared haplotypes among accessions, whereas the highest genetic components of AMOVA variation were found within accessions. Genetic diversity observed in the common-bean core collection represents an important sample of the total Phaseolus genetic variability at the main Germplasm Bank of INIFAP. Molecular marker strategies could contribute to a better understanding of the genetic structure of the core collection as well as to its improvement and validation.

  17. Childhood constipation; an overview of genetic studies and associated syndromes

    NARCIS (Netherlands)

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

    2011-01-01

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

  18. Genetic differentiation in Elaeocarpus photiniifolia (Elaeocarpaceae) associated with geographic distribution and habitat variation in the Bonin (Ogasawara) Islands.

    Science.gov (United States)

    Sugai, Kyoko; Setsuko, Suzuki; Nagamitsu, Teruyoshi; Murakami, Noriaki; Kato, Hidetoshi; Yoshimaru, Hiroshi

    2013-11-01

    Gene flow between populations in different environmental conditions can be limited due to divergent natural selection, thus promoting genetic differentiation. Elaeocarpus photiniifolia, an endemic tree species in the Bonin Islands, is distributed in two types of habitats, dry scrubs and mesic forests. We aim to elucidate the genetic differentiation in E. photiniifolia within and between islands and between the habitat types. We investigated genotypes of 639 individuals from 19 populations of E. photiniifolia and its closely-related E. sylvestris at 24 microsatellite loci derived from expressed sequence tags. The data revealed genetic differentiation (1) between E. photiniifolia and E. sylvestris (0.307 ≤ F ST ≤ 0.470), (2) between the E. photiniifolia populations of the Chichijima and Hahajima Island Groups in the Bonin Islands (0.033 ≤ F ST ≤ 0.121) and (3) between E. photiniifolia populations associated with dry scrubs and mesic forests in the Chichijima Island Group (0.005 ≤ F ST ≤ 0.071). Principal coordinate analysis and Bayesian clustering analysis also showed that genetically distinct groups were associated with the habitat types, and isolation by distance was not responsible for the genetic differentiation. These findings suggest that E. photiniifolia is divided into genetically differentiated groups associated with different environmental conditions in the Bonin Islands.

  19. Is an Early Age at Illness Onset in Schizophrenia Associated With Increased Genetic Susceptibility?

    DEFF Research Database (Denmark)

    Hilker, Rikke; Helenius, Dorte; Fagerlund, Birgitte

    2017-01-01

    with schizophrenia spectrum) and a subsample of N = 448 (affected with schizophrenia). Survival analysis was applied to investigate the effect of age at illness onset. Findings We found that early age at illness onset compared to later onset in the first diagnosed twin can be considered a major risk factor......Background Early age at illness onset has been viewed as an important liability marker for schizophrenia, which may be associated with an increased genetic vulnerability. A twin approach can be valuable, because it allows for the investigation of specific illness markers in individuals...... with a shared genetic background. Methods We linked nationwide registers to identify a cohort of twin pairs born in Denmark from 1951 to 2000 (N = 31,524 pairs), where one or both twins had a diagnosis in the schizophrenia spectrum. We defined two groups consisting of; N = 788 twin pairs (affected...

  20. Complex Multi-Block Analysis Identifies New Immunologic and Genetic Disease Progression Patterns Associated with the Residual β-Cell Function 1 Year after Diagnosis of Type 1 Diabetes

    Science.gov (United States)

    Andersen, Marie Louise Max; Rasmussen, Morten Arendt; Pörksen, Sven; Svensson, Jannet; Vikre-Jørgensen, Jennifer; Thomsen, Jane; Hertel, Niels Thomas; Johannesen, Jesper; Pociot, Flemming; Petersen, Jacob Sten; Hansen, Lars; Mortensen, Henrik Bindesbøl; Nielsen, Lotte Brøndum

    2013-01-01

    The purpose of the present study is to explore the progression of type 1 diabetes (T1D) in Danish children 12 months after diagnosis using Latent Factor Modelling. We include three data blocks of dynamic paraclinical biomarkers, baseline clinical characteristics and genetic profiles of diabetes related SNPs in the analyses. This method identified a model explaining 21.6% of the total variation in the data set. The model consists of two components: (1) A pattern of declining residual β-cell function positively associated with young age, presence of diabetic ketoacidosis and long duration of disease symptoms (P = 0.0004), and with risk alleles of WFS1, CDKN2A/2B and RNLS (P = 0.006). (2) A second pattern of high ZnT8 autoantibody levels and low postprandial glucagon levels associated with risk alleles of IFIH1, TCF2, TAF5L, IL2RA and PTPN2 and protective alleles of ERBB3 gene (P = 0.0005). These results demonstrate that Latent Factor Modelling can identify associating patterns in clinical prospective data – future functional studies will be needed to clarify the relevance of these patterns. PMID:23755131

  1. A genetic analysis of retinitis pigmentosa

    Directory of Open Access Journals (Sweden)

    Shanker Jayashree

    1993-01-01

    Full Text Available The data consists of sixty probands affected with Retinitis pigmentosa. Syndromic cases were found in five percent of the RP probands. Segregation analysis was carried out on proband sibship data. The ascertainment probability was estimated at 0.5517. Analysis of the data by parental mating types of proband sibships indicated the presence of dominant forms of RP (2.05%. Analysis of proband sibships indicated the presence of low risk families in the Normal x Normal matings (45% and in the consanguineous matings (40%. The hypothesis of recessive inheritance could be confirmed only in multiplex sibships (p = 0.383 +/- 0.0793. Data on proband matings though incomplete conformed in general to autosomal recessive gene hypothesis.

  2. A genetic analysis of Adh1 regulation

    Energy Technology Data Exchange (ETDEWEB)

    Freeling, M.

    1992-01-01

    The overall goal of our research proposal is to understand the meaning of the various cis-acting sites responsible for AdH1 expression in the entire maize plant. Progress is reported in the following areas: Studies on the TATA box and analysis of revertants of the Adh1-3F1124 allele; screening for more different mutants that affect Adh1 expression differentially; studies on cis-acting sequences required for root-specific Adh1 expression; refinement of the use of the particle gun; and functional analysis of a non- glycolytic anaerobic protein.

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

    Science.gov (United States)

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

    2016-02-01

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

  4. Genetic association in chronic periodontitis through dermatoglyphics: An unsolved link?

    Directory of Open Access Journals (Sweden)

    Sowmya Astekar

    2017-01-01

    Full Text Available Introduction: Because dermatoglyphic features are strongly affected by genetic and environmental factors, using it as supportive evidence in the diagnosis of hereditary disorders becomes a reality. Offspring of patients suffering from chronic periodontitis have a high prevalence rate of periodontal breakdown, suggesting strong familial influence. Aims: The present study intends to evaluate and compare the dermatoglyphic patterns in controls and periodontally compromised patients. Settings and Design: A hospital based cross-sectional study was conducted, including a total of 60 individuals, divided into study and control groups of 30 each. The study group included clinically diagnosed periodontitis patients.Materials and Methods: The digital prints were collected using biometric scanner and palmer prints using digital flatbed scanner. Care was taken to ensure that full prints of ridges were obtained. The periodontal status of all 60 participants was assessed clinically for attachment level and pocket depth. Later, Russell's periodontal index was also calculated. Statistical Analysis: The data obtained was subjected to statistical analysis using chi square and Student's t-test. Results: Among the finger ridge patterns, whorl pattern was found to be the most common in the study group whereas loop pattern was the most common in the control group. Mean total finger ridge count in the study group (165.69 ± 25.30 was significantly higher (P = 0.001 than the control group (125.4 ± 16.38. Mean dat angle was significantly higher (P = 0.039 in the study group (60.60 ± 2.76 than the control group (59.20 ± 2.62. Conclusion: Dermatoglyphics may serve as an early predictor in identifying high risk group individuals of developing diseases like periodontitis.

  5. Longitudinal Analysis of Genetic Susceptibility and BMI Throughout Adult Life.

    Science.gov (United States)

    Song, Mingyang; Zheng, Yan; Qi, Lu; Hu, Frank B; Chan, Andrew T; Giovannucci, Edward L

    2018-02-01

    Little is known about the genetic influence on BMI trajectory throughout adulthood. We created a genetic risk score (GRS) comprising 97 adult BMI-associated variants among 9,971 women and 6,405 men of European ancestry. Serial measures of BMI were assessed from 18 (women) or 21 (men) years to 85 years of age. We also examined BMI change in early (from 18 or 21 to 45 years of age), middle (from 45 to 65 years of age), and late adulthood (from 65 to 80 years of age). GRS was positively associated with BMI across all ages, with stronger associations in women than in men. The associations increased from early to middle adulthood, peaked at 45 years of age in men and at 60 years of age in women (0.91 and 1.35 kg/m 2 per 10-allele increment, respectively) and subsequently declined in late adulthood. For women, each 10-allele increment in the GRS was associated with an average BMI gain of 0.54 kg/m 2 in early adulthood, whereas no statistically significant association was found for BMI change in middle or late adulthood or for BMI change in any life period in men. Our findings indicate that genetic predisposition exerts a persistent effect on adiposity throughout adult life and increases early adulthood weight gain in women. © 2017 by the American Diabetes Association.

  6. Genetic analysis for grain quality traits in pakistani wheat varieties

    International Nuclear Information System (INIS)

    Minhas, N.M.; Ajmal, S.U.; Iqbal, Z.; Munir, M.

    2014-01-01

    A set of eight parental diallel involving seven commercial wheat cultivars and one breeding line was made to investigate the nature of gene action determining inheritance pattern of grain quality characters. Highly significant differences were observed among the genotypes for 1000 grain weight, protein content, wet gluten and lysine content. Adequacy tests were employed to estimate the fitness of data sets to additive dominance model. Both the tests i.e. analysis of uniformity of Wr, Vr and joint regression analysis validated the data of these traits for genetic analysis. Gene actions for grain quality traits were ascertained following Hayman's analysis of variance. Results of the genetic analysis revealed that both additive and dominance genetic components were involved in the manifestation of characters under study. However, additive gene effects were more pronounced in the genetic control of these traits. Non significance of b1, b2 and b3 values revealed the absence of directional dominance, symmetrical distribution of genes among the parental lines and absence of specific genes action respectively in all the traits. Maternal effects were also noted in 1000 grain weight, protein content and wet gluten percentage. It is concluded that additive effects are crucial in the expression of grain quality characters of wheat in germplasm under study and single plant selection may be recommended in segregating generations for effective improvement in these characters. (author)

  7. Analysis of genetic variation of inducible nitric oxide synthase and ...

    African Journals Online (AJOL)

    The genetic diversity of 100 Malaysian native chickens was investigated using polymerase chain reaction-restriction fragment polymorphism (PCR-RFLP) for two candidate genes: inducible nitric oxide synthase (INOS) and natural resistance-associated macrophage protein 1 (NRAMP1). The two genes were selected ...

  8. Genetic analysis of repeated, biparental, diploid, hydatidiform moles

    DEFF Research Database (Denmark)

    Sunde, Lone; Vejerslev, Lars O.; Jensen, Mie Poulsen

    1993-01-01

    for the abnormal development can be envisaged, environmental as well as genetic. To conform to current ideas of molar pathogenesis, it is suggested that the present conceptuses might have arisen from imbalances in imprinted genomic regions. This could be a consequence of uniparental disomy in critical regions......A woman presented with five consecutive pregnancies displaying molar morphology. In the fifth pregnancy, a non-malformed, liveborn infant was delivered. Genetic analyses (RFLP analysis, cytogenetics, flow cytometry) were performed in pregnancies II-V. It was demonstrated that these pregnancies...... originated in separate conceptions, all conceptuses were diploid, and all had maternally as well as paternally derived genetic markers. By cytogenetic analysis, aberrant heteromorphisms were noted; no other abnormalities were observed in chromosome structure or in DNA sequence. Many different causes...

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

    Science.gov (United States)

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

    2018-04-17

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

  10. SSR Analysis of Genetic Diversity Among 192 Diploid Potato Cultivars

    Directory of Open Access Journals (Sweden)

    Xiaoyan Song

    2016-05-01

    Full Text Available In potato breeding, it is difficult to improve the traits of interest at the tetraploid level due to the tetrasomic inheritance. A promising alternative is diploid breeding. Thus it is necessary to assess the genetic diversity of diploid potato germplasm for efficient exploration and deployment of desirable traits. In this study, we used SSR markers to evaluate the genetic diversity of diploid potato cultivars. To screen polymorphic SSR markers, 55 pairs of SSR primers were employed to amplify 39 cultivars with relatively distant genetic relationships. Among them, 12 SSR markers with high polymorphism located at 12 chromosomes were chosen to evaluate the genetic diversity of 192 diploid potato cultivars. The primers produced 6 to 18 bands with an average of 8.2 bands per primer. In total, 98 bands were amplified from 192 cultivars, and 97 of them were polymorphic. Cluster analysis using UPGMA showed the genetic relationships of all accessions tested: 186 of the 192 accessions could be distinguished by only 12 pairs of SSR primers, and the 192 diploid cultivars were divided into 11 groups, and 83.3% constituted the first group. Clustering results showed relatively low genetic diversity among 192 diploid cultivars, with closer relationship at the molecular level. The results can provide molecular basis for diploid potato breeding.

  11. Genetic characteristics of mitochondrial DNA was associated with colorectal carcinogenesis and its prognosis.

    Directory of Open Access Journals (Sweden)

    Jae-Ho Lee

    Full Text Available Clinical value of mitochondrial DNA has been described in colorectal cancer (CRC. To clarify its role in colorectal carcinogenesis, mitochondrial microsatellite instability (mtMSI and other markers were investigated in CRCs and their precancerous lesions, as a multitier genetic study. DNA was isolated from paired normal and tumoral tissues in 78 tubular adenomas (TAs, 34 serrated polyps (SPs, and 100 CRCs. mtMSI, nucleus microsatellite instability (nMSI, KRAS mutation, and BRAF mutation were investigated in these tumors and their statistical analysis was performed. mtMSI was found in 30% of CRCs and 21.4% of precancerous lesions. Mitochondrial copy number was higher in SPs than TAs and it was associated with mtMSI in low grade TAs. KRAS and BRAF mutations were mutually exclusive in TAs and SPs. CRCs with mtMSI showed shorter overall survival times than the patients without mtMSI. In CRCs without nMSI or BRAF mutation, mtMSI was a more accurate marker for predicting prognosis. The genetic change of mitochondrial DNA is an early and independent event in colorectal precancerous lesions and mtMSI and mitochondrial contents are associated with the tubular adenoma-carcinoma sequence, resulting in poor prognosis. This result suggested that the genetic change in mitochondrial DNA appears to be a possible prognosis marker in CRC.

  12. Environmental and genetic effects on tomato seed metabolic balance and its association with germination vigor.

    Science.gov (United States)

    Rosental, Leah; Perelman, Adi; Nevo, Noa; Toubiana, David; Samani, Talya; Batushansky, Albert; Sikron, Noga; Saranga, Yehoshua; Fait, Aaron

    2016-12-19

    The metabolite content of a seed and its ability to germinate are determined by genetic makeup and environmental effects during development. The interaction between genetics, environment and seed metabolism and germination was studied in 72 tomato homozygous introgression lines (IL) derived from Solanum pennelli and S. esculentum M82 cultivar. Plants were grown in the field under saline and fresh water irrigation during two consecutive seasons, and collected seeds were subjected to morphological analysis, gas chromatograph-mass spectrometry (GC-MS) metabolic profiling and germination tests. Seed weight was under tight genetic regulation, but it was not related to germination vigor. Salinity significantly reduced seed number but had little influence on seed metabolites, affecting only 1% of the statistical comparisons. The metabolites negatively correlated to germination were simple sugars and most amino acids, while positive correlations were found for several organic acids and the N metabolites urea and dopamine. Germination tests identified putative loci for improved germination as compared to M82 and in response to salinity, which were also characterized by defined metabolic changes in the seed. An integrative analysis of the metabolite and germination data revealed metabolite levels unambiguously associated with germination percentage and rate, mostly conserved in the different tested seed development environments. Such consistent relations suggest the potential for developing a method of germination vigor prediction by metabolic profiling, as well as add to our understanding of the importance of primary metabolic processes in germination.

  13. Genetic association of FTO/IRX region with obesity and overweight in the Polish population.

    Directory of Open Access Journals (Sweden)

    Marta Sobalska-Kwapis

    Full Text Available Genome-wide association studies (GWAS have identified many loci associated with body mass index (BMI in many different populations. Variants in the FTO locus are reported to be one of the strongest genetic predictors of obesity. Recent publications pointed also to a topologically associated domain (TAD which is identified as a novel region affecting BMI. The TAD area encompasses the IRXB cluster (IRX3, IRX5, IRX6, FTO and RPGRIP1L genes.In this study, we investigated the relationship between variation of the FTO and IRX genes and obesity in Poles. We presented a case-control association analysis (normal versus overweight and/or obesity group of Polish adult individuals (N = 5418. We determined whether or not the chromosomal region 16:53 500 000-55 500 000 contains polymorphic variants which are correlated with BMI in Polish population, including sex and age stratified analysis.The obtained results showed that the problem of weight-height abnormalities differently affects populations of Polish women and men (χ2 = 187.1; p0.98, r2>0.80. We confirmed presence of the genetic susceptibility loci located in intron 1 of the FTO gene, which were correlated with BMI in our study group. For the first time, our analyses revealed strong association of FTO intronic variants (block 8 with overweight in group of men only. We have also identified association of the IRX region with overweight and/or obesity in Polish individuals.Our study demonstrated how tested SNPs make differential contributions to obesity and overweight risk. We revealed sex dependent differences in the distribution of tested loci which are associated with BMI in the population of Poles.

  14. Genetic diversity of popcorn genotypes using molecular analysis.

    Science.gov (United States)

    Resh, F S; Scapim, C A; Mangolin, C A; Machado, M F P S; do Amaral, A T; Ramos, H C C; Vivas, M

    2015-08-19

    In this study, we analyzed dominant molecular markers to estimate the genetic divergence of 26 popcorn genotypes and evaluate whether using various dissimilarity coefficients with these dominant markers influences the results of cluster analysis. Fifteen random amplification of polymorphic DNA primers produced 157 amplified fragments, of which 65 were monomorphic and 92 were polymorphic. To calculate the genetic distances among the 26 genotypes, the complements of the Jaccard, Dice, and Rogers and Tanimoto similarity coefficients were used. A matrix of Dij values (dissimilarity matrix) was constructed, from which the genetic distances among genotypes were represented in a more simplified manner as a dendrogram generated using the unweighted pair-group method with arithmetic average. Clusters determined by molecular analysis generally did not group material from the same parental origin together. The largest genetic distance was between varieties 17 (UNB-2) and 18 (PA-091). In the identification of genotypes with the smallest genetic distance, the 3 coefficients showed no agreement. The 3 dissimilarity coefficients showed no major differences among their grouping patterns because agreement in determining the genotypes with large, medium, and small genetic distances was high. The largest genetic distances were observed for the Rogers and Tanimoto dissimilarity coefficient (0.74), followed by the Jaccard coefficient (0.65) and the Dice coefficient (0.48). The 3 coefficients showed similar estimations for the cophenetic correlation coefficient. Correlations among the matrices generated using the 3 coefficients were positive and had high magnitudes, reflecting strong agreement among the results obtained using the 3 evaluated dissimilarity coefficients.

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

    Indian Academy of Sciences (India)

    2012-04-05

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

  16. Genetics Home Reference: uromodulin-associated kidney disease

    Science.gov (United States)

    ... disease Related Information How are genetic conditions and genes named? Additional Information & Resources MedlinePlus (3 links) Health Topic: Gout Health Topic: Kidney Diseases Health Topic: Kidney Failure ...

  17. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

    NARCIS (Netherlands)

    Hobbs, Brian D.; de Jong, Kim; Lamontagne, Maxime; Bosse, Yohan; Shrine, Nick; Artigas, Maria Soler; Wain, Louise V.; Hall, Ian P.; Jackson, Victoria E.; Wyss, Annah B.; London, Stephanie J.; North, Kari E.; Franceschini, Nora; Strachan, David P.; Beaty, Terri H.; Hokanson, John E.; Crapo, James D.; Castaldi, Peter J.; Chase, Robert P.; Bartz, Traci M.; Heckbert, Susan R.; Psaty, Bruce M.; Gharib, Sina A.; Zanen, Pieter; Lammers, Jan W.; Oudkerk, Matthijs; Groen, H. J.; Locantore, Nicholas; Tal-Singer, Ruth; Rennard, Stephen I.; Vestbo, Jurgen; Timens, Wim; Pare, Peter D.; Latourelle, Jeanne C.; Dupuis, Josee; O'Connor, George T.; Wilk, Jemma B.; Kim, Woo Jin; Lee, Mi Kyeong; Oh, Yeon-Mok; Vonk, Judith M.; de Koning, Harry J.; Leng, Shuguang; Belinsky, Steven A.; Tesfaigzi, Yohannes; Manichaikul, Ani; Wang, Xin-Qun; Rich, Stephen S.; Postma, Dirkje S.; Boezen, H. Marike

    Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide(1). We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P <5 x 10(-6)) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we

  18. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

    NARCIS (Netherlands)

    Hobbs, Brian D; de Jong, Kim; Lamontagne, Maxime; Bossé, Yohan; Shrine, Nick; Artigas, María Soler; Wain, Louise V; Hall, Ian P; Jackson, Victoria E; Wyss, Annah B; London, Stephanie J; North, Kari E; Franceschini, Nora; Strachan, David P; Beaty, Terri H; Hokanson, John E; Crapo, James D; Castaldi, Peter J; Chase, Robert P; Bartz, Traci M; Heckbert, Susan R; Psaty, Bruce M; Gharib, Sina A; Zanen, Pieter; Lammers, Jan W; Oudkerk, Matthijs; Groen, H J; Locantore, Nicholas; Tal-Singer, Ruth; Rennard, Stephen I; Vestbo, Jørgen; Timens, Wim; Paré, Peter D; Latourelle, Jeanne C; Dupuis, Josée; O'Connor, George T; Wilk, Jemma B; Kim, Woo Jin; Lee, Mi Kyeong; Oh, Yeon-Mok; Vonk, Judith M; de Koning, Harry J; Leng, Shuguang; Belinsky, Steven A; Tesfaigzi, Yohannes; Manichaikul, Ani; Wang, Xin-Qun; Rich, Stephen S; Barr, R Graham; Sparrow, David; Litonjua, Augusto A; Bakke, Per; Gulsvik, Amund; Lahousse, Lies; Brusselle, Guy G; Stricker, Bruno H; Uitterlinden, André G; Ampleford, Elizabeth J; Bleecker, Eugene R; Woodruff, Prescott G; Meyers, Deborah A; Qiao, Dandi; Lomas, David A; Yim, Jae-Joon; Kim, Deog Kyeom; Hawrylkiewicz, Iwona; Sliwinski, Pawel; Hardin, Megan; Fingerlin, Tasha E; Schwartz, David A; Postma, Dirkje S; MacNee, William; Tobin, Martin D; Silverman, Edwin K; Boezen, H Marike; Cho, Michael H

    Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10(-6)) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we

  19. A genetic analysis of Adhl regulation

    Energy Technology Data Exchange (ETDEWEB)

    Freeling, M.

    1992-01-01

    Several separate but related studies are reported on the mechanism of alcohol dehydrogenase (Adh-1) are reported. A study of a deletion mutation in the TATA box region which resulted in an increase from 6--60% of wildtype Adh-1 expression in the revertant has led to a focus on trans-acting protein factors that bind the TATA box. Analysis of another revertant has led to study of cis-acting sequences in Adh-1 expression. Screening efforts aimed at defining different mutants affecting Adh-1 expression are reported.

  20. Primary cardiac tumors associated with genetic syndromes. A comprehensive review

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Elizabeth; Agarwal, Prachi P. [University of Michigan Health System, University Hospital Division of Cardiothoracic Radiology, Department of Radiology, Ann Arbor, MI (United States); Mahani, Maryam Ghadimi [University of Michigan Health System, University Hospital Division of Cardiothoracic Radiology, Department of Radiology, Ann Arbor, MI (United States); University of Michigan Health System, Section of Pediatric Radiology, C.S. Mott Children' s Hospital, Department of Radiology, Ann Arbor, MI (United States); Lu, Jimmy C.; Dorfman, Adam L. [University of Michigan Health System, Section of Pediatric Radiology, C.S. Mott Children' s Hospital, Department of Radiology, Ann Arbor, MI (United States); C.S. Mott Children' s Hospital, University of Michigan Health System, Section of Pediatric Cardiology, Department of Pediatrics, Ann Arbor, MI (United States); Srinivasan, Ashok [University of Michigan Health System, Division of Neuroradiology, Department of Radiology, Ann Arbor, MI (United States)

    2018-02-15

    Various cardiac tumors occur in the setting of a genetic syndrome such as myxomas in Carney complex and rhabdomyomas in tuberous sclerosis. Tumor biology can be different in syndromic forms, and on imaging children sometimes demonstrate additional manifestations of the underlying syndrome. We discuss the imaging appearance of cardiac tumors occurring in the framework of a genetic syndrome, the findings that suggest an underlying syndrome, and the impact on management. (orig.)

  1. Primary cardiac tumors associated with genetic syndromes. A comprehensive review

    International Nuclear Information System (INIS)

    Lee, Elizabeth; Agarwal, Prachi P.; Mahani, Maryam Ghadimi; Lu, Jimmy C.; Dorfman, Adam L.; Srinivasan, Ashok

    2018-01-01

    Various cardiac tumors occur in the setting of a genetic syndrome such as myxomas in Carney complex and rhabdomyomas in tuberous sclerosis. Tumor biology can be different in syndromic forms, and on imaging children sometimes demonstrate additional manifestations of the underlying syndrome. We discuss the imaging appearance of cardiac tumors occurring in the framework of a genetic syndrome, the findings that suggest an underlying syndrome, and the impact on management. (orig.)

  2. Molecular analysis of genetic diversity in elite II synthetic hexaploid ...

    African Journals Online (AJOL)

    The present study was conducted to assess the genetic diversity of Elite-II synthetic hexaploid (SH) wheat by genome DNA fingerprinting as revealed by random amplified polymorphic DNA (RAPD) analysis. Ten decamer RAPD primers (OPG-1, OPG-2, OPG-3, OPG-4, OPG-5, OPA-3, OPA-4, OPA-5, OPA-8, and OPA-15) ...

  3. Analysis of genetic diversity in pigeon pea germplasm using ...

    Indian Academy of Sciences (India)

    MANEESHA

    2017-08-16

    Aug 16, 2017 ... Th, Thailand; It, Italy; B, Barbados; Ta, Taiwan; J, Jamaica; V, Venezuela; UK, United Kingdom; My, Myanmar; U, Uganda; G,. Germany. .... from Orissa (105) and AP (15) do not group with any .... In the present work, comparison between SSAP and ... fied polymorphism) for genetic analysis of sweet potato.

  4. Genetic and phylogenetic analysis of ten Gobiidae species in China ...

    African Journals Online (AJOL)

    To study the genetic and phylogenetic relationship of gobioid fishes in China, the representatives of 10 gobioid fishes from 2 subfamilies in China were examined by amplified fragment length polymorphism (AFLP) analysis. We established 220 AFLP bands for 45 individuals from the 10 species, and the percentage of ...

  5. Genetic analysis on the competitive ability of barley ( Hordeum ...

    African Journals Online (AJOL)

    Genetic analysis on the competitive ability of barley ( Hordeum vulgare L.) recombinant inbred lines intercropped with oat ( Avena sativa L.) weeds. ... Furthermore, the commonly used herbicide price is soaring from time to time and out of the reach of the poor farmers in the developing countries. Therefore, this method is an ...

  6. Genetic analysis of feather pecking behavior in laying hens

    NARCIS (Netherlands)

    Buitenhuis, A.J.

    2003-01-01

    This thesis describes the genetic analysis of feather pecking behavior in laying hens. Feather pecking (FP) is a major welfare problem in laying hens.In the European

  7. Genetic analysis of yield in peanut (Arachis hypogaea L.) using ...

    African Journals Online (AJOL)

    Jane

    2011-07-20

    Jul 20, 2011 ... only should the two major genes' effects be considered but also the polygene's effect should be considered in breeding to increase peanut yield. Key words: Peanut, yield, major gene plus polygene inheritance model, genetic analysis. INTRODUCTION. Peanut consists of diploid (2n = 2x = 20), tetraploid ...

  8. Genetic analysis of yield in peanut ( Arachis hypogaea L.) using ...

    African Journals Online (AJOL)

    The yield had significant major gene effect and the results implied that not only should the two major genes' effects be considered but also the polygene's effect should be considered in breeding to increase peanut yield. Key words: Peanut, yield, major gene plus polygene inheritance model, genetic analysis.

  9. The genetic analysis of repeated measures I: Simplex models

    NARCIS (Netherlands)

    Molenaar, P.C.M.; Boomsma, D.I.

    1987-01-01

    Extends the simplex model to a model that may be used for the genetic and environmental analysis of covariance (ANCOVA) structures. This "double" simplex structure can be specified as a linear structural relationships model. It is shown that data that give rise to a simplex correlation structure,

  10. Host-associated genetic differentiation in the goldenrod elliptical-gall moth, Gnorimoschema gallaesolidaginis (Lepidoptera: Gelechiidae).

    Science.gov (United States)

    Nason, John D; Heard, Stephen B; Williams, Frederick R

    2002-07-01

    Careful study of apparently generalist phytophagous insects often reveals that they instead represent complexes of genetically differentiated host races or cryptic species. The goldenrod elliptical-gall moth, Gnorimoschema gallaesolidaginis, attacks two goldenrods in the Solidago canadensis complex: S. altissima and S. gigantea (Asteraceae). We tested for host-associated genetic differentiation in G. gallaesolidaginis via analysis of variation at 12 allozyme loci among larvae collected at six sites in Iowa, Minnesota, and Nebraska. Gnorimoschema gallaesolidaginis from each host are highly polymorphic (3.6-4.7 alleles/locus and expected heterozygosity 0.28-0.38 within site-host combinations). Although there were no fixed differences between larvae from S. altissima and S. gigantea at any site, these represent well differentiated host forms, with 11 of 12 loci showing significantly different allele frequencies between host-associated collections at one or more sites. Host plant has a larger effect on genetic structure among populations than does location (Wright's FST = 0.16 between host forms vs. F(ST) = 0.061 and 0.026 among altissima and gigantea populations, respectively). The estimated F(ST) between host forms suggests that the historical effective rate of gene flow has been low (N(e)m approximately 1.3). Consistent with this historical estimate is the absence of detectable recombinant (hybrid and introgressant between host form) individuals in contemporary populations (none of 431 genotyped individuals). Upper 95% confidence limits for the frequency of recombinant individuals range from 5% to 9%. Host association is tight, but imperfect, with only one likely example of a host mismatch (a larva galling the wrong host species). Our inferences about hybridization and host association are based on new maximum-likelihood methods for estimating frequencies of genealogical classes (in this case, two parental classes, F1 and F2 hybrids, and backcrosses) in a population

  11. Meta-analysis of susceptibility of woody plants to loss of genetic diversity through habitat fragmentation.

    Science.gov (United States)

    Vranckx, Guy; Jacquemyn, Hans; Muys, Bart; Honnay, Olivier

    2012-04-01

    Shrubs and trees are assumed less likely to lose genetic variation in response to habitat fragmentation because they have certain life-history characteristics such as long lifespans and extensive pollen flow. To test this assumption, we conducted a meta-analysis with data on 97 woody plant species derived from 98 studies of habitat fragmentation. We measured the weighted response of four different measures of population-level genetic diversity to habitat fragmentation with Hedge's d and Spearman rank correlation. We tested whether the genetic response to habitat fragmentation was mediated by life-history traits (longevity, pollination mode, and seed dispersal vector) and study characteristics (genetic marker and plant material used). For both tests of effect size habitat fragmentation was associated with a substantial decrease in expected heterozygosity, number of alleles, and percentage of polymorphic loci, whereas the population inbreeding coefficient was not associated with these measures. The largest proportion of variation among effect sizes was explained by pollination mechanism and by the age of the tissue (progeny or adult) that was genotyped. Our primary finding was that wind-pollinated trees and shrubs appeared to be as likely to lose genetic variation as insect-pollinated species, indicating that severe habitat fragmentation may lead to pollen limitation and limited gene flow. In comparison with results of previous meta-analyses on mainly herbaceous species, we found trees and shrubs were as likely to have negative genetic responses to habitat fragmentation as herbaceous species. We also found that the genetic variation in offspring was generally less than that of adult trees, which is evidence of a genetic extinction debt and probably reflects the genetic diversity of the historical, less-fragmented landscape. ©2011 Society for Conservation Biology.

  12. The Genetic Diversity of Mesodinium and Associated Cryptophytes.

    Science.gov (United States)

    Johnson, Matthew D; Beaudoin, David J; Laza-Martinez, Aitor; Dyhrman, Sonya T; Fensin, Elizabeth; Lin, Senjie; Merculief, Aaron; Nagai, Satoshi; Pompeu, Mayza; Setälä, Outi; Stoecker, Diane K

    2016-01-01

    Ciliates from the genus Mesodinium are globally distributed in marine and freshwater ecosystems and may possess either heterotrophic or mixotrophic nutritional modes. Members of the Mesodinium major/rubrum species complex photosynthesize by sequestering and maintaining organelles from cryptophyte prey, and under certain conditions form periodic or recurrent blooms (= red tides). Here, we present an analysis of the genetic diversity of Mesodinium and cryptophyte populations from 10 environmental samples (eight globally dispersed habitats including five Mesodinium blooms), using group-specific primers for Mesodinium partial 18S, ITS, and partial 28S rRNA genes as well as cryptophyte large subunit RuBisCO genes ( rbcL ). In addition, 22 new cryptophyte and four new M. rubrum cultures were used to extract DNA and sequence rbcL and 18S-ITS-28S genes, respectively, in order to provide a stronger phylogenetic context for our environmental sequences. Bloom samples were analyzed from coastal Brazil, Chile, two Northeastern locations in the United States, and the Pribilof Islands within the Bering Sea. Additionally, samples were also analyzed from the Baltic and Barents Seas and coastal California under non-bloom conditions. Most blooms were dominated by a single Mesodinium genotype, with coastal Brazil and Chile blooms composed of M. major and the Eastern USA blooms dominated by M. rubrum variant B. Sequences from all four blooms were dominated by Teleaulax amphioxeia -like cryptophytes. Non-bloom communities revealed more diverse assemblages of Mesodinium spp., including heterotrophic species and the mixotrophic Mesodinium chamaeleon . Similarly, cryptophyte diversity was also higher in non-bloom samples. Our results confirm that Mesodinium blooms may be caused by M. major , as well as multiple variants of M. rubrum , and further implicate T. amphioxeia as the key cryptophyte species linked to these phenomena in temperate and subtropical regions.

  13. The genetic diversity of Mesodinium and associated cryptophytes

    Directory of Open Access Journals (Sweden)

    Matthew David Johnson

    2016-12-01

    Full Text Available Ciliates from the genus Mesodinium are globally distributed in marine and freshwater ecosystems and may possess either heterotrophic or mixotrophic nutritional modes. Members of the M. major/rubrum species complex photosynthesize by sequestering and maintaining organelles from cryptophyte prey, and under certain conditions form periodic or recurrent blooms (= red tides. Here we present an analysis of the genetic diversity of Mesodinium and cryptophyte populations from 10 environmental samples (8 globally dispersed habitats including 5 Mesodinium blooms, using group-specific primers for Mesodinium partial 18S, ITS, and partial 28S rRNA genes as well as cryptophyte large subunit RuBisCO genes (rbcL. In addition, 22 new cryptophyte and 4 new M. rubrum cultures were used to extract DNA and sequence rbcL and 18S-ITS-28S genes, respectively, in order to provide a stronger phylogenetic context for our environmental sequences. Bloom samples were analyzed from coastal Brazil, Chile, two Northeastern locations in the United States, and the Pribilof Islands within the Bering Sea. Additionally, samples were also analyzed from the Baltic and Barents Seas and coastal California under non-bloom conditions. Most blooms were dominated by a single Mesodinium genotype, with coastal Brazil and Chile blooms composed of M. major and the Eastern USA blooms dominated by M. rubrum variant B. Sequences from all 4 blooms were dominated by T. amphioxeia-like cryptophytes. Non-bloom communities revealed more diverse assemblages of Mesodinium spp., including heterotrophic species and the mixotrophic M. chamaeleon. Similarly, cryptophyte diversity was also higher in non-bloom samples. Our results confirm that Mesodinium blooms may be caused by M. major, as well as multiple variants of M. rubrum, and further implicate T. amphioxeia as the key cryptophyte species linked to these phenomena in temperate and subtropical regions.

  14. Genetic analysis of intracapillary glomerular lipoprotein deposits in aging mice.

    Directory of Open Access Journals (Sweden)

    Gerda A Noordmans

    Full Text Available Renal aging is characterized by functional and structural changes like decreased glomerular filtration rate, and glomerular, tubular and interstitial damage. To gain insight in pathways involved in renal aging, we studied aged mouse strains and used genetic analysis to identify genes associated with aging phenotypes.Upon morphological screening in kidneys from 20-month-old mice from 26 inbred strains we noted intracapillary PAS-positive deposits. The severity of these deposits was quantified by scoring of a total of 50 glomeruli per section (grade 0-4. Electron microscopy and immunohistochemical staining for apoE, apoB, apoA-IV and perilipin-2 was performed to further characterize the lesions. To identify loci associated with these PAS-positive intracapillary glomerular deposits, we performed haplotype association mapping.Six out of 26 mouse strains showed glomerular PAS-positive deposits. The severity of these deposits varied: NOD(0.97, NZW(0.41, NON(0.30, B10(0.21, C3 H(0.9 and C57BR(0.7. The intracapillary deposits were strongly positive for apoE and weakly positive for apoB and apoA-IV. Haplotype association mapping showed a strong association with a 30-Kb haplotype block on Chr 1 within the Esrrg gene. We investigated 1 Mb on each site of this region, which includes the genes Spata17, Gpatch2, Esrrg, Ush2a and Kctd3.By analyzing 26 aged mouse strains we found that some strains developed an intracapillary PAS and apoE-positive lesion and identified a small haplotype block on Chr 1 within the Esrrg gene to be associated with these lipoprotein deposits. The region spanning this haplotype block contains the genes Spata17, Gpatch2, Esrrg, Ush2a and Kctd3, which are all highly expressed in the kidney. Esrrg might be involved in the evolvement of these glomerular deposits by influencing lipid metabolism and possibly immune reponses.

  15. Challenges in reproducibility of genetic association studies: lessons learned from the obesity field.

    Science.gov (United States)

    Li, A; Meyre, D

    2013-04-01

    A robust replication of initial genetic association findings has proved to be difficult in human complex diseases and more specifically in the obesity field. An obvious cause of non-replication in genetic association studies is the initial report of a false positive result, which can be explained by a non-heritable phenotype, insufficient sample size, improper correction for multiple testing, population stratification, technical biases, insufficient quality control or inappropriate statistical analyses. Replication may, however, be challenging even when the original study describes a true positive association. The reasons include underpowered replication samples, gene × gene, gene × environment interactions, genetic and phenotypic heterogeneity and subjective interpretation of data. In this review, we address classic pitfalls in genetic association studies and provide guidelines for proper discovery and replication genetic association studies with a specific focus on obesity.

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

    Directory of Open Access Journals (Sweden)

    Sharon M Lutz

    2013-11-01

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

  17. A Simple Test of Class-Level Genetic Association Can Reveal Novel Cardiometabolic Trait Loci.

    Directory of Open Access Journals (Sweden)

    Jing Qian

    Full Text Available Characterizing the genetic determinants of complex diseases can be further augmented by incorporating knowledge of underlying structure or classifications of the genome, such as newly developed mappings of protein-coding genes, epigenetic marks, enhancer elements and non-coding RNAs.We apply a simple class-level testing framework, termed Genetic Class Association Testing (GenCAT, to identify protein-coding gene association with 14 cardiometabolic (CMD related traits across 6 publicly available genome wide association (GWA meta-analysis data resources. GenCAT uses SNP-level meta-analysis test statistics across all SNPs within a class of elements, as well as the size of the class and its unique correlation structure, to determine if the class is statistically meaningful. The novelty of findings is evaluated through investigation of regional signals. A subset of findings are validated using recently updated, larger meta-analysis resources. A simulation study is presented to characterize overall performance with respect to power, control of family-wise error and computational efficiency. All analysis is performed using the GenCAT package, R version 3.2.1.We demonstrate that class-level testing complements the common first stage minP approach that involves individual SNP-level testing followed by post-hoc ascribing of statistically significant SNPs to genes and loci. GenCAT suggests 54 protein-coding genes at 41 distinct loci for the 13 CMD traits investigated in the discovery analysis, that are beyond the discoveries of minP alone. An additional application to biological pathways demonstrates flexibility in defining genetic classes.We conclude that it would be prudent to include class-level testing as standard practice in GWA analysis. GenCAT, for example, can be used as a simple, complementary and efficient strategy for class-level testing that leverages existing data resources, requires only summary level data in the form of test statistics, and

  18. Genetic dissection of memory for associative and non-associative learning in Caenorhabditis elegans.

    Science.gov (United States)

    Lau, H L; Timbers, T A; Mahmoud, R; Rankin, C H

    2013-03-01

    The distinction between non-associative and associative forms of learning has historically been based on the behavioral training paradigm. Through discovering the molecular mechanisms that mediate learning, we can develop a deeper understanding of the relationships between different forms of learning. Here, we genetically dissect short- and long-term memory for a non-associative form of learning, habituation and an associative form of learning, context conditioning for habituation, in the nematode Caenorhabditis elegans. In short-term chemosensory context conditioning for habituation, worms trained and tested in the presence of either a taste (sodium acetate) or smell (diacetyl) context cue show greater retention of habituation to tap stimuli when compared with animals trained and tested without a salient cue. Long-term memory for olfactory context conditioning was observed 24 h after a training procedure that does not normally induce 24 h memory. Like long-term habituation, this long-term memory was dependent on the transcription factor cyclic AMP-response element-binding protein. Worms with mutations in glr-1 [a non-N-methyl-d-aspartate (NMDA)-type glutamate receptor subunit] showed short-term but not long-term habituation or short- or long-term context conditioning. Worms with mutations in nmr-1 (an NMDA-receptor subunit) showed normal short- and long-term memory for habituation but did not show either short- or long-term context conditioning. Rescue of nmr-1 in the RIM interneurons rescued short- and long-term olfactory context conditioning leading to the hypothesis that these interneurons function to integrate information from chemosensory and mechanosensory systems for associative learning. © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

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

    Science.gov (United States)

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

    2018-05-01

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

  20. Breeding experiments and genome-wide association analysis elucidate two genetically different forms of non-syndromic congenital cleft lip and jaw in Vorderwald × Montbéliarde cattle.

    Science.gov (United States)

    Reinartz, S; Distl, O

    2017-10-01

    Non-syndromic congenital cleft lip and jaw (CLJ) is a condition reported in Vorderwald × Montbéliarde cattle. The objective of the present study was to perform a genome-wide association study (GWAS) for 10 CLJ-affected and 50 unaffected Vorderwald × Montbéliarde cattle using the bovine Illumina high density bead chip to identify loci for this condition. Phenotypic classification of CLJ was based on a detailed recording of orofacial structures using computed tomography. A breeding experiment among CLJ-affected Vorderwald × Montbéliarde cattle and CLJ-affected Vorderwald × Montbéliarde cattle with unaffected Holsteins confirmed recessive inheritance and different loci for bilateral or left-sided versus right-sided CLJ. The GWAS for the five cases with right-sided CLJ gave a genome-wide signal on bovine chromosome (BTA) 29 at 16 Mb. For the four left-sided and one bilateral CLJ case, a genome-wide significant association was identified on BTA4 at 32 Mb. Two different loci are very likely to be involved in CLJ in Vorderwald × Montbéliarde cattle because experimental matings among affected cows and bulls with different types of CLJ did not result in CLJ-affected progeny, and in addition, two different loci were also found through GWAS and mapped on two different bovine chromosomes. Validation in 346 Vorderwald × Montbéliarde cattle for the highly associated SNPs on BTA4 and 29 gave ratios of 33/346 (0.095, BTA4) and 6/346 (0.017, BTA29) homozygous mutant genotypes. Further studies should elucidate the responsible mutations underlying the different types of CLJ in Vorderwald × Montbéliarde cattle. © 2017 Stichting International Foundation for Animal Genetics.

  1. Genetic variants in MARCO are associated with the susceptibility to pulmonary tuberculosis in Chinese Han population.

    Directory of Open Access Journals (Sweden)

    Mai-Juan Ma

    Full Text Available BACKGROUND: Susceptibility to tuberculosis is not only determined by Mycobacterium tuberculosis infection, but also by the genetic component of the host. Macrophage receptor with a collagenous structure (MARCO is essential components required for toll like receptor-signaling in macrophage response to Mycobacterium tuberculosis, which may contribute to tuberculosis risk. PRINCIPAL FINDINGS: To specifically investigated whether single nucleotide polymorphisms (SNPs in MARCO gene are associated with pulmonary tuberculosis in Chinese Han population. By selecting tagging SNPs in MARCO gene, 17 tag SNPs were identified and genotyped in 923 pulmonary tuberculosis patients and 1033 healthy control subjects using a hospital based case-control association study. Single-point and haplotype analysis revealed an association in intron and exon region of MARCO gene. One SNP (rs17009726 was associated with susceptibility to pulmonary tuberculosis, where the carriers of the G allele had a 1.65 fold (95% CI = 1.32-2.05, p(corrected = 9.27E-5 increased risk of pulmonary tuberculosis. Haplotype analysis revealed that haplotype GC containing G allele of 17009726 and haplotype TGCC (rs17795618T/A, rs1371562G/T, rs6761637T/C, rs2011839C/T were also associated with susceptibility to pulmonary tuberculosis (p(corrected = 0.0001 and 0.029, respectively. CONCLUSIONS: Our study suggested that genetic variants in MARCO gene were associated with pulmonary tuberculosis susceptibility in Chinese Han population, and the findings emphasize the importance of MARCO mediated immune responses in the pathogenesis of tuberculosis.

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

    NARCIS (Netherlands)

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

    2017-01-01

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

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

    NARCIS (Netherlands)

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

    2018-01-01

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

  4. Borderline personality traits and adult attention-deficit hyperactivity disorder symptoms: a genetic analysis of comorbidity.

    Science.gov (United States)

    Distel, Marijn A; Carlier, Angela; Middeldorp, Christel M; Derom, Catherine A; Lubke, Gitta H; Boomsma, Dorret I

    2011-12-01

    Previous research has established the comorbidity of adult Attention-Deficit Hyperactivity Disorder (ADHD) with different personality disorders including Borderline Personality Disorder (BPD). The association between adult ADHD and BPD has primarily been investigated at the phenotypic level and not yet at the genetic level. The present study investigates the genetic and environmental contributions to the association between borderline personality traits (BPT) and ADHD symptoms in a sample of 7,233 twins and siblings (aged 18-90 years) registered with the Netherlands Twin Register and the East Flanders Prospective Twin Survey (EFPTS) . Participants completed the Conners' Adult ADHD Rating Scales (CAARS-S:SV) and the Personality Assessment Inventory-Borderline Features Scale (PAI-BOR). A bivariate genetic analysis was performed to determine the extent to which genetic and environmental factors influence variation in BPT and ADHD symptoms and the covariance between them. The heritability of BPT and ADHD symptoms was estimated at 45 and 36%, respectively. The remaining variance in BPT and ADHD symptoms was explained by unique environmental influences. The phenotypic correlation between BPT and ADHD symptoms was estimated at r = 0.59, and could be explained for 49% by genetic factors and 51% by environmental factors. The genetic and environmental correlations between BPT and ADHD symptoms were 0.72 and 0.51, respectively. The shared etiology between BPT and ADHD symptoms is thus a likely cause for the comorbidity of the two disorders. Copyright © 2011 Wiley-Liss, Inc.

  5. Genetic evidence for the association between the early growth response 3 (EGR3 gene and schizophrenia.

    Directory of Open Access Journals (Sweden)

    Rui Zhang

    Full Text Available Recently, two genome scan meta-analysis studies have found strong evidence for the association of loci on chromosome 8p with schizophrenia. The early growth response 3 (EGR3 gene located in chromosome 8p21.3 was also found to be involved in the etiology of schizophrenia. However, subsequent studies failed to replicate this finding. To investigate the genetic role of EGR3 in Chinese patients, we genotyped four SNPs (average interval ∼2.3 kb in the chromosome region of EGR3 in 470 Chinese schizophrenia patients and 480 healthy control subjects. The SNP rs35201266 (located in intron 1 of EGR3 showed significant differences between cases and controls in both genotype frequency distribution (P = 0.016 and allele frequency distribution (P = 0.009. Analysis of the haplotype rs35201266-rs3750192 provided significant evidence for association with schizophrenia (P = 0.0012; a significant difference was found for the common haplotype AG (P = 0.0005. Furthermore, significant associations were also found in several other two-, and three-SNP tests of haplotype analyses. The meta-analysis revealed a statistically significant association between rs35201266 and schizophrenia (P = 0.0001. In summary, our study supports the association of EGR3 with schizophrenia in our Han Chinese sample, and further functional exploration of the EGR3 gene will contribute to the molecular basis for the complex network underlying schizophrenia pathogenesis.

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

    NARCIS (Netherlands)

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

    2016-01-01

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

  7. Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy.

    Directory of Open Access Journals (Sweden)

    Olga Gorlova

    2011-07-01

    Full Text Available The aim of this study was to determine, through a genome-wide association study (GWAS, the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc. We considered limited (lcSSc and diffuse (dcSSc cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA, and anti-topoisomerase I (ATA. Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32×10(-12, OR = 0.75. Also, rs12540874 in GRB10 gene (P = 1.27 × 10(-6, OR = 1.15 and rs11047102 in SOX5 gene (P = 1.39×10(-7, OR = 1.36 showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79×10(-61, OR = 2.48, in the HLA-DPA1/B1 loci with ATA (P = 4.57×10(-76, OR = 8.84, and in NOTCH4 with ACA P = 8.84×10(-21, OR = 0.55 and ATA (P = 1.14×10(-8, OR = 0.54. We have identified three new non-HLA genes (IRF8, GRB10, and SOX5 associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.

  8. Coronary artery disease-associated genetic variants and biomarkers of inflammation

    DEFF Research Database (Denmark)

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

    2017-01-01

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

  9. Analysis of genetic diversity in Bolivian llama populations using microsatellites.

    Science.gov (United States)

    Barreta, J; Gutiérrez-Gil, B; Iñiguez, V; Romero, F; Saavedra, V; Chiri, R; Rodríguez, T; Arranz, J J

    2013-08-01

    South American camelids (SACs) have a major role in the maintenance and potential future of rural Andean human populations. More than 60% of the 3.7 million llamas living worldwide are found in Bolivia. Due to the lack of studies focusing on genetic diversity in Bolivian llamas, this analysis investigates both the genetic diversity and structure of 12 regional groups of llamas that span the greater part of the range of distribution for this species in Bolivia. The analysis of 42 microsatellite markers in the considered regional groups showed that, in general, there were high levels of polymorphism (a total of 506 detected alleles; average PIC across per marker: 0.66), which are comparable with those reported for other populations of domestic SACs. The estimated diversity parameters indicated that there was high intrapopulational genetic variation (average number of alleles and average expected heterozygosity per marker: 12.04 and 0.68, respectively) and weak genetic differentiation among populations (FST range: 0.003-0.052). In agreement with these estimates, Bolivian llamas showed a weak genetic structure and an intense gene flow between all the studied regional groups, which is due to the exchange of reproductive males between the different flocks. Interestingly, the groups for which the largest pairwise FST estimates were observed, Sud Lípez and Nor Lípez, showed a certain level of genetic differentiation that is probably due to t