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Sample records for genetic association studies

  1. Genetic association studies in lumbar disc degeneration

    DEFF Research Database (Denmark)

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

    2012-01-01

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

  2. Understanding Salesforce Behavior using Genetic Association Studies

    NARCIS (Netherlands)

    W.E. van den Berg (Wouter)

    2014-01-01

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

  3. Understanding Salesforce Behavior using Genetic Association Studies

    NARCIS (Netherlands)

    W.E. van den Berg (Wouter)

    2014-01-01

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

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

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    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.

  5. Genetics in psychiatry: common variant association studies

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    Buxbaum Joseph D

    2010-03-01

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

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

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    Lee, Wen-Chung

    2016-06-09

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

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

    OpenAIRE

    Savage, Sharon A

    2008-01-01

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

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

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    Pasi J Eskola

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

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

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

    2014-02-01

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

  10. Methods for Analyzing Multivariate Phenotypes in Genetic Association Studies

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    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.

  11. Disease-Concordant Twins Empower Genetic Association Studies.

    Science.gov (United States)

    Tan, Qihua; Li, Weilong; Vandin, Fabio

    2017-01-01

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

  12. Genetic association studies in drug-induced liver injury.

    Science.gov (United States)

    Daly, Ann K; Day, Chris P

    2009-11-01

    Genetic studies on drug-induced liver injury (DILI) have proved challenging, both because of their rarity and their difficulty in replicating observed effects. However, significant progress has now been achieved by both candidate-gene and genome-wide association studies. These two approaches are considered in detail, together with examples of DILI due to specific drugs where consistent associations have been reported. Particular consideration is given to associations between antituberculosis drug-related liver injury and the "slow acetylator" genotype for N-acetyltransferase 2, amoxicillin/clavulanate-related liver injury, and the human leukocyte antigen (HLA) class II DRB1*1501 allele and flucloxacillin-related injury and the HLA class I B*5701 allele. Although these associations are drug-specific, the possibility that additional, more general susceptibility genes for DILI exist requires further investigation, ideally by genome-wide association studies involving international collaboration. The possibility of interethnic variation in susceptibility to DILI also requires further study.

  13. Disease-Concordant Twins Empower Genetic Association Studies

    DEFF Research Database (Denmark)

    Tan, Qihua; Li, Weilong; Vandin, Fabio

    2017-01-01

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

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

    Science.gov (United States)

    Yang, Qiong; Wang, Yuanjia

    2012-05-01

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

  15. Multiethnic genetic association studies improve power for locus discovery.

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    Sara L Pulit

    Full Text Available To date, genome-wide association studies have focused almost exclusively on populations of European ancestry. These studies continue with the advent of next-generation sequencing, designed to systematically catalog and test low-frequency variation for a role in disease. A complementary approach would be to focus further efforts on cohorts of multiple ethnicities. This leverages the idea that population genetic drift may have elevated some variants to higher allele frequency in different populations, boosting statistical power to detect an association. Based on empirical allele frequency distributions from eleven populations represented in HapMap Phase 3 and the 1000 Genomes Project, we simulate a range of genetic models to quantify the power of association studies in multiple ethnicities relative to studies that exclusively focus on samples of European ancestry. In each of these simulations, a first phase of GWAS in exclusively European samples is followed by a second GWAS phase in any of the other populations (including a multiethnic design. We find that nontrivial power gains can be achieved by conducting future whole-genome studies in worldwide populations, where, in particular, African populations contribute the largest relative power gains for low-frequency alleles (<5% of moderate effect that suffer from low power in samples of European descent. Our results emphasize the importance of broadening genetic studies to worldwide populations to ensure efficient discovery of genetic loci contributing to phenotypic trait variability, especially for those traits for which large numbers of samples of European ancestry have already been collected and tested.

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

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

    2016-01-01

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

  17. Recommendations for using standardised phenotypes in genetic association studies

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    Naylor Melissa G

    2009-07-01

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

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

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    del Giacco Stefano

    2011-07-01

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

  19. Genetic Association Study of KCNQ5 Polymorphisms with High Myopia

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    Xuan Liao

    2017-01-01

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

  20. Replication of genetic association studies in aortic stenosis in adults.

    Science.gov (United States)

    Gaudreault, Nathalie; Ducharme, Valérie; Lamontagne, Maxime; Guauque-Olarte, Sandra; Mathieu, Patrick; Pibarot, Philippe; Bossé, Yohan

    2011-11-01

    Only a handful of studies have attempted to unravel the genetic architecture of calcific aortic valve stenosis (AS). The goal of this study was to validate genes previously associated with AS. Seven genes were assessed: APOB, APOE, CTGF, IL10, PTH, TGFB1, and VDR. Each gene was tested for a comprehensive set of single-nucleotide polymorphisms (SNPs). SNPs were genotyped in 457 patients who underwent surgical aortic valve replacement, and allele frequencies were compared to 3,294 controls. A missense mutation in the APOB gene was significantly associated with AS (rs1042031, E4181K, p = 0.00001). A second SNP located 5.6 kilobases downstream of the APOB stop codon was also associated with the disease (rs6725189, p = 0.000013). Six SNPs surrounding the IL10 locus were strongly associated with AS (0.02 > p > 6.2 × 10⁻¹¹). The most compelling association for IL10 was found with a promoter polymorphism (rs1800872) well known to regulate the production of the encoded anti-inflammatory cytokine. The frequency of the low-producing allele was greater in cases compared to controls (30% vs 20%, p = 6.2 × 10⁻¹¹). SNPs in PTH, TGFB1, and VDR had nominal p values <0.05 but did not resist Bonferroni correction. In conclusion, this study suggests that subjects carrying specific polymorphisms in the IL10 and APOB genes are at higher risk for developing AS.

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

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    Benjamin Smith

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

  2. ‘Smoking Genes’: A Genetic Association Study

    Science.gov (United States)

    Rodríguez González-Moro, José Miguel; de Lucas Ramos, Pilar; López Martín, Soledad; Bandrés, Fernando; Lucia, Alejandro; Gómez-Gallego, Félix

    2011-01-01

    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). PMID:22046326

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

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    Giuseppe Matullo

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

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

    Science.gov (United States)

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

    2013-01-01

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

  5. Folate network genetic variation, plasma homocysteine, and global genomic methylation content: a genetic association study

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    Wernimont Susan M

    2011-11-01

    Full Text Available Abstract Background Sequence variants in genes functioning in folate-mediated one-carbon metabolism are hypothesized to lead to changes in levels of homocysteine and DNA methylation, which, in turn, are associated with risk of cardiovascular disease. Methods 330 SNPs in 52 genes were studied in relation to plasma homocysteine and global genomic DNA methylation. SNPs were selected based on functional effects and gene coverage, and assays were completed on the Illumina Goldengate platform. Age-, smoking-, and nutrient-adjusted genotype--phenotype associations were estimated in regression models. Results Using a nominal P ≤ 0.005 threshold for statistical significance, 20 SNPs were associated with plasma homocysteine, 8 with Alu methylation, and 1 with LINE-1 methylation. Using a more stringent false discovery rate threshold, SNPs in FTCD, SLC19A1, and SLC19A3 genes remained associated with plasma homocysteine. Gene by vitamin B-6 interactions were identified for both Alu and LINE-1 methylation, and epistatic interactions with the MTHFR rs1801133 SNP were identified for the plasma homocysteine phenotype. Pleiotropy involving the MTHFD1L and SARDH genes for both plasma homocysteine and Alu methylation phenotypes was identified. Conclusions No single gene was associated with all three phenotypes, and the set of the most statistically significant SNPs predictive of homocysteine or Alu or LINE-1 methylation was unique to each phenotype. Genetic variation in folate-mediated one-carbon metabolism, other than the well-known effects of the MTHFR c.665C>T (known as c.677 C>T, rs1801133, p.Ala222Val, is predictive of cardiovascular disease biomarkers.

  6. Small Sample Kernel Association Tests for Human Genetic and Microbiome Association Studies.

    Science.gov (United States)

    Chen, Jun; Chen, Wenan; Zhao, Ni; Wu, Michael C; Schaid, Daniel J

    2016-01-01

    Kernel machine based association tests (KAT) have been increasingly used in testing the association between an outcome and a set of biological measurements due to its power to combine multiple weak signals of complex relationship with the outcome through the specification of a relevant kernel. Human genetic and microbiome association studies are two important applications of KAT. However, the classic KAT framework relies on large sample theory, and conservativeness has been observed for small sample studies, especially for microbiome association studies. The common approach for addressing the small sample problem relies on computationally intensive resampling methods. Here, we derive an exact test for KAT with continuous traits, which resolve the small sample conservatism of KAT without the need for resampling. The exact test has significantly improved power to detect association for microbiome studies. For binary traits, we propose a similar approximate test, and we show that the approximate test is very powerful for a wide range of kernels including common variant- and microbiome-based kernels, and the approximate test controls the type I error well for these kernels. In contrast, the sequence kernel association tests have slightly inflated genomic inflation factors after small sample adjustment. Extensive simulations and application to a real microbiome association study are used to demonstrate the utility of our method. © 2015 WILEY PERIODICALS, INC.

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

    Science.gov (United States)

    Neupane, Binod; Beyene, Joseph

    2015-01-01

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

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

    DEFF Research Database (Denmark)

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

    2010-01-01

    Recently, an indirect genetic association approach that compares genotype frequencies in offspring of long-lived subjects and offspring from random families has been introduced to study gene-longevity associations. Although the indirect genetic association has certain advantages over the direct...... and the proportional hazard model for generating individual lifespan. Family genotype data is generated using a genetic linkage program for given SNP allele frequency. Power is estimated by setting the type I error rate at 0.05 and by calculating the Armitage's chi-squared test statistic for 200 replicate samples...... for each setting of the specified allele risk and frequency parameters under different modes of inheritance and for different sample sizes. The indirect genetic association analysis is a valid approach for studying gene-longevity association, but the sample size requirement is about 3-4 time larger than...

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

    OpenAIRE

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

    2009-01-01

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

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

    DEFF Research Database (Denmark)

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

    2007-01-01

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

  13. Integrated analyses of gene expression and genetic association studies in a founder population

    Science.gov (United States)

    Cusanovich, Darren A.; Caliskan, Minal; Billstrand, Christine; Michelini, Katelyn; Chavarria, Claudia; De Leon, Sherryl; Mitrano, Amy; Lewellyn, Noah; Elias, Jack A.; Chupp, Geoffrey L.; Lang, Roberto M.; Shah, Sanjiv J.; Decara, Jeanne M.; Gilad, Yoav; Ober, Carole

    2016-01-01

    Genome-wide association studies (GWASs) have become a standard tool for dissecting genetic contributions to disease risk. However, these studies typically require extraordinarily large sample sizes to be adequately powered. Strategies that incorporate functional information alongside genetic associations have proved successful in increasing GWAS power. Following this paradigm, we present the results of 20 different genetic association studies for quantitative traits related to complex diseases, conducted in the Hutterites of South Dakota. To boost the power of these association studies, we collected RNA-sequencing data from lymphoblastoid cell lines for 431 Hutterite individuals. We then used Sherlock, a tool that integrates GWAS and expression quantitative trait locus (eQTL) data, to identify weak GWAS signals that are also supported by eQTL data. Using this approach, we found novel associations with quantitative phenotypes related to cardiovascular disease, including carotid intima-media thickness, left atrial volume index, monocyte count and serum YKL-40 levels. PMID:26931462

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

    Science.gov (United States)

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

    2010-07-01

    Recently, an indirect genetic association approach that compares genotype frequencies in offspring of long-lived subjects and offspring from random families has been introduced to study gene-longevity associations. Although the indirect genetic association has certain advantages over the direct association approach that compares genotype frequency between centenarians and young controls, the power has been of concern. This paper reports a power study performed on the indirect approach using computer simulation. We perform our simulation study by introducing the current Danish population life table and the proportional hazard model for generating individual lifespan. Family genotype data is generated using a genetic linkage program for given SNP allele frequency. Power is estimated by setting the type I error rate at 0.05 and by calculating the Armitage's chi-squared test statistic for 200 replicate samples for each setting of the specified allele risk and frequency parameters under different modes of inheritance and for different sample sizes. The indirect genetic association analysis is a valid approach for studying gene-longevity association, but the sample size requirement is about 3-4 time larger than the direct approach. It also has low power in detecting non-additive effect genes. Indirect genetic association using offspring from families with both parents as nonagenarians is nearly as powerful as using offspring from families with one centenarian parent. In conclusion, the indirect design can be a good choice for studying longevity in comparison with other alternatives, when relatively large sample size is available.

  15. Genome-wide Association Studies from the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative | Office of Cancer Genomics

    Science.gov (United States)

    CGEMS identifies common inherited genetic variations associated with a number of cancers, including breast and prostate. Data from these genome-wide association studies (GWAS) are available through the Division of Cancer Epidemiology & Genetics website.

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

    Directory of Open Access Journals (Sweden)

    Christine E McLaren

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

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

    Science.gov (United States)

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

    2013-02-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

  19. Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes

    Science.gov (United States)

    Tin, Adrienne; Sorice, Rossella; Gorski, Mathias; Yeo, Nan Cher; Chu, Audrey Y.; Li, Man; Li, Yong; Mijatovic, Vladan; Ko, Yi-An; Taliun, Daniel; Luciani, Alessandro; Chen, Ming-Huei; Yang, Qiong; Foster, Meredith C.; Olden, Matthias; Hiraki, Linda T.; Tayo, Bamidele O.; Fuchsberger, Christian; Dieffenbach, Aida Karina; Shuldiner, Alan R.; Smith, Albert V.; Zappa, Allison M.; Lupo, Antonio; Kollerits, Barbara; Ponte, Belen; Stengel, Bénédicte; Krämer, Bernhard K.; Paulweber, Bernhard; Mitchell, Braxton D.; Hayward, Caroline; Helmer, Catherine; Meisinger, Christa; Gieger, Christian; Shaffer, Christian M.; Müller, Christian; Langenberg, Claudia; Ackermann, Daniel; Siscovick, David; Boerwinkle, Eric; Kronenberg, Florian; Ehret, Georg B.; Homuth, Georg; Waeber, Gerard; Navis, Gerjan; Gambaro, Giovanni; Malerba, Giovanni; Eiriksdottir, Gudny; Li, Guo; Wichmann, H. Erich; Grallert, Harald; Wallaschofski, Henri; Völzke, Henry; Brenner, Herrmann; Kramer, Holly; Leach, I. Mateo; Rudan, Igor; Hillege, Hans L.; Beckmann, Jacques S.; Lambert, Jean Charles; Luan, Jian'an; Zhao, Jing Hua; Chalmers, John; Coresh, Josef; Denny, Joshua C.; Butterbach, Katja; Launer, Lenore J.; Ferrucci, Luigi; Kedenko, Lyudmyla; Haun, Margot; Metzger, Marie; Woodward, Mark; Hoffman, Matthew J.; Nauck, Matthias; Waldenberger, Melanie; Pruijm, Menno; Bochud, Murielle; Rheinberger, Myriam; Verweij, Niek; Wareham, Nicholas J.; Endlich, Nicole; Soranzo, Nicole; Polasek, Ozren; van der Harst, Pim; Pramstaller, Peter Paul; Vollenweider, Peter; Wild, Philipp S.; Gansevoort, Ron T.; Rettig, Rainer; Biffar, Reiner; Carroll, Robert J.; Katz, Ronit; Loos, Ruth J.F.; Hwang, Shih-Jen; Coassin, Stefan; Bergmann, Sven; Rosas, Sylvia E.; Stracke, Sylvia; Harris, Tamara B.; Corre, Tanguy; Zeller, Tanja; Illig, Thomas; Aspelund, Thor; Tanaka, Toshiko; Lendeckel, Uwe; Völker, Uwe; Gudnason, Vilmundur; Chouraki, Vincent; Koenig, Wolfgang; Kutalik, Zoltan; O'Connell, Jeffrey R.; Parsa, Afshin; Heid, Iris M.; Paterson, Andrew D.; de Boer, Ian H.; Devuyst, Olivier; Lazar, Jozef; Endlich, Karlhans; Susztak, Katalin; Tremblay, Johanne; Hamet, Pavel; Jacob, Howard J.; Böger, Carsten A.

    2016-01-01

    Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10−10). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10–7) and 13% for RAB38/CTSC (P = 5.8 × 10−7). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria. PMID:26631737

  20. Evaluation of the Endorsement of the STrengthening the REporting of Genetic Association Studies (STREGA) Statement on the Reporting Quality of Published Genetic Association Studies.

    Science.gov (United States)

    Nedovic, Darko; Panic, Nikola; Pastorino, Roberta; Ricciardi, Walter; Boccia, Stefania

    2016-08-05

    The STrengthening the REporting of Genetic Association studies (STREGA) statement was based on the STrengthening the REporting of OBservational studies in Epidemiology (STROBE) statement, and it was published in 2009 in order to improve the reporting of genetic association (GA) studies. Our aim was to evaluate the impact of STREGA endorsement on the quality of reporting of GA studies published in journals in the field of genetics and heredity (GH). Quality of reporting was evaluated by assessing the adherence of papers to the STREGA checklist. After identifying the GH journals that endorsed STREGA in their instructions for authors, we randomly appraised papers published in 2013 from journals endorsing STREGA that published GA studies (Group A); in GH journals that never endorsed STREGA (Group B); in GH journals endorsing STREGA, but in the year preceding its endorsement (Group C); and in the same time period as Group C from GH journals that never endorsed STREGA (Group D). The STREGA statement was referenced in 29 (18.1%) of 160 GH journals, of which 18 (62.1%) journals published GA studies. Among the 18 journals endorsing STREGA, we found a significant increase in the overall adherence to the STREGA checklist over time (A vs C; P 0.05). The endorsement of STREGA resulted in an increase in quality of reporting of GA studies over time, while no similar improvement was reported for journals that never endorsed STREGA.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1995-08-14

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

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

    DEFF Research Database (Denmark)

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

    2010-01-01

    Recently, an indirect genetic association approach that compares genotype frequencies in offspring of long-lived subjects and offspring from random families has been introduced to study gene-longevity associations. Although the indirect genetic association has certain advantages over the direct...... association approach that compares genotype frequency between centenarians and young controls, the power has been of concern. This paper reports a power study performed on the indirect approach using computer simulation. We perform our simulation study by introducing the current Danish population life table...... and the proportional hazard model for generating individual lifespan. Family genotype data is generated using a genetic linkage program for given SNP allele frequency. Power is estimated by setting the type I error rate at 0.05 and by calculating the Armitage's chi-squared test statistic for 200 replicate samples...

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

    NARCIS (Netherlands)

    Setiawan, A.

    2007-01-01

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

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

    NARCIS (Netherlands)

    Setiawan, A.

    2007-01-01

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

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

    DEFF Research Database (Denmark)

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

    2013-01-01

    Background Epistasis has been historically used to describe the phenomenon that the effect of a given gene on a phenotype can be dependent on one or more other genes, and is an essential element for understanding the association between genetic and phenotypic variations. Quantifying epistasis....... In the tuberculosis data, we found a statistically significant pure three-way epistatic interaction effect that was stronger than any lower-order associations. Conclusion Our study provides a methodological basis for detecting and characterizing high-order gene-gene interactions in genetic association studies....

  6. Genetic susceptibility to male infertility: news from genome-wide association studies.

    Science.gov (United States)

    Aston, K I

    2014-05-01

    A thorough understanding of the genetic basis of male infertility has eluded researchers in spite of significant efforts to identify novel genetic causes of the disease, particularly over the past decade. Approximately half of male factor infertility cases have no known cause; however, it is likely that the majority of idiopathic male factor infertility cases have some unidentified genetic basis. Well-established genetic causes of male infertility are limited to Y chromosome microdeletions and Klinefelter's syndrome, together accounting for 10-20% of cases of severe spermatogenic failure. In addition to these, several genetic polymorphisms have been demonstrated to be significantly associated with male infertility. The discovery of new genetic associations with male infertility has been hampered by two primary factors. First, most studies are underpowered because of insufficient sample size and ethnic and phenotypic heterogeneity. Second, most studies evaluate a single gene, an approach that is very inefficient in the context of male infertility, considering that many hundreds of genes are involved in the process of testicular development and spermatogenesis. Significant recent advances in microarray and next-generation sequencing technologies have enabled the application of whole-genome approaches to the study of male infertility. We recently performed a pilot genome-wide association study (GWAS) for severe spermatogenic failure, and several additional male infertility GWAS have since been published. More recently, genomic microarray tools have been applied to the association of copy number variants with male infertility. These studies are beginning to shed additional light on the genetic architecture of male infertility, and whole-genome studies have proven effective in identifying novel genetic causes of the disease. This review will discuss some of the recent findings of these whole-genome studies as well as future directions for this research that will likely

  7. 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

  8. Statistical methods for genetic association studies with response-selective sampling designs

    NARCIS (Netherlands)

    Balliu, Brunilda

    2015-01-01

    This dissertation describes new statistical methods designed to improve the power of genetic association studies. Of particular interest are studies with a response-selective sampling design, i.e. case-control studies of unrelated individuals and case-control studies of family members. The

  9. The Generalized Higher Criticism for Testing SNP-Set Effects in Genetic Association Studies.

    Science.gov (United States)

    Barnett, Ian; Mukherjee, Rajarshi; Lin, Xihong

    2017-01-01

    It is of substantial interest to study the effects of genes, genetic pathways, and networks on the risk of complex diseases. These genetic constructs each contain multiple SNPs, which are often correlated and function jointly, and might be large in number. However, only a sparse subset of SNPs in a genetic construct is generally associated with the disease of interest. In this article, we propose the generalized higher criticism (GHC) to test for the association between an SNP set and a disease outcome. The higher criticism is a test traditionally used in high-dimensional signal detection settings when marginal test statistics are independent and the number of parameters is very large. However, these assumptions do not always hold in genetic association studies, due to linkage disequilibrium among SNPs and the finite number of SNPs in an SNP set in each genetic construct. The proposed GHC overcomes the limitations of the higher criticism by allowing for arbitrary correlation structures among the SNPs in an SNP-set, while performing accurate analytic p-value calculations for any finite number of SNPs in the SNP-set. We obtain the detection boundary of the GHC test. We compared empirically using simulations the power of the GHC method with existing SNP-set tests over a range of genetic regions with varied correlation structures and signal sparsity. We apply the proposed methods to analyze the CGEM breast cancer genome-wide association study. Supplementary materials for this article are available online.

  10. Association of genetic variation with systolic and diastolic blood pressure among African Americans : the Candidate Gene Association Resource study

    NARCIS (Netherlands)

    Fox, Ervin R.; Young, J. Hunter; Li, Yali; Dreisbach, Albert W.; Keating, Brendan J.; Musani, Solomon K.; Liu, Kiang; Morrison, Alanna C.; Ganesh, Santhi; Kutlar, Abdullah; Ramachandran, Vasan S.; Polak, Josef F.; Fabsitz, Richard R.; Dries, Daniel L.; Farlow, Deborah N.; Redline, Susan; Adeyemo, Adebowale; Hirschorn, Joel N.; Sun, Yan V.; Wyatt, Sharon B.; Penman, Alan D.; Palmas, Walter; Rotter, Jerome I.; Townsend, Raymond R.; Doumatey, Ayo P.; Tayo, Bamidele O.; Mosley, Thomas H.; Lyon, Helen N.; Kang, Sun J.; Rotimi, Charles N.; Cooper, Richard S.; Franceschini, Nora; Curb, J. David; Martin, Lisa W.; Eaton, Charles B.; Kardia, Sharon L. R.; Taylor, Herman A.; Caulfield, Mark J.; Ehret, Georg B.; Johnson, Toby; Chakravarti, Aravinda; Zhu, Xiaofeng; Levy, Daniel

    2011-01-01

    The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unkno

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

    Science.gov (United States)

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

    2016-02-01

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

  12. Influence from genetic variability on opioid use for cancer pain: a European genetic association study of 2294 cancer pain patients

    DEFF Research Database (Denmark)

    Klepstad, P; Fladvad, T; Skorpen, F;

    2011-01-01

    Cancer pain patients need variable opioid doses. Preclinical and clinical studies suggest that opioid efficacy is related to genetic variability. However, the studies have small samples, findings are not replicated, and several candidate genes have not been studied. Therefore, a study of genetic...... mechanisms. The patients' mean age was 62.5 years, and the average pain intensity was 3.5. The patients' primary opioids were morphine (n=830), oxycodone (n=446), fentanyl (n=699), or other opioids (n=234). Pain intensity, time on opioids, age, gender, performance status, and bone or CNS metastases predicted......C, HTR3D, HTR3E, HTR1, or CNR1 showed significant associations with opioid dose in both the development and the validation analyzes. These findings do not support the use of pharmacogenetic analyses for the assessed SNPs to guide opioid treatment. The study also demonstrates the importance...

  13. Experimental evolution, behavior and genetics: Associative learning as a case study

    Institute of Scientific and Technical Information of China (English)

    Elisabetta VERSACE

    2015-01-01

    The evolutionary dynamics of behavioral traits reflect phenotypic and genetic changes.Methodological difficulties in analyzing the genetic dynamics of complex traits have left open questions on the mechanisms that have shaped complex behaviors and cognitive abilities.A strategy to investigate the change of behavior across generations is to assume that genetic constraints have a negligible role in evolution (the phenotypic gambit) and focus on the phenotype as a proxy for genetic evolution.Empirical evidence and technologic advances in genomics question the choice of neglecting the genetic underlying the dynamics of behavioral evolution.I first discuss the relevance of genetic factors-e.g.genetic variability,genetic linkage,gene interactions -in shaping evolution,showing the importance of taking genetic factors into account when dealing with evolutionary dynamics.I subsequently describe the recent advancements in genetics and genomics that make the investigation of the ongoing evolutionary process of behavioral traits finally attainable.In particular,by applying genomic resequencing to experimental evolution-a method called Evolve & Resequence-it is possible to monitor at the same time phenotypic and genomic changes in populations exposed to controlled selective pressures.Experimental evolution of associative learning,a well-known trait that promptly responds to selection,is a convenient model to illustrate this approach applied to behavior and cognition.Taking into account the recent achievements of the field,I discuss how to design and conduct an effective Evolve & Resequence study on associative learning in Drosophila.By integrating phenotypic and genomic data in the investigation of evolutionary dynamics,new insights can be gained on longstanding questions such as the modularity of mind and its evolution [Current Zoology 61 (2):226-241,2015].

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

    Directory of Open Access Journals (Sweden)

    Daniel eShriner

    2012-01-01

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

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

    Science.gov (United States)

    Shin, Jimin; Lee, Chaeyoung

    2015-04-01

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

  16. Genetics of Myasthenia Gravis: A Case-Control Association Study in the Hellenic Population

    Directory of Open Access Journals (Sweden)

    Zoi Zagoriti

    2012-01-01

    Full Text Available Myasthenia gravis (MG is an heterogeneous autoimmune disease characterized by the production of autoantibodies against proteins of the postsynaptic membrane, in the neuromuscular junction. The contribution of genetic factors to MG susceptibility has been evaluated through family and twin studies however, the precise genetic background of the disease remains elusive. We conducted a case-control association study in 101 unrelated MG patients of Hellenic origin and 101 healthy volunteers in order to assess the involvement of common genetic variants in susceptibility to MG. We focused on three candidate genes which have been clearly associated with several autoimmune diseases, aiming to investigate their potential implication in MG pathogenesis. These are interferon regulatory factor 5 (IRF-5, TNFα-induced protein 3 (TNFAIP3, also known as A20, and interleukin-10 (IL-10, key molecules in the regulation of immune function. A statistical trend of association (P=0.068 between IL-10 promoter single nucleotide polymorphisms (SNPs and the subgroups of early and late-onset MG patients was revealed. No statistically significant differences were observed in the rest of the variants examined. As far as we are aware, this is the first worldwide attempt to address the possible association between IRF-5 and TNFAIP3 common genetic variants and the genetic basis of MG.

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

    Science.gov (United States)

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

    2015-08-01

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

  18. A twin and molecular genetics study of sleep paralysis and associated factors.

    OpenAIRE

    Denis, Dan; French, Christopher C.; Rowe, Richard; Zavos, Helena M S; Nolan, Patrick M.; Parsons, Michael J.; Gregory, Alice M

    2015-01-01

    Sleep paralysis is a relatively common but under-researched phenomenon. In this paper we examine prevalence in a UK sample and associations with candidate risk factors. This is the first study to investigate the heritability of sleep paralysis in a twin sample and to explore genetic associations between sleep paralysis and a number of circadian expressed single nucleotide polymorphisms. Analyses are based on data from the Genesis1219 twin/sibling study, a community sample of twins/siblings fr...

  19. A twin and molecular genetics study of sleep paralysis and associated factors.

    OpenAIRE

    Denis, Dan; French, Christopher C.; Rowe, Richard; Zavos, Helena M. S.; Nolan, Patrick M.; Parsons, Michael J.; Gregory, Alice M.

    2015-01-01

    Sleep paralysis is a relatively common but under-researched phenomenon. In this paper we examine prevalence in a UK sample and associations with candidate risk factors. This is the first study to investigate the heritability of sleep paralysis in a twin sample and to explore genetic associations between sleep paralysis and a number of circadian expressed single nucleotide polymorphisms. Analyses are based on data from the Genesis1219 twin/sibling study, a community sample of twins/siblings fr...

  20. 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.

  1. STrengthening the REporting of Genetic Association Studies (STREGA: an extension of the STROBE statement.

    Directory of Open Access Journals (Sweden)

    Julian Little

    2009-02-01

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

  2. Phenotype-Based Genetic Association Studies (PGAS—Towards Understanding the Contribution of Common Genetic Variants to Schizophrenia Subphenotypes

    Directory of Open Access Journals (Sweden)

    Hannelore Ehrenreich

    2014-02-01

    Full Text Available Neuropsychiatric diseases ranging from schizophrenia to affective disorders and autism are heritable, highly complex and heterogeneous conditions, diagnosed purely clinically, with no supporting biomarkers or neuroimaging criteria. Relying on these “umbrella diagnoses”, genetic analyses, including genome-wide association studies (GWAS, were undertaken but failed to provide insight into the biological basis of these disorders. “Risk genotypes” of unknown significance with low odds ratios of mostly <1.2 were extracted and confirmed by including ever increasing numbers of individuals in large multicenter efforts. Facing these results, we have to hypothesize that thousands of genetic constellations in highly variable combinations with environmental co-factors can cause the individual disorder in the sense of a final common pathway. This would explain why the prevalence of mental diseases is so high and why mutations, including copy number variations, with a higher effect size than SNPs, constitute only a small part of variance. Elucidating the contribution of normal genetic variation to (disease phenotypes, and so re-defining disease entities, will be extremely labor-intense but crucial. We have termed this approach PGAS (“phenotype-based genetic association studies”. Ultimate goal is the definition of biological subgroups of mental diseases. For that purpose, the GRAS (Göttingen Research Association for Schizophrenia data collection was initiated in 2005. With >3000 phenotypical data points per patient, it comprises the world-wide largest currently available schizophrenia database (N > 1200, combining genome-wide SNP coverage and deep phenotyping under highly standardized conditions. First PGAS results on normal genetic variants, relevant for e.g., cognition or catatonia, demonstrated proof-of-concept. Presently, an autistic subphenotype of schizophrenia is being defined where an unfortunate accumulation of normal genotypes, so

  3. Phenotype-Based Genetic Association Studies (PGAS)-Towards Understanding the Contribution of Common Genetic Variants to Schizophrenia Subphenotypes.

    Science.gov (United States)

    Ehrenreich, Hannelore; Nave, Klaus-Armin

    2014-02-27

    Neuropsychiatric diseases ranging from schizophrenia to affective disorders and autism are heritable, highly complex and heterogeneous conditions, diagnosed purely clinically, with no supporting biomarkers or neuroimaging criteria. Relying on these "umbrella diagnoses", genetic analyses, including genome-wide association studies (GWAS), were undertaken but failed to provide insight into the biological basis of these disorders. "Risk genotypes" of unknown significance with low odds ratios of mostly definition of biological subgroups of mental diseases. For that purpose, the GRAS (Göttingen Research Association for Schizophrenia) data collection was initiated in 2005. With >3000 phenotypical data points per patient, it comprises the world-wide largest currently available schizophrenia database (N > 1200), combining genome-wide SNP coverage and deep phenotyping under highly standardized conditions. First PGAS results on normal genetic variants, relevant for e.g., cognition or catatonia, demonstrated proof-of-concept. Presently, an autistic subphenotype of schizophrenia is being defined where an unfortunate accumulation of normal genotypes, so-called pro-autistic variants of synaptic genes, explains part of the phenotypical variance. Deep phenotyping and comprehensive clinical data sets, however, are expensive and it may take years before PGAS will complement conventional GWAS approaches in psychiatric genetics.

  4. 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.

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

    Directory of Open Access Journals (Sweden)

    Jorim J Tielbeek

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

  6. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study

    Science.gov (United States)

    Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke; Schumm, L Philip; Zeissig, Sebastian; Ahmad, Tariq; Andersen, Vibeke; Andrews, Jane M; Annese, Vito; Brand, Stephan; Brant, Steven R; Cho, Judy H; Daly, Mark J; Dubinsky, Marla; Duerr, Richard H; Ferguson, Lynnette R; Franke, Andre; Gearry, Richard B; Goyette, Philippe; Hakonarson, Hakon; Halfvarson, Jonas; Hov, Johannes R; Huang, Hailang; Kennedy, Nicholas A; Kupcinskas, Limas; Lawrance, Ian C; Lee, James C; Satsangi, Jack; Schreiber, Stephan; Théâtre, Emilie; van der Meulen-de Jong, Andrea E; Weersma, Rinse K; Wilson, David C; Parkes, Miles; Vermeire, Severine; Rioux, John D; Mansfield, John; Silverberg, Mark S; Radford-Smith, Graham; McGovern, Dermot P B; Barrett, Jeffrey C; Lees, Charlie W

    2016-01-01

    Summary Background Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. Methods This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohn's disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype–phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. Findings After quality control, the primary analysis included 29 838 patients (16 902 with Crohn's disease, 12 597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for

  7. An alternative experimental case-control design for genetic association studies on bovine mastitis.

    Science.gov (United States)

    Biffani, S; Del Corvo, M; Capoferri, R; Pedretti, A; Luini, M; Williams, J L; Pagnacco, G; Minvielle, F; Minozzi, G

    2017-04-01

    The possibility of using genetic control strategies to increase disease resistance to infectious diseases relies on the identification of markers to include in the breeding plans. Possible incomplete exposure of mastitis-free (control) animals, however, is a major issue to find relevant markers in genetic association studies for infectious diseases. Usually, designs based on elite dairy sires are used in association studies, but an epidemiological case-control strategy, based on cows repeatedly field-tested could be an alternative for disease traits. To test this hypothesis, genetic association results obtained in the present work from a cohort of Italian Holstein cows tested for mastitis over time were compared with those from a previous genome-wide scan on Italian Holstein sires genotyped with 50k single nucleotide polymorphisms for de-regressed estimated breeding values for somatic cell counts (SCCs) on Bos taurus autosome (BTA6) and BTA14. A total of 1121 cows were selected for the case-control approach (cases=550, controls=571), on a combination of herd level of SCC incidence and of within herd individual level of SCC. The association study was conducted on nine previously identified markers, six on BTA6 and four on BTA14, using the R statistical environment with the 'qtscore' function of the GenABEL package, on high/low adjusted linear score as a binomial trait. The results obtained in the cow cohort selected on epidemiological information were in agreement with those obtained from the previous sire genome-wide association study (GWAS). Six out of the nine markers showed significant association, four on BTA14 (rs109146371, rs109234250, rs109421300, rs109162116) and two on BTA6 (rs110527224 and rs42766480). Most importantly, using mastitis as a case study, the current work further validated the alternative use of historical field disease data in case-control designs for genetic analysis of infectious diseases in livestock.

  8. Systematic testing of literature reported genetic variation associated with coronary restenosis: results of the GENDER Study.

    Directory of Open Access Journals (Sweden)

    Jeffrey J W Verschuren

    Full Text Available BACKGROUND: Coronary restenosis after percutaneous coronary intervention still remains a significant problem, despite all medical advances. Unraveling the mechanisms leading to restenosis development remains challenging. Many studies have identified genetic markers associated with restenosis, but consistent replication of the reported markers is scarce. The aim of the current study was to analyze the joined effect of previously in literature reported candidate genes for restenosis in the GENetic DEterminants of Restenosis (GENDER databank. METHODOLOGY/PRINCIPAL FINDINGS: Candidate genes were selected using a MEDLINE search including the terms 'genetic polymorphism' and 'coronary restenosis'. The final set included 36 genes. Subsequently, all single nucleotide polymorphisms (SNPs in the genomic region of these genes were analyzed in GENDER using set-based analysis in PLINK. The GENDER databank contains genotypic data of 2,571,586 SNPs of 295 cases with restenosis and 571 matched controls. The set, including all 36 literature reported genes, was, indeed, significantly associated with restenosis, p = 0.024 in the GENDER study. Subsequent analyses of the individual genes demonstrated that the observed association of the complete set was determined by 6 of the 36 genes. CONCLUSION: Despite overt inconsistencies in literature, with regard to individual candidate gene studies, this is the first study demonstrating that the joint effect of all these genes together, indeed, is associated with restenosis.

  9. A twin and molecular genetics study of sleep paralysis and associated factors.

    Science.gov (United States)

    Denis, Dan; French, Christopher C; Rowe, Richard; Zavos, Helena M S; Nolan, Patrick M; Parsons, Michael J; Gregory, Alice M

    2015-08-01

    Sleep paralysis is a relatively common but under-researched phenomenon. In this paper we examine prevalence in a UK sample and associations with candidate risk factors. This is the first study to investigate the heritability of sleep paralysis in a twin sample and to explore genetic associations between sleep paralysis and a number of circadian expressed single nucleotide polymorphisms. Analyses are based on data from the Genesis1219 twin/sibling study, a community sample of twins/siblings from England and Wales. In total, data from 862 participants aged 22-32 years (34% male) were used in the study. This sample consisted of monozygotic and dizygotic twins and siblings. It was found that self-reports of general sleep quality, anxiety symptoms and exposure to threatening events were all associated independently with sleep paralysis. There was moderate genetic influence on sleep paralysis (53%). Polymorphisms in the PER2 gene were associated with sleep paralysis in additive and dominant models of inheritance-although significance was not reached once a Bonferroni correction was applied. It is concluded that factors associated with disrupted sleep cycles appear to be associated with sleep paralysis. In this sample of young adults, sleep paralysis was moderately heritable. Future work should examine specific polymorphisms associated with differences in circadian rhythms and sleep homeostasis further in association with sleep paralysis.

  10. Phenotypic and Genetic Associations between Reading Comprehension, Decoding Skills, and ADHD Dimensions: Evidence from Two Population-Based Studies

    Science.gov (United States)

    Plourde, Vickie; Boivin, Michel; Forget-Dubois, Nadine; Brendgen, Mara; Vitaro, Frank; Marino, Cecilia; Tremblay, Richard T.; Dionne, Ginette

    2015-01-01

    Background: The phenotypic and genetic associations between decoding skills and ADHD dimensions have been documented but less is known about the association with reading comprehension. The aim of the study is to document the phenotypic and genetic associations between reading comprehension and ADHD dimensions of inattention and…

  11. Phenotypic and Genetic Associations between Reading Comprehension, Decoding Skills, and ADHD Dimensions: Evidence from Two Population-Based Studies

    Science.gov (United States)

    Plourde, Vickie; Boivin, Michel; Forget-Dubois, Nadine; Brendgen, Mara; Vitaro, Frank; Marino, Cecilia; Tremblay, Richard T.; Dionne, Ginette

    2015-01-01

    Background: The phenotypic and genetic associations between decoding skills and ADHD dimensions have been documented but less is known about the association with reading comprehension. The aim of the study is to document the phenotypic and genetic associations between reading comprehension and ADHD dimensions of inattention and…

  12. Using volcano plots and regularized-chi statistics in genetic association studies.

    Science.gov (United States)

    Li, Wentian; Freudenberg, Jan; Suh, Young Ju; Yang, Yaning

    2014-02-01

    Labor intensive experiments are typically required to identify the causal disease variants from a list of disease associated variants in the genome. For designing such experiments, candidate variants are ranked by their strength of genetic association with the disease. However, the two commonly used measures of genetic association, the odds-ratio (OR) and p-value may rank variants in different order. To integrate these two measures into a single analysis, here we transfer the volcano plot methodology from gene expression analysis to genetic association studies. In its original setting, volcano plots are scatter plots of fold-change and t-test statistic (or -log of the p-value), with the latter being more sensitive to sample size. In genetic association studies, the OR and Pearson's chi-square statistic (or equivalently its square root, chi; or the standardized log(OR)) can be analogously used in a volcano plot, allowing for their visual inspection. Moreover, the geometric interpretation of these plots leads to an intuitive method for filtering results by a combination of both OR and chi-square statistic, which we term "regularized-chi". This method selects associated markers by a smooth curve in the volcano plot instead of the right-angled lines which corresponds to independent cutoffs for OR and chi-square statistic. The regularized-chi incorporates relatively more signals from variants with lower minor-allele-frequencies than chi-square test statistic. As rare variants tend to have stronger functional effects, regularized-chi is better suited to the task of prioritization of candidate genes.

  13. 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

  14. Genome-wide Association Study of Cannabis Dependence Severity, Novel Risk Variants, and Shared Genetic Risks.

    Science.gov (United States)

    Sherva, Richard; Wang, Qian; Kranzler, Henry; Zhao, Hongyu; Koesterer, Ryan; Herman, Aryeh; Farrer, Lindsay A; Gelernter, Joel

    2016-05-01

    Cannabis dependence (CAD) is a serious problem worldwide and is of growing importance in the United States because cannabis is increasingly available legally. Although genetic factors contribute substantially to CAD risk, at present no well-established specific genetic risk factors for CAD have been elucidated. To report findings for DSM-IV CAD criteria from association analyses performed in large cohorts of African American and European American participants from 3 studies of substance use disorder genetics. This genome-wide association study for DSM-IV CAD criterion count was performed in 3 independent substance dependence cohorts (the Yale-Penn Study, Study of Addiction: Genetics and Environment [SAGE], and International Consortium on the Genetics of Heroin Dependence [ICGHD]). A referral sample and volunteers recruited in the community and from substance abuse treatment centers included 6000 African American and 8754 European American participants, including some from small families. Participants from the Yale-Penn Study were recruited from 2000 to 2013. Data were collected for the SAGE trial from 1990 to 2007 and for the ICGHD from 2004 to 2009. Data were analyzed from January 2, 2013, to November 9, 2015. Criterion count for DSM-IV CAD. Among the 14 754 participants, 7879 were male, 6875 were female, and the mean (SD) age was 39.2 (10.2) years. Three independent regions with genome-wide significant single-nucleotide polymorphism associations were identified, considering the largest possible sample. These included rs143244591 (β = 0.54, P = 4.32 × 10-10 for the meta-analysis) in novel antisense transcript RP11-206M11.7;rs146091982 (β = 0.54, P = 1.33 × 10-9 for the meta-analysis) in the solute carrier family 35 member G1 gene (SLC35G1); and rs77378271 (β = 0.29, P = 2.13 × 10-8 for the meta-analysis) in the CUB and Sushi multiple domains 1 gene (CSMD1). Also noted was evidence of genome-level pleiotropy between CAD and

  15. Genetics of venous thrombosis: insights from a new genome wide association study.

    Directory of Open Access Journals (Sweden)

    Marine Germain

    Full Text Available BACKGROUND: Venous Thrombosis (VT is a common multifactorial disease associated with a major public health burden. Genetics factors are known to contribute to the susceptibility of the disease but how many genes are involved and their contribution to VT risk still remain obscure. We aimed to identify genetic variants associated with VT risk. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a genome-wide association study (GWAS based on 551,141 SNPs genotyped in 1,542 cases and 1,110 controls. Twelve SNPs reached the genome-wide significance level of 2.0×10(-8 and encompassed four known VT-associated loci, ABO, F5, F11 and FGG. By means of haplotype analyses, we also provided novel arguments in favor of a role of HIVEP1, PROCR and STAB2, three loci recently hypothesized to participate in the susceptibility to VT. However, no novel VT-associated loci came out of our GWAS. Using a recently proposed statistical methodology, we also showed that common variants could explain about 35% of the genetic variance underlying VT susceptibility among which 3% could be attributable to the main identified VT loci. This analysis additionally suggested that the common variants left to be identified are not uniformly distributed across the genome and that chromosome 20, itself, could contribute to ∼7% of the total genetic variance. CONCLUSIONS/SIGNIFICANCE: This study might also provide a valuable source of information to expand our understanding of biological mechanisms regulating quantitative biomarkers for VT.

  16. Genetic contribution of catechol-O-methyltransferase variants in treatment outcome of low back pain: a prospective genetic association study

    Directory of Open Access Journals (Sweden)

    Omair Ahmad

    2012-05-01

    Full Text Available Abstract Background Treatment outcome of low back pain (LBP is associated with inter-individual variations in pain relief and functional disability. Genetic variants of catechol-O-methyltransferase (COMT gene have previously been shown to be associated with pain sensitivity and pain medication. This study examines the association between COMT polymorphisms and 7–11 year change in Oswestry Disability Index (ODI and Visual Analog Score (VAS for LBP as clinical outcome variables in patients treated with surgical instrumented lumbar fusion or cognitive intervention and exercise. Methods 93 unrelated patients with chronic LBP for duration of >1 year and lumbar disc degeneration (LDD were treated with lumbar fusion (N = 60 or cognitive therapy and exercises (N = 33. Standardised questionnaires assessing the ODI, VAS LBP, psychological factors and use of analgesics, were answered by patients both at baseline and at 7–11 years follow-up. Four SNPs in the COMT gene were successfully genotyped. Single marker as well as haplotype association with change in ODI and VAS LBP, were analyzed using Haploview, linear regression and R-package Haplostats. P-values were not formally corrected for multiple testing as this was an explorative study. Results Association analysis of individual SNPs adjusted for covariates revealed association of rs4633 and rs4680 with post treatment improvement in VAS LBP (p = 0.02, mean difference (β = 13.5 and p = 0.02, β = 14.2 respectively. SNPs, rs4633 and rs4680 were found to be genotypically similar and in strong linkage disequilibrium (LD. A significant association was found with covariates, analgesics (p = 0.001, β = 18.6; anxiety and depression (p = 0.008, β = 15.4 and age (p = 0.03, mean difference per year (β = 0.7 at follow-up. There was a tendency for better improvement among heterozygous patients compared to the homozygous. No association was observed for the

  17. Extracting Primary Open-Angle Glaucoma from Electronic Medical Records for Genetic Association Studies.

    Directory of Open Access Journals (Sweden)

    Nicole A Restrepo

    Full Text Available Electronic medical records (EMRs are being widely implemented for use in genetic and genomic studies. As a phenotypic rich resource, EMRs provide researchers with the opportunity to identify disease cohorts and perform genotype-phenotype association studies. The Epidemiologic Architecture for Genes Linked to Environment (EAGLE study, as part of the Population Architecture using Genomics and Epidemiology (PAGE I study, has genotyped more than 15,000 individuals of diverse genetic ancestry in BioVU, the Vanderbilt University Medical Center's biorepository linked to a de-identified version of the EMR (EAGLE BioVU. Here we develop and deploy an algorithm utilizing data mining techniques to identify primary open-angle glaucoma (POAG in African Americans from EAGLE BioVU for genetic association studies. The algorithm described here was designed using a combination of diagnostic codes, current procedural terminology billing codes, and free text searches to identify POAG status in situations where gold-standard digital photography cannot be accessed. The case algorithm identified 267 potential POAG subjects but underperformed after manual review with a positive predictive value of 51.6% and an accuracy of 76.3%. The control algorithm identified controls with a negative predictive value of 98.3%. Although the case algorithm requires more downstream manual review for use in large-scale studies, it provides a basis by which to extract a specific clinical subtype of glaucoma from EMRs in the absence of digital photographs.

  18. 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.

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

    Science.gov (United States)

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

    2009-09-01

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

  20. 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.

  1. A Validated Phenotyping Algorithm for Genetic Association Studies in Age-related Macular Degeneration

    Science.gov (United States)

    Simonett, Joseph M.; Sohrab, Mahsa A.; Pacheco, Jennifer; Armstrong, Loren L.; Rzhetskaya, Margarita; Smith, Maureen; Geoffrey Hayes, M.; Fawzi, Amani A.

    2015-01-01

    Age-related macular degeneration (AMD), a multifactorial, neurodegenerative disease, is a leading cause of vision loss. With the rapid advancement of DNA sequencing technologies, many AMD-associated genetic polymorphisms have been identified. Currently, the most time consuming steps of these studies are patient recruitment and phenotyping. In this study, we describe the development of an automated algorithm to identify neovascular (wet) AMD, non-neovascular (dry) AMD and control subjects using electronic medical record (EMR)-based criteria. Positive predictive value (91.7%) and negative predictive value (97.5%) were calculated using expert chart review as the gold standard to assess algorithm performance. We applied the algorithm to an EMR-linked DNA bio-repository to study previously identified AMD-associated single nucleotide polymorphisms (SNPs), using case/control status determined by the algorithm. Risk alleles of three SNPs, rs1061170 (CFH), rs1410996 (CFH), and rs10490924 (ARMS2) were found to be significantly associated with the AMD case/control status as defined by the algorithm. With the rapid growth of EMR-linked DNA biorepositories, patient selection algorithms can greatly increase the efficiency of genetic association study. We have found that stepwise validation of such an algorithm can result in reliable cohort selection and, when coupled within an EMR-linked DNA biorepository, replicates previously published AMD-associated SNPs. PMID:26255974

  2. Genome-wide association study identifies three novel genetic markers associated with elite endurance performance

    Science.gov (United States)

    Kulemin, NA; Popov, DV; Naumov, VA; Akimov, EB; Bravy, YR; Egorova, ES; Galeeva, AA; Generozov, EV; Kostryukova, ES; Larin, AK; Mustafina, LJ; Ospanova, EA; Pavlenko, AV; Starnes, LM; Żmijewski, P; Alexeev, DG; Vinogradova, OL; Govorun, VM

    2014-01-01

    To investigate the association between multiple single-nucleotide polymorphisms (SNPs), aerobic performance and elite endurance athlete status in Russians. By using GWAS approach, we examined the association between 1,140,419 SNPs and relative maximal oxygen consumption rate (V.O2max) in 80 international-level Russian endurance athletes (46 males and 34 females). To validate obtained results, we further performed case-control studies by comparing the frequencies of the most significant SNPs (with P < 10−5-10−8) between 218 endurance athletes and opposite cohorts (192 Russian controls, 1367 European controls, and 230 Russian power athletes). Initially, six ‘endurance alleles’ were identified showing discrete associations with V.O2max both in males and females. Next, case-control studies resulted in remaining three SNPs (NFIA-AS2 rs1572312, TSHR rs7144481, RBFOX1 rs7191721) associated with endurance athlete status. The C allele of the most significant SNP, rs1572312, was associated with high values of V.O2max (males: P = 0.0051; females: P = 0.0005). Furthermore, the frequency of the rs1572312 C allele was significantly higher in elite endurance athletes (95.5%) in comparison with non-elite endurance athletes (89.8%, P = 0.0257), Russian (88.8%, P = 0.007) and European (90.6%, P = 0.0197) controls and power athletes (86.2%, P = 0.0005). The rs1572312 SNP is located on the nuclear factor I A antisense RNA 2 (NFIA-AS2) gene which is supposed to regulate the expression of the NFIA gene (encodes transcription factor involved in activation of erythropoiesis and repression of the granulopoiesis). Our data show that the NFIA-AS2 rs1572312, TSHR rs7144481 and RBFOX1 rs7191721 polymorphisms are associated with aerobic performance and elite endurance athlete status. PMID:25729143

  3. Genetic distance as an alternative to physical distance for definition of gene units in association studies.

    Science.gov (United States)

    Rodriguez-Fontenla, Cristina; Calaza, Manuel; Gonzalez, Antonio

    2014-05-28

    Some association studies, as the implemented in VEGAS, ALIGATOR, i-GSEA4GWAS, GSA-SNP and other software tools, use genes as the unit of analysis. These genes include the coding sequence plus flanking sequences. Polymorphisms in the flanking sequences are of interest because they involve cis-regulatory elements or they inform on untyped genetic variants trough linkage disequilibrium. Gene extensions have customarily been defined as ±50 Kb. This approach is not fully satisfactory because genetic relationships between neighbouring sequences are a function of genetic distances, which are only poorly replaced by physical distances. Standardized recombination rates (SRR) from the deCODE recombination map were used as units of genetic distances. We searched for a SRR producing flanking sequences near the ±50 Kb offset that has been common in previous studies. A SRR≥2 was selected because it led to gene extensions with median length=45.3 Kb and the simplicity of an integer value. As expected, boundaries of the genes defined with the ±50 Kb and with the SRR≥2 rules were rarely concordant. The impact of these differences was illustrated with the interpretation of top association signals from two large studies including many hits and their detailed analysis based in different criteria. The definition based in genetic distance was more concordant with the results of these studies than the based in physical distance. In the analysis of 18 top disease associated loci form the first study, the SRR≥2 genes led to a fully concordant interpretation in 17 loci; the ±50 Kb genes only in 6. Interpretation of the 43 putative functional genes of the second study based in the SRR≥2 definition only missed 4 of the genes, whereas the based in the ±50 Kb definition missed 10 genes. A gene definition based on genetic distance led to results more concordant with expert detailed analyses than the commonly used based in physical distance. The genome coordinates for each

  4. Functional complementation studies identify candidate genes and common genetic variants associated with ovarian cancer survival

    DEFF Research Database (Denmark)

    Quaye, Lydia; Dafou, Dimitra; Ramus, Susan J;

    2009-01-01

    Common germline genetic variation and/or somatic alterations in tumours may be associated with survival in women diagnosed with ovarian cancer. The successful identification of genetic associations relies on a suitable strategy for identifying and testing candidate genes. We used microcell-mediat...

  5. A genome-wide association study of Cloninger’s Temperament scales: Implications for the evolutionary genetics of personality

    OpenAIRE

    Verweij, Karin J.H.; Zietsch, Brendan P.; Medland, Sarah E.; Gordon, Scott D.; Benyamin, Beben; Nyholt, Dale R.; McEvoy, Brian P.; Sullivan, Patrick F.; Heath, Andrew C.; Pamela A F Madden; Henders, Anjali K.; Montgomery, Grant W.; Martin, Nicholas G.; Wray, Naomi R

    2010-01-01

    Variation in personality traits is 30% to 60% attributed to genetic influences. Attempts to unravel these genetic influences at the molecular level have, so far, been inconclusive. We performed the first genome-wide association study of Cloninger’s temperament scales in a sample of 5117 individuals, in order to identify common genetic variants underlying variation in personality. Participants’ scores on Harm Avoidance, Novelty Seeking, Reward Dependence, and Persistence were tested for associ...

  6. Genome-wide association studies and the genetic dissection of complex traits

    Science.gov (United States)

    Sebastiani, Paola; Timofeev, Nadia; Dworkis, Daniel A.; Perls, Thomas T.; Steinberg, Martin H.

    2010-01-01

    The availability of affordable high throughput technology for parallel genotyping has opened the field of genetics to genome-wide association studies (GWAS), and in the last few years hundreds of articles reporting results of GWAS for a variety of heritable traits have been published. What do these results tell us? Although GWAS have discovered a few hundred reproducible associations, this number is underwhelming in relation to the huge amount of data produced, and challenges the conjecture that common variants may be the genetic causes of common diseases. We argue that the massive amount of genetic data that result from these studies remains largely unexplored and unexploited because of the challenge of mining and modeling enormous data sets, the difficulty of using nontraditional computational techniques and the focus of accepted statistical analyses on controlling the false positive rate rather than limiting the false negative rate. In this article, we will review the common approach to analysis of GWAS data and then discuss options to learn more from these data. We will use examples from our ongoing studies of sickle cell anemia and also GWAS in multigenic traits. PMID:19569043

  7. Study of the association between ITPKC genetic polymorphisms and calcium nephrolithiasis.

    Science.gov (United States)

    Kan, Wei-Chih; Chou, Yii-Her; Chiu, Siou-Jin; Hsu, Yu-Wen; Lu, Hsing-Fang; Hsu, Wenli; Chang, Wei-Chiao

    2014-01-01

    Nephrolithiasis is a multifactorial disease caused by environmental, hormonal, and genetic factors. Genetic polymorphisms of ORAI1, which codes for the main subunit of the store-operated calcium (SOC) channel, were reported to be associated with the risk and recurrence of calcium nephrolithiasis. Inositol 1,4,5-trisphosphate (IP3) 3-kinase C (ITPKC) is a negative regulator of the SOC channel-mediated signaling pathway. We investigated the association between calcium containing nephrolithiasis and genetic variants of ITPKC gene in Taiwanese patients. 365 patients were recruited in this study. Eight tagging single nucleotide polymorphisms of ITPKC were selected for genotyping. ITPKC genotypes were determined by TaqMan assay. ITPKC plasmids were transfected into cells to evaluate the intracellular calcium mobilization. Our results indicated that rs2607420 CC genotype in the intron region of the ITPKC gene is associated with a lower eGFR by both Modification of Diet in Renal Diseases (P = 0.0405) and Cockcroft-Gault (P = 0.0215) equations in patients with calcium nephrolithiasis. Our results identify a novel polymorphism for renal function and highlight the importance of ITPKC as a key molecule to regulate calcium signaling.

  8. Study of the Association between ITPKC Genetic Polymorphisms and Calcium Nephrolithiasis

    Directory of Open Access Journals (Sweden)

    Wei-Chih Kan

    2014-01-01

    Full Text Available Nephrolithiasis is a multifactorial disease caused by environmental, hormonal, and genetic factors. Genetic polymorphisms of ORAI1, which codes for the main subunit of the store-operated calcium (SOC channel, were reported to be associated with the risk and recurrence of calcium nephrolithiasis. Inositol 1,4,5-trisphosphate (IP3 3-kinase C (ITPKC is a negative regulator of the SOC channel-mediated signaling pathway. We investigated the association between calcium containing nephrolithiasis and genetic variants of ITPKC gene in Taiwanese patients. 365 patients were recruited in this study. Eight tagging single nucleotide polymorphisms of ITPKC were selected for genotyping. ITPKC genotypes were determined by TaqMan assay. ITPKC plasmids were transfected into cells to evaluate the intracellular calcium mobilization. Our results indicated that rs2607420 CC genotype in the intron region of the ITPKC gene is associated with a lower eGFR by both Modification of Diet in Renal Diseases (P=0.0405 and Cockcroft-Gault (P=0.0215 equations in patients with calcium nephrolithiasis. Our results identify a novel polymorphism for renal function and highlight the importance of ITPKC as a key molecule to regulate calcium signaling.

  9. Estimates of genetic variability and association studies in quantitative plant traits of Eruca spp. landraces

    Directory of Open Access Journals (Sweden)

    Bozokalfa Kadri Mehmet

    2010-01-01

    Full Text Available Despite the increasing of economical importance of rocket plant limited information is available on genetic variability for the agronomic traits among Eruca spp. Hence, heritability and association studies of plant properties are necessities for a successful further rocket breeding programme. The objective of this study was to examine phenotypic and genotypic variability, broad sense heritability, genetic advance, genotypic and phenotypic correlation and mean for agronomic traits of rocket plant. The magnitude of phenotypic coefficient of variation values for all the traits were higher than the corresponding values and broad sense heritability estimates exceeded 65% for all traits. Phenotypic coefficients of variability (PCV ranged from 7.60 to 34.34% and genotypic coefficients of variability (GCV ranged between 5.58% for petiole thickness and 34.30% for plant weight. The results stated that plant weight, siliqua width, seed per siliqua and seed weight could be useful character for improved Eruca spp. breeding programme.

  10. The genetics of preterm birth: using what we know to design better association studies.

    Science.gov (United States)

    Weinberg, Clarice R; Shi, Min

    2009-12-01

    Women delivering preterm are at greatly increased risk of another preterm birth in subsequent pregnancies, reflecting effects of the environment, genetics, or both. Recent literature tells an increasingly coherent story about genetic susceptibility. Women who change partners after delivering preterm retain their elevated risk, whereas fathers who change partners do not. Women who themselves were preterm are at increased risk, an association not seen in fathers. Women with a half-sister who delivered preterm are at increased risk only if the shared parent was the mother. Concordance for preterm delivery is elevated in monozygotic compared with dizygotic twin mothers but not in monozygotic twin fathers. Several mechanisms could be operating: mitochondrial genes, maternal genes, or fetal genes expressing only the maternally derived copy. The authors compare 3 study designs for their ability to detect variants and to distinguish among mechanisms underlying heritability of this common outcome. The case-parent triad design offers robustness against self-selection and genetic population stratification, providing for estimation of genetic effects that are fetal, maternal, or that depend on the parent of origin. A case-base approach compares case-mothers with randomly sampled baby-mother pairs and permits estimation of the same relative risk parameters. Both designs offer important advantages over the commonly applied case-mother/control-mother design.

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

    Directory of Open Access Journals (Sweden)

    Mehrnoosh Khodaeian

    2015-01-01

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

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

    Science.gov (United States)

    Gieger, Christian; Geistlinger, Ludwig; Altmaier, Elisabeth; Hrabé de Angelis, Martin; Kronenberg, Florian; Meitinger, Thomas; Mewes, Hans-Werner; Wichmann, H-Erich; Weinberger, Klaus M; Adamski, Jerzy; Illig, Thomas; Suhre, Karsten

    2008-11-01

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

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

    Directory of Open Access Journals (Sweden)

    Christian Gieger

    2008-11-01

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

  15. A design of multi-source samples as a shared control for association studies in genetically stratified populations

    Institute of Scientific and Technical Information of China (English)

    Yungang He; Shuhua Xu; Chuan Jia; Li Jin

    2009-01-01

    @@ Dear Editors, More and more genetic variants which contribute to human complex traits were identified recently in genome-wide association studies (GWAS), an approach that shows more efficiency than any other genetic ap-proaches ever before [1].It holds the promise to disclose genetic mechanism underlying the mystery of human diseases, since the most, if not all, of the genetic variants in the human genome could be investigated for their pos-sible association with diseases by comparing the frequen-cies of alleles in the cases (patients) and controls (healthy subjects).

  16. A systematic review evaluating the methodological aspects of meta-analyses of genetic association studies in cancer research

    OpenAIRE

    Boccia, Stefania; De Feo, Emma; Gallì, Paola; Gianfagna, Francesco; Amore, Rosarita; Ricciardi, Gualtiero

    2010-01-01

    Abstract Meta-analyses and Individual Patient Data (IPD) meta-analyses of genetic association studies are a powerful tool to summarize the scientific evidences, however their application present considerable potential and several pitfalls. We reviewed systematically all published meta-analyses and IPD meta-analyses of genetic association studies in the field of cancer research, searching for relevant studies on the Medline, Embase, and HuGE Reviews Archive databases until January 2...

  17. Web-based, participant-driven studies yield novel genetic associations for common traits.

    Directory of Open Access Journals (Sweden)

    Nicholas Eriksson

    2010-06-01

    Full Text Available Despite the recent rapid growth in genome-wide data, much of human variation remains entirely unexplained. A significant challenge in the pursuit of the genetic basis for variation in common human traits is the efficient, coordinated collection of genotype and phenotype data. We have developed a novel research framework that facilitates the parallel study of a wide assortment of traits within a single cohort. The approach takes advantage of the interactivity of the Web both to gather data and to present genetic information to research participants, while taking care to correct for the population structure inherent to this study design. Here we report initial results from a participant-driven study of 22 traits. Replications of associations (in the genes OCA2, HERC2, SLC45A2, SLC24A4, IRF4, TYR, TYRP1, ASIP, and MC1R for hair color, eye color, and freckling validate the Web-based, self-reporting paradigm. The identification of novel associations for hair morphology (rs17646946, near TCHH; rs7349332, near WNT10A; and rs1556547, near OFCC1, freckling (rs2153271, in BNC2, the ability to smell the methanethiol produced after eating asparagus (rs4481887, near OR2M7, and photic sneeze reflex (rs10427255, near ZEB2, and rs11856995, near NR2F2 illustrates the power of the approach.

  18. Web-based, participant-driven studies yield novel genetic associations for common traits.

    Science.gov (United States)

    Eriksson, Nicholas; Macpherson, J Michael; Tung, Joyce Y; Hon, Lawrence S; Naughton, Brian; Saxonov, Serge; Avey, Linda; Wojcicki, Anne; Pe'er, Itsik; Mountain, Joanna

    2010-06-24

    Despite the recent rapid growth in genome-wide data, much of human variation remains entirely unexplained. A significant challenge in the pursuit of the genetic basis for variation in common human traits is the efficient, coordinated collection of genotype and phenotype data. We have developed a novel research framework that facilitates the parallel study of a wide assortment of traits within a single cohort. The approach takes advantage of the interactivity of the Web both to gather data and to present genetic information to research participants, while taking care to correct for the population structure inherent to this study design. Here we report initial results from a participant-driven study of 22 traits. Replications of associations (in the genes OCA2, HERC2, SLC45A2, SLC24A4, IRF4, TYR, TYRP1, ASIP, and MC1R) for hair color, eye color, and freckling validate the Web-based, self-reporting paradigm. The identification of novel associations for hair morphology (rs17646946, near TCHH; rs7349332, near WNT10A; and rs1556547, near OFCC1), freckling (rs2153271, in BNC2), the ability to smell the methanethiol produced after eating asparagus (rs4481887, near OR2M7), and photic sneeze reflex (rs10427255, near ZEB2, and rs11856995, near NR2F2) illustrates the power of the approach.

  19. A genome-wide association study of Cloninger's temperament scales: Implications for the evolutionary genetics of personality

    NARCIS (Netherlands)

    Verweij, K.J.H.; Zietsch, B.P.; Medland, S.E.; Gordon, S.D.; Benyamin, B.; Nyholt, D.R.; McEvoy, B.P.; Sullivan, P.F.; Heath, A.C.; Madden, P.A.F.; Henders, A.K.; Montgomery, G.W.; Martin, N.G.; Wray, N.R.

    2010-01-01

    Variation in personality traits is 30-60% attributed to genetic influences. Attempts to unravel these genetic influences at the molecular level have, so far, been inconclusive. We performed the first genome-wide association study of Cloninger's temperament scales in a sample of 5117 individuals, in

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

    NARCIS (Netherlands)

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

    2013-01-01

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

  1. Genetics of skin color variation in Europeans: genome-wide association studies with functional follow-up

    NARCIS (Netherlands)

    F. Liu; M. Visser (Mijke); D.L. Duffy (David); P.G. Hysi (Pirro); L.C. Jacobs (Leonie); O. Lao Grueso (Oscar); K. Zhong (Kaiyin); S. Walsh (Susan); L. Chaitanya (Lakshmi); A. Wollstein (Andreas); G. Zhu (Gu); G.W. Montgomery (Grant); A.K. Henders (Anjali); M. Mangino (Massimo); D. Glass (Daniel); V. Bataille (Veronique); R.A. Sturm (Richard A.); F. Rivadeneira Ramirez (Fernando); A. Hofman (Albert); W.F.J. van IJcken (Wilfred); A.G. Uitterlinden (André); R.-J.T.S. Palstra (Robert-Jan); T.D. Spector (Timothy); N.G. Martin (Nicholas); T.E.C. Nijsten (Tamar); M.H. Kayser (Manfred)

    2015-01-01

    textabstractIn the International Visible Trait Genetics (VisiGen) Consortium, we investigated the genetics of human skin color by combining a series of genome-wide association studies (GWAS) in a total of 17,262 Europeans with functional follow-up of discovered loci. Our GWAS provide the first genom

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

    Science.gov (United States)

    Kavvoura, Fotini K; Ioannidis, John P A

    2008-02-01

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

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

    Directory of Open Access Journals (Sweden)

    Klaus Stark

    2010-10-01

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

  4. Phenotypic and genetic associations between reading comprehension, decoding skills, and ADHD dimensions: evidence from two population-based studies.

    Science.gov (United States)

    Plourde, Vickie; Boivin, Michel; Forget-Dubois, Nadine; Brendgen, Mara; Vitaro, Frank; Marino, Cecilia; Tremblay, Richard T; Dionne, Ginette

    2015-10-01

    The phenotypic and genetic associations between decoding skills and ADHD dimensions have been documented but less is known about the association with reading comprehension. The aim of the study is to document the phenotypic and genetic associations between reading comprehension and ADHD dimensions of inattention and hyperactivity/impulsivity in early schooling and compare them to those with decoding skills. Data were collected in two population-based samples of twins (Quebec Newborn Twin Study - QNTS) and singletons (Quebec Longitudinal Study of Child Development - QLSCD) totaling ≈ 2300 children. Reading was assessed with normed measures in second or third grade. Teachers assessed ADHD dimensions in kindergarten and first grade. Both decoding and reading comprehension were correlated with ADHD dimensions in a similar way: associations with inattention remained after controlling for the other ADHD dimension, behavior disorder symptoms and nonverbal abilities, whereas associations with hyperactivity/impulsivity did not. Genetic modeling showed that decoding and comprehension largely shared the same genetic etiology at this age and that their associations with inattention were mostly explained by shared genetic influences. Both reading comprehension and decoding are uniquely associated with inattention through a shared genetic etiology. © 2015 Association for Child and Adolescent Mental Health.

  5. Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes

    NARCIS (Netherlands)

    Teumer, Alexander; Tin, Adrienne; Sorice, Rossella; Gorski, Mathias; Yeo, Nan Cher; Chu, Audrey Y; Li, Man; Li, Yong; Mijatovic, Vladan; Ko, Yi-An; Taliun, Daniel; Luciani, Alessandro; Chen, Ming-Huei; Yang, Qiong; Foster, Meredith C; Olden, Matthias; Hiraki, Linda T; Tayo, Bamidele O; Fuchsberger, Christian; Dieffenbach, Aida Karina; Shuldiner, Alan R; Smith, Albert V; Zappa, Allison M; Lupo, Antonio; Kollerits, Barbara; Ponte, Belen; Stengel, Bénédicte; Krämer, Bernhard K; Paulweber, Bernhard; Mitchell, Braxton D; Hayward, Caroline; Helmer, Catherine; Meisinger, Christa; Gieger, Christian; Shaffer, Christian M; Müller, Christian; Langenberg, Claudia; Ackermann, Daniel; Siscovick, David; Boerwinkle, Eric; Kronenberg, Florian; Ehret, Georg B; Homuth, Georg; Waeber, Gerard; Navis, Gerjan; Gambaro, Giovanni; Malerba, Giovanni; Eiriksdottir, Gudny; Li, Guo; Wichmann, H Erich; Grallert, Harald; Wallaschofski, Henri; Völzke, Henry; Brenner, Herrmann; Kramer, Holly; Mateo Leach, I; Rudan, Igor; Hillege, Hans L; Beckmann, Jacques S; Lambert, Jean Charles; Luan, Jian'an; Zhao, Jing Hua; Chalmers, John; Coresh, Josef; Denny, Joshua C; Butterbach, Katja; Launer, Lenore J; Ferrucci, Luigi; Kedenko, Lyudmyla; Haun, Margot; Metzger, Marie; Woodward, Mark; Hoffman, Matthew J; Nauck, Matthias; Waldenberger, Melanie; Pruijm, Menno; Bochud, Murielle; Rheinberger, Myriam; Verweij, Niek; Wareham, Nicholas J; Endlich, Nicole; Soranzo, Nicole; Polasek, Ozren; van der Harst, Pim; Pramstaller, Peter Paul; Vollenweider, Peter; Wild, Philipp S; Gansevoort, Ron T; Rettig, Rainer; Biffar, Reiner; Carroll, Robert J; Katz, Ronit; Loos, Ruth J F; Hwang, Shih-Jen; Coassin, Stefan; Bergmann, Sven; Rosas, Sylvia E; Stracke, Sylvia; Harris, Tamara B; Corre, Tanguy; Zeller, Tanja; Illig, Thomas; Aspelund, Thor; Tanaka, Toshiko; Lendeckel, Uwe; Völker, Uwe; Gudnason, Vilmundur; Chouraki, Vincent; Koenig, Wolfgang; Kutalik, Zoltan; O'Connell, Jeffrey R; Parsa, Afshin; Heid, Iris M; Paterson, Andrew D; de Boer, Ian H; Devuyst, Olivier; Lazar, Jozef; Endlich, Karlhans; Susztak, Katalin; Tremblay, Johanne; Hamet, Pavel; Jacob, Howard J; Böger, Carsten A; Fox, Caroline S; Pattaro, Cristian; Köttgen, Anna

    2016-01-01

    Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-an

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

    Science.gov (United States)

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

    2016-09-01

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

  7. Novel genetic matching methods for handling population stratification in genome-wide association studies.

    Science.gov (United States)

    Lacour, André; Schüller, Vitalia; Drichel, Dmitriy; Herold, Christine; Jessen, Frank; Leber, Markus; Maier, Wolfgang; Noethen, Markus M; Ramirez, Alfredo; Vaitsiakhovich, Tatsiana; Becker, Tim

    2015-03-14

    A usually confronted problem in association studies is the occurrence of population stratification. In this work, we propose a novel framework to consider population matchings in the contexts of genome-wide and sequencing association studies. We employ pairwise and groupwise optimal case-control matchings and present an agglomerative hierarchical clustering, both based on a genetic similarity score matrix. In order to ensure that the resulting matches obtained from the matching algorithm capture correctly the population structure, we propose and discuss two stratum validation methods. We also invent a decisive extension to the Cochran-Armitage Trend test to explicitly take into account the particular population structure. We assess our framework by simulations of genotype data under the null hypothesis, to affirm that it correctly controls for the type-1 error rate. By a power study we evaluate that structured association testing using our framework displays reasonable power. We compare our result with those obtained from a logistic regression model with principal component covariates. Using the principal components approaches we also find a possible false-positive association to Alzheimer's disease, which is neither supported by our new methods, nor by the results of a most recent large meta analysis or by a mixed model approach. Matching methods provide an alternative handling of confounding due to population stratification for statistical tests for which covariates are hard to model. As a benchmark, we show that our matching framework performs equally well to state of the art models on common variants.

  8. Multilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studies

    Science.gov (United States)

    Malik, R; Bevan, S; Nalls, MA; Holliday, EG; Devan, WJ; Cheng, YC; Ibrahim-Verbaas, CA; Verhaaren, BF; Bis, JC; Joon, AY; de Stefano, AL; Fornage, M; Psaty, BM; Ikram, MA; Launer, LJ; van Duijn, CM; Sharma, P; Mitchell, BD; Rosand, J; Meschia, JF; Levi, C; Rothwell, PM; Sudlow, C; Markus, HS; Seshadri, S; Dichgans, M

    2014-01-01

    BACKGROUND AND PURPOSE Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts. METHODS Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS. RESULTS A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification. CONCLUSIONS A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small. PMID:24436234

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

    Science.gov (United States)

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

    2000-01-01

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

  10. The Genetics of Preterm Birth: Using What We Know to Design Better Association Studies

    OpenAIRE

    Weinberg, Clarice R.; Shi, Min

    2009-01-01

    Women delivering preterm are at greatly increased risk of another preterm birth in subsequent pregnancies, reflecting effects of the environment, genetics, or both. Recent literature tells an increasingly coherent story about genetic susceptibility. Women who change partners after delivering preterm retain their elevated risk, whereas fathers who change partners do not. Women who themselves were preterm are at increased risk, an association not seen in fathers. Women with a half-sister who de...

  11. Is attributing smoking to genetic causes associated with a reduced probability of quit attempt success? A cohort study.

    Science.gov (United States)

    Wright, Alison J; Aveyard, Paul; Guo, Boliang; Murphy, Michael; Brown, Karen; Marteau, Theresa M

    2007-10-01

    Pharmacogenetic smoking cessation interventions would involve smokers being given information about the influence of genes on their behaviour. However, attributing smoking to genetic causes may reduce perceived control over smoking, reducing quit attempt success. This study examines whether attributing smoking to genetic influences is associated with reduced quitting and whether this effect is mediated by perceived control over smoking. Cohort study. A total of 792 smokers, participating in a trial of nicotine replacement therapy (NRT)-assisted smoking cessation. Participants were informed that the trial investigated relationships between genetic markers and smoking behaviour, but personalized genetic feedback was not provided. Primary care in Oxfordshire and Buckinghamshire, UK. Perceived control over smoking and perceived importance of genetic factors in causing smoking assessed pre-quit; abstinence 4, 12, 26 and 52 weeks after the start of treatment. A total of 515 smokers (65.0%) viewed genetic factors as playing some role in causing their smoking. They had lower perceived control over smoking than smokers who viewed genetic factors as having no role in causing their smoking. Attributing smoking to genetic causes was not associated significantly with a lower probability of quit attempt success. Attributing smoking to genetic factors was associated with lower levels of perceived control over smoking but not lower quit rates. This suggests that learning of one's genetic predisposition to smoking during a pharmacogenetically tailored smoking cessation intervention may not deter quitting. Further research should examine whether the lack of impact of genetic attributions on quit attempt success is also found in smokers provided with personalized genetic feedback.

  12. Influence from genetic variability on opioid use for cancer pain: a European genetic association study of 2294 cancer pain patients

    DEFF Research Database (Denmark)

    Klepstad, P; Fladvad, T; Skorpen, F;

    2011-01-01

    Cancer pain patients need variable opioid doses. Preclinical and clinical studies suggest that opioid efficacy is related to genetic variability. However, the studies have small samples, findings are not replicated, and several candidate genes have not been studied. Therefore, a study of genetic...... variability with opioid doses in a large population using a confirmatory validation population was warranted. We recruited 2294 adult European patients using a World Health Organization (WHO) step III opioid and analyzed single nucleotide polymorphisms (SNPs) in genes with a putative influence on opioid...... mechanisms. The patients' mean age was 62.5 years, and the average pain intensity was 3.5. The patients' primary opioids were morphine (n=830), oxycodone (n=446), fentanyl (n=699), or other opioids (n=234). Pain intensity, time on opioids, age, gender, performance status, and bone or CNS metastases predicted...

  13. Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study.

    Science.gov (United States)

    Hou, Liping; Heilbronner, Urs; Degenhardt, Franziska; Adli, Mazda; Akiyama, Kazufumi; Akula, Nirmala; Ardau, Raffaella; Arias, Bárbara; Backlund, Lena; Banzato, Claudio E M; Benabarre, Antoni; Bengesser, Susanne; Bhattacharjee, Abesh Kumar; Biernacka, Joanna M; Birner, Armin; Brichant-Petitjean, Clara; Bui, Elise T; Cervantes, Pablo; Chen, Guo-Bo; Chen, Hsi-Chung; Chillotti, Caterina; Cichon, Sven; Clark, Scott R; Colom, Francesc; Cousins, David A; Cruceanu, Cristiana; Czerski, Piotr M; Dantas, Clarissa R; Dayer, Alexandre; Étain, Bruno; Falkai, Peter; Forstner, Andreas J; Frisén, Louise; Fullerton, Janice M; Gard, Sébastien; Garnham, Julie S; Goes, Fernando S; Grof, Paul; Gruber, Oliver; Hashimoto, Ryota; Hauser, Joanna; Herms, Stefan; Hoffmann, Per; Hofmann, Andrea; Jamain, Stephane; Jiménez, Esther; Kahn, Jean-Pierre; Kassem, Layla; Kittel-Schneider, Sarah; Kliwicki, Sebastian; König, Barbara; Kusumi, Ichiro; Lackner, Nina; Laje, Gonzalo; Landén, Mikael; Lavebratt, Catharina; Leboyer, Marion; Leckband, Susan G; Jaramillo, Carlos A López; MacQueen, Glenda; Manchia, Mirko; Martinsson, Lina; Mattheisen, Manuel; McCarthy, Michael J; McElroy, Susan L; Mitjans, Marina; Mondimore, Francis M; Monteleone, Palmiero; Nievergelt, Caroline M; Nöthen, Markus M; Ösby, Urban; Ozaki, Norio; Perlis, Roy H; Pfennig, Andrea; Reich-Erkelenz, Daniela; Rouleau, Guy A; Schofield, Peter R; Schubert, K Oliver; Schweizer, Barbara W; Seemüller, Florian; Severino, Giovanni; Shekhtman, Tatyana; Shilling, Paul D; Shimoda, Kazutaka; Simhandl, Christian; Slaney, Claire M; Smoller, Jordan W; Squassina, Alessio; Stamm, Thomas; Stopkova, Pavla; Tighe, Sarah K; Tortorella, Alfonso; Turecki, Gustavo; Volkert, Julia; Witt, Stephanie; Wright, Adam; Young, L Trevor; Zandi, Peter P; Potash, James B; DePaulo, J Raymond; Bauer, Michael; Reininghaus, Eva Z; Novák, Tomas; Aubry, Jean-Michel; Maj, Mario; Baune, Bernhard T; Mitchell, Philip B; Vieta, Eduard; Frye, Mark A; Rybakowski, Janusz K; Kuo, Po-Hsiu; Kato, Tadafumi; Grigoroiu-Serbanescu, Maria; Reif, Andreas; Del Zompo, Maria; Bellivier, Frank; Schalling, Martin; Wray, Naomi R; Kelsoe, John R; Alda, Martin; Rietschel, Marcella; McMahon, Francis J; Schulze, Thomas G

    2016-03-12

    Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0). The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. Deutsche Forschungsgemeinschaft, National Institute of Mental Health

  14. Molecular evaluation of genetic diversity and association studies in rice (Oryza sativa L.)

    Indian Academy of Sciences (India)

    C. Vanniarajan; K. K. Vinod; Andy Pereira

    2011-04-01

    In the present study, we tested rice genotypes that included un(der)exploited landraces of Tamil Nadu along with indica and japonica test cultivars to ascertain their genetic diversity structure. Highly polymorphic microsatellite markers were used for generating marker segregation data. A novel measure, allele discrimination index, was used to determine subpopulation differentiation power of each marker. Phenotypic data were collected for yield and component traits. Pattern of molecular differentiation separated indica and japonica genotypes; indica genotypes had two subpopulations within. Landraces were found to have indica genome, but formed a separate subgroup with low linkage disequilibrium. The landraces further separated into distinct group in both hierarchical clustering analysis using neighbour-joining method as well as in the model based population structure analysis. Japonica and the remaining indica cultivars formed two other distinct groups. Linkage disequilibrium observed in the whole population was considerably reduced in subpopulations. Low linkage disequilibrium of landforms suggests their narrow adaptation in local geographical niche. Many population specific alleles could be identified particularly for japonica cultivars and landraces. Association analysis revealed nine marker–trait associations with three agronomic traits, of which 67% were previously reported. Although the testing landraces together with known cultivars had permitted genomewide association mapping, the experiment offers scope to study more landraces collected from the entire geographical region for drawing more reliable information.

  15. G-STRATEGY: Optimal Selection of Individuals for Sequencing in Genetic Association Studies.

    Science.gov (United States)

    Wang, Miaoyan; Jakobsdottir, Johanna; Smith, Albert V; McPeek, Mary Sara

    2016-09-01

    In a large-scale genetic association study, the number of phenotyped individuals available for sequencing may, in some cases, be greater than the study's sequencing budget will allow. In that case, it can be important to prioritize individuals for sequencing in a way that optimizes power for association with the trait. Suppose a cohort of phenotyped individuals is available, with some subset of them possibly already sequenced, and one wants to choose an additional fixed-size subset of individuals to sequence in such a way that the power to detect association is maximized. When the phenotyped sample includes related individuals, power for association can be gained by including partial information, such as phenotype data of ungenotyped relatives, in the analysis, and this should be taken into account when assessing whom to sequence. We propose G-STRATEGY, which uses simulated annealing to choose a subset of individuals for sequencing that maximizes the expected power for association. In simulations, G-STRATEGY performs extremely well for a range of complex disease models and outperforms other strategies with, in many cases, relative power increases of 20-40% over the next best strategy, while maintaining correct type 1 error. G-STRATEGY is computationally feasible even for large datasets and complex pedigrees. We apply G-STRATEGY to data on high-density lipoprotein and low-density lipoprotein from the AGES-Reykjavik and REFINE-Reykjavik studies, in which G-STRATEGY is able to closely approximate the power of sequencing the full sample by selecting for sequencing a only small subset of the individuals.

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

    Science.gov (United States)

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

    2015-01-01

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

  17. Application of two machine learning algorithms to genetic association studies in the presence of covariates

    Directory of Open Access Journals (Sweden)

    Foulkes Andrea S

    2008-11-01

    Full Text Available Abstract Background Population-based investigations aimed at uncovering genotype-trait associations often involve high-dimensional genetic polymorphism data as well as information on multiple environmental and clinical parameters. Machine learning (ML algorithms offer a straightforward analytic approach for selecting subsets of these inputs that are most predictive of a pre-defined trait. The performance of these algorithms, however, in the presence of covariates is not well characterized. Methods and Results In this manuscript, we investigate two approaches: Random Forests (RFs and Multivariate Adaptive Regression Splines (MARS. Through multiple simulation studies, the performance under several underlying models is evaluated. An application to a cohort of HIV-1 infected individuals receiving anti-retroviral therapies is also provided. Conclusion Consistent with more traditional regression modeling theory, our findings highlight the importance of considering the nature of underlying gene-covariate-trait relationships before applying ML algorithms, particularly when there is potential confounding or effect mediation.

  18. Bayesian model selection in complex linear systems, as illustrated in genetic association studies.

    Science.gov (United States)

    Wen, Xiaoquan

    2014-03-01

    Motivated by examples from genetic association studies, this article considers the model selection problem in a general complex linear model system and in a Bayesian framework. We discuss formulating model selection problems and incorporating context-dependent a priori information through different levels of prior specifications. We also derive analytic Bayes factors and their approximations to facilitate model selection and discuss their theoretical and computational properties. We demonstrate our Bayesian approach based on an implemented Markov Chain Monte Carlo (MCMC) algorithm in simulations and a real data application of mapping tissue-specific eQTLs. Our novel results on Bayes factors provide a general framework to perform efficient model comparisons in complex linear model systems.

  19. Application of two machine learning algorithms to genetic association studies in the presence of covariates.

    Science.gov (United States)

    Nonyane, Bareng A S; Foulkes, Andrea S

    2008-11-14

    Population-based investigations aimed at uncovering genotype-trait associations often involve high-dimensional genetic polymorphism data as well as information on multiple environmental and clinical parameters. Machine learning (ML) algorithms offer a straightforward analytic approach for selecting subsets of these inputs that are most predictive of a pre-defined trait. The performance of these algorithms, however, in the presence of covariates is not well characterized. In this manuscript, we investigate two approaches: Random Forests (RFs) and Multivariate Adaptive Regression Splines (MARS). Through multiple simulation studies, the performance under several underlying models is evaluated. An application to a cohort of HIV-1 infected individuals receiving anti-retroviral therapies is also provided. Consistent with more traditional regression modeling theory, our findings highlight the importance of considering the nature of underlying gene-covariate-trait relationships before applying ML algorithms, particularly when there is potential confounding or effect mediation.

  20. 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.

  1. Association of ADH4 genetic variants with alcohol dependence risk and related phenotypes: results from a larger multicenter association study.

    Science.gov (United States)

    Preuss, Ulrich W; Ridinger, Monika; Rujescu, Dan; Samochowiec, Jerzy; Fehr, Christoph; Wurst, Friedrich M; Koller, Gabriele; Bondy, Brigitta; Wodarz, Norbert; Debniak, Tadeusz; Grzywacz, Anna; Soyka, Michael; Zill, Peter

    2011-04-01

    Genetic variants of the alcohol-metabolizing enzyme ADH4, located on chromosome 4q22-4q23, have been related to alcohol dependence (AD) risk in previous research. The aim of this association study in a large multicenter sample of alcohol-dependent individuals and controls is to confirm ADH4 single nucleotide polymorphism (SNP) and haplotype association with AD and relevant related phenotypes. One thousand, six hundred and twenty-two (1622) inpatient subjects and 1469 control subjects with DSM-IV. AD from four addiction treatment centres were included. Characteristics of AD and related phenotypes including alcohol withdrawal, Cloninger's type I and II and first ages of drinking, regular drinking and AD onset were obtained using standardized structured interviews. After subjects were genotyped for 2 ADH4 polymorphisms, single SNP case-control and haplotype analyses were conducted. Both variants--rs1800759 and rs1042364--and the A-A and C-G haplotypes were significantly related to AD across samples. Furthermore, associations with AD-related phenotypes and subtypes revealed a potential protective influence of this haplotype. This study confirms the significant relationship of ADH4 variants with AD and related phenotypes. While the rs1800759 and rs1042364 A-A haplotype had a potential protective influence on the risk for several AD-related phenotypes, this effect is rather small compared to functional variants of other alcohol or acetaldehyde-metabolizing enzymes like ALDH2*2 or ADH1B*2.

  2. G-STRATEGY: Optimal Selection of Individuals for Sequencing in Genetic Association Studies

    Science.gov (United States)

    Wang, Miaoyan; Jakobsdottir, Johanna; Smith, Albert V.; McPeek, Mary Sara

    2017-01-01

    In a large-scale genetic association study, the number of phenotyped individuals available for sequencing may, in some cases, be greater than the study’s sequencing budget will allow. In that case, it can be important to prioritize individuals for sequencing in a way that optimizes power for association with the trait. Suppose a cohort of phenotyped individuals is available, with some subset of them possibly already sequenced, and one wants to choose an additional fixed-size subset of individuals to sequence in such a way that the power to detect association is maximized. When the phenotyped sample includes related individuals, power for association can be gained by including partial information, such as phenotype data of ungenotyped relatives, in the analysis, and this should be taken into account when assessing whom to sequence. We propose G-STRATEGY, which uses simulated annealing to choose a subset of individuals for sequencing that maximizes the expected power for association. In simulations, G-STRATEGY performs extremely well for a range of complex disease models and outperforms other strategies with, in many cases, relative power increases of 20–40% over the next best strategy, while maintaining correct type 1 error. G-STRATEGY is computationally feasible even for large datasets and complex pedigrees. We apply G-STRATEGY to data on HDL and LDL from the AGES-Reykjavik and REFINE-Reykjavik studies, in which G-STRATEGY is able to closely-approximate the power of sequencing the full sample by selecting for sequencing a only small subset of the individuals. PMID:27256766

  3. Advancement in genetic variants conferring obesity susceptibility from genome-wide association studies.

    Science.gov (United States)

    Wang, Tao; Jia, Weiping; Hu, Cheng

    2015-06-01

    Obesity prevalence has increased in recent years. Lifestyle change fuels obesity, but genetic factors cause more than 50% of average variations in obesity. The advent of genome-wide association studies (GWAS) has hastened the progress of polygenic obesity research. As of this writing, more than 73 obesity susceptibility loci have been identified in ethnic groups through GWAS. The identified loci explain only 2% to 4% of obesity heritability, thereby indicating that a large proportion of loci remain undiscovered. Thus, the next step is to identify and confirm novel loci, which may exhibit smaller effects and lower allele frequencies than established loci. However, achieving these tasks has been difficult for researchers. GWAS help researchers discover the causal loci. Moreover, numerous biological studies have been performed on the polygenic effects on obesity, such as studies on fat mass- and obesity-associated gene (FTO), but the role of these polygenic effects in the mechanism of obesity remains unclear. Thus, obesity-causing variations should be identified, and insights into the biology of polygenic effects on obesity are needed.

  4. Is attributing smoking to genetic causes associated with a reduced probability of quit attempt success? A cohort study

    OpenAIRE

    Wright, Alison J.; Aveyard, Paul; Guo, Boliang; Murphy, Michael; Brown, Karen; Marteau, Theresa M.

    2007-01-01

    Aims Pharmacogenetic smoking cessation interventions would involve smokers being given information about the influence of genes on their behaviour. However, attributing smoking to genetic causes may reduce perceived control over smoking, reducing quit attempt success. This study examines whether attributing smoking to genetic influences is associated with reduced quitting and whether this effect is mediated by perceived control over smoking. Design Cohort study. Participants A total of 792 sm...

  5. 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.

  6. Genome-wide association study identifies genetic risk underlying primary rhegmatogenous retinal detachment

    NARCIS (Netherlands)

    Kirin, M.; Chandra, A.; Charteris, D.G.; Hayward, C.; Campbell, S.; Celap, I.; Bencic, G.; Vatavuk, Z.; Kirac, I.; Richards, A.J.; Tenesa, A.; Snead, M.P.; Fleck, B.W.; Singh, J.; Harsum, S.; Maclaren, R.E.; Hollander, A.I. den; Dunlop, M.G.; Hoyng, C.B.; Wright, A.F.; Campbell, H.; Vitart, V.; Mitry, D.

    2013-01-01

    Rhegmatogenous retinal detachment (RRD) is an important cause of vision loss and can potentially lead to blindness. The underlying pathogenesis is complex and incompletely understood. We applied a two-stage genetic association discovery phase followed by a replication phase in a combined total of

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

    Directory of Open Access Journals (Sweden)

    Markus Schürks

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

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

    NARCIS (Netherlands)

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

    2016-01-01

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

  9. Genetic studies of Polish migraine patients: screening for causative mutations in four migraine-associated genes.

    Science.gov (United States)

    Domitrz, Izabela; Kosiorek, Michalina; Żekanowski, Cezary; Kamińska, Anna

    2016-01-08

    Migraine is the most common neurological disorder, affecting approximately 12 % of the adult population worldwide, caused by both environmental and genetic factors. Three causative genes have been identified in familial hemiplegic migraine (FHM) families: CACNA1A, ATP1A2, and SCNA1A. Recently, several mutations in KCNK18 have also been found as causative factors in migraine development. The aim of our study was to identify the genetic background of migraine in the Polish population. Sixty patients with migraine without aura (MO) or with different types of migraine with aura (MA), including sporadic hemiplegic, familial hemiplegic, and probable familial hemiplegic, were screened for mutations in the four genes previously linked with different types of migraine (ATP1A2, CACNA1A, SCN1A, and KCNK18). Two missense mutations were found. One novel mutation in SCN1A, encoding α subunit of sodium channel, causing amino acid change M1500V localized to a region encoding inactivation loop between transmembrane domains III and IV of the channel, was detected in a female FHM patient. The M1500V mutation was absent in a group of 62 controls, as well as in the ExAC database. The second, already known missense mutation S231P in KCNK18 was found in a female MA patient. Additionally, a novel intronic polymorphism possibly affecting alternative splicing of SCN1A, at chr2:16685249, g.77659T>C, and c.4581+32A>G, located between exons 24 and 25, in a region encoding the inactivation loop of the sodium channel was found in a female MO patient. No mutations in ATP1A2 or CACNA1A were found in the study group. The presence of SCN1A mutations and absence of mutations in ATP1A2 or CACNA1A suggest that the Polish patients represent FHM type 3. On the other hand, the presence of KCNK18 mutation indicated another FHM subtype. It could be speculated that contrary to other European populations, the genetic basis of migraine in the Polish population involves mutations in genes not included in the

  10. Genetic association study of phosphodiesterase 8B gene with subclinical hypothyroidism in pregnant women.

    Science.gov (United States)

    Yang, Shuai; Tao, Jun; Zhang, Junyu; Fan, Jianxia; Qian, Wei; Shu, Khor

    2015-01-01

    To explore whether phosphodiesterase 8B (PDE8B) gene is involved in the etiology of subclinical hypothyroidism (SCH) in pregnant women. A total of 180 pregnant patients with SCH and 311 healthy, pregnant control subjects were recruited in this study to detect 4 (rs4704397, rs6885099, rs2046045, and rs12514694 in PDE8B) single nucleotide polymorphisms (SNPs). Univariate associations were studied using Pearson's χ(2) test for categorical variables and Student t/ANOVA tests for continuous ones. Nonparametric Kruskal-Wallis test were used to study the associations of TSH level in different genotypes. Genotyping of SNPs was performed by the MassARRAY(®) iPLEX(®) Gold SNP genotyping analysis technique. The SHEsis program was used to analyze the genotyping data. There was a significant difference in the rate of high TSH in three genotypes of rs4704397 in all pregnant women. After adjusting for multiple testing by the program SNPSpD, allelic frequencies of rs4704397 (p = 0.016, OR = 1.692), rs6885099 (p = 0.031, OR = 0.621), and rs2046045 (p = 0.023, OR = 0.602) in PDE8B gene showed significant differences between patients with SCH and control subjects. There were no significant differences of genotype frequencies between patients and controls at any of the analyzed SNPs (p > 0.05).The haplotypes ''A G C G'' (p = 0.002; OR, 1.533; 95% CI, 1.172-2.006) and "G A A G" (p = 0.014; OR, 0.576; 95% CI, 0.369-0.899) in PDE8B were observed to be significantly associated with SCH in pregnant women. Genetic variation of the PDE8B gene may be involved in the etiology of SCH in pregnant women.

  11. Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies.

    Science.gov (United States)

    Zhu, Hao; Shah, Samar; Shyh-Chang, Ng; Shinoda, Gen; Einhorn, William S; Viswanathan, Srinivas R; Takeuchi, Ayumu; Grasemann, Corinna; Rinn, John L; Lopez, Mary F; Hirschhorn, Joel N; Palmert, Mark R; Daley, George Q

    2010-07-01

    Recently, genome-wide association studies have implicated the human LIN28B locus in regulating height and the timing of menarche. LIN28B and its homolog LIN28A are functionally redundant RNA-binding proteins that block biogenesis of let-7 microRNAs. lin-28 and let-7 were discovered in Caenorhabditis elegans as heterochronic regulators of larval and vulval development but have recently been implicated in cancer, stem cell aging and pluripotency. The let-7 targets Myc, Kras, Igf2bp1 and Hmga2 are known regulators of mammalian body size and metabolism. To explore the function of the Lin28-Let-7 pathway in vivo, we engineered transgenic mice to express Lin28a and observed in them increased body size, crown-rump length and delayed onset of puberty. Investigation of metabolic and endocrine mechanisms of overgrowth in these transgenic mice revealed increased glucose metabolism and insulin sensitivity. Here we report a mouse that models the human phenotypes associated with genetic variation in the Lin28-Let-7 pathway.

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    BOJAN MIRKOVIC

    2016-09-01

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

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

    Science.gov (United States)

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

    2011-03-01

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

  15. Kernel Approach for Modeling Interaction Effects in Genetic Association Studies of Complex Quantitative Traits.

    Science.gov (United States)

    Broadaway, K Alaine; Duncan, Richard; Conneely, Karen N; Almli, Lynn M; Bradley, Bekh; Ressler, Kerry J; Epstein, Michael P

    2015-07-01

    The etiology of complex traits likely involves the effects of genetic and environmental factors, along with complicated interaction effects between them. Consequently, there has been interest in applying genetic association tests of complex traits that account for potential modification of the genetic effect in the presence of an environmental factor. One can perform such an analysis using a joint test of gene and gene-environment interaction. An optimal joint test would be one that remains powerful under a variety of models ranging from those of strong gene-environment interaction effect to those of little or no gene-environment interaction effect. To fill this demand, we have extended a kernel machine based approach for association mapping of multiple SNPs to consider joint tests of gene and gene-environment interaction. The kernel-based approach for joint testing is promising, because it incorporates linkage disequilibrium information from multiple SNPs simultaneously in analysis and permits flexible modeling of interaction effects. Using simulated data, we show that our kernel machine approach typically outperforms the traditional joint test under strong gene-environment interaction models and further outperforms the traditional main-effect association test under models of weak or no gene-environment interaction effects. We illustrate our test using genome-wide association data from the Grady Trauma Project, a cohort of highly traumatized, at-risk individuals, which has previously been investigated for interaction effects. © 2015 WILEY PERIODICALS, INC.

  16. Genetic variation and population substructure in outbred CD-1 mice: implications for genome-wide association studies.

    Directory of Open Access Journals (Sweden)

    Kimberly A Aldinger

    Full Text Available Outbred laboratory mouse populations are widely used in biomedical research. Since little is known about the degree of genetic variation present in these populations, they are not widely used for genetic studies. Commercially available outbred CD-1 mice are drawn from an extremely large breeding population that has accumulated many recombination events, which is desirable for genome-wide association studies. We therefore examined the degree of genome-wide variation within CD-1 mice to investigate their suitability for genetic studies. The CD-1 mouse genome displays patterns of linkage disequilibrium and heterogeneity similar to wild-caught mice. Population substructure and phenotypic differences were observed among CD-1 mice obtained from different breeding facilities. Differences in genetic variation among CD-1 mice from distinct facilities were similar to genetic differences detected between closely related human populations, consistent with a founder effect. This first large-scale genetic analysis of the outbred CD-1 mouse strain provides important considerations for the design and analysis of genetic studies in CD-1 mice.

  17. Genetic and lifestyle causal beliefs about obesity and associated diseases among ethnically diverse patients: a structured interview study

    Science.gov (United States)

    Diefenbach, Michael A.; Streicher, Samantha A.; Jabs, Ethylin Wang; Smirnoff, Margaret; Horowitz, Carol R.; Zinberg, Randi; Clesca, Cindy; Richardson, Lynne D.

    2015-01-01

    Background New genetic associations with obesity are rapidly being discovered. People’s causal beliefs about obesity may influence their obesity-related behaviors. Little is known about genetic compared to lifestyle causal beliefs regarding obesity, and obesity-related diseases, among minority populations. This study examined genetic and lifestyle causal beliefs about obesity and three obesity-related diseases among a low-income, ethnically diverse patient sample. Methods Structured interviews were conducted with patients attending an inner-city hospital outpatient clinic. Participants (n=205) were asked how much they agreed that genetics influence risk of obesity, type 2 diabetes, heart disease and cancer. Similar questions were asked regarding lifestyle causal beliefs (overeating, eating certain types of food, chemicals in food, not exercising, smoking). Forty-eight percent of participants were Non-Hispanic Black, 29% Hispanic, and 10% Non-Hispanic White. Results Over two thirds (69%) of participants believed genetics cause obesity ‘some’ or ‘a lot’, compared to 82% for type 2 diabetes, 79% for heart disease, and 75% for cancer. Participants who held genetic causal beliefs about obesity held more lifestyle causal beliefs in total than those who did not hold genetic causal beliefs about obesity (4.4 vs. 3.7 lifestyle causal beliefs respectively, possible range 0 to 5, p=0.025). There were few associations between causal beliefs and socio-demographic characteristics. Conclusions Higher beliefs in genetic causation of obesity and related diseases are not automatically associated with decreased lifestyle beliefs. Future research efforts are needed to determine whether public health messages aimed at reducing obesity and its consequences in racially and ethnically diverse urban communities may benefit from incorporating an acknowledgement of the role of genetics in these conditions. PMID:23235350

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

    DEFF Research Database (Denmark)

    Benfield, Thomas; Ejrnaes, Karen; Juul, Klaus

    2010-01-01

    . METHODS: A genetic association study involving four case cohorts comprising two Gram negative sepsis, one invasive pneumococcal disease and one intensive care unit cohort with a total of 1,249 patients. Controls were derived from a population-based cohort study (N = 8,147). DNA from patients and controls...

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

    Science.gov (United States)

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

    2012-10-01

    The primary objective of this study was to determine genetic and genomic parameters among swine (Sus scrofa) farrowing traits. Genetic parameters were obtained using MTDFREML. Genomic parameters were obtained using GENSEL. Genetic and residual variances obtained from MTDFREML were used as priors for the Bayes C analysis of GENSEL. Farrowing traits included total number born (TNB), number born alive (NBA), number born dead (NBD), number stillborn (NSB), number of mummies (MUM), litter birth weight (LBW), and average piglet birth weight (ABW). Statistically significant heritabilities included TNB (0.09, P = 0.048), NBA (0.09, P = 0.041), LBW (0.20, P = 0.002), and ABW (0.26, P ABW (0.63, P ABW (0.31). Limited information is available in the literature about genomic parameters. Only the GP estimate for NSB is significantly lower than what has been published. The GP estimate for ABW is greater than the estimate for heritability found in this study. Other traits with significant heritability had GP estimates half the value of heritability. This research indicates that significant genetic markers will be found for TNB, NBA, LBW, and ABW that will have either immediate use in industry or provide a roadmap to further research with fine mapping or sequencing of areas of significance. Furthermore, these results indicate that genomic selection implemented at an early age would have similar annual progress as traditional selection, and could be incorporated along with traditional selection procedures to improve genetic progress of litter traits.

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

    NARCIS (Netherlands)

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

    2012-01-01

    Crime poses a major burden for society. The heterogeneous nature of criminal behavior makes it difficult to unravel its causes. Relatively little research has been conducted on the genetic influences of criminal behavior. The few twin and adoption studies that have been undertaken suggest that about

  1. Pilot Study: Association of Traditional and Genetic Risk Factors and New-Onset Diabetes Mellitus Following Kidney Transplantation

    Science.gov (United States)

    Chakkera, H.A.; Hanson, R.L.; Raza, S.M.; DiStefano, J.K.; Millis, M.P.; Heilman, R.L.; Mulligan, D.C.; Reddy, K.S.; Mazur, M.J.; Hamawi, K.; Moss, A.A.; Mekeel, K.L.; Cerhan, J.R.

    2012-01-01

    Introduction New-onset diabetes mellitus, which occurs after kidney transplant and type 2 diabetes mellitus (T2DM), shares common risk factors and antecedents in impaired insulin secretion and action. Several genetic polymorphisms have been shown to be associated with T2DM. We hypothesized that transplant recipients who carry risk alleles for T2DM are “tipped over” to develop diabetes mellitus in the posttransplant milieu. Methods We investigated the association of genetic and traditional risk factors present before transplantation and the development of new-onset diabetes mellitus after kidney transplantation (NODAT). Markers in 8 known T2DM-linked genes were genotyped using either the iPLEX assay or allelic discrimination (AD)-PCR in the study cohort testing for association with NODAT. We used univariate and multivariate logistic regression models for the association of pretransplant nongenetic and genetic variables with the development of NODAT. Results The study cohort included 91 kidney transplant recipients with at least 1 year posttransplant follow-up, including 22 who developed NODAT. We observed that increased age, family history of T2DM, pretransplant obesity, and triglyceridemia were associated with NODAT development. In addition, we observed positive trends, although statistically not significant, for association between T2DM-associated genes and NODAT. Conclusions These findings demonstrated an increased NODAT risk among patient with a positive family history for T2DM, which, in conjunction with the observed positive predictive trends of known T2DM-associated genetic polymorphisms with NODAT, was suggestive of a genetic predisposition to NODAT. PMID:20005362

  2. 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.

  3. Genetic Diversity and Association Studies in US Hispanic/Latino Populations: Applications in the Hispanic Community Health Study/Study of Latinos

    Science.gov (United States)

    Conomos, Matthew P.; Laurie, Cecelia A.; Stilp, Adrienne M.; Gogarten, Stephanie M.; McHugh, Caitlin P.; Nelson, Sarah C.; Sofer, Tamar; Fernández-Rhodes, Lindsay; Justice, Anne E.; Graff, Mariaelisa; Young, Kristin L.; Seyerle, Amanda A.; Avery, Christy L.; Taylor, Kent D.; Rotter, Jerome I.; Talavera, Gregory A.; Daviglus, Martha L.; Wassertheil-Smoller, Sylvia; Schneiderman, Neil; Heiss, Gerardo; Kaplan, Robert C.; Franceschini, Nora; Reiner, Alex P.; Shaffer, John R.; Barr, R. Graham; Kerr, Kathleen F.; Browning, Sharon R.; Browning, Brian L.; Weir, Bruce S.; Avilés-Santa, M. Larissa; Papanicolaou, George J.; Lumley, Thomas; Szpiro, Adam A.; North, Kari E.; Rice, Ken; Thornton, Timothy A.; Laurie, Cathy C.

    2016-01-01

    US Hispanic/Latino individuals are diverse in genetic ancestry, culture, and environmental exposures. Here, we characterized and controlled for this diversity in genome-wide association studies (GWASs) for the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We simultaneously estimated population-structure principal components (PCs) robust to familial relatedness and pairwise kinship coefficients (KCs) robust to population structure, admixture, and Hardy-Weinberg departures. The PCs revealed substantial genetic differentiation within and among six self-identified background groups (Cuban, Dominican, Puerto Rican, Mexican, and Central and South American). To control for variation among groups, we developed a multi-dimensional clustering method to define a “genetic-analysis group” variable that retains many properties of self-identified background while achieving substantially greater genetic homogeneity within groups and including participants with non-specific self-identification. In GWASs of 22 biomedical traits, we used a linear mixed model (LMM) including pairwise empirical KCs to account for familial relatedness, PCs for ancestry, and genetic-analysis groups for additional group-associated effects. Including the genetic-analysis group as a covariate accounted for significant trait variation in 8 of 22 traits, even after we fit 20 PCs. Additionally, genetic-analysis groups had significant heterogeneity of residual variance for 20 of 22 traits, and modeling this heteroscedasticity within the LMM reduced genomic inflation for 19 traits. Furthermore, fitting an LMM that utilized a genetic-analysis group rather than a self-identified background group achieved higher power to detect previously reported associations. We expect that the methods applied here will be useful in other studies with multiple ethnic groups, admixture, and relatedness. PMID:26748518

  4. A Genetic Predictive Model for Canine Hip Dysplasia: Integration of Genome Wide Association Study (GWAS) and Candidate Gene Approaches

    Science.gov (United States)

    Bartolomé, Nerea; Segarra, Sergi; Artieda, Marta; Francino, Olga; Sánchez, Elisenda; Szczypiorska, Magdalena; Casellas, Joaquim; Tejedor, Diego; Cerdeira, Joaquín; Martínez, Antonio; Velasco, Alfonso; Sánchez, Armand

    2015-01-01

    Canine hip dysplasia is one of the most prevalent developmental orthopedic diseases in dogs worldwide. Unfortunately, the success of eradication programs against this disease based on radiographic diagnosis is low. Adding the use of diagnostic genetic tools to the current phenotype-based approach might be beneficial. The aim of this study was to develop a genetic prognostic test for early diagnosis of hip dysplasia in Labrador Retrievers. To develop our DNA test, 775 Labrador Retrievers were recruited. For each dog, a blood sample and a ventrodorsal hip radiograph were taken. Dogs were divided into two groups according to their FCI hip score: control (A/B) and case (D/E). C dogs were not included in the sample. Genetic characterization combining a GWAS and a candidate gene strategy using SNPs allowed a case-control population association study. A mathematical model which included 7 SNPs was developed using logistic regression. The model showed a good accuracy (Area under the ROC curve = 0.85) and was validated in an independent population of 114 dogs. This prognostic genetic test represents a useful tool for choosing the most appropriate therapeutic approach once genetic predisposition to hip dysplasia is known. Therefore, it allows a more individualized management of the disease. It is also applicable during genetic selection processes, since breeders can benefit from the information given by this test as soon as a blood sample can be collected, and act accordingly. In the authors’ opinion, a shift towards genomic screening might importantly contribute to reducing canine hip dysplasia in the future. In conclusion, based on genetic and radiographic information from Labrador Retrievers with hip dysplasia, we developed an accurate predictive genetic test for early diagnosis of hip dysplasia in Labrador Retrievers. However, further research is warranted in order to evaluate the validity of this genetic test in other dog breeds. PMID:25874693

  5. A genetic predictive model for canine hip dysplasia: integration of Genome Wide Association Study (GWAS and candidate gene approaches.

    Directory of Open Access Journals (Sweden)

    Nerea Bartolomé

    Full Text Available Canine hip dysplasia is one of the most prevalent developmental orthopedic diseases in dogs worldwide. Unfortunately, the success of eradication programs against this disease based on radiographic diagnosis is low. Adding the use of diagnostic genetic tools to the current phenotype-based approach might be beneficial. The aim of this study was to develop a genetic prognostic test for early diagnosis of hip dysplasia in Labrador Retrievers. To develop our DNA test, 775 Labrador Retrievers were recruited. For each dog, a blood sample and a ventrodorsal hip radiograph were taken. Dogs were divided into two groups according to their FCI hip score: control (A/B and case (D/E. C dogs were not included in the sample. Genetic characterization combining a GWAS and a candidate gene strategy using SNPs allowed a case-control population association study. A mathematical model which included 7 SNPs was developed using logistic regression. The model showed a good accuracy (Area under the ROC curve = 0.85 and was validated in an independent population of 114 dogs. This prognostic genetic test represents a useful tool for choosing the most appropriate therapeutic approach once genetic predisposition to hip dysplasia is known. Therefore, it allows a more individualized management of the disease. It is also applicable during genetic selection processes, since breeders can benefit from the information given by this test as soon as a blood sample can be collected, and act accordingly. In the authors' opinion, a shift towards genomic screening might importantly contribute to reducing canine hip dysplasia in the future. In conclusion, based on genetic and radiographic information from Labrador Retrievers with hip dysplasia, we developed an accurate predictive genetic test for early diagnosis of hip dysplasia in Labrador Retrievers. However, further research is warranted in order to evaluate the validity of this genetic test in other dog breeds.

  6. A genetic predictive model for canine hip dysplasia: integration of Genome Wide Association Study (GWAS) and candidate gene approaches.

    Science.gov (United States)

    Bartolomé, Nerea; Segarra, Sergi; Artieda, Marta; Francino, Olga; Sánchez, Elisenda; Szczypiorska, Magdalena; Casellas, Joaquim; Tejedor, Diego; Cerdeira, Joaquín; Martínez, Antonio; Velasco, Alfonso; Sánchez, Armand

    2015-01-01

    Canine hip dysplasia is one of the most prevalent developmental orthopedic diseases in dogs worldwide. Unfortunately, the success of eradication programs against this disease based on radiographic diagnosis is low. Adding the use of diagnostic genetic tools to the current phenotype-based approach might be beneficial. The aim of this study was to develop a genetic prognostic test for early diagnosis of hip dysplasia in Labrador Retrievers. To develop our DNA test, 775 Labrador Retrievers were recruited. For each dog, a blood sample and a ventrodorsal hip radiograph were taken. Dogs were divided into two groups according to their FCI hip score: control (A/B) and case (D/E). C dogs were not included in the sample. Genetic characterization combining a GWAS and a candidate gene strategy using SNPs allowed a case-control population association study. A mathematical model which included 7 SNPs was developed using logistic regression. The model showed a good accuracy (Area under the ROC curve = 0.85) and was validated in an independent population of 114 dogs. This prognostic genetic test represents a useful tool for choosing the most appropriate therapeutic approach once genetic predisposition to hip dysplasia is known. Therefore, it allows a more individualized management of the disease. It is also applicable during genetic selection processes, since breeders can benefit from the information given by this test as soon as a blood sample can be collected, and act accordingly. In the authors' opinion, a shift towards genomic screening might importantly contribute to reducing canine hip dysplasia in the future. In conclusion, based on genetic and radiographic information from Labrador Retrievers with hip dysplasia, we developed an accurate predictive genetic test for early diagnosis of hip dysplasia in Labrador Retrievers. However, further research is warranted in order to evaluate the validity of this genetic test in other dog breeds.

  7. Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up

    Science.gov (United States)

    Martin, Jose-Ezequiel; Broen, Jasper C.; Carmona, F. David; Teruel, Maria; Simeon, Carmen P.; Vonk, Madelon C.; van ‘t Slot, Ruben; Rodriguez-Rodriguez, Luis; Vicente, Esther; Fonollosa, Vicente; Ortego-Centeno, Norberto; González-Gay, Miguel A.; García-Hernández, Francisco J.; de la Peña, Paloma García; Carreira, Patricia; Voskuyl, Alexandre E.; Schuerwegh, Annemie J.; van Riel, Piet L.C.M.; Kreuter, Alexander; Witte, Torsten; Riemekasten, Gabriella; Airo, Paolo; Scorza, Raffaella; Lunardi, Claudio; Hunzelmann, Nicolas; Distler, Jörg H.W.; Beretta, Lorenzo; van Laar, Jacob; Chee, Meng May; Worthington, Jane; Herrick, Ariane; Denton, Christopher; Tan, Filemon K.; Arnett, Frank C.; Assassi, Shervin; Fonseca, Carmen; Mayes, Maureen D.; Radstake, Timothy R.D.J.; Koeleman, Bobby P.C.; Martin, Javier

    2012-01-01

    Systemic sclerosis (SSc) is complex autoimmune disease affecting the connective tissue; influenced by genetic and environmental components. Recently, we performed the first successful genome-wide association study (GWAS) of SSc. Here, we perform a large replication study to better dissect the genetic component of SSc. We selected 768 polymorphisms from the previous GWAS and genotyped them in seven replication cohorts from Europe. Overall significance was calculated for replicated significant SNPs by meta-analysis of the replication cohorts and replication-GWAS cohorts (3237 cases and 6097 controls). Six SNPs in regions not previously associated with SSc were selected for validation in another five independent cohorts, up to a total of 5270 SSc patients and 8326 controls. We found evidence for replication and overall genome-wide significance for one novel SSc genetic risk locus: CSK [P-value = 5.04 × 10−12, odds ratio (OR) = 1.20]. Additionally, we found suggestive association in the loci PSD3 (P-value = 3.18 × 10−7, OR = 1.36) and NFKB1 (P-value = 1.03 × 10−6, OR = 1.14). Additionally, we strengthened the evidence for previously confirmed associations. This study significantly increases the number of known putative genetic risk factors for SSc, including the genes CSK, PSD3 and NFKB1, and further confirms six previously described ones. PMID:22407130

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

    Science.gov (United States)

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

    2010-05-01

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

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

    Science.gov (United States)

    Bauchet, Guillaume; Grenier, Stéphane; Samson, Nicolas; Bonnet, Julien; Grivet, Laurent; Causse, Mathilde

    2017-05-01

    A panel of 300 tomato accessions including breeding materials was built and characterized with >11,000 SNP. A population structure in six subgroups was identified. Strong heterogeneity in linkage disequilibrium and recombination landscape among groups and chromosomes was shown. GWAS identified several associations for fruit weight, earliness and plant growth. Genome-wide association studies (GWAS) have become a method of choice in quantitative trait dissection. First limited to highly polymorphic and outcrossing species, it is now applied in horticultural crops, notably in tomato. Until now GWAS in tomato has been performed on panels of heirloom and wild accessions. Using modern breeding materials would be of direct interest for breeding purpose. To implement GWAS on a large panel of 300 tomato accessions including 168 breeding lines, this study assessed the genetic diversity and linkage disequilibrium decay and revealed the population structure and performed GWA experiment. Genetic diversity and population structure analyses were based on molecular markers (>11,000 SNP) covering the whole genome. Six genetic subgroups were revealed and associated to traits of agronomical interest, such as fruit weight and disease resistance. Estimates of linkage disequilibrium highlighted the heterogeneity of its decay among genetic subgroups. Haplotype definition allowed a fine characterization of the groups and their recombination landscape revealing the patterns of admixture along the genome. Selection footprints showed results in congruence with introgressions. Taken together, all these elements refined our knowledge of the genetic material included in this panel and allowed the identification of several associations for fruit weight, plant growth and earliness, deciphering the genetic architecture of these complex traits and identifying several new loci useful for tomato breeding.

  10. Web-based, participant-driven studies yield novel genetic associations for common traits.

    OpenAIRE

    Nicholas Eriksson; J Michael Macpherson; Joyce Y Tung; Hon, Lawrence S.; Brian Naughton; Serge Saxonov; Linda Avey; Anne Wojcicki; Itsik Pe'er; Joanna Mountain

    2010-01-01

    Despite the recent rapid growth in genome-wide data, much of human variation remains entirely unexplained. A significant challenge in the pursuit of the genetic basis for variation in common human traits is the efficient, coordinated collection of genotype and phenotype data. We have developed a novel research framework that facilitates the parallel study of a wide assortment of traits within a single cohort. The approach takes advantage of the interactivity of the Web both to gather data and...

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

    OpenAIRE

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

    2012-01-01

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

  12. Genome-wide association study of positive emotion identifies a genetic variant and a role for microRNAs

    Science.gov (United States)

    Wingo, Aliza P.; Almli, Lynn M.; Stevens, Jennifer S.; Jovanovic, Tanja; Wingo, Thomas S.; Tharp, Gregory; Li, Yujing; Lori, Adriana; Briscione, Maria; Jin, Peng; Binder, Elisabeth B.; Bradley, Bekh; Gibson, Greg; Ressler, Kerry J.

    2016-01-01

    Positive affect denotes a state of pleasurable engagement with the environment eliciting positive emotion such as contentment, enthusiasm, or happiness. Positive affect is associated with favorable psychological, physical, and economic outcomes in many longitudinal studies. With a heritability of ≤64%, positive affect is substantially influenced by genetic factors; however, our understanding of genetic pathways underlying individual differences in positive affect is still limited. Here, through a genome-wide association study (GWAS) of positive affect in African American participants, we identify a single nucleotide polymorphism (SNP), rs322931, significantly associated with positive affect at pmiR-181b in human brain and blood, greater nucleus accumbens reactivity to positive emotional stimuli, and enhanced fear inhibition. Prior studies have suggested that miR-181a is part of the reward neurocircuitry. Taken together, we identify a novel genetic variant for further elucidation of genetic underpinning of positive affect that mediates positive emotionality potentially via the nucleus accumbens and miR-181. PMID:27595594

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

    Science.gov (United States)

    Dodig, Dejan; Zoric, Miroslav; Kobiljski, Borislav; Savic, Jasna; Kandic, Vesna; Quarrie, Steve; Barnes, Jeremy

    2012-01-01

    Genetic analyses and association mapping were performed on a winter wheat core collection of 96 accessions sampled from a variety of geographic origins. Twenty-four agronomic traits were evaluated over 3 years under fully irrigated, rainfed and drought treatments. Grain yield was the most sensitive trait to water deficit and was highly correlated with above-ground biomass per plant and number of kernels per m2. The germplasm was structured into four subpopulations. The association of 46 SSR loci distributed throughout the wheat genome with yield and agronomic traits was analyzed using a general linear model, where subpopulation information was used to control false-positive or spurious marker-trait associations (MTAs). A total of 26, 21 and 29 significant (P < 0.001) MTAs were identified in irrigated, rainfed and drought treatments, respectively. The marker effects ranged from 14.0 to 50.8%. Combined across all treatments, 34 significant (P < 0.001) MTAs were identified with nine markers, and R2 ranged from 14.5 to 50.2%. Marker psp3200 (6DS) and particularly gwm484 (2DS) were associated with many significant MTAs in each treatment and explained the greatest proportion of phenotypic variation. Although we were not able to recognize any marker related to grain yield under drought stress, a number of MTAs associated with developmental and agronomic traits highly correlated with grain yield under drought were identified. PMID:22754357

  14. Genetic markers associated with dihydroartemisinin-piperaquine failure in Plasmodium falciparum malaria in Cambodia: a genotype-phenotype association study.

    Science.gov (United States)

    Amato, Roberto; Lim, Pharath; Miotto, Olivo; Amaratunga, Chanaki; Dek, Dalin; Pearson, Richard D; Almagro-Garcia, Jacob; Neal, Aaron T; Sreng, Sokunthea; Suon, Seila; Drury, Eleanor; Jyothi, Dushyanth; Stalker, Jim; Kwiatkowski, Dominic P; Fairhurst, Rick M

    2017-02-01

    As the prevalence of artemisinin-resistant Plasmodium falciparum malaria increases in the Greater Mekong subregion, emerging resistance to partner drugs in artemisinin combination therapies seriously threatens global efforts to treat and eliminate this disease. Molecular markers that predict failure of artemisinin combination therapy are urgently needed to monitor the spread of partner drug resistance, and to recommend alternative treatments in southeast Asia and beyond. We did a genome-wide association study of 297 P falciparum isolates from Cambodia to investigate the relationship of 11 630 exonic single-nucleotide polymorphisms (SNPs) and 43 copy number variations (CNVs) with in-vitro piperaquine 50% inhibitory concentrations (IC50s), and tested whether these genetic variants are markers of treatment failure with dihydroartemisinin-piperaquine. We then did a survival analysis of 133 patients to determine whether candidate molecular markers predicted parasite recrudescence following dihydroartemisinin-piperaquine treatment. Piperaquine IC50s increased significantly from 2011 to 2013 in three Cambodian provinces (2011 vs 2013 median IC50s: 20·0 nmol/L [IQR 13·7-29·0] vs 39·2 nmol/L [32·8-48·1] for Ratanakiri, 19·3 nmol/L [15·1-26·2] vs 66·2 nmol/L [49·9-83·0] for Preah Vihear, and 19·6 nmol/L [11·9-33·9] vs 81·1 nmol/L [61·3-113·1] for Pursat; all p≤10(-3); Kruskal-Wallis test). Genome-wide analysis of SNPs identified a chromosome 13 region that associates with raised piperaquine IC50s. A non-synonymous SNP (encoding a Glu415Gly substitution) in this region, within a gene encoding an exonuclease, associates with parasite recrudescence following dihydroartemisinin-piperaquine treatment. Genome-wide analysis of CNVs revealed that a single copy of the mdr1 gene on chromosome 5 and a novel amplification of the plasmepsin 2 and plasmepsin 3 genes on chromosome 14 also associate with raised piperaquine IC50s. After adjusting for covariates, both

  15. Single nucleotide polymorphisms in the vitamin D pathway associating with circulating concentrations of vitamin D metabolites and non-skeletal health outcomes: Review of genetic association studies.

    Science.gov (United States)

    Jolliffe, David A; Walton, Robert T; Griffiths, Christopher J; Martineau, Adrian R

    2016-11-01

    Polymorphisms in genes encoding proteins involved in vitamin D metabolism and transport are recognised to influence vitamin D status. Syntheses of genetic association studies linking these variants to non-skeletal health outcomes are lacking. We therefore conducted a literature review to identify reports of statistically significant associations between single nucleotide polymorphisms (SNP) in 11 vitamin D pathway genes (DHCR7, CYP2R1, CYP3A4, CYP27A1, DBP, LRP2, CUB, CYP27B1, CYP24A1, VDR and RXRA) and non-bone health outcomes and circulating levels of 25-hydroxyvitamin D (25[OH]D and 1,25-dihydroxyvitamin D (1,25[OH]2D). A total of 120 genetic association studies reported positive associations, of which 44 investigated determinants of circulating 25(OH)D and/or 1,25(OH)2D concentrations, and 76 investigated determinants of non-skeletal health outcomes. Statistically significant associations were reported for a total of 55 SNP in the 11 genes investigated. There was limited overlap between genetic determinants of vitamin D status and those associated with non-skeletal health outcomes: polymorphisms in DBP, CYP2R1 and DHCR7 were the most frequent to be reported to associate with circulating concentrations of 25(OH)D, while polymorphisms in VDR were most commonly reported to associate with non-skeletal health outcomes, among which infectious and autoimmune diseases were the most represented. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Genetic association study of WNT10B polymorphisms with BMD and adiposity parameters in Danish and Belgian males

    DEFF Research Database (Denmark)

    Van Camp, Jasmijn K; Beckers, Sigri; Zegers, Doreen;

    2013-01-01

    Because of the importance of the Wnt pathway in the development and maintenance of both adipose and bone tissue, we wanted to evaluate the involvement of WNT10B, a Wnt pathway activator, in adipogenesis and osteoblastogenesis in humans. Genetic association between WNT10B polymorphisms and adiposity...... a previously shown negative effect on BMD. No significant associations were observed in the SIBLOS population. In the present study, no association between WNT10B polymorphisms and adiposity parameters was found. However, our results clearly illustrate a role for WNT10B variants in determining human BMD...

  17. Genetic Susceptibility to Type 2 Diabetes and Obesity: Follow-Up of Findings from Genome-Wide Association Studies

    Directory of Open Access Journals (Sweden)

    Kevin J. Basile

    2014-01-01

    Full Text Available Elucidating the underlying genetic variations influencing various complex diseases is one of the major challenges currently facing clinical genetic research. Although these variations are often difficult to uncover, approaches such as genome-wide association studies (GWASs have been successful at finding statistically significant associations between specific genomic loci and disease susceptibility. GWAS has been especially successful in elucidating genetic variants that influence type 2 diabetes (T2D and obesity/body mass index (BMI. Specifically, several GWASs have confirmed that a variant in transcription factor 7-like 2 (TCF7L2 confers risk for T2D, while a variant in fat mass and obesity-associated protein (FTO confers risk for obesity/BMI; indeed both of these signals are considered the most statistically associated loci discovered for these respective traits to date. The discovery of these two key loci in this context has been invaluable for providing novel insight into mechanisms of heritability and disease pathogenesis. As follow-up studies of TCF7L2 and FTO have typically lead the way in how to follow up a GWAS discovery, we outline what has been learned from such investigations and how they have implications for the myriad of other loci that have been subsequently reported in this disease context.

  18. Evaluation of shared genetic susceptibility loci between autoimmune diseases and schizophrenia based on genome-wide association studies

    DEFF Research Database (Denmark)

    Hoeffding, Louise K; Rosengren, Anders; Thygesen, Johan H;

    2016-01-01

    BACKGROUND: Epidemiological studies have documented higher than expected comorbidity (or, in some cases, inverse comorbidity) between schizophrenia and several autoimmune disorders. It remains unknown whether this comorbidity reflects shared genetic susceptibility loci. AIMS: The present study...... aimed to investigate whether verified genome wide significant variants of autoimmune disorders confer risk of schizophrenia, which could suggest a common genetic basis. METHODS: Seven hundred and fourteen genome wide significant risk variants of 25 autoimmune disorders were extracted from the NHGRI GWAS...... catalogue and examined for association to schizophrenia in the Psychiatric Genomics Consortium schizophrenia GWAS samples (36,989 cases and 113,075 controls). RESULTS: Two independent loci at 4q24 and 6p21.32-33 originally identified from GWAS of autoimmune diseases were found genome wide associated...

  19. A review on experimental and clinical genetic associations studies on fear conditioning, extinction and cognitive-behavioral treatment.

    Science.gov (United States)

    Lonsdorf, T B; Kalisch, R

    2011-09-20

    Fear conditioning and extinction represent basic forms of associative learning with considerable clinical relevance and have been implicated in the pathogenesis of anxiety disorders. There is considerable inter-individual variation in the ability to acquire and extinguish conditioned fear reactions and the study of genetic variants has recently become a focus of research. In this review, we give an overview of the existing genetic association studies on human fear conditioning and extinction in healthy individuals and of related studies on cognitive-behavioral treatment (CBT) and exposure, as well as pathology development after trauma. Variation in the serotonin transporter (5HTT) and the catechol-o-methyltransferase (COMT) genes has consistently been associated with effects in pre-clinical and clinical studies. Interesting new findings, which however require further replication, have been reported for genetic variation in the dopamine transporter (DAT1) and the pituitary adenylate cyclase 1 receptor (ADCYAP1R1) genes, whereas the current picture is inconsistent for variation in the brain-derived neurotrophic factor (BDNF) gene. We end with a discussion of the findings and their limitations, as well as future directions that we hope will aid the field to develop further.

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

    Directory of Open Access Journals (Sweden)

    Alexander Statnikov

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

  1. Case studies on genetically modified organisms (GMOs): Potential risk scenarios and associated health indicators.

    Science.gov (United States)

    De Santis, Barbara; Stockhofe, Norbert; Wal, Jean-Michel; Weesendorp, Eefke; Lallès, Jean-Paul; van Dijk, Jeroen; Kok, Esther; De Giacomo, Marzia; Einspanier, Ralf; Onori, Roberta; Brera, Carlo; Bikker, Paul; van der Meulen, Jan; Gijs, Kleter

    2017-08-30

    Within the frame of the EU-funded MARLON project, background data were reviewed to explore the possibility of measuring health indicators during post-market monitoring for potential effects of feeds, particularly genetically modified (GM) feeds, on livestock animal health, if applicable. Four case studies (CSs) of potential health effects on livestock were framed and the current knowledge of a possible effect of GM feed was reviewed. Concerning allergenicity (CS-1), there are no case-reports of allergic reactions or immunotoxic effects resulting from GM feed consumption as compared with non-GM feed. The likelihood of horizontal gene transfer (HGT; CS-2) of GMO-related DNA to different species is not different from that for other DNA and is unlikely to raise health concerns. Concerning mycotoxins (CS-3), insect-resistant GM maize may reduce fumonisins contamination as a health benefit, yet other Fusarium toxins and aflatoxins show inconclusive results. For nutritionally altered crops (CS-4), the genetic modifications applied lead to compositional changes which require special considerations of their nutritional impacts. No health indicators were thus identified except for possible beneficial impacts of reduced mycotoxins and nutritional enhancement. More generally, veterinary health data should ideally be linked with animal exposure information so as to be able to establish cause-effect relationships. Copyright © 2017. Published by Elsevier Ltd.

  2. Genetic Diversity and Genome Wide Association Study of β-Glucan Content in Tetraploid Wheat Grains.

    Science.gov (United States)

    Marcotuli, Ilaria; Houston, Kelly; Schwerdt, Julian G; Waugh, Robbie; Fincher, Geoffrey B; Burton, Rachel A; Blanco, Antonio; Gadaleta, Agata

    2016-01-01

    Non-starch polysaccharides (NSPs) have many health benefits, including immunomodulatory activity, lowering serum cholesterol, a faecal bulking effect, enhanced absorption of certain minerals, prebiotic effects and the amelioration of type II diabetes. The principal components of the NSP in cereal grains are (1,3;1,4)-β-glucans and arabinoxylans. Although (1,3;1,4)-β-glucan (hereafter called β-glucan) is not the most representative component of wheat cell walls, it is one of the most important types of soluble fibre in terms of its proven beneficial effects on human health. In the present work we explored the genetic variability of β-glucan content in grains from a tetraploid wheat collection that had been genotyped with a 90k-iSelect array, and combined this data to carry out an association analysis. The β-glucan content, expressed as a percentage w/w of grain dry weight, ranged from 0.18% to 0.89% across the collection. Our analysis identified seven genomic regions associated with β-glucan, located on chromosomes 1A, 2A (two), 2B, 5B and 7A (two), confirming the quantitative nature of this trait. Analysis of marker trait associations (MTAs) in syntenic regions of several grass species revealed putative candidate genes that might influence β-glucan levels in the endosperm, possibly via their participation in carbon partitioning. These include the glycosyl hydrolases endo-β-(1,4)-glucanase (cellulase), β-amylase, (1,4)-β-xylan endohydrolase, xylanase inhibitor protein I, isoamylase and the glycosyl transferase starch synthase II.

  3. Genetic Diversity and Genome Wide Association Study of β-Glucan Content in Tetraploid Wheat Grains.

    Directory of Open Access Journals (Sweden)

    Ilaria Marcotuli

    Full Text Available Non-starch polysaccharides (NSPs have many health benefits, including immunomodulatory activity, lowering serum cholesterol, a faecal bulking effect, enhanced absorption of certain minerals, prebiotic effects and the amelioration of type II diabetes. The principal components of the NSP in cereal grains are (1,3;1,4-β-glucans and arabinoxylans. Although (1,3;1,4-β-glucan (hereafter called β-glucan is not the most representative component of wheat cell walls, it is one of the most important types of soluble fibre in terms of its proven beneficial effects on human health. In the present work we explored the genetic variability of β-glucan content in grains from a tetraploid wheat collection that had been genotyped with a 90k-iSelect array, and combined this data to carry out an association analysis. The β-glucan content, expressed as a percentage w/w of grain dry weight, ranged from 0.18% to 0.89% across the collection. Our analysis identified seven genomic regions associated with β-glucan, located on chromosomes 1A, 2A (two, 2B, 5B and 7A (two, confirming the quantitative nature of this trait. Analysis of marker trait associations (MTAs in syntenic regions of several grass species revealed putative candidate genes that might influence β-glucan levels in the endosperm, possibly via their participation in carbon partitioning. These include the glycosyl hydrolases endo-β-(1,4-glucanase (cellulase, β-amylase, (1,4-β-xylan endohydrolase, xylanase inhibitor protein I, isoamylase and the glycosyl transferase starch synthase II.

  4. Genetic diversity studies and identification of SSR markers associated with Fusarium wilt (Fusarium udum) resistance in cultivated pigeonpea (Cajanus cajan)

    Indian Academy of Sciences (India)

    A. K. Singh; V. P. Rai; R. Chand; R. P. Singh; M. N. Singh

    2013-08-01

    Genetic diversity and identification of simple sequence repeat markers correlated with Fusarium wilt resistance was performed in a set of 36 elite cultivated pigeonpea genotypes differing in levels of resistance to Fusarium wilt. Twenty-four polymorphic sequence repeat markers were screened across these genotypes, and amplified a total of 59 alleles with an average high polymorphic information content value of 0.52. Cluster analysis, done by UPGMA and PCA, grouped the 36 pigeonpea genotypes into two main clusters according to their Fusarium wilt reaction. Based on the Kruskal–Wallis ANOVA and simple regression analysis, six simple sequence repeat markers were found to be significantly associated with Fusarium wilt resistance. The phenotypic variation explained by these markers ranged from 23.7 to 56.4%. The present study helps in finding out feasibility of prescreened SSR markers to be used in genetic diversity analysis and their potential association with disease resistance.

  5. Genetic variants in the apelin system and blood pressure responses to dietary sodium interventions: a family-based association study.

    Science.gov (United States)

    Zhao, Qi; Hixson, James E; Rao, Dabeeru C; Gu, Dongfeng; Jaquish, Cashell E; Rice, Treva; Shimmin, Lawrence C; Chen, Jichun; Cao, Jie; Kelly, Tanika N; Hamm, Lotuce Lee; He, Jiang

    2010-04-01

    We examined the association between genetic variants in the apelin system and blood pressure (BP) responses to low-sodium and high-sodium interventions in the GenSalt Study. A 7-day low-sodium intervention (51.3 mmol sodium per day) followed by a 7-day high-sodium intervention (307.8 mmol sodium per day) was conducted among 1906 participants from 637 Han Chinese families. BP measurements were obtained at baseline and following each intervention using a random-zero sphygmomanometer. Twenty-three single nucleotide polymorphisms (SNPs), including both tag and functional SNPs, were selected from three candidate genes (APLN, APLNR, and ACE2). Single marker and haplotype analyses were conducted using the Family Based Association Test program. The false discovery rate method was used to correct for multiple testing. SNPs rs2282623 and rs746886 of the APLNR gene were significantly associated with DBP (both P = 0.002) and mean arterial pressure (MAP) (P = 0.001 and 0.005, respectively) responses to low-sodium intervention. Six SNPs of the ACE2 gene were significantly associated with SBP, DBP, or MAP responses to low-sodium intervention. Three of them, rs1514283, rs1514282, and rs4646176, were also significantly associated with MAP response to high-sodium intervention (all P family-based study indicates that genetic variants in the APLNR and ACE2 genes are significantly associated with BP responses to dietary sodium intervention.

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

    Science.gov (United States)

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

    2016-02-01

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

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

    2015-01-01

    Background and Purpose The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African-Americans despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population genome-wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations. Methods Using METAL, we conducted meta-analyses of GWAS in 14,746 African-Americans (1,365 ischemic and 1,592 total stroke cases) from COMPASS, and tested SNPs with Pstroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations. Results The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613, P=3.9×10−8) in African-Americans. Nominal associations (Pstroke were observed for 18 variants in or near genes implicated in cell cycle/ mRNA pre-splicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, IL1F10-IL1RN), and histone modification (HDAC9). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 (P=0.03), and 1p31.1 (P=0.018). Four of 7 previously reported ischemic stroke loci (PITX2, HDAC9, CDKN2A/CDKN2B and ZFHX3) were nominally associated (Pstroke in COMPASS. Conclusions We identified a novel SNP associated with total stroke in African-Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African-Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations. PMID:26089329

  8. Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank.

    Science.gov (United States)

    Wain, Louise V; Shrine, Nick; Miller, Suzanne; Jackson, Victoria E; Ntalla, Ioanna; Soler Artigas, María; Billington, Charlotte K; Kheirallah, Abdul Kader; Allen, Richard; Cook, James P; Probert, Kelly; Obeidat, Ma'en; Bossé, Yohan; Hao, Ke; Postma, Dirkje S; Paré, Peter D; Ramasamy, Adaikalavan; Mägi, Reedik; Mihailov, Evelin; Reinmaa, Eva; Melén, Erik; O'Connell, Jared; Frangou, Eleni; Delaneau, Olivier; Freeman, Colin; Petkova, Desislava; McCarthy, Mark; Sayers, Ian; Deloukas, Panos; Hubbard, Richard; Pavord, Ian; Hansell, Anna L; Thomson, Neil C; Zeggini, Eleftheria; Morris, Andrew P; Marchini, Jonathan; Strachan, David P; Tobin, Martin D; Hall, Ian P

    2015-10-01

    Understanding the genetic basis of airflow obstruction and smoking behaviour is key to determining the pathophysiology of chronic obstructive pulmonary disease (COPD). We used UK Biobank data to study the genetic causes of smoking behaviour and lung health. We sampled individuals of European ancestry from UK Biobank, from the middle and extremes of the forced expiratory volume in 1 s (FEV1) distribution among heavy smokers (mean 35 pack-years) and never smokers. We developed a custom array for UK Biobank to provide optimum genome-wide coverage of common and low-frequency variants, dense coverage of genomic regions already implicated in lung health and disease, and to assay rare coding variants relevant to the UK population. We investigated whether there were shared genetic causes between different phenotypes defined by extremes of FEV1. We also looked for novel variants associated with extremes of FEV1 and smoking behaviour and assessed regions of the genome that had already shown evidence for a role in lung health and disease. We set genome-wide significance at pgenetic causes of low FEV1 between heavy smokers and never smokers (p=2.29 × 10(-16)) and between individuals with and without doctor-diagnosed asthma (p=6.06 × 10(-11)). We discovered six novel genome-wide significant signals of association with extremes of FEV1, including signals at four novel loci (KANSL1, TSEN54, TET2, and RBM19/TBX5) and independent signals at two previously reported loci (NPNT and HLA-DQB1/HLA-DQA2). These variants also showed association with COPD, including in individuals with no history of smoking. The number of copies of a 150 kb region containing the 5' end of KANSL1, a gene that is important for epigenetic gene regulation, was associated with extremes of FEV1. We also discovered five new genome-wide significant signals for smoking behaviour, including a variant in NCAM1 (chromosome 11) and a variant on chromosome 2 (between TEX41 and PABPC1P2) that has a trans effect

  9. 139 Genetic Association Study of the IgE Immunodeficiency in Mexican Population

    Science.gov (United States)

    Malpica Cruz, Jose Augusto; Vera, Javier Gomez; Del Pozo María Elena, Ramírez; Tiro, Jesus Lopez; Morales, Silvia Jimenez; Orozco, Lorena

    2012-01-01

    Background Primary immunodeficiencies (PID) are genetic diseases in which one or multiple components of the immune system, including cells (i.e. B cells, T cells, natural killer cells, phagocytes, complement components) or molecules (cytokines, chemokines, etc) are affected, leading to a low capacity to eliminate microorganisms and a high susceptibility to infection diseases. Most of the PID are multifactorial entities were the environmental and multiple genetic factor are involved. The single nucleotide polymorphisms (SNPs) analysis in case and control groups has been increasing the knowledge of the etiopathogenesis of several diseases and the opportunity to identify molecular markers useful in the clinical diagnosis. Methods We performed a case control study including 19 pediatric patients with IgE deficiency (5 U/mL), and 180 healthy controls. 25 SNPs distributed in the IL-13, IL-10, IL-5, IL4, FCER1B, INF γ, GM-CSF, STAT 3, GATA 3 and TIK-2 were analyzed. Genotyping was performed using sondas TaqMan. Hardy-Weinberg Equilibrium (HWE) and statistical significance were evaluated using FINETTI and STATCAL software. Results All genotypes, both in cases and controls were in HWE. We documented statistically significant differences in the distribution of the SNPs located in IL-4 rs4986964, P = 0.018, OR = 14.74, IL-4R, rs18005010, P = 0.018, OR = 2.22, FCER-1B, rs556917, P = 0.00001, OR = 16.9, GM-CSF, STAT-3 and GATA-3 genes: GMFCS-130 (P = 4986964, OR = 0.22), STAT-3 rs2293152 (P = 5.06 × 10−9, OR = 6.18), GATA-3 rs2229360 (P = 0.005, OR = 13.52). The highest difference was found in the T allele of rs556917, which was more frequent in cases than controls (42.1 and 1.5%, respectively, P = 0.00001 OR = 16.907, 95% CI, 5.02-54.93). Interestingly, the C allele of 4986964 (IL-4) increased significantly in homozygote genotype (C: OR = 14.74, 95% CI, 2.38-91.234, P = 0.018 to CC OR = 29.4, 95% CI, 1.154-749.32, P = 0.002). Conclusions Our results suggest that SNPs

  10. Genetic basis of interindividual susceptibility to cancer cachexia: selection of potential candidate gene polymorphisms for association studies.

    Science.gov (United States)

    Johns, N; Tan, B H; MacMillan, M; Solheim, T S; Ross, J A; Baracos, V E; Damaraju, S; Fearon, K C H

    2014-12-01

    Cancer cachexia is a complex and multifactorial disease. Evolving definitions highlight the fact that a diverse range of biological processes contribute to cancer cachexia. Part of the variation in who will and who will not develop cancer cachexia may be genetically determined. As new definitions, classifications and biological targets continue to evolve, there is a need for reappraisal of the literature for future candidate association studies. This review summarizes genes identified or implicated as well as putative candidate genes contributing to cachexia, identified through diverse technology platforms and model systems to further guide association studies. A systematic search covering 1986-2012 was performed for potential candidate genes / genetic polymorphisms relating to cancer cachexia. All candidate genes were reviewed for functional polymorphisms or clinically significant polymorphisms associated with cachexia using the OMIM and GeneRIF databases. Pathway analysis software was used to reveal possible network associations between genes. Functionality of SNPs/genes was explored based on published literature, algorithms for detecting putative deleterious SNPs and interrogating the database for expression of quantitative trait loci (eQTLs). A total of 154 genes associated with cancer cachexia were identified and explored for functional polymorphisms. Of these 154 genes, 119 had a combined total of 281 polymorphisms with functional and/or clinical significance in terms of cachexia associated with them. Of these, 80 polymorphisms (in 51 genes) were replicated in more than one study with 24 polymorphisms found to influence two or more hallmarks of cachexia (i.e., inflammation, loss of fat mass and/or lean mass and reduced survival). Selection of candidate genes and polymorphisms is a key element of multigene study design. The present study provides a contemporary basis to select genes and/or polymorphisms for further association studies in cancer cachexia, and

  11. Genetic basis of interindividual susceptibility to cancer cachexia: selection of potential candidate gene polymorphisms for association studies

    Indian Academy of Sciences (India)

    N. Johns; B. H. Tan; M. Macmillan; T. S. Solheim; J. A. Ross; V. E. Baracos; S. Damaraju; K. C. H. Fearon

    2014-12-01

    Cancer cachexia is a complex and multifactorial disease. Evolving definitions highlight the fact that a diverse range of biological processes contribute to cancer cachexia. Part of the variation in who will and who will not develop cancer cachexia may be genetically determined. As new definitions, classifications and biological targets continue to evolve, there is a need for reappraisal of the literature for future candidate association studies. This review summarizes genes identified or implicated as well as putative candidate genes contributing to cachexia, identified through diverse technology platforms and model systems to further guide association studies. A systematic search covering 1986–2012 was performed for potential candidate genes / genetic polymorphisms relating to cancer cachexia. All candidate genes were reviewed for functional polymorphisms or clinically significant polymorphisms associated with cachexia using the OMIM and GeneRIF databases. Pathway analysis software was used to reveal possible network associations between genes. Functionality of SNPs/genes was explored based on published literature, algorithms for detecting putative deleterious SNPs and interrogating the database for expression of quantitative trait loci (eQTLs). A total of 154 genes associated with cancer cachexia were identified and explored for functional polymorphisms. Of these 154 genes, 119 had a combined total of 281 polymorphisms with functional and/or clinical significance in terms of cachexia associated with them. Of these, 80 polymorphisms (in 51 genes) were replicated in more than one study with 24 polymorphisms found to influence two or more hallmarks of cachexia (i.e., inflammation, loss of fat mass and/or lean mass and reduced survival). Selection of candidate genes and polymorphisms is a key element of multigene study design. The present study provides a contemporary basis to select genes and/or polymorphisms for further association studies in cancer cachexia, and

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

    Science.gov (United States)

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

    2017-07-01

    Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14-1·83) and the presence of either LPA SNP (1·88, 1·40-2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81-1·11 and either LPA SNP 1·10, 0·92-1·31) or cardiovascular mortality (0·99, 0·81-1·2 and 1·13, 0·90-1·40, respectively) or in the validation studies. In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed

  13. Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP

    Science.gov (United States)

    Mead, Simon; Uphill, James; Beck, John; Poulter, Mark; Campbell, Tracy; Lowe, Jessica; Adamson, Gary; Hummerich, Holger; Klopp, Norman; Rückert, Ina-Maria; Wichmann, H-Erich; Azazi, Dhoyazan; Plagnol, Vincent; Pako, Wandagi H.; Whitfield, Jerome; Alpers, Michael P.; Whittaker, John; Balding, David J.; Zerr, Inga; Kretzschmar, Hans; Collinge, John

    2012-01-01

    Prion diseases are fatal neurodegenerative diseases of humans and animals caused by the misfolding and aggregation of prion protein (PrP). Mammalian prion diseases are under strong genetic control but few risk factors are known aside from the PrP gene locus (PRNP). No genome-wide association study (GWAS) has been done aside from a small sample of variant Creutzfeldt–Jakob disease (CJD). We conducted GWAS of sporadic CJD (sCJD), variant CJD (vCJD), iatrogenic CJD, inherited prion disease, kuru and resistance to kuru despite attendance at mortuary feasts. After quality control, we analysed 2000 samples and 6015 control individuals (provided by the Wellcome Trust Case Control Consortium and KORA-gen) for 491032-511862 SNPs in the European study. Association studies were done in each geographical and aetiological group followed by several combined analyses. The PRNP locus was highly associated with risk in all geographical and aetiological groups. This association was driven by the known coding variation at rs1799990 (PRNP codon 129). No non-PRNP loci achieved genome-wide significance in the meta-analysis of all human prion disease. SNPs at the ZBTB38–RASA2 locus were associated with CJD in the UK (rs295301, P = 3.13 × 10−8; OR, 0.70) but these SNPs showed no replication evidence of association in German sCJD or in Papua New Guinea-based tests. A SNP in the CHN2 gene was associated with vCJD [P = 1.5 × 10−7; odds ratio (OR), 2.36], but not in UK sCJD (P = 0.049; OR, 1.24), in German sCJD or in PNG groups. In the overall meta-analysis of CJD, 14 SNPs were associated (P < 10−5; two at PRNP, three at ZBTB38–RASA2, nine at nine other independent non-PRNP loci), more than would be expected by chance. None of the loci recently identified as genome-wide significant in studies of other neurodegenerative diseases showed any clear evidence of association in prion diseases. Concerning common genetic variation, it is likely that the PRNP locus contains the only

  14. Genetic architecture of bone quality variation in layer chickens revealed by a genome-wide association study

    Science.gov (United States)

    Guo, Jun; Sun, Congjiao; Qu, Liang; Shen, Manman; Dou, Taocun; Ma, Meng; Wang, Kehua; Yang, Ning

    2017-01-01

    Skeletal problems in layer chickens are gaining attention due to animal welfare and economic losses in the egg industry. The genetic improvement of bone traits has been proposed as a potential solution to these issues; however, genetic architecture is not well understood. We conducted a genome-wide association study (GWAS) on bone quality using a sample of 1534 hens genotyped with a 600 K Chicken Genotyping Array. Using a linear mixed model approach, a novel locus close to GSG1L, associated with femur bone mineral density (BMD), was uncovered in this study. In addition, nine SNPs in genes were associated with bone quality. Three of these genes, RANKL, ADAMTS and SOST, were known to be associated with osteoporosis in humans, which makes them good candidate genes for osteoporosis in chickens. Genomic partitioning analysis supports the fact that common variants contribute to the variations of bone quality. We have identified several strong candidate genes and genomic regions associated with bone traits measured in end-of-lay cage layers, which accounted for 1.3–7.7% of the phenotypic variance. These SNPs could provide the relevant information to help elucidate which genes affect bone quality in chicken. PMID:28383518

  15. Designs and Methods for Association Studies and Population Size Inference in Statistical Genetics

    DEFF Research Database (Denmark)

    Waltoft, Berit Lindum

    2016-01-01

    . Population genetics In population genetics two methods concerning the inference of the population size back in time are described. Both methods are based on the site iii iv frequency spectrum (SFS), and the fact that the expected SFS only depends on the time between coalescent events back in time. The rst...

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

    Directory of Open Access Journals (Sweden)

    Chuong B Do

    2011-06-01

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

  17. Genetic variants associated with lean and obese type 2 diabetes in a Han Chinese population: A case-control study.

    Science.gov (United States)

    Kong, Xiaomu; Xing, Xiaoyan; Hong, Jing; Zhang, Xuelian; Yang, Wenying

    2016-06-01

    Type 2 diabetes (T2D) is highly phenotypically heterogeneous. Genetics of the heterogeneity of lean and obese T2D is not clear. The aim of the present study was to identify the associations of T2D-related genetic variants with the risks for lean and obese T2D among the Chinese Han population. A case-control study consisting of 5338 T2D patients and 4663 normal glycemic controls of Chinese Han recruited in the Chinese National Diabetes and Metabolic Disorders Study was conducted. T2D cases were identified according to the 1999 World Health Organization criteria. Lean T2D was defined as T2D patient with a body mass index (BMI) CAMK1D, HHEX, and TCF2 were associated with the risk for lean T2D, and SNPs in or near KCNQ1 and FTO were associated with the risk for obese T2D. The results showed that the GRS for 25 T2D-related SNPs was more strongly associated with the risk for lean T2D (Ptrend = 2.66 × 10) than for obese T2D (Ptrend = 2.91 × 10) in our study population. Notably, the T2D GRS contributed to lower obesity-related measurements and greater β-cell dysfunction, including lower insulin levels in oral glucose tolerance test, decreased insulinogenic index, and Homeostasis Model Assessment for β-cell Function. In conclusion, our findings identified T2D-related genetic loci that contribute to the risk of lean and obese T2D individually and additively in a Chinese Han population. Moreover, the study highlights the contribution of known T2D genomic loci to the heterogeneity of lean and obese T2D in Chinese Hans.

  18. [Phenotype-based genetic association studies (PGAS): a new approach to understanding the genotype contribution to schizophrenic phenotypes].

    Science.gov (United States)

    Ehrenreich, H

    2013-05-01

    Schizophrenias are diagnosed purely clinically. The biological basis for this clinical entity is still fully unknown. Genetic studies have revealed some interesting hints but have not led to the identification of actual disease genotypes. On the contrary, it has become more and more probable that widely differing genotype constellations together with manifold environmental factors can trigger schizophrenia according to the motto "many roads lead to Rome...". Thus, new strategies that allow a better insight into complex genotype-phenotype relationships, e. g. PGAS (phenotype-based genetic associations studies) are urgently needed. PGAS became possible on the basis of the GRAS data collection, the as yet largest worldwide phenotypical databank of schizophrenic patients. First PGAS proof-of-concept results on cognition or development-relevant genes are already available.

  19. Genetic variants on 3q21 and in the Sp8 transcription factor gene (SP8 as susceptibility loci for psychotic disorders: a genetic association study.

    Directory of Open Access Journals (Sweden)

    Kenji Kondo

    Full Text Available BACKGROUND: Recent genome-wide association studies (GWASs investigating bipolar disorder (BD have detected a number of susceptibility genes. These studies have also provided novel insight into shared genetic components between BD and schizophrenia (SCZ, two major psychotic disorders. To examine the replication of the risk variants for BD and the pleiotropic effect of the variants associated with BD, we conducted a genetic association study of single nucleotide polymorphisms (SNPs that were selected based upon previous BD GWASs, which targeted psychotic disorders (BD and SCZ in the Japanese population. METHODS: Forty-eight SNPs were selected based upon previous GWASs. A two-stage analysis was conducted using first-set screening (for all SNPs: BD = 1,012, SCZ = 1,032 and control = 993 and second-set replication samples (for significant SNPs in the screening analysis: BD = 821, SCZ = 1,808 and control = 2,149. We assessed allelic association between BD, SCZ, psychosis (BD+SCZ and the SNPs selected for the analysis. RESULTS: Eight SNPs revealed nominal association signals for all comparisons (Puncorrected<0.05. Among these SNPs, the top two SNPs (associated with psychosis: Pcorrected = 0.048 and 0.037 for rs2251219 and rs2709722, respectively were further assessed in the second-set samples, and we replicated the signals from the initial screening analysis (associated with psychosis: Pcorrected = 0.0070 and 0.033 for rs2251219 and rs2709722, respectively. The meta-analysis between the current and previous GWAS results showed that rs2251219 in Polybromo1 (PBRM1 was significant on genome-wide association level (P = 5×10(-8 only for BD (P = 9.4×10(-9 and psychosis (P = 2.0×10(-10. Although the association of rs2709722 in Sp8 transcription factor (SP8 was suggestive in the Asian population (P = 2.1×10(-7 for psychosis, this signal weakened when the samples size was increased by including data from a

  20. Genetic Variants on 3q21 and in the Sp8 Transcription Factor Gene (SP8) as Susceptibility Loci for Psychotic Disorders: A Genetic Association Study

    Science.gov (United States)

    Kondo, Kenji; Ikeda, Masashi; Kajio, Yusuke; Saito, Takeo; Iwayama, Yoshimi; Aleksic, Branko; Yamada, Kazuo; Toyota, Tomoko; Hattori, Eiji; Ujike, Hiroshi; Inada, Toshiya; Kunugi, Hiroshi; Kato, Tadafumi; Yoshikawa, Takeo; Ozaki, Norio; Iwata, Nakao

    2013-01-01

    Background Recent genome-wide association studies (GWASs) investigating bipolar disorder (BD) have detected a number of susceptibility genes. These studies have also provided novel insight into shared genetic components between BD and schizophrenia (SCZ), two major psychotic disorders. To examine the replication of the risk variants for BD and the pleiotropic effect of the variants associated with BD, we conducted a genetic association study of single nucleotide polymorphisms (SNPs) that were selected based upon previous BD GWASs, which targeted psychotic disorders (BD and SCZ) in the Japanese population. Methods Forty-eight SNPs were selected based upon previous GWASs. A two-stage analysis was conducted using first-set screening (for all SNPs: BD = 1,012, SCZ = 1,032 and control = 993) and second-set replication samples (for significant SNPs in the screening analysis: BD = 821, SCZ = 1,808 and control = 2,149). We assessed allelic association between BD, SCZ, psychosis (BD+SCZ) and the SNPs selected for the analysis. Results Eight SNPs revealed nominal association signals for all comparisons (Puncorrected<0.05). Among these SNPs, the top two SNPs (associated with psychosis: Pcorrected = 0.048 and 0.037 for rs2251219 and rs2709722, respectively) were further assessed in the second-set samples, and we replicated the signals from the initial screening analysis (associated with psychosis: Pcorrected = 0.0070 and 0.033 for rs2251219 and rs2709722, respectively). The meta-analysis between the current and previous GWAS results showed that rs2251219 in Polybromo1 (PBRM1) was significant on genome-wide association level (P = 5×10−8) only for BD (P = 9.4×10−9) and psychosis (P = 2.0×10−10). Although the association of rs2709722 in Sp8 transcription factor (SP8) was suggestive in the Asian population (P = 2.1×10−7 for psychosis), this signal weakened when the samples size was increased by including data from a

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

    Directory of Open Access Journals (Sweden)

    Hoal Eileen G

    2010-06-01

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

  2. Control for Population Structure and Relatedness for Binary Traits in Genetic Association Studies via Logistic Mixed Models

    Science.gov (United States)

    Chen, Han; Wang, Chaolong; Conomos, Matthew P.; Stilp, Adrienne M.; Li, Zilin; Sofer, Tamar; Szpiro, Adam A.; Chen, Wei; Brehm, John M.; Celedón, Juan C.; Redline, Susan; Papanicolaou, George J.; Thornton, Timothy A.; Laurie, Cathy C.; Rice, Kenneth; Lin, Xihong

    2016-01-01

    Linear mixed models (LMMs) are widely used in genome-wide association studies (GWASs) to account for population structure and relatedness, for both continuous and binary traits. Motivated by the failure of LMMs to control type I errors in a GWAS of asthma, a binary trait, we show that LMMs are generally inappropriate for analyzing binary traits when population stratification leads to violation of the LMM’s constant-residual variance assumption. To overcome this problem, we develop a computationally efficient logistic mixed model approach for genome-wide analysis of binary traits, the generalized linear mixed model association test (GMMAT). This approach fits a logistic mixed model once per GWAS and performs score tests under the null hypothesis of no association between a binary trait and individual genetic variants. We show in simulation studies and real data analysis that GMMAT effectively controls for population structure and relatedness when analyzing binary traits in a wide variety of study designs. PMID:27018471

  3. Power for genetic association study of human longevity using the case-control design

    DEFF Research Database (Denmark)

    Tan, Qihua; Zhao, Jing Hua; Zhang, Dongfeng

    2008-01-01

    The efficiency of the popular case-control design in gene-longevity association studies needs to be verified because, different from a binary trait, longevity represents only the extreme end of the continuous life span distribution without a clear cutoff for defining the phenotype. In this paper...

  4. Gene set analyses of genome-wide association studies on 49 quantitative traits measured in a single genetic epidemiology dataset.

    Science.gov (United States)

    Kim, Jihye; Kwon, Ji-Sun; Kim, Sangsoo

    2013-09-01

    Gene set analysis is a powerful tool for interpreting a genome-wide association study result and is gaining popularity these days. Comparison of the gene sets obtained for a variety of traits measured from a single genetic epidemiology dataset may give insights into the biological mechanisms underlying these traits. Based on the previously published single nucleotide polymorphism (SNP) genotype data on 8,842 individuals enrolled in the Korea Association Resource project, we performed a series of systematic genome-wide association analyses for 49 quantitative traits of basic epidemiological, anthropometric, or blood chemistry parameters. Each analysis result was subjected to subsequent gene set analyses based on Gene Ontology (GO) terms using gene set analysis software, GSA-SNP, identifying a set of GO terms significantly associated to each trait (pcorr neuronal or nerve systems.

  5. Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest.

    Directory of Open Access Journals (Sweden)

    Dan E Arking

    Full Text Available Existing studies indicate a significant genetic component for sudden cardiac arrest (SCA and genome-wide association studies (GWAS provide an unbiased approach for identification of novel genes. We performed a GWAS to identify genetic determinants of SCA.We used a case-control design within the ongoing Oregon Sudden Unexpected Death Study (Oregon-SUDS. Cases (n = 424 were SCAs with coronary artery disease (CAD among residents of Portland, OR (2002-07, population approximately 1,000,000 and controls (n = 226 were residents with CAD, but no history of SCA. All subjects were of White-European ancestry and GWAS was performed using Affymetrix 500K/5.0 and 6.0 arrays. High signal markers were genotyped in SCA cases (n = 521 identified from the Atherosclerosis Risk in Communities Study (ARIC and the Cardiovascular Health Study (CHS (combined n = 19,611. No SNPs reached genome-wide significance (p<5x10(-8. SNPs at 6 loci were prioritized for follow-up primarily based on significance of p<10(-4 and proximity to a known gene (CSMD2, GPR37L1, LIN9, B4GALNT3, GPC5, and ZNF592. The minor allele of GPC5 (GLYPICAN 5, rs3864180 was associated with a lower risk of SCA in Oregon-SUDS, an effect that was also observed in ARIC/CHS whites (p<0.05 and blacks (p<0.04. In a combined Cox proportional hazards model analysis that adjusted for race, the minor allele exhibited a hazard ratio of 0.85 (95% CI 0.74 to 0.98; p<0.01.A novel genetic locus for SCA, GPC5, was identified from Oregon-SUDS and successfully validated in the ARIC and CHS cohorts. Three other members of the Glypican family have been previously implicated in human disease, including cardiac conditions. The mechanism of this specific association requires further study.

  6. Genetic Syndromes Associated with Craniosynostosis.

    Science.gov (United States)

    Ko, Jung Min

    2016-05-01

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

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

    Science.gov (United States)

    Chikkagoudar, Satish; Wang, Kai; Li, Mingyao

    2011-05-26

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

  8. Genetic association study of common mitochondrial variants on body fat mass.

    Directory of Open Access Journals (Sweden)

    Tie-Lin Yang

    Full Text Available Mitochondria play a central role in ATP production and energy metabolism. Previous studies suggest that common variants in mtDNA are associated with several common complex diseases, including obesity. To test the hypothesis that common mtDNA variants influence obesity-related phenotypes, including BMI and body fat mass, we genotyped a total of 445 mtSNPs across the whole mitochondrial genome in a large sample of 2,286 unrelated Caucasian subjects. 72 of these 445 mtSNPs passed quality control criteria, and were used for subsequent analyses. We also classified all subjects into nine common European haplogroups. Association analyses were conducted for both BMI and body fat mass with single mtSNPs and mtDNA haplogroups. Two mtSNPs, mt4823 and mt8873 were detected to be significantly associated with body fat mass, with adjusted P values of 4.94 × 10⁻³ and 4.58 × 10⁻², respectively. The minor alleles mt4823 C and mt8873 A were associated with reduced fat mass values and the effect size (β was estimated to be 3.52 and 3.18, respectively. These two mtSNPs also achieved nominally significant levels for association with BMI. For haplogroup analyses, we found that haplogroup X was strongly associated with both BMI (adjusted P = 8.31 × 10⁻³ and body fat mass (adjusted P = 5.67×10⁻⁴ Subjects classified as haplogroup X had lower BMI and fat mass values, with the β estimated to be 2.86 and 6.03, respectively. Our findings suggest that common variants in mitochondria might play a role in variations of body fat mass. Further molecular and functional studies will be needed to clarify the potential mechanism.

  9. Genetic Association Study of Ancestry-Matched African American Prostate Cancer Cases and Control

    Science.gov (United States)

    2009-04-01

    the American Cancer Society [CNE-101119 (J.J. Hu)]. Note: Supplementary data for this article are available at Cancer Epidemiology , Biomarkers... Cancer Epidemiology , Biomarkers & Prevention Cancer Epidemiol Biomarkers Prev 2009;18(7). July 2009 2147 and Xp11 (P < 0.1). Notably, SNP rs2735839...using multilocus genotype data. Genetics 2000;155:945 –59. 20. Tang H. Confronting ethnicity-specific disease risk. Nat Genet 2006; 38:13 –5. Cancer

  10. Genetic association between BDNF gene polymorphisms and phobic disorders: a case-control study among mainland Han Chinese.

    Science.gov (United States)

    Xie, Bing; Wang, Binbin; Suo, Peisu; Kou, Changgui; Wang, Jing; Meng, Xiangfei; Cheng, Longfei; Ma, Xu; Yu, Yaqin

    2011-07-01

    Phobic disorders are a common group of syndromes comprising persistently recurring, irrational severe anxiety of specific objects, activities, or situations with avoidance behavior of the phobic stimulus. The present study investigated the association between whole region polymorphisms, (including the Val66Met variant), in the BDNF gene and phobic disorders among Han Chinese young adults. We conducted a case-control study to investigate the genetic association between BDNF polymorphisms and phobic disorders among mainland Chinese. One hundred and twenty young adults with phobic disorders and 267 matched controls were recruited. Three tag SNPs of BDNF were successfully genotyped by using PCR-based ligase detection reaction (PCR-LDR). We found significant differences in allele distributions of SNP rs10835210 (Pphobic disorders and BDNF haplotype CAC (P=0.004). Association was significant after 10(4) permutation tests (Petiology of phobic disorders in the Han Chinese population. Copyright © 2010. Published by Elsevier B.V.

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

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    Sura Thanyachai

    2011-09-01

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

  12. A twin study of problematic internet use: its heritability and genetic association with effortful control.

    Science.gov (United States)

    Li, Mengjiao; Chen, Jie; Li, Naishi; Li, Xinying

    2014-08-01

    Our goal was to estimate genetic and environmental sources of influence on adolescent problematic internet use, and whether these individual differences can be explained by effortful control, an important aspect of self-regulation. A sample of 825 pairs of Chinese adolescent twins and their parents provided reports of problematic internet use and effortful control. Univariate analysis revealed that genetic factors explained 58-66% of variance in problematic internet use, with the rest explained by non-shared environmental factors. Sex difference was found, suggesting boys' problematic internet use was more influenced by genetic influences than girls' problematic internet use. Bivariate analysis indicated that effortful control accounted for a modest portion of the genetic and non-shared environmental variance in problematic internet use among girls. In contrast, among boys, effortful control explained between 6% (parent report) and 20% (self-report) of variance in problematic internet use through overlapping genetic pathways. Adolescent problematic internet use is heritable, and poor effortful control can partly explain adolescent problematic internet use, with effects stronger for boys. Implications for future research are discussed.

  13. An association study between Heme oxygenase-1 genetic variants and Parkinson's disease

    Science.gov (United States)

    Ayuso, Pedro; Martínez, Carmen; Pastor, Pau; Lorenzo-Betancor, Oswaldo; Luengo, Antonio; Jiménez-Jiménez, Félix J.; Alonso-Navarro, Hortensia; Agúndez, José A. G.; García-Martín, Elena

    2014-01-01

    The blood-brain barrier (BBB) supplies brain tissues with nutrients, filters harmful compounds from the brain back to the bloodstream, and plays a key role in iron homeostasis in the human brain. Disruptions of the BBB are associated with several neurodegenerative conditions including Parkinson's disease (PD). Oxidative stress, iron deposition and mitochondrial impaired function are considered as risk factors for degeneration of the central nervous system. Heme oxygenase (HMOX) degrades heme ring to biliverdin, free ferrous iron and carbon monoxide being the rate-limiting activity in heme catabolism. The isoform HMOX1 is highly inducible in response to reactive oxygen species, which induce an increase in BBB permeability and impair its pathophysiology. Consequently, an over- expression of this enzyme may contribute to the marked iron deposition found in PD. We analyzed the HMOX1 SNPs rs2071746, rs2071747, and rs9282702, a microsatellite (GT)n polymorphism and copy number variations in 691 patients suffering from PD and 766 healthy control individuals. Copy number variations in the HMOX1 gene exist, but these do not seem to be associated with PD risk. In contrast two polymorphisms that modify the transcriptional activity of the gene, namely a VNTR (GT)n and the SNP rs2071746, are strongly associated with PD risk, particularly with the classic PD phenotype and with early onset of the disease. This study indicates that HMOX1 gene variants are associated to the risk of developing some forms of PD, thus adding new information that supports association of HMOX gene variations with PD risk. PMID:25309329

  14. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

    Science.gov (United States)

    Arking, Dan E.; Pulit, Sara L.; Crotti, Lia; van der Harst, Pim; Munroe, Patricia B.; Koopmann, Tamara T.; Sotoodehnia, Nona; Rossin, Elizabeth J.; Morley, Michael; Wang, Xinchen; Johnson, Andrew D.; Lundby, Alicia; Gudbjartsson, Daníel F.; Noseworthy, Peter A.; Eijgelsheim, Mark; Bradford, Yuki; Tarasov, Kirill V.; Dörr, Marcus; Müller-Nurasyid, Martina; Lahtinen, Annukka M.; Nolte, Ilja M.; Smith, Albert Vernon; Bis, Joshua C.; Isaacs, Aaron; Newhouse, Stephen J.; Evans, Daniel S.; Post, Wendy S.; Waggott, Daryl; Lyytikäinen, Leo-Pekka; Hicks, Andrew A.; Eisele, Lewin; Ellinghaus, David; Hayward, Caroline; Navarro, Pau; Ulivi, Sheila; Tanaka, Toshiko; Tester, David J.; Chatel, Stéphanie; Gustafsson, Stefan; Kumari, Meena; Morris, Richard W.; Naluai, Åsa T.; Padmanabhan, Sandosh; Kluttig, Alexander; Strohmer, Bernhard; Panayiotou, Andrie G.; Torres, Maria; Knoflach, Michael; Hubacek, Jaroslav A.; Slowikowski, Kamil; Raychaudhuri, Soumya; Kumar, Runjun D.; Harris, Tamara B.; Launer, Lenore J.; Shuldiner, Alan R.; Alonso, Alvaro; Bader, Joel S.; Ehret, Georg; Huang, Hailiang; Kao, W.H. Linda; Strait, James B.; Macfarlane, Peter W.; Brown, Morris; Caulfield, Mark J.; Samani, Nilesh J.; Kronenberg, Florian; Willeit, Johann; Smith, J. Gustav; Greiser, Karin H.; zu Schwabedissen, Henriette Meyer; Werdan, Karl; Carella, Massimo; Zelante, Leopoldo; Heckbert, Susan R.; Psaty, Bruce M.; Rotter, Jerome I.; Kolcic, Ivana; Polašek, Ozren; Wright, Alan F.; Griffin, Maura; Daly, Mark J.; Arnar, David O.; Hólm, Hilma; Thorsteinsdottir, Unnur; Denny, Joshua C.; Roden, Dan M.; Zuvich, Rebecca L.; Emilsson, Valur; Plump, Andrew S.; Larson, Martin G.; O'Donnell, Christopher J.; Yin, Xiaoyan; Bobbo, Marco; D'Adamo, Adamo P.; Iorio, Annamaria; Sinagra, Gianfranco; Carracedo, Angel; Cummings, Steven R.; Nalls, Michael A.; Jula, Antti; Kontula, Kimmo K.; Marjamaa, Annukka; Oikarinen, Lasse; Perola, Markus; Porthan, Kimmo; Erbel, Raimund; Hoffmann, Per; Jöckel, Karl-Heinz; Kälsch, Hagen; Nöthen, Markus M.; consortium, HRGEN; den Hoed, Marcel; Loos, Ruth J.F.; Thelle, Dag S.; Gieger, Christian; Meitinger, Thomas; Perz, Siegfried; Peters, Annette; Prucha, Hanna; Sinner, Moritz F.; Waldenberger, Melanie; de Boer, Rudolf A.; Franke, Lude; van der Vleuten, Pieter A.; Beckmann, Britt Maria; Martens, Eimo; Bardai, Abdennasser; Hofman, Nynke; Wilde, Arthur A.M.; Behr, Elijah R.; Dalageorgou, Chrysoula; Giudicessi, John R.; Medeiros-Domingo, Argelia; Barc, Julien; Kyndt, Florence; Probst, Vincent; Ghidoni, Alice; Insolia, Roberto; Hamilton, Robert M.; Scherer, Stephen W.; Brandimarto, Jeffrey; Margulies, Kenneth; Moravec, Christine E.; Fabiola Del, Greco M.; Fuchsberger, Christian; O'Connell, Jeffrey R.; Lee, Wai K.; Watt, Graham C.M.; Campbell, Harry; Wild, Sarah H.; El Mokhtari, Nour E.; Frey, Norbert; Asselbergs, Folkert W.; Leach, Irene Mateo; Navis, Gerjan; van den Berg, Maarten P.; van Veldhuisen, Dirk J.; Kellis, Manolis; Krijthe, Bouwe P.; Franco, Oscar H.; Hofman, Albert; Kors, Jan A.; Uitterlinden, André G.; Witteman, Jacqueline C.M.; Kedenko, Lyudmyla; Lamina, Claudia; Oostra, Ben A.; Abecasis, Gonçalo R.; Lakatta, Edward G.; Mulas, Antonella; Orrú, Marco; Schlessinger, David; Uda, Manuela; Markus, Marcello R.P.; Völker, Uwe; Snieder, Harold; Spector, Timothy D.; Ärnlöv, Johan; Lind, Lars; Sundström, Johan; Syvänen, Ann-Christine; Kivimaki, Mika; Kähönen, Mika; Mononen, Nina; Raitakari, Olli T.; Viikari, Jorma S.; Adamkova, Vera; Kiechl, Stefan; Brion, Maria; Nicolaides, Andrew N.; Paulweber, Bernhard; Haerting, Johannes; Dominiczak, Anna F.; Nyberg, Fredrik; Whincup, Peter H.; Hingorani, Aroon; Schott, Jean-Jacques; Bezzina, Connie R.; Ingelsson, Erik; Ferrucci, Luigi; Gasparini, Paolo; Wilson, James F.; Rudan, Igor; Franke, Andre; Mühleisen, Thomas W.; Pramstaller, Peter P.; Lehtimäki, Terho J.; Paterson, Andrew D.; Parsa, Afshin; Liu, Yongmei; van Duijn, Cornelia; Siscovick, David S.; Gudnason, Vilmundur; Jamshidi, Yalda; Salomaa, Veikko; Felix, Stephan B.; Sanna, Serena; Ritchie, Marylyn D.; Stricker, Bruno H.; Stefansson, Kari; Boyer, Laurie A.; Cappola, Thomas P.; Olsen, Jesper V.; Lage, Kasper; Schwartz, Peter J.; Kääb, Stefan; Chakravarti, Aravinda; Ackerman, Michael J.; Pfeufer, Arne; de Bakker, Paul I.W.; Newton-Cheh, Christopher

    2014-01-01

    The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD. PMID:24952745

  15. Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP

    OpenAIRE

    Mead, Simon; Uphill, James; Beck, John; Poulter, Mark; Campbell, Tracy; Lowe, Jessica; Adamson, Gary; Hummerich, Holger; Klopp, Norman; Rückert, Ina-Maria; Wichmann, H-Erich; Azazi, Dhoyazan; Plagnol, Vincent; Pako, Wandagi H.; Whitfield, Jerome

    2011-01-01

    Prion diseases are fatal neurodegenerative diseases of humans and animals caused by the misfolding and aggregation of prion protein (PrP). Mammalian prion diseases are under strong genetic control but few risk factors are known aside from the PrP gene locus (PRNP). No genome-wide association study (GWAS) has been done aside from a small sample of variant Creutzfeldt–Jakob disease (CJD). We conducted GWAS of sporadic CJD (sCJD), variant CJD (vCJD), iatrogenic CJD, inherited prion disease, kuru...

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

    Science.gov (United States)

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

    2013-10-01

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

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

    Science.gov (United States)

    Bagos, Pantelis G

    2013-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Finch Stephen J

    2005-04-01

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

  19. Developments in obesity genetics in the era of genome-wide association studies.

    Science.gov (United States)

    Day, Felix R; Loos, Ruth J F

    2011-01-01

    Obesity is an important factor contributing to the global burden of morbidity and mortality. By identifying obesity susceptibility genes, scientists aim to elucidate some of its aetiology. Early studies used candidate gene and genome-wide linkage approaches to search for such genes with limited success. However, the advent of genome-wide association studies (GWAS) has dramatically increased the pace of gene discovery. So far, GWAS have identified at least 50 loci robustly associated with body mass index (BMI), waist-to-hip ratio, body fat percentage and extreme obesity. Some of these have been shown to replicate in non-white populations and in children and adolescents. Furthermore, for some loci interaction studies have shown that the BMI-increasing effect is attenuated in physically active individuals. Despite many successful discoveries, the effect sizes of the established loci are small, and combined they explain only a fraction of the inter-individual variation in BMI. The low predictive value means that their value in mainstream health care is limited. However, as most of these newly established loci were not previously linked to obesity, they may provide new insights into body weight regulation. Continued efforts in gene discovery, using a range of approaches, will be needed to increase our understanding of obesity. Copyright © 2011 S. Karger AG, Basel.

  20. Unravelling the genetics of iron status in African populations : candidate gene association studies

    NARCIS (Netherlands)

    Gichohi-Wainaina, W.N.

    2015-01-01

    Abstract Background: Investigating the manner in which genetic and environmental factors interact to increase susceptibility to iron deficiency, has the potential to impact on strategies to overcome iron deficiency as well as the development of biomarkers to monitor

  1. Combining high-throughput phenotyping and genome-wide association studies to reveal natural genetic variation in rice.

    Science.gov (United States)

    Yang, Wanneng; Guo, Zilong; Huang, Chenglong; Duan, Lingfeng; Chen, Guoxing; Jiang, Ni; Fang, Wei; Feng, Hui; Xie, Weibo; Lian, Xingming; Wang, Gongwei; Luo, Qingming; Zhang, Qifa; Liu, Qian; Xiong, Lizhong

    2014-10-08

    Even as the study of plant genomics rapidly develops through the use of high-throughput sequencing techniques, traditional plant phenotyping lags far behind. Here we develop a high-throughput rice phenotyping facility (HRPF) to monitor 13 traditional agronomic traits and 2 newly defined traits during the rice growth period. Using genome-wide association studies (GWAS) of the 15 traits, we identify 141 associated loci, 25 of which contain known genes such as the Green Revolution semi-dwarf gene, SD1. Based on a performance evaluation of the HRPF and GWAS results, we demonstrate that high-throughput phenotyping has the potential to replace traditional phenotyping techniques and can provide valuable gene identification information. The combination of the multifunctional phenotyping tools HRPF and GWAS provides deep insights into the genetic architecture of important traits.

  2. Genetic Variation of Myeloperoxidase Gene Contributes to Aggressive Periodontitis: A Preliminary Association Study in Turkish Population

    Directory of Open Access Journals (Sweden)

    Kamile Erciyas

    2010-01-01

    Full Text Available Myeloperoxidase (MPO is a lysosomal enzyme found in the azurophilic granules of polymorphonuclear leukocytes. It is involved in the defense against periodontal bacteria, and is also able to mediate inflammatory tissue destruction in aggressive and chronic periodontitis. The aim of this study was to explore the association between MPO-463G/A gene polymorphism and aggressive periodontitis (AgP and chronic periodontitis (CP. The study included 147 subjects. Probing depth (PD, clinical attachment loss (CAL, plaque index (PI, and gingival index (GI were recorded as the clinical parameters. Genomic DNA was obtained from the peripheral blood of 32 subjects with AgP, 25 with CP, and 90 reference controls. We genotyped the MPO-463G/A polymorphism using the PCR-RFLP method. All data were analyzed using SPSS version 13.0 for windows. There were no significant differences between the CP patients and controls regarding MPO-463A/G gene polymorphism either in terms of allele frequency or genotype frequency of MPO-463A/G. However, either in terms of allele frequency or genotype frequency of MPO-463A/G, there were significant differences between the AgP patients and the controls. In conclusion, our data suggest that MPO-463G/A may be associated with increased risk of aggressive periodontitis in Turkish patients.

  3. Genetic association studies in complex disease : Disentangling additional predisposing loci from associated neutral loci using a constrained - permutation approach

    NARCIS (Netherlands)

    Spijker, G T; Nolte, I.M.; Jansen, R.C.; te Meerman, G.J.

    2005-01-01

    In the process of genetically mapping a complex disease, the question may arise whether a certain polymorphism is the only causal variant in a region. A number of methods can answer this question, but unfortunately these methods are optimal for bi-allelic loci only. We wanted to develop a method tha

  4. A genome-wide association study to detect genetic variation for postpartum dysgalactia syndrome in five commercial pig breeding lines.

    Science.gov (United States)

    Preissler, Regine; Tetens, Jens; Reiners, Kerstin; Looft, Holger; Kemper, Nicole

    2013-08-01

    Postpartum dysgalactia syndrome (PDS) in sows is an important disease after parturition with a relevant economic impact, affecting the health and welfare of both sows and piglets. The genetic background of this disease has been discussed and its heritability estimated, but further genetic analyses are lacking in detail. The aim of the current study was to detect loci affecting the susceptibility to PDS through a genome-wide association approach. The study was designed as a family-based association study with matched sampling of affected sows and healthy half- or full-sib control sows on six farms. For the study, 597 sows (322 affected vs. 275 healthy control sows) were genotyped on 62 163 single nucleotide polymorphisms (SNPs) using the Illumina PorcineSNP60 BeadChip. After quality control, 585 sows (314 affected vs. 271 healthy control sows) and 49 740 SNPs remained for further analysis. Statistics were performed mainly with the r package genabel and included a principal component analysis. A statistically significant genome-wide associated SNP was identified on porcine chromosome (SSC) 17. Further promising results with moderate significance were detected on SSC 13 and on an unplaced scaffold with an older annotation on SSC 15. The PRICKLE2 and NRP2 genes were identified as candidate genes near associated SNPs. Several quantitative trait loci (QTL) have been previously described in these genomic regions, including QTL for mammary gland condition, as teat number and non-functional nipples QTL, as well as QTL for body temperature and gestation length.

  5. Genome-wide association study to identify the genetic determinants of otitis media susceptibility in childhood.

    Directory of Open Access Journals (Sweden)

    Marie S Rye

    Full Text Available BACKGROUND: Otitis media (OM is a common childhood disease characterised by middle ear inflammation and effusion. Susceptibility to recurrent acute OM (rAOM; ≥ 3 episodes of AOM in 6 months and chronic OM with effusion (COME; MEE ≥ 3 months is 40-70% heritable. Few underlying genes have been identified to date, and no genome-wide association study (GWAS of OM has been reported. METHODS AND FINDINGS: Data for 2,524,817 single nucleotide polymorphisms (SNPs; 535,544 quality-controlled SNPs genotyped by Illumina 660W-Quad; 1,989,273 by imputation were analysed for association with OM in 416 cases and 1,075 controls from the Western Australian Pregnancy Cohort (Raine Study. Logistic regression analyses under an additive model undertaken in GenABEL/ProbABEL adjusting for population substructure using principal components identified SNPs at CAPN14 (rs6755194: OR = 1.90; 95%CI 1.47-2.45; P(adj-PCA = 8.3 × 10(-7 on chromosome 2p23.1 as the top hit, with independent effects (rs1862981: OR = 1.60; 95%CI 1.29-1.99; P(adj-PCA = 2.2 × 10(-5 observed at the adjacent GALNT14 gene. In a gene-based analysis in VEGAS, BPIFA3 (P(Gene = 2 × 10(-5 and BPIFA1 (P(Gene = 1.07 × 10(-4 in the BPIFA gene cluster on chromosome 20q11.21 were the top hits. In all, 32 genomic regions show evidence of association (P(adj-PCA<10(-5 in this GWAS, with pathway analysis showing a connection between top candidates and the TGFβ pathway. However, top and tag-SNP analysis for seven selected candidate genes in this pathway did not replicate in 645 families (793 affected individuals from the Western Australian Family Study of Otitis Media (WAFSOM. Lack of replication may be explained by sample size, difference in OM disease severity between primary and replication cohorts or due to type I error in the primary GWAS. CONCLUSIONS: This first discovery GWAS for an OM phenotype has identified CAPN14 and GALNT14 on chromosome 2p23.1 and the BPIFA gene cluster on chromosome 20q11.21 as

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

    NARCIS (Netherlands)

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

    2013-01-01

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

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

    DEFF Research Database (Denmark)

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

    2013-01-01

    Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although...... that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed...... no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size....

  8. A genome-wide association study identifies a genetic variant in the SIAH2 locus associated with hormonal receptor-positive breast cancer in Japanese.

    Science.gov (United States)

    Elgazzar, Seham; Zembutsu, Hitoshi; Takahashi, Atsushi; Kubo, Michiaki; Aki, Fuminori; Hirata, Koichi; Takatsuka, Yuichi; Okazaki, Minoru; Ohsumi, Shozo; Yamakawa, Takashi; Sasa, Mitsunori; Katagiri, Toyomasa; Miki, Yoshio; Nakamura, Yusuke

    2012-12-01

    In Japan, breast cancer is the most common cancer among women and the second leading cause of cancer death among women worldwide. To identify genetic variants associated with the disease susceptibility, we performed a genome-wide association study (GWAS) using a total of 1086 Japanese female patients with hormonal receptor-positive (HRP) breast cancer and 1816 female controls. We selected 33 single-nucleotide polymorphisms (SNPs) with suggestive associations in GWAS (P-value of rs3750817 in intron 2 of the fibroblast growth factor receptor 2 gene, which was reported to be associated with breast cancer susceptibility, was significantly replicated with P(combined) of 8.47 × 10(-8) with OR=1.22. Our results suggest a novel susceptibility locus on chromosome 3q25.1 for a HRP breast cancer.

  9. Electron-microprobe study of chromitites associated with alpine ultramafic complexes and some genetic implications

    Science.gov (United States)

    Bird, M.L.

    1978-01-01

    Electron-microprobe and petrographic studies of alpine chromite deposits from around the world demonstrate that they are bimodal with respect to the chromic oxide content of their chromite. The two modes occur at 54 ? 4 and 37 ? 3 weight per cent chromic oxide corresponding to chromite designated as high-chromium and high-aluminum chromite respectively. The high-chromium chromite occurs exclusively with highly magnesian olivine (Fo92-97) and some interstitial diopside. The high-aluminum chromite is associated with more ferrous olivine (Fo88-92), diopside, enstatite, and feldspar. The plot of the mole ratios Cr/(Cr+Al+Fe3+) vs. Mg/(Mg+Fe2+) usually presented for alpine chromite is shown to have a high-chromium, high-iron to low-chromium, low-iron trend contrary to that shown by stratiform chromite. This trend is characteristic of alpine type chromite and is termed the alpine trend. However, a trend similar to that for startiform chromite is discernable on the graph for the high-chromium chromite data. This latter trend is well-developed at Red Mountain, Seldovia, Alaska. Analysis of the iron-magnesium distribution coefficient, Kd=(Fe/Mg)ol/(Fe/Mg)ch, between olivine and chromite shows that Kd for the high-chromium chromite from all ultramafic complexes has essentially the same constant value of .05 while the distribution coefficient for the high-aluminum chromite varies with composition of the chromite. These distribution coefficients are also characteristic of alpine-type chromites. The constant value for Kd for the high-chromium chromite and associated high-magnesium olivine in all alpine complexes suggests that they all crystallized under similar physico-chemical conditions. The two types of massive chromite and their associations of silicate minerals suggest the possibility of two populations with different origins. Recrystallization textures associated with the high-aluminum chromite together with field relationships between the gabbro and the chromite pods

  10. The USDA barley core collection: genetic diversity, population structure, and potential for genome-wide association studies.

    Directory of Open Access Journals (Sweden)

    María Muñoz-Amatriaín

    Full Text Available New sources of genetic diversity must be incorporated into plant breeding programs if they are to continue increasing grain yield and quality, and tolerance to abiotic and biotic stresses. Germplasm collections provide a source of genetic and phenotypic diversity, but characterization of these resources is required to increase their utility for breeding programs. We used a barley SNP iSelect platform with 7,842 SNPs to genotype 2,417 barley accessions sampled from the USDA National Small Grains Collection of 33,176 accessions. Most of the accessions in this core collection are categorized as landraces or cultivars/breeding lines and were obtained from more than 100 countries. Both STRUCTURE and principal component analysis identified five major subpopulations within the core collection, mainly differentiated by geographical origin and spike row number (an inflorescence architecture trait. Different patterns of linkage disequilibrium (LD were found across the barley genome and many regions of high LD contained traits involved in domestication and breeding selection. The genotype data were used to define 'mini-core' sets of accessions capturing the majority of the allelic diversity present in the core collection. These 'mini-core' sets can be used for evaluating traits that are difficult or expensive to score. Genome-wide association studies (GWAS of 'hull cover', 'spike row number', and 'heading date' demonstrate the utility of the core collection for locating genetic factors determining important phenotypes. The GWAS results were referenced to a new barley consensus map containing 5,665 SNPs. Our results demonstrate that GWAS and high-density SNP genotyping are effective tools for plant breeders interested in accessing genetic diversity in large germplasm collections.

  11. Association Study of Vitamin D Receptor (VDR) - Related Genetic Polymorphisms and their Haplotypes with Chronic Periodontitis in Colombian Population

    Science.gov (United States)

    Isaza-Guzmán, Diana María; Pineda-Trujillo, Nicolás

    2017-01-01

    Introduction There is strong evidence that both genetic and environmental factors may affect the periodontal clinical status. However, epidemiological evidence on the association between Vitamin D Receptor (VDR) polymorphisms and Chronic Periodontitis (CP) has been inconsistent. Aim The focus of this study was to identify if a possible association between VDR Single-Nucleotide Polymorphisms (SNPs) may be implicated in the aetiopathogenesis of CP in Colombian population. Materials and Methods One hundred and ten CP patients and 50 Healthy Controls (HC) were recruited. Periodontal status was assessed based on probing depth, clinical attachment level, extent, and severity of periodontal breakdown. The polymerase chain reaction-restriction fragment length polymorphism method was used to identify the VDR rs7975232, rs1544410, rs2228570, and rs731236 SNPs from saliva samples. Odds Ratios (ORs) along with their 95% Confidence Intervals (CIs) were computed to compare the distribution of genotypes/alleles between HC and CP patients, alongside with analysis of Linkage Disequilibrium (LD) and haplotype associations between SNPs. Also, an analysis of the interaction between genetic findings and those significant demographic factors was performed for all SNPs. Results There was no association neither between the different genotypes/allele frequencies nor haplotypes and CP. Similarly, no significant differences in extent or severity amongst genotype/allele groups were observed. Even so, interaction analysis revealed significant synergistic interactions between each SNP and age associated with the disease status. Conclusion Although these results do not support that VDR SNPs could be identified as independent risk predictor variables for CP in the Colombian population, synergistic biological interactive effects of all these SNPs related to age might play a significant role in the pathogenic pathways of CP. PMID:28384983

  12. Gene set analysis for interpreting genetic studies

    DEFF Research Database (Denmark)

    Pers, Tune H

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Yang Hsin-Chou

    2008-05-01

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

  14. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.

    Science.gov (United States)

    Aung, Tin; Ozaki, Mineo; Lee, Mei Chin; Schlötzer-Schrehardt, Ursula; Thorleifsson, Gudmar; Mizoguchi, Takanori; Igo, Robert P; Haripriya, Aravind; Williams, Susan E; Astakhov, Yury S; Orr, Andrew C; Burdon, Kathryn P; Nakano, Satoko; Mori, Kazuhiko; Abu-Amero, Khaled; Hauser, Michael; Li, Zheng; Prakadeeswari, Gopalakrishnan; Bailey, Jessica N Cooke; Cherecheanu, Alina Popa; Kang, Jae H; Nelson, Sarah; Hayashi, Ken; Manabe, Shin-Ichi; Kazama, Shigeyasu; Zarnowski, Tomasz; Inoue, Kenji; Irkec, Murat; Coca-Prados, Miguel; Sugiyama, Kazuhisa; Järvelä, Irma; Schlottmann, Patricio; Lerner, S Fabian; Lamari, Hasnaa; Nilgün, Yildirim; Bikbov, Mukharram; Park, Ki Ho; Cha, Soon Cheol; Yamashiro, Kenji; Zenteno, Juan C; Jonas, Jost B; Kumar, Rajesh S; Perera, Shamira A; Chan, Anita S Y; Kobakhidze, Nino; George, Ronnie; Vijaya, Lingam; Do, Tan; Edward, Deepak P; de Juan Marcos, Lourdes; Pakravan, Mohammad; Moghimi, Sasan; Ideta, Ryuichi; Bach-Holm, Daniella; Kappelgaard, Per; Wirostko, Barbara; Thomas, Samuel; Gaston, Daniel; Bedard, Karen; Greer, Wenda L; Yang, Zhenglin; Chen, Xueyi; Huang, Lulin; Sang, Jinghong; Jia, Hongyan; Jia, Liyun; Qiao, Chunyan; Zhang, Hui; Liu, Xuyang; Zhao, Bowen; Wang, Ya-Xing; Xu, Liang; Leruez, Stéphanie; Reynier, Pascal; Chichua, George; Tabagari, Sergo; Uebe, Steffen; Zenkel, Matthias; Berner, Daniel; Mossböck, Georg; Weisschuh, Nicole; Hoja, Ursula; Welge-Luessen, Ulrich-Christoph; Mardin, Christian; Founti, Panayiota; Chatzikyriakidou, Anthi; Pappas, Theofanis; Anastasopoulos, Eleftherios; Lambropoulos, Alexandros; Ghosh, Arkasubhra; Shetty, Rohit; Porporato, Natalia; Saravanan, Vijayan; Venkatesh, Rengaraj; Shivkumar, Chandrashekaran; Kalpana, Narendran; Sarangapani, Sripriya; Kanavi, Mozhgan R; Beni, Afsaneh Naderi; Yazdani, Shahin; Lashay, Alireza; Naderifar, Homa; Khatibi, Nassim; Fea, Antonio; Lavia, Carlo; Dallorto, Laura; Rolle, Teresa; Frezzotti, Paolo; Paoli, Daniela; Salvi, Erika; Manunta, Paolo; Mori, Yosai; Miyata, Kazunori; Higashide, Tomomi; Chihara, Etsuo; Ishiko, Satoshi; Yoshida, Akitoshi; Yanagi, Masahide; Kiuchi, Yoshiaki; Ohashi, Tsutomu; Sakurai, Toshiya; Sugimoto, Takako; Chuman, Hideki; Aihara, Makoto; Inatani, Masaru; Miyake, Masahiro; Gotoh, Norimoto; Matsuda, Fumihiko; Yoshimura, Nagahisa; Ikeda, Yoko; Ueno, Morio; Sotozono, Chie; Jeoung, Jin Wook; Sagong, Min; Park, Kyu Hyung; Ahn, Jeeyun; Cruz-Aguilar, Marisa; Ezzouhairi, Sidi M; Rafei, Abderrahman; Chong, Yaan Fun; Ng, Xiao Yu; Goh, Shuang Ru; Chen, Yueming; Yong, Victor H K; Khan, Muhammad Imran; Olawoye, Olusola O; Ashaye, Adeyinka O; Ugbede, Idakwo; Onakoya, Adeola; Kizor-Akaraiwe, Nkiru; Teekhasaenee, Chaiwat; Suwan, Yanin; Supakontanasan, Wasu; Okeke, Suhanya; Uche, Nkechi J; Asimadu, Ifeoma; Ayub, Humaira; Akhtar, Farah; Kosior-Jarecka, Ewa; Lukasik, Urszula; Lischinsky, Ignacio; Castro, Vania; Grossmann, Rodolfo Perez; Megevand, Gordana Sunaric; Roy, Sylvain; Dervan, Edward; Silke, Eoin; Rao, Aparna; Sahay, Priti; Fornero, Pablo; Cuello, Osvaldo; Sivori, Delia; Zompa, Tamara; Mills, Richard A; Souzeau, Emmanuelle; Mitchell, Paul; Wang, Jie Jin; Hewitt, Alex W; Coote, Michael; Crowston, Jonathan G; Astakhov, Sergei Y; Akopov, Eugeny L; Emelyanov, Anton; Vysochinskaya, Vera; Kazakbaeva, Gyulli; Fayzrakhmanov, Rinat; Al-Obeidan, Saleh A; Owaidhah, Ohoud; Aljasim, Leyla Ali; Chowbay, Balram; Foo, Jia Nee; Soh, Raphael Q; Sim, Kar Seng; Xie, Zhicheng; Cheong, Augustine W O; Mok, Shi Qi; Soo, Hui Meng; Chen, Xiao Yin; Peh, Su Qin; Heng, Khai Koon; Husain, Rahat; Ho, Su-Ling; Hillmer, Axel M; Cheng, Ching-Yu; Escudero-Domínguez, Francisco A; González-Sarmiento, Rogelio; Martinon-Torres, Frederico; Salas, Antonio; Pathanapitoon, Kessara; Hansapinyo, Linda; Wanichwecharugruang, Boonsong; Kitnarong, Naris; Sakuntabhai, Anavaj; Nguyn, Hip X; Nguyn, Giang T T; Nguyn, Trình V; Zenz, Werner; Binder, Alexander; Klobassa, Daniela S; Hibberd, Martin L; Davila, Sonia; Herms, Stefan; Nöthen, Markus M; Moebus, Susanne; Rautenbach, Robyn M; Ziskind, Ari; Carmichael, Trevor R; Ramsay, Michele; Álvarez, Lydia; García, Montserrat; González-Iglesias, Héctor; Rodríguez-Calvo, Pedro P; Cueto, Luis Fernández-Vega; Oguz, Çilingir; Tamcelik, Nevbahar; Atalay, Eray; Batu, Bilge; Aktas, Dilek; Kasım, Burcu; Wilson, M Roy; Coleman, Anne L; Liu, Yutao; Challa, Pratap; Herndon, Leon; Kuchtey, Rachel W; Kuchtey, John; Curtin, Karen; Chaya, Craig J; Crandall, Alan; Zangwill, Linda M; Wong, Tien Yin; Nakano, Masakazu; Kinoshita, Shigeru; den Hollander, Anneke I; Vesti, Eija; Fingert, John H; Lee, Richard K; Sit, Arthur J; Shingleton, Bradford J; Wang, Ningli; Cusi, Daniele; Qamar, Raheel; Kraft, Peter; Pericak-Vance, Margaret A; Raychaudhuri, Soumya; Heegaard, Steffen; Kivelä, Tero; Reis, André; Kruse, Friedrich E; Weinreb, Robert N; Pasquale, Louis R; Haines, Jonathan L; Thorsteinsdottir, Unnur; Jonasson, Fridbert; Allingham, R Rand; Milea, Dan; Ritch, Robert; Kubota, Toshiaki; Tashiro, Kei; Vithana, Eranga N; Micheal, Shazia; Topouzis, Fotis; Craig, Jamie E; Dubina, Michael; Sundaresan, Periasamy; Stefansson, Kari; Wiggs, Janey L; Pasutto, Francesca; Khor, Chiea Chuen

    2017-07-01

    Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10(-14)) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10(-8)). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

  15. Genetic factors associated with intestinal metaplasia in a high risk Singapore-Chinese population: a cohort study

    Directory of Open Access Journals (Sweden)

    Salto-Tellez Manuel

    2009-10-01

    Full Text Available Abstract Background Intestinal metaplasia (IM is an important precursor lesion in the development of gastric cancer (GC. The aim of this study was to investigate genetic factors previously linked to GC risk for their possible association with IM. A total of 18 polymorphisms in 14 candidate genes were evaluated in a Singapore-Chinese population at high risk of developing GC. Methods Genotype frequencies were compared between individuals presenting with (n = 128 or without (n = 246 IM by both univariate and multivariate analysis. Results Carriers of the NQO1 609 T allele showed an association with IM in individuals who were seropositive for Helicobacter pylori (HP+; OR = 2.61, 95%CI: 1.18-5.80, P = .018. The IL-10 819 C allele was also associated with IM in HP+ individuals (OR = 2.32, 95%CI: 1.21-4.43, P = 0.011, while the PTPN11 A allele was associated with IM in HP- individuals (OR = 2.51, 95%CI: 1.16-5.40, P = 0.019, but showed an inverse association in HP+ subjects (OR = 0.46, 95%CI: 0.21-0.99, P = 0.048. Conclusion Polymorphisms in NQO1, IL-10 and PTPN11, in combination with HP status, could be used to identify individuals who are more likely to develop IM and therefore GC.

  16. Association study between genetic monoaminergic polymorphisms and OCD response to clomipramine treatment

    Directory of Open Access Journals (Sweden)

    K Miguita

    2011-01-01

    Full Text Available In the present paper, we investigated the 5HTTLPR and STin2 polymorphisms in the promoter region of the serotonin transporter gene (SLC6A4, the G861C polymorphism (rs6296 of the serotonin receptor 1D beta (HTR1B, the T102C (rs6113 and C516T (rs6305 polymorphisms of the serotonin receptor gene subtype 2A (HTR2A, the DAT UTR, DAT intron 8 and DAT intron 14 of the dopamine transporter gene (SLC6A3, the Val-158-Met (rs4680 polymorphism of the COMT and the silent mutation G1287A (rs5569 in the norepinephrine transporter gene (SLC6A2. We genotyped 41 obsessive-compulsive disorder (OCD outpatients, classified as good-responders (n=27 and poor-responders (n=14 to treatment with clomipramine according to the Yale Brown Obsessive-Compulsive Scale (YBOCS. Patients who achieved a reduction in symptoms of 40% or more in YBOCS after 14 weeks of treatment were considered good-responders. Genotypes and alleles distribution of the investigated polymorphisms were compared between both groups. We did not find association between the studied polymorphisms and clomipramine response in our sample.

  17. Power for genetic association study of human longevity using the case-control design.

    Science.gov (United States)

    Tan, Qihua; Zhao, Jing Hua; Zhang, Dongfeng; Kruse, Torben A; Christensen, Kaare

    2008-10-15

    The efficiency of the popular case-control design in gene-longevity association studies needs to be verified because, different from a binary trait, longevity represents only the extreme end of the continuous life span distribution without a clear cutoff for defining the phenotype. In this paper, the authors use the current Danish life tables to simulate individual life span by using a variety of scenarios and assess the empirical power for different sample sizes when cases are defined as centenarians or as nonagenarians. Results show that, although using small samples of centenarians (several hundred) provides power to detect only common alleles with large effects (a >20% reduction in hazard rate), large samples of centenarians (>1,000) achieve power to capture genes responsible for minor effects (5%-10% hazard reduction depending on the mode of inheritance). Although the method provides good power for rare alleles with multiplicative or dominant effects, it performs poorly for rare recessive alleles. Power is drastically reduced when nonagenarians are considered cases, with a more than 5-fold difference in the size of the case sample required to achieve comparable power as that found with centenarians.

  18. Genetic variants associated with lung function

    DEFF Research Database (Denmark)

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

    2014-01-01

    BACKGROUND: Reduced forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) are strong predictors of mortality and lung function is higher among individuals with exceptional longevity. However, genetic factors associated with lung function in individuals...... with exceptional longevity have not been identified. METHOD: We conducted a genome wide association study (GWAS) to identify novel genetic variants associated with lung function in the Long Life Family Study (LLFS) (n = 3,899). Replication was performed using data from the CHARGE/SpiroMeta consortia...... used the residuals of the FEV1 and FEV1/FVC, adjusted for age, sex, height, ancestry principal components (PCs), smoking status, pack-years, and field center. RESULTS: We identified nine SNPs in strong linkage disequilibrium in the CYP2U1 gene to be associated with FEV1 and a novel SNP (rs889574...

  19. Replication of recently identified systemic lupus erythematosus genetic associations : a case-control study

    NARCIS (Netherlands)

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

    2009-01-01

    Introduction We aimed to replicate association of newly identified systemic lupus erythematosus (SLE) loci. Methods We selected the most associated SNP in 10 SLE loci. These 10 SNPs were analysed in 1,579 patients with SLE and 1,726 controls of European origin by single-base extension. Comparison of

  20. Discovering epistasis in large scale genetic association studies by exploiting graphics cards.

    Science.gov (United States)

    Chen, Gary K; Guo, Yunfei

    2013-12-03

    Despite the enormous investments made in collecting DNA samples and generating germline variation data across thousands of individuals in modern genome-wide association studies (GWAS), progress has been frustratingly slow in explaining much of the heritability in common disease. Today's paradigm of testing independent hypotheses on each single nucleotide polymorphism (SNP) marker is unlikely to adequately reflect the complex biological processes in disease risk. Alternatively, modeling risk as an ensemble of SNPs that act in concert in a pathway, and/or interact non-additively on log risk for example, may be a more sensible way to approach gene mapping in modern studies. Implementing such analyzes genome-wide can quickly become intractable due to the fact that even modest size SNP panels on modern genotype arrays (500k markers) pose a combinatorial nightmare, require tens of billions of models to be tested for evidence of interaction. In this article, we provide an in-depth analysis of programs that have been developed to explicitly overcome these enormous computational barriers through the use of processors on graphics cards known as Graphics Processing Units (GPU). We include tutorials on GPU technology, which will convey why they are growing in appeal with today's numerical scientists. One obvious advantage is the impressive density of microprocessor cores that are available on only a single GPU. Whereas high end servers feature up to 24 Intel or AMD CPU cores, the latest GPU offerings from nVidia feature over 2600 cores. Each compute node may be outfitted with up to 4 GPU devices. Success on GPUs varies across problems. However, epistasis screens fare well due to the high degree of parallelism exposed in these problems. Papers that we review routinely report GPU speedups of over two orders of magnitude (>100x) over standard CPU implementations.

  1. Discovering epistasis in large scale genetic association studies by exploiting graphics cards

    Directory of Open Access Journals (Sweden)

    Gary K Chen

    2013-12-01

    Full Text Available Despite the enormous investments made in collecting DNA samples and generating germline variation data across thousands of individuals in modern genome wide association studies (GWAS, progress has been frustratingly slow in explaining much of the heritability in common disease. Today’s paradigm of testing independent hypotheses on each SNP marker is unlikely to adequately reflect the complex biological processes in disease risk. Alternatively, modeling risk as an ensemble of SNPs that act in concert in a pathway, and/or interact non-additively on log risk for example, may be a more sensible way to approach gene mapping in modern studies. Implementing such analyses genome-wide can quickly become intractable due to the fact that even modest size SNP panels on modern genotype arrays (500k markers pose a combinatorial nightmare, require tens of billions of models to be tested for evidence of interaction. In this article, we provide an in-depth analysis of programs that have been developed to explicitly overcome these enormous computational barriers through the use of processors on graphics cards known as Graphics Processing Units (GPU. We include tutorials on GPU technology, which will convey why they are growing in appeal with today’s numerical scientists. One obvious advantage is the impressive density of microprocessor cores that are available on only a single GPU. Whereas high end servers feature up to 24 Intel or AMD CPU cores, the latest GPU offerings from nVidia feature over 2,600 cores. Each compute node may be outfitted with up to 4 GPU devices. Success on GPUs varies across problems. However epistasis screens fare well due to the high degree of parallelism exposed in these problems. Papers that we review routinely report GPU speedups of over two orders of magnitude (>100x over standard CPU implementations.

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

    Directory of Open Access Journals (Sweden)

    Stefan Norbert

    2008-11-01

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

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

    Science.gov (United States)

    Weyrich, Peter; Machicao, Fausto; Reinhardt, Julia; Machann, Jürgen; Schick, Fritz; Tschritter, Otto; Stefan, Norbert; Fritsche, Andreas; Häring, Hans-Ulrich

    2008-11-12

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

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

    Science.gov (United States)

    Weyrich, Peter; Machicao, Fausto; Reinhardt, Julia; Machann, Jürgen; Schick, Fritz; Tschritter, Otto; Stefan, Norbert; Fritsche, Andreas; Häring, Hans-Ulrich

    2008-01-01

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

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

    Science.gov (United States)

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

    2012-04-01

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

  6. Using public control genotype data to increase power and decrease cost of case-control genetic association studies.

    Science.gov (United States)

    Ho, Lindsey A; Lange, Ethan M

    2010-12-01

    Genome-wide association (GWA) studies are a powerful approach for identifying novel genetic risk factors associated with human disease. A GWA study typically requires the inclusion of thousands of samples to have sufficient statistical power to detect single nucleotide polymorphisms that are associated with only modest increases in risk of disease given the heavy burden of a multiple test correction that is necessary to maintain valid statistical tests. Low statistical power and the high financial cost of performing a GWA study remains prohibitive for many scientific investigators anxious to perform such a study using their own samples. A number of remedies have been suggested to increase statistical power and decrease cost, including the utilization of free publicly available genotype data and multi-stage genotyping designs. Herein, we compare the statistical power and relative costs of alternative association study designs that use cases and screened controls to study designs that are based only on, or additionally include, free public control genotype data. We describe a novel replication-based two-stage study design, which uses free public control genotype data in the first stage and follow-up genotype data on case-matched controls in the second stage that preserves many of the advantages inherent when using only an epidemiologically matched set of controls. Specifically, we show that our proposed two-stage design can substantially increase statistical power and decrease cost of performing a GWA study while controlling the type-I error rate that can be inflated when using public controls due to differences in ancestry and batch genotype effects.

  7. Association studies of genetic scores of serum vitamin B12 and folate levels with symptoms of depression and anxiety in two danish population studies

    DEFF Research Database (Denmark)

    Møllehave, L T; Skaaby, T; Simonsen, K S

    2017-01-01

    BACKGROUND/OBJECTIVES: Observational studies have suggested low serum levels of vitamin B12 or folate to be risk factors of depression and anxiety. However, these results may be biased by confounding and reverse causation. Mendelian randomization studies are not subject to these limitations....... The aim was to examine the association of genetic scores of vitamin B12 and folate-associated alleles with depression and anxiety. SUBJECTS/METHODS: The study included 4126 participants from two Danish population-based studies. Serum vitamin B12 and folate were measured. Weighed allele scores were...... calculated as the sum of weights (genetic effect sizes) for 12 and two variants increasing circulating levels of vitamin B12 and folate, respectively. Symptoms of depression and anxiety were assessed by the Symptom Check List (SCL)-90-R, and self-reported doctor-diagnosed depression and anxiety. RESULTS...

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

    Science.gov (United States)

    Pahikkala, Tapio; Okser, Sebastian; Airola, Antti; Salakoski, Tapio; Aittokallio, Tero

    2012-05-02

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

  9. The associations between two vital GSTs genetic polymorphisms and lung cancer risk in the Chinese population: evidence from 71 studies.

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    Kui Liu

    Full Text Available BACKGROUND: The genetic polymorphisms of glutathione S-transferase (GSTs have been suspected to be related to the development of lung cancer while the current results are conflicting, especially in the Chinese population. METHODS: Data on genetic polymorphisms of glutathione S-transferase Mu 1 (GSTM1 from 68 studies, glutathione S-transferase theta 1 (GSTT1 from 17 studies and GSTM1-GSTT1 from 8 studies in the Chinese population were reanalyzed on their association with lung cancer risk. Odds ratios (OR were pooled using forest plots. 9 subgroups were all or partly performed in the subgroup analyses. The Galbraith plot was used to identify the heterogeneous records. Potential publication biases were detected by Begg's and Egger's tests. RESULTS: 71 eligible studies were identified after screening of 1608 articles. The increased association between two vital GSTs genetic polymorphisms and lung cancer risk was detected by random-effects model based on a comparable heterogeneity. Subgroup analysis showed a significant relationship between squamous carcinoma (SC, adenocarcinoma (AC or small cell lung carcinoma (SCLC and GSTM1 null genotype, as well as SC or AC and GSTT1 null genotype. Additionally, smokers with GSTM1 null genotype had a higher lung cancer risk than non-smokers. Our cumulative meta-analysis demonstrated a stable and reliable result of the relationship between GSTM1 null genotype and lung cancer risk. After the possible heterogeneous articles were omitted, the adjusted risk of GSTs and lung cancer susceptibility increased (fixed-effects model: ORGSTM1 = 1.23, 95% CI: 1.19 to 1.27, P<0.001; ORGSTT1 = 1.18, 95% CI: 1.10 to 1.26, P<0.001; ORGSTM1-GSTT1 = 1.33, 95% CI: 1.10 to 1.61, P = 0.004. CONCLUSIONS: An increased risk of lung cancer with GSTM1 and GSTT1 null genotype, especially with dual null genotype, was found in the Chinese population. In addition, special histopathological classification of lung cancers and a

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

    Directory of Open Access Journals (Sweden)

    Monica Chang

    2008-06-01

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

  11. 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.

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

    Science.gov (United States)

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

    2016-08-01

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

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

    Science.gov (United States)

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

    2012-01-01

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

  14. Genetic association study of selected candidate genes (ApoB, LPL, Leptin and telomere length in obese and hypertensive individuals

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    Saini Divyalakshmi

    2009-09-01

    Full Text Available Abstract Background A genetic study was carried out among obese and hypertensive individuals from India to assess allelic association, if any, at three candidate loci: Apolipoprotein B (ApoB minisatellite and two tetranucleotide repeat loci; LPL (Lipoprotein lipase and Leptin. Attempt has also been made to find out whether telomere length attrition is associated with hypertension and obese individuals. Methods Venous blood samples were collected from 37 normal, 35 obese and 47 hypertensive individuals. Genomic DNA was extracted from peripheral blood mononuclear cells (PBMC and PCR amplifications were achieved using locus specific primers. Genotyping of ApoB minisatellite was performed using 4% polyacrylamide gel electrophoresis (PAGE followed by silver staining, whereas LPL and Leptin loci were genotyped using ALF Express™ DNA sequencer. Telomere length was determined using a recently developed real time based quantitative PCR, where the relative telomere length was determined by calculating the relative ratio of telomere (T and single copy gene (S PCR products which is expressed as T/S ratio. Results All the three loci are highly polymorphic, display high heterozygosity and conform to Hardy-Weinberg's equilibrium expectations. ApoB minisatellite displayed 14 alleles, whereas LPL and Leptin tetranucleotide loci were having 9 and 17 alleles, respectively. Interestingly two new alleles (9 and 11 repeats were detected at ApoB locus for the first time. The alleles at Leptin locus were classified as Class I (lower alleles: 149-200 bp and Class II alleles (higher alleles: >217 bp. Higher alleles at ApoB (>39 repeats, predominant allele 9 at LPL and alleles 164 bp and 224 bp at Leptin loci have shown allelic association with hypertensive individuals. After adjusting the influence of age and gender, the analysis of co-variance (ANCOVA revealed the relative telomere length (T/S ratio in hypertensive individuals to be (1.01 ± 0.021, which was

  15. Association study of genetic polymorphism in ABCC4 with cyclophosphamide-induced adverse drug reactions in breast cancer patients.

    Science.gov (United States)

    Low, Siew-Kee; Kiyotani, Kazuma; Mushiroda, Taisei; Daigo, Yataro; Nakamura, Yusuke; Zembutsu, Hitoshi

    2009-10-01

    Cyclophosphamide (CPA)-based combination treatment has known to be effective for breast cancer, but often causes adverse drug reactions (ADRs). Hence, the identification of patients at risk for toxicity by CPA is clinically significant. In this study, a stepwise case-control association study was conducted using 403 patients with breast cancer who received the CPA combination therapy. A total of 143 genetic polymorphisms in 13 candidate genes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, ALDH1A1, ALDH3A1, GSTA1, GSTM1, GSTP1, GSTT1, ABCC2 and ABCC4), possibly involved in the activation, metabolism and transport of CPA, were genotyped using 184 cases who developed either > or =grade 3 leukopenia/neutropenia or > or =grade 2 gastrointestinal toxicity and 219 controls who did not show any ADRs throughout the treatment. The association study revealed that one SNP, rs9561778 in ABCC4, showed a significant association with CPA-induced ADRs (Cochran-Armitage trend's P-value=0.00031; odds ratio (OR)=2.06). Subgroup analysis also indicated that the SNP rs9561778 was significantly associated with two major ADR subgroups; gastrointestinal toxicity and leukopenia/neutropenia (Cochran-Armitage trend's P-value=0.00019 and 0.014; OR=2.31 and 1.83). Furthermore, the SNP rs9561778 showed an association with breast cancer patients who were treated with CA(F) drug regimen-induced ADR (Cochran-Armitage trend's P-value=0.00028; OR=3.13). The SNPs in ABCC4 might be applicable in predicting the risk of ADRs in patients receiving CPA combination chemotherapy.

  16. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

    DEFF Research Database (Denmark)

    Arking, Dan E; Pulit, Sara L; Crotti, Lia

    2014-01-01

    The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Usi....... Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. © 2014 Nature America, Inc....

  17. Evaluation of genome-wide power of genetic association studies based on empirical data from the HapMap project.

    Science.gov (United States)

    Nannya, Yasuhito; Taura, Kenjiro; Kurokawa, Mineo; Chiba, Shigeru; Ogawa, Seishi

    2007-10-15

    With recent advances in high-throughput single nucleotide polymorphism (SNP) typing technologies, genome-wide association studies have become a realistic approach to identify the causative genes that are responsible for common diseases of complex genetic traits. In this strategy, a trade-off between the increased genome coverage and a chance of finding SNPs incidentally showing a large statistics becomes serious due to extreme multiple-hypothesis testing. We investigated the extent to which this trade-off limits the genome-wide power with this approach by simulating a large number of case-control panels based on the empirical data from the HapMap Project. In our simulations, statistical costs of multiple hypothesis testing were evaluated by empirically calculating distributions of the maximum value of the chi(2) statistics for a series of marker sets having increasing numbers of SNPs, which were used to determine a genome-wide threshold in the following power simulations. With a practical study size, the cost of multiple testing largely offsets the potential benefits from increased genome coverage given modest genetic effects and/or low frequencies of causal alleles. In most realistic scenarios, increasing genome coverage becomes less influential on the power, while sample size is the predominant determinant of the feasibility of genome-wide association tests. Increasing genome coverage without corresponding increase in sample size will only consume resources without little gain in power. For common causal alleles with relatively large effect sizes [genotype relative risk > or =1.7], we can expect satisfactory power with currently available large-scale genotyping platforms using realistic sample size ( approximately 1000 per arm).

  18. Positive Association between Aspirin-Intolerant Asthma and Genetic Polymorphisms of FSIP1: a Case-Case Study

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    Choi Inseon S

    2010-06-01

    Full Text Available Abstract Background Aspirin-intolerant asthma (AIA, which is caused by non-steroidal anti-inflammatory drugs (NSAIDs such as aspirin, causes lung inflammation and reversal bronchi reduction, leading to difficulty in breathing. Aspirin is known to affect various parts inside human body, ranging from lung to spermatogenesis. FSIP1, also known as HDS10, is a recently discovered gene that encodes fibrous sheath interacting protein 1, and is regulated by amyloid beta precursor protein (APP. Recently, it has been reported that a peptide derived from APP is cleaved by α disintegrin and metalloproteinase 33 (ADAM33, which is an asthma susceptibility gene. It has also been known that the FSIP1 gene is expressed in airway epithelium. Objectives Aim of this study is to find out whether FSIP1 polymorphisms affect the onset of AIA in Korean population, since it is known that AIA is genetically affected by various genes. Methods We conducted association study between 66 single nucleotide polymorphisms (SNPs of the FSIP1 gene and AIA in total of 592 Korean subjects including 163 AIA and 429 aspirin-tolerant asthma (ATA patients. Associations between polymorphisms of FSIP1 and AIA were analyzed with sex, smoking status, atopy, and body mass index (BMI as covariates. Results Initially, 18 SNPs and 4 haplotypes showed associations with AIA. However, after correcting the data for multiple testing, only one SNP showed an association with AIA (corrected P-value = 0.03, OR = 1.63, 95% CI = 1.23-2.16, showing increased susceptibility to AIA compared with that of ATA cases. Our findings suggest that FSIP1 gene might be a susceptibility gene for aspirin intolerance in asthmatics. Conclusion Although our findings did not suggest that SNPs of FSIP1 had an effect on the reversibility of lung function abnormalities in AIA patients, they did show significant evidence of association between the variants in FSIP1 and AIA occurrence among asthmatics in a Korean population.

  19. An endophenotype approach to the genetics of alcohol dependence: a genome wide association study of fast beta EEG in families of African ancestry.

    Science.gov (United States)

    Meyers, J L; Zhang, J; Wang, J C; Su, J; Kuo, S I; Kapoor, M; Wetherill, L; Bertelsen, S; Lai, D; Salvatore, J E; Kamarajan, C; Chorlian, D; Agrawal, A; Almasy, L; Bauer, L; Bucholz, K K; Chan, G; Hesselbrock, V; Koganti, L; Kramer, J; Kuperman, S; Manz, N; Pandey, A; Seay, M; Scott, D; Taylor, R E; Dick, D M; Edenberg, H J; Goate, A; Foroud, T; Porjesz, B

    2017-01-10

    Fast beta (20-28 Hz) electroencephalogram (EEG) oscillatory activity may be a useful endophenotype for studying the genetics of disorders characterized by neural hyperexcitability, including substance use disorders (SUDs). However, the genetic underpinnings of fast beta EEG have not previously been studied in a population of African-American ancestry (AA). In a sample of 2382 AA individuals from 482 families drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a genome-wide association study (GWAS) on resting-state fast beta EEG power. To further characterize our genetic findings, we examined the functional and clinical/behavioral significance of GWAS variants. Ten correlated single-nucleotide polymorphisms (SNPs) (r(2)>0.9) located in an intergenic region on chromosome 3q26 were associated with fast beta EEG power at PMolecular Psychiatry advance online publication, 10 January 2017; doi:10.1038/mp.2016.239.

  20. A scalable and portable framework for massively parallel variable selection in genetic association studies.

    Science.gov (United States)

    Chen, Gary K

    2012-03-01

    The deluge of data emerging from high-throughput sequencing technologies poses large analytical challenges when testing for association to disease. We introduce a scalable framework for variable selection, implemented in C++ and OpenCL, that fits regularized regression across multiple Graphics Processing Units. Open source code and documentation can be found at a Google Code repository under the URL http://bioinformatics.oxfordjournals.org/content/early/2012/01/10/bioinformatics.bts015.abstract. Supplementary data are available at Bioinformatics online.

  1. Next-Generation Sequencing of the HLA locus: Methods and impacts on HLA typing, population genetics and disease association studies.

    Science.gov (United States)

    Carapito, Raphael; Radosavljevic, Mirjana; Bahram, Seiamak

    2016-11-01

    The human Major Histocompatibility Complex, known as the "Human Leukocyte Antigen (HLA)", could be defined as a "super locus" (historically called "supergene") governing the adaptive immune system in vertebrates. It also harbors genes involved in innate immunity. HLA is the most gene-dense, polymorphic and disease-associated region of the human genome. It is of critical medical relevance given its involvement in the fate of the transplanted organs/tissues and its association with more than 100 diseases. However, despite these important roles, comprehensive sequence analysis of the 4 megabase HLA locus has been limited due to technological challenges. Thanks to recent improvements in Next-Generation Sequencing (NGS) technologies however, one is now able to handle the peculiarities of the MHC notably the tight linkage disequilibrium between genes as well as their high degree of polymorphism (and hence heterozygosity). Increased read lengths, throughput, accuracy, as well as development of new bioinformatics tools now enable to efficiently generate complete and accurate full-length HLA haplotypes without phase ambiguities. The present report reviews current NGS approaches to capture, sequence and analyze HLA genes and loci. The impact of these new methodologies on various applications including HLA typing, population genetics and disease association studies are discussed. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  2. Genome wide association studies using a new nonparametric model reveal the genetic architecture of 17 agronomic traits in an enlarged maize association panel.

    Science.gov (United States)

    Yang, Ning; Lu, Yanli; Yang, Xiaohong; Huang, Juan; Zhou, Yang; Ali, Farhan; Wen, Weiwei; Liu, Jie; Li, Jiansheng; Yan, Jianbing

    2014-09-01

    Association mapping is a powerful approach for dissecting the genetic architecture of complex quantitative traits using high-density SNP markers in maize. Here, we expanded our association panel size from 368 to 513 inbred lines with 0.5 million high quality SNPs using a two-step data-imputation method which combines identity by descent (IBD) based projection and k-nearest neighbor (KNN) algorithm. Genome-wide association studies (GWAS) were carried out for 17 agronomic traits with a panel of 513 inbred lines applying both mixed linear model (MLM) and a new method, the Anderson-Darling (A-D) test. Ten loci for five traits were identified using the MLM method at the Bonferroni-corrected threshold -log10 (P) >5.74 (α=1). Many loci ranging from one to 34 loci (107 loci for plant height) were identified for 17 traits using the A-D test at the Bonferroni-corrected threshold -log10 (P) >7.05 (α=0.05) using 556809 SNPs. Many known loci and new candidate loci were only observed by the A-D test, a few of which were also detected in independent linkage analysis. This study indicates that combining IBD based projection and KNN algorithm is an efficient imputation method for inferring large missing genotype segments. In addition, we showed that the A-D test is a useful complement for GWAS analysis of complex quantitative traits. Especially for traits with abnormal phenotype distribution, controlled by moderate effect loci or rare variations, the A-D test balances false positives and statistical power. The candidate SNPs and associated genes also provide a rich resource for maize genetics and breeding.

  3. Genome wide association studies using a new nonparametric model reveal the genetic architecture of 17 agronomic traits in an enlarged maize association panel.

    Directory of Open Access Journals (Sweden)

    Ning Yang

    2014-09-01

    Full Text Available Association mapping is a powerful approach for dissecting the genetic architecture of complex quantitative traits using high-density SNP markers in maize. Here, we expanded our association panel size from 368 to 513 inbred lines with 0.5 million high quality SNPs using a two-step data-imputation method which combines identity by descent (IBD based projection and k-nearest neighbor (KNN algorithm. Genome-wide association studies (GWAS were carried out for 17 agronomic traits with a panel of 513 inbred lines applying both mixed linear model (MLM and a new method, the Anderson-Darling (A-D test. Ten loci for five traits were identified using the MLM method at the Bonferroni-corrected threshold -log10 (P >5.74 (α=1. Many loci ranging from one to 34 loci (107 loci for plant height were identified for 17 traits using the A-D test at the Bonferroni-corrected threshold -log10 (P >7.05 (α=0.05 using 556809 SNPs. Many known loci and new candidate loci were only observed by the A-D test, a few of which were also detected in independent linkage analysis. This study indicates that combining IBD based projection and KNN algorithm is an efficient imputation method for inferring large missing genotype segments. In addition, we showed that the A-D test is a useful complement for GWAS analysis of complex quantitative traits. Especially for traits with abnormal phenotype distribution, controlled by moderate effect loci or rare variations, the A-D test balances false positives and statistical power. The candidate SNPs and associated genes also provide a rich resource for maize genetics and breeding.

  4. Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population.

    Science.gov (United States)

    Cho, Y M; Kim, T H; Lim, S; Choi, S H; Shin, H D; Lee, H K; Park, K S; Jang, H C

    2009-02-01

    New genetic variants associated with susceptibility to type 2 diabetes mellitus have been discovered in recent genome-wide association (GWA) studies. The aim of the present study was to examine the association between these diabetogenic variants and gestational diabetes mellitus (GDM). The study included 869 Korean women with GDM and 345 female and 287 male Korean non-diabetic controls. We genotyped the single nucleotide polymorphisms (SNPs) rs7756992 and rs7754840 in CDKAL1; rs564398, rs1333040, rs10757278 and rs10811661 in the CDKN2A-CDKN2B region; rs8050136 in FTO; rs1111875, rs5015480 and rs7923837 in HHEX; rs4402960 in IGF2BP2; and rs13266634 in SLC30A8. In addition, rs7903146 and rs12255372 in TCF7L2; rs5215 and rs5219 in KCNJ11; and rs3856806 and rs1801282 in PPARG were genotyped. The genotype frequencies in the GDM patients were compared with those in the non-diabetic controls. Compared with controls (men and women combined), GDM was associated with rs7756992 and rs7754840 (OR 1.55, 95% CI 1.34-1.79, p = 4.17 x 10(-9)) in CDKAL1; rs10811661 (OR 1.49, 95% CI 1.29-1.72, p = 1.05 x 10(-7)) in the CDKN2A-CDKN2B region; rs1111875 (OR 1.27, 95% CI 1.09-1.49, p = 0.003), rs5015480, and rs7923837 in HHEX; rs4402960 (OR 1.18, 95% CI 1.01-1.38, p = 0.03) in IGF2BP2; rs13266634 (OR 1.24, 95% CI 1.07-1.43, p = 0.005) in SLC30A8; and rs7903146 (OR 1.58, 95% CI 1.03-2.43, p = 0.038) in TCF7L2. The risk alleles of the SNPs rs7756992 and rs7754840 in CDKAL1; rs10811661 in the CDKN2A-CDKN2B region; and rs1111875, rs5015480 and rs7923837 in HHEX were associated with significant decreases in the insulin AUC during a 100 g OGTT performed at the time of diagnosis of GDM. Some of the type 2 diabetes-associated genetic variants that were discovered in the recent GWA studies are also associated with GDM in Koreans.

  5. Generalised Anxiety Disorder--A Twin Study of Genetic Architecture, Genome-Wide Association and Differential Gene Expression.

    Directory of Open Access Journals (Sweden)

    Matthew N Davies

    Full Text Available Generalised Anxiety Disorder (GAD is a common anxiety-related diagnosis, affecting approximately 5% of the adult population. One characteristic of GAD is a high degree of anxiety sensitivity (AS, a personality trait which describes the fear of arousal-related sensations. Here we present a genome-wide association study of AS using a cohort of 730 MZ and DZ female twins. The GWAS showed a significant association for a variant within the RBFOX1 gene. A heritability analysis of the same cohort also confirmed a significant genetic component with h2 of 0.42. Additionally, a subset of the cohort (25 MZ twins discordant for AS was studied for evidence of differential expression using RNA-seq data. Significant differential expression of two exons with the ITM2B gene within the discordant MZ subset was observed, a finding that was replicated in an independent cohort. While previous research has shown that anxiety has a high comorbidity with a variety of psychiatric and neurodegenerative disorders, our analysis suggests a novel etiology specific to AS.

  6. Generalised Anxiety Disorder--A Twin Study of Genetic Architecture, Genome-Wide Association and Differential Gene Expression.

    Science.gov (United States)

    Davies, Matthew N; Verdi, Serena; Burri, Andrea; Trzaskowski, Maciej; Lee, Minyoung; Hettema, John M; Jansen, Rick; Boomsma, Dorret I; Spector, Tim D

    2015-01-01

    Generalised Anxiety Disorder (GAD) is a common anxiety-related diagnosis, affecting approximately 5% of the adult population. One characteristic of GAD is a high degree of anxiety sensitivity (AS), a personality trait which describes the fear of arousal-related sensations. Here we present a genome-wide association study of AS using a cohort of 730 MZ and DZ female twins. The GWAS showed a significant association for a variant within the RBFOX1 gene. A heritability analysis of the same cohort also confirmed a significant genetic component with h2 of 0.42. Additionally, a subset of the cohort (25 MZ twins discordant for AS) was studied for evidence of differential expression using RNA-seq data. Significant differential expression of two exons with the ITM2B gene within the discordant MZ subset was observed, a finding that was replicated in an independent cohort. While previous research has shown that anxiety has a high comorbidity with a variety of psychiatric and neurodegenerative disorders, our analysis suggests a novel etiology specific to AS.

  7. Designs and Methods for Association Studies and Population Size Inference in Statistical Genetics

    DEFF Research Database (Denmark)

    Waltoft, Berit Lindum

    diseases. In the second part statistical methods for inferring population history is discussed. Knowledge on e.g. the common ancestor of the human species, possible bottlenecks back in time, and the expected number of rare variants in each genome, may be factors in the full picture of any disease aetiology....... Epidemiology In epidemiology the wording "odds ratio" is used for the estimator of any case-control study independent of the sampling of the controls. This phrase is ambiguous without specications of the sampling schemes of the controls. When controls are sampled among the non-diseased individuals at the end......). The OR is interpreted as the eect of an exposure on the probability of being diseased at the end of follow-up, while the interpretation of the IRR is the eect of an exposure on the probability of becoming diseased. Through a simulation study, the OR from a classical case-control study is shown to be an inconsistent...

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

    Directory of Open Access Journals (Sweden)

    Ilja M Nolte

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

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

    NARCIS (Netherlands)

    Kato, Norihiro; Loh, Marie; Takeuchi, Fumihiko; Verweij, Niek; Wang, Xu; Zhang, Weihua; Kelly, Tanika N.; Saleheen, Danish; Lehne, Benjamin; Leach, Irene Mateo; Drong, Alexander W.; Abbott, James; Wahl, Simone; Tan, Sian-Tsung; Scott, William R.; Campanella, Gianluca; Chadeau-Hyam, Marc; Afzal, Uzma; Ahluwalia, Tarunveer S.; Bonder, Marc Jan; Chen, Peng; Dehghan, Abbas; Edwards, Todd L.; Esko, Tonu; Go, Min Jin; Harris, Sarah E.; Hartiala, Jaana; Kasela, Silva; Kasturiratne, Anuradhani; Khor, Chiea-Chuen; Kleber, Marcus E.; Li, Huaixing; Mok, Zuan Yu; Nakatochi, Masahiro; Sapari, Nur Sabrina; Saxena, Richa; Stewart, Alexandre F. R.; Stolk, Lisette; Tabara, Yasuharu; Teh, Ai Ling; Wu, Ying; Wu, Jer-Yuarn; Zhang, Yi; Aits, Imke; Alves, Alexessander Da Silva Couto; Das, Shikta; Dorajoo, Rajkumar; Hopewell, Jemma C.; Kim, Yun Kyoung; Koivula, Robert W.; Luan, Jian'an; Lyytikainen, Leo-Pekka; Nguyen, Quang N.; Pereira, Mark A.; Postmus, Iris; Raitakari, Olli T.; Bryan, Molly Scannell; Scott, Robert A.; Sorice, Rossella; Tragante, Vinicius; Traglia, Michela; White, Jon; Yamamoto, Ken; Zhang, Yonghong; Adair, Linda S.; Ahmed, Alauddin; Akiyama, Koichi; Asif, Rasheed; Aung, Tin; Barroso, Ines; Bjonnes, Andrew; Braun, Timothy R.; Cai, Hui; Chang, Li-Ching; Chen, Chien-Hsiun; Cheng, Ching-Yu; Chong, Yap-Seng; Collins, Rory; Courtney, Regina; Davies, Gail; Delgado, Graciela; Do, Loi D.; Doevendans, Pieter A.; Gansevoort, Ron T.; Gao, Yu-Tang; Grammer, Tanja B.; Grarup, Niels; Grewal, Jagvir; Gu, Dongfeng; Wander, Gurpreet S.; Hartikainen, Anna-Liisa; Hazen, Stanley L.; He, Jing; Heng, Chew-Kiat; Hixson, James E.; Hofman, Albert; Hsu, Chris; Huang, Wei; Husemoen, Lise L. N.; Hwang, Joo-Yeon; Ichihara, Sahoko; Igase, Michiya; Isono, Masato; Justesen, Johanne M.; Katsuy, Tomohiro; Kibriya, Muhammad G.; Kim, Young Jin; Kishimoto, Miyako; Koh, Woon-Puay; Kohara, Katsuhiko; Kumari, Meena; Kwek, Kenneth; Lee, Nanette R.; Lee, Jeannette; Liao, Jiemin; Lieb, Wolfgang; Liewald, David C. M.; Matsubara, Tatsuaki; Matsushita, Yumi; Meitinger, Thomas; Mihailov, Evelin; Milani, Lili; Mills, Rebecca; Mononen, Nina; Mueller-Nurasyid, Martina; Nabika, Toru; Nakashima, Eitaro; Ng, Hong Kiat; Nikus, Kjell; Nutile, Teresa; Ohkubo, Takayoshi; Ohnaka, Keizo; Parish, Sarah; Paternoster, Lavinia; Peng, Hao; Peters, Annette; Pham, Son T.; Pinidiyapathirage, Mohitha J.; Rahman, Mahfuzar; Rakugi, Hiromi; Rolandsson, Olov; Rozario, Michelle Ann; Ruggiero, Daniela; Sala, Cinzia F.; Sarju, Ralhan; Shimokawa, Kazuro; Snieder, Harold; Sparso, Thomas; Spiering, Wilko; Starr, John M.; Stott, David J.; Stram, Daniel O.; Sugiyama, Takao; Szymczak, Silke; Tang, W. H. Wilson; Tong, Lin; Trompet, Stella; Turjanmaa, Vaino; Ueshima, Hirotsugu; Uitterlinden, Andre G.; Umemura, Satoshi; Vaarasmaki, Marja; van Dam, Rob M.; van Gilst, Wiek H.; van Veldhuisen, Dirk J.; Viikari, Jorma S.; Waldenberger, Melanie; Wang, Yiqin; Wang, Aili; Wilson, Rory; Wong, Tien-Yin; Xiang, Yong-Bing; Yamaguchi, Shuhei; Ye, Xingwang; Young, Robin D.; Young, Terri L.; Yuan, Jian-Min; Zhou, Xueya; Asselbergs, Folkert W.; Ciullo, Marina; Clarke, Robert; Deloukas, Panos; Franke, Andre; Franks, Paul W.; Franks, Steve; Friedlander, Yechiel; Gross, Myron D.; Guo, Zhirong; Hansen, Torben; Jarvelin, Marjo-Riitta; Jorgensen, Torben; Jukema, J. Wouter; Kahonen, Mika; Kajio, Hiroshi; Kivimaki, Mika; Lee, Jong-Young; Lehtimaki, Terho; Linneberg, Allan; Miki, Tetsuro; Pedersen, Oluf; Samani, Nilesh J.; Sorensen, Thorkild I. A.; Takayanagi, Ryoichi; Toniolo, Daniela; Ahsan, Habibul; Allayee, Hooman; Chen, Yuan-Tsong; Danesh, John; Deary, Ian J.; Franco, Oscar H.; Franke, Lude; Heijman, Bastiaan T.; Holbrook, Joanna D.; Isaacs, Aaron; Kim, Bong-Jo; Lin, Xu; Liu, Jianjun; Maerz, Winfried; Metspalu, Andres; Mohlke, Karen L.; Sanghera, Dharambir K.; Shu, Xiao-Ou; van Meurs, Joyce B. J.; Vithana, Eranga; Wickremasinghe, Ananda R.; Wijmenga, Cisca; Wolffenbuttel, Bruce H. W.; Yokota, Mitsuhiro; Zheng, Wei; Zhu, Dingliang; Vineis, Paolo; Kyrtopoulos, Soterios A.; Kleinjans, Jos C. S.; McCarthy, Mark I.; Soong, Richie; Gieger, Christian; Scott, James; Teo, Yik-Ying; He, Jiang; Elliott, Paul; Tai, E. Shyong; van der Harst, Pim; Kooner, Jaspal S.; Chambers, John C.; Doevendans, PAFM

    2015-01-01

    We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 x 10(-11) to 5.0 x 10(-21

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

    NARCIS (Netherlands)

    N. Kato (Norihiro); M. Loh (Marie); F. Takeuchi (Fumihiko); N. Verweij (Niek); X. Wang (Xu); W. Zhang (Weihua); T. NKelly (Tanika); D. Saleheen; B. Lehne (Benjamin); I.M. Leach (Irene Mateo); A. Drong (Alexander); J. Abbott (James); S. Wahl (Simone); S.-T. Tan (Sian-Tsung); W.R. Scott (William R.); G. Campanella (Gianluca); M. Chadeau-Hyam (Marc); U. Afzal (Uzma); T.S. Ahluwalia (Tarunveer Singh); M.J. Bonder (Marc Jan); P. Chen (Ping); A. Dehghan (Abbas); T.L. Edwards (Todd L.); T. Esko (Tõnu); M.J. Go (Min Jin); S.E. Harris (Sarah); J. Hartiala (Jaana); S. Kasela (Silva); A. Kasturiratne (Anuradhani); C.C. Khor; M.E. Kleber (Marcus); H. Li (Huaixing); Z.Y. Mok (Zuan Yu); M. Nakatochi (Masahiro); N.S. Sapari (Nur Sabrina); R. Saxena (Richa); A.F. Stewart (Alexandre F.); L. Stolk (Lisette); Y. Tabara (Yasuharu); A.L. Teh (Ai Ling); Y. Wu (Ying); J.-Y. Wu (Jer-Yuarn); Y. Zhang (Yi); I. Aits (Imke); A. Da Silva Couto Alves (Alexessander); S. Das; R. Dorajoo (Rajkumar); J. CHopewell (Jemma); Y.K. Kim (Yun Kyoung); R. WKoivula (Robert); J. Luan (Jian'An); L.-P. Lyytikäinen (Leo-Pekka); Q. NNguyen (Quang); M.A. Pereira (Mark A); D. Postmus (Douwe); O. TRaitakari (Olli); M. Scannell Bryan (Molly); R.A. Scott (Robert); R. Sorice; V. Tragante (Vinicius); M. Traglia (Michela); J. White (Jon); K. Yamamoto (Ken); Y. Zhang (Yonghong); L.S. Adair (Linda); A. Ahmed (Alauddin); K. Akiyama (Koichi); R. Asif (Rasheed); T. Aung (Tin); I. Barroso (Inês); A. Bjonnes (Andrew); T.R. Braun (Timothy R.); H. Cai (Hui); L.-C. Chang (Li-Ching); C.-H. Chen; C-Y. Cheng (Ching-Yu); Y.-S. Chong (Yap-Seng); F.S. Collins (Francis); R. Courtney (Regina); G. Davies (Gail); G. Delgado; L.D. Do (Loi D.); P.A. Doevendans (Pieter); R.T. Gansevoort (Ron); Y. Gao; T.B. Grammer (Tanja B); N. Grarup (Niels); J. Grewal (Jagvir); D. Gu (D.); G. SWander (Gurpreet); A.L. Hartikainen; S.L. Hazen (Stanley); J. He (Jing); C.K. Heng (Chew-Kiat); E.J.A. Hixso (E. James Ames); A. Hofman (Albert); C. Hsu (Chris); W. Huang (Wei); L.L.N. Husemoen (Lise Lotte); J.-Y. Hwang (Joo-Yeon); S. Ichihara (Sahoko); M. Igase (Michiya); M. Isono (Masato); J.M. Justesen (Johanne M.); T. Katsuya (Tomohiro); M. GKibriya (Muhammad); Y.J. Kim; M. Kishimoto (Miyako); W.-P. Koh (Woon-Puay); K. Kohara (Katsuhiko); M. Kumari (Meena); K. Kwek (Kenneth); N.R. Lee (Nanette); J. Lee (Jeannette); J. Liao (Jie); W. Lieb (Wolfgang); D.C. Liewald (David C.); T. Matsubara (Tatsuaki); Y. Matsushita (Yumi); T. Meitinger (Thomas); E. Mihailov (Evelin); L. Milani (Lili); R. Mills (Rebecca); K. Mononen (Kari); M. Müller-Nurasyid (Martina); T. Nabika (Toru); E. Nakashima (Eitaro); H.K. Ng (Hong Kiat); K. Nikus (Kjell); T. Nutile; T. Ohkubo (Takayoshi); K. Ohnaka (Keizo); S. Parish (Sarah); L. Paternoster (Lavinia); H. Peng (Hao); A. Peters (Annette); S. TPham (Son); M.J. Pinidiyapathirage (Mohitha J.); M. Rahman (Mahfuzar); H. Rakugi (Hiromi); O. Rolandsson (Olov); M.A. Rozario (Michelle Ann); D. Ruggiero; C. Sala (Cinzia); R. Sarju (Ralhan); K. Shimokawa (Kazuro); H. Snieder (Harold); T. Sparsø (Thomas); W. Spiering (Wilko); J.M. Starr (John); D.J. Stott (David J.); D. OStram (Daniel); T. Sugiyama (Takao); S. Szymczak (Silke); W.H.W. Tang (W.H. Wilson); L. Tong (Lin); S. Trompet (Stella); V. Turjanmaa (Väinö); H. Ueshima (Hirotsugu); A.G. Uitterlinden (André); S. Umemura (Satoshi); M. Vaarasmaki (Marja); R.M. Dam (Rob Mvan); W.H. van Gilst (Wiek); D.J. van Veldhuisen (Dirk); J. Viikari (Jorma); M. Waldenberger (Melanie); Y. Wang (Yiqin); A. Wang (Aili); R. Wilson (Rory); T.-Y. Wong (Tien-Yin); Y.-B. Xiang (Yong-Bing); S. Yamaguchi (Shuhei); X. Ye (Xingwang); R. Young (Robin); T.L. Young (Terri); J.-M. Yuan (Jian-Min); X. Zhou (Xueya); F.W. Asselbergs (Folkert); M. Ciullo; R. Clarke (Robert); P. Deloukas (Panagiotis); A. Franke (Andre); W.F. Paul (W. Frank); S. Franks (Steve); Y. Friedlander (Yechiel); M.D. Gross (Myron D.); Z. Guo (Zhirong); T. Hansen (T.); M.-R. Jarvelin (Marjo-Riitta); T. Jørgensen (Torben); J.W. Jukema (Jan Wouter); M. Kähönen (Mika); H. Kajio (Hiroshi); M. Kivimaki (Mika); J.-Y. Lee (Jong-Young); T. Lehtimäki (Terho); A. Linneberg (Allan); T. Miki (Tetsuro); O. Pedersen (Oluf); N.J. Samani (Nilesh); T.I.A. Sørensen (Thorkild); R. Takayanagi (Ryoichi); D. Toniolo (Daniela); H. Ahsan (Habibul); H. Allayee (Hooman); Y.-T. Chen (Yuan-Tsong); J. Danesh (John); I.J. Deary (Ian J.); O.H. Franco (Oscar); L. Franke (Lude); B. THeijman (Bastiaan); J.D. Holbrook (Joanna D.); A.J. Isaacs (Aaron); B.-J. Kim (Bong-Jo); X. Lin (Xu); J. Liu (Jianjun); W. März (Winfried); A. Metspalu (Andres); K.L. Mohlke (Karen); K. Sangher; D. Harambir (Dharambir); X.-O. Shu (Xiao-Ou); J.B.J. van Meurs (Joyce); E.N. Vithana (Eranga); A.R. Wickremasinghe (Ananda); C. Wijmenga (Cisca); B.H.W. Wolffenbuttel (Bruce H.W.); M. Yokota (Mitsuhiro); W. Zheng (Wei); D. Zhu (Dingliang); P. Vineis (Paolo); S.A. Kyrtopoulos (Soterios A.); J.C.S. Kleinjans (Jos C.S.); M.I. McCarthy (Mark); R. Soong (Richie); C. Gieger (Christian); J. Scott (James); Y.Y. Teo (Yik Ying); J. He (Jiang); P. Elliott (Paul); E.S. Tai (Shyong); P. van der Harst (Pim); J.S. Kooner (Jaspal S.); J.C. Chambers (John)

    2015-01-01

    textabstractWe carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10 -11 to 5

  11. Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium

    NARCIS (Netherlands)

    Q. Li (Qing); R. Wojciechowski (Robert); C.L. Simpson (Claire); P.G. Hysi (Pirro); V.J.M. Verhoeven (Virginie); M.K. Ikram (Kamran); R. Höhn (René); V. Vitart (Veronique); A.W. Hewit (Alex); K. Oexle (Konrad); K.M. Makela (Kari Matti); S. MacGregor (Stuart); M. Pirastu (Mario); Q. Fan (Qiao); C-Y. Cheng (Ching-Yu); B. St Pourcain (Beate); G. Mcmahon (George); J.P. Kemp (John); K. Northstone (Kate); J.S. Rahi (Jugnoo); P. Cumberland (Phillippa); N.G. Martin (Nicholas); P.G. Sanfilippo (Paul G.); Y. Lu (Yi); Y. Wang (Ying); C. Hayward (Caroline); O. Polasek (Ozren); H. Campbell (Harry); G. Bencic (Goran); A. Wright (Alan); J. Wedenoja (Juho); T. Zeller (Tanja); A. Schillert (Arne); A. Mirshahi (Alireza); K.J. Lackner (Karl); S.P. Yip (Shea Ping); M.K.H. Yap (Maurice K. H.); J.S. Ried (Janina); C. Gieger (Christian); D. Murgia (Daniela); J.F. Wilson (James F); B.W. Fleck (Brian W.); S. Yazar (Seyhan); J.R. Vingerling (Hans); A. Hofman (Albert); A.G. Uitterlinden (André); F. Rivadeneira Ramirez (Fernando); N. Amin (Najaf); L.C. Karssen (Lennart); B.A. Oostra (Ben); X. Zhou (Xin); Y.Y. Teo (Yik Ying); E.S. Tai (Shyong); E.N. Vithana (Eranga); V.A. Barathi (Veluchamy); Y. Zheng (Yingfeng); R. Siantar (Rosalynn); K. Neelam (Kumari); Y. Shin (Youchan); J. Lam (Janice); E. Yonova-Doing (Ekaterina); C. Venturini (Cristina); S.M. Hosseini (S Mohsen); H.-S. Wong (Hoi-Suen); T. Lehtimäki (Terho); M. Kähönen (Mika); O. Raitakari (Olli); N. Timpson (Nicholas); D.M. Evans (David M.); C.C. Khor; T. Aung (Tin); T.L. Young (Terri); P. Mitchell (Paul); B.E.K. Klein (Barbara); C.M. van Duijn (Cock); T. Meitinger (Thomas); J.B. Jonas (Jost B.); P.N. Baird (Paul); D.A. Mackey (David); T.Y. Wong (Tien); S-M. Saw (Seang-Mei); O. Pärssinen (Olavi); D.E. Stambolian (Dwight); C.J. Hammond (Christopher); C.C.W. Klaver (Caroline); C. Williams (Cathy); A.D. Paterson (Andrew); J.E. Bailey-Wilson (Joan E.); J. Guggenheim (Jean)

    2015-01-01

    textabstractTo identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295

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

    NARCIS (Netherlands)

    N. Kato (Norihiro); M. Loh (Marie); F. Takeuchi (Fumihiko); N. Verweij (Niek); X. Wang (Xu); W. Zhang (Weihua); T. NKelly (Tanika); D. Saleheen; B. Lehne (Benjamin); I.M. Leach (Irene Mateo); A. Drong (Alexander); J. Abbott (James); S. Wahl (Simone); S.-T. Tan (Sian-Tsung); W.R. Scott (William R.); G. Campanella (Gianluca); M. Chadeau-Hyam (Marc); U. Afzal (Uzma); T.S. Ahluwalia (Tarunveer Singh); M.J. Bonder (Marc); P. Chen (Ping); A. Dehghan (Abbas); T.L. Edwards (Todd L.); T. Esko (Tõnu); M.J. Go (Min Jin); S.E. Harris (Sarah); J. Hartiala (Jaana); S. Kasela (Silva); A. Kasturiratne (Anuradhani); C.C. Khor; M.E. Kleber (Marcus); H. Li (Huaixing); Z.Y. Mok (Zuan Yu); M. Nakatochi (Masahiro); N.S. Sapari (Nur Sabrina); R. Saxena (Richa); A.F. Stewart (Alexandre F.); L. Stolk (Lisette); Y. Tabara (Yasuharu); A.L. Teh (Ai Ling); Y. Wu (Ying); J.-Y. Wu (Jer-Yuarn); Y. Zhang (Yi); I. Aits (Imke); A. Da Silva Couto Alves (Alexessander); S. Das (Shikta); R. Dorajoo (Rajkumar); J. CHopewell (Jemma); Y.K. Kim (Yun Kyoung); R. WKoivula (Robert); J. Luan (Jian'An); L.-P. Lyytikäinen (Leo-Pekka); Q. NNguyen (Quang); M.A. Pereira (Mark A); D. Postmus (Douwe); O. TRaitakari (Olli); M. Scannell Bryan (Molly); R.A. Scott (Robert); R. Sorice; V. Tragante (Vinicius); M. Traglia (Michela); J. White (Jon); K. Yamamoto (Ken); Y. Zhang (Yonghong); L.S. Adair (Linda); A. Ahmed (Alauddin); K. Akiyama (Koichi); R. Asif (Rasheed); T. Aung (Tin); I. Barroso (Inês); A. Bjonnes (Andrew); T.R. Braun (Timothy R.); H. Cai (Hui); L.-C. Chang (Li-Ching); C.-H. Chen; C-Y. Cheng (Ching-Yu); Y.-S. Chong (Yap-Seng); F.S. Collins (Francis); R. Courtney (Regina); G. Davies (Gail); G. Delgado; L.D. Do (Loi D.); P.A. Doevendans (Pieter); R.T. Gansevoort (Ron); Y. Gao; T.B. Grammer (Tanja B); N. Grarup (Niels); J. Grewal (Jagvir); D. Gu (D.); G. SWander (Gurpreet); A.L. Hartikainen; S.L. Hazen (Stanley); J. He (Jing); C.K. Heng (Chew-Kiat); E.J.A. Hixso (E. James Ames); A. Hofman (Albert); C. Hsu (Chris); W. Huang (Wei); L.L.N. Husemoen (Lise Lotte); J.-Y. Hwang (Joo-Yeon); S. Ichihara (Sahoko); M. Igase (Michiya); M. Isono (Masato); J.M. Justesen (Johanne M.); T. Katsuya (Tomohiro); M. GKibriya (Muhammad); Y.J. Kim; M. Kishimoto (Miyako); W.-P. Koh (Woon-Puay); K. Kohara (Katsuhiko); M. Kumari (Meena); K. Kwek (Kenneth); N.R. Lee (Nanette); J. Lee (Jeannette); J. Liao (Jie); W. Lieb (Wolfgang); D.C. Liewald (David C.); T. Matsubara (Tatsuaki); Y. Matsushita (Yumi); T. Meitinger (Thomas); E. Mihailov (Evelin); L. Milani (Lili); R. Mills (Rebecca); K. Mononen (Kari); M. Müller-Nurasyid (Martina); T. Nabika (Toru); E. Nakashima (Eitaro); H.K. Ng (Hong Kiat); K. Nikus (Kjell); T. Nutile; T. Ohkubo (Takayoshi); K. Ohnaka (Keizo); S. Parish (Sarah); L. Paternoster (Lavinia); H. Peng (Hao); A. Peters (Annette); S. TPham (Son); M.J. Pinidiyapathirage (Mohitha J.); M. Rahman (Mahfuzar); H. Rakugi (Hiromi); O. Rolandsson (Olov); M.A. Rozario (Michelle Ann); D. Ruggiero; C. Sala (Cinzia); R. Sarju (Ralhan); K. Shimokawa (Kazuro); H. Snieder (Harold); T. Sparsø (Thomas); W. Spiering (Wilko); J.M. Starr (John); D.J. Stott (David J.); D. OStram (Daniel); T. Sugiyama (Takao); S. Szymczak (Silke); W.H.W. Tang (W.H. Wilson); L. Tong (Lin); S. Trompet (Stella); V. Turjanmaa (Väinö); H. Ueshima (Hirotsugu); A.G. Uitterlinden (André); S. Umemura (Satoshi); M. Vaarasmaki (Marja); R.M. Dam (Rob Mvan); W.H. van Gilst (Wiek); D.J. van Veldhuisen (Dirk); J. Viikari (Jorma); M. Waldenberger (Melanie); Y. Wang (Yiqin); A. Wang (Aili); R. Wilson (Rory); T.-Y. Wong (Tien-Yin); Y.-B. Xiang (Yong-Bing); S. Yamaguchi (Shuhei); X. Ye (Xingwang); R. Young (Robin); T.L. Young (Terri); J.-M. Yuan (Jian-Min); X. Zhou (Xueya); F.W. Asselbergs (Folkert); M. Ciullo; R. Clarke (Robert); P. Deloukas (Panagiotis); A. Franke (Andre); W.F. Paul (W. Frank); S. Franks (Steve); Y. Friedlander (Yechiel); M.D. Gross (Myron D.); Z. Guo (Zhirong); T. Hansen (T.); M.-R. Jarvelin (Marjo-Riitta); T. Jørgensen (Torben); J.W. Jukema (Jan Wouter); M. Kähönen (Mika); H. Kajio (Hiroshi); M. Kivimaki (Mika); J.-Y. Lee (Jong-Young); T. Lehtimäki (Terho); A. Linneberg (Allan); T. Miki (Tetsuro); O. Pedersen (Oluf); N.J. Samani (Nilesh); T.I.A. Sørensen (Thorkild); R. Takayanagi (Ryoichi); D. Toniolo (Daniela); H. Ahsan (Habibul); H. Allayee (Hooman); Y.-T. Chen (Yuan-Tsong); J. Danesh (John); I.J. Deary (Ian J.); O.H. Franco (Oscar); L. Franke (Lude); B. THeijman (Bastiaan); J.D. Holbrook (Joanna D.); A.J. Isaacs (Aaron)

    2015-01-01

    textabstractWe carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10 -11 to

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

    DEFF Research Database (Denmark)

    Kato, Norihiro; Loh, Marie; Takeuchi, Fumihiko

    2015-01-01

    We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(...

  14. The genetic susceptibility to type 2 diabetes may be modulated by obesity status: implications for association studies

    Directory of Open Access Journals (Sweden)

    Charpentier Guillaume

    2008-05-01

    Full Text Available Abstract Background Considering that a portion of the heterogeneity amongst previous replication studies may be due to a variable proportion of obese subjects in case-control designs, we assessed the association of genetic variants with type 2 diabetes (T2D in large groups of obese and non-obese subjects. Methods We genotyped RETN, KCNJ11, HNF4A, HNF1A, GCK, SLC30A8, ENPP1, ADIPOQ, PPARG, and TCF7L2 polymorphisms in 1,283 normoglycemic (NG and 1,581 T2D obese individuals as well as in 3,189 NG and 1,244 T2D non-obese subjects of European descent, allowing us to examine T2D risk over a wide range of BMI. Results Amongst non-obese individuals, we observed significant T2D associations with HNF1A I27L [odds ratio (OR = 1.14, P = 0.04], GCK -30G>A (OR = 1.23, P = 0.01, SLC30A8 R325W (OR = 0.87, P = 0.04, and TCF7L2 rs7903146 (OR = 1.89, P = 4.5 × 10-23, and non-significant associations with PPARG Pro12Ala (OR = 0.85, P = 0.14, ADIPOQ -11,377C>G (OR = 1.00, P = 0.97 and ENPP1 K121Q (OR = 0.99, P = 0.94. In obese subjects, associations with T2D were detected with PPARG Pro12Ala (OR = 0.73, P = 0.004, ADIPOQ -11,377C>G (OR = 1.26, P = 0.02, ENPP1 K121Q (OR = 1.30, P = 0.003 and TCF7L2 rs7903146 (OR = 1.30, P = 1.1 × 10-4, and non-significant associations with HNF1A I27L (OR = 0.96, P = 0.53, GCK -30G>A (OR = 1.15, P = 0.12 and SLC30A8 R325W (OR = 0.95, P = 0.44. However, a genotypic heterogeneity was only found for TCF7L2 rs7903146 (P = 3.2 × 10-5 and ENPP1 K121Q (P = 0.02. No association with T2D was found for KCNJ11, RETN, and HNF4A polymorphisms in non-obese or in obese individuals. Conclusion Genetic variants modulating insulin action may have an increased effect on T2D susceptibility in the presence of obesity, whereas genetic variants acting on insulin secretion may have a greater impact on T2D susceptibility in non-obese individuals.

  15. Genetic, maternal and placental factors in the association between birth weight and physical fitness: a longitudinal twin study.

    Directory of Open Access Journals (Sweden)

    Robbert N H Touwslager

    Full Text Available BACKGROUND: Adult cardiorespiratory fitness and muscle strength are related to all-cause and cardiovascular mortality. Both are possibly related to birth weight, but it is unclear what the importance is of genetic, maternal and placental factors in these associations. DESIGN: Peak oxygen uptake and measures of strength, flexibility and balance were obtained yearly during adolescence (10-18 years in 114 twin pairs in the Leuven Longitudinal Twin Study. Their birth weights had been collected prospectively within the East Flanders Prospective Twin Survey. RESULTS: We identified linear associations between birth weight and adolescent vertical jump (b = 1.96 cm per kg birth weight, P = 0.02, arm pull (b = 1.85 kg per kg birth weight P = 0.03 and flamingo balance (b = -1.82 attempts to stand one minute per kg birth weight, P = 0.03. Maximum oxygen uptake appeared to have a U-shaped association with birth weight (the smallest and largest children had the lowest uptake, P = 0.01, but this association was no longer significant after adjustment for parental BMI. Using the individual twin's deviation from his own twin pair's average birth weight, we found positive associations between birth weight and adolescent vertical jump (b = 3.49, P = 0.0007 and arm pull (b = 3.44, P = 0.02. Δ scores were calculated within the twin pairs as first born twin minus second born twin. Δ birth weight was associated with Δ vertical jump within MZ twin pairs only (b = 2.63, P = 0.009, which indicates importance of placental factors. CONCLUSIONS: We found evidence for an association between adolescent physical performance (strength, balance and possibly peak oxygen uptake and birth weight. The associations with vertical jump and arm pull were likely based on individual, more specifically placental (in the case of vertical jump factors. Our results should be viewed as hypothesis-generating and need confirmation, but potentially support preventive strategies to optimize

  16. SNPFile - A software library and file format for large scale association mapping and population genetics studies

    DEFF Research Database (Denmark)

    Nielsen, Jesper; Mailund, Thomas

    2008-01-01

    and manipulate the data. While spreadsheets and at text files were adequate solutions earlier, the increased data size mandates more efficient solutions. Results We describe a new binary file format for SNP data, together with a software library for file manipulation. The file format stores genotype data...... together with any kind of additional data, using a flexible serialisation mechanism. The format is designed to be IO efficient for the access patterns of most multi-locus analysis methods. Conclusion The new file format has been very useful for our own studies where it has significantly reduced...... the informatics burden in keeping track of various secondary data, and where the memory and IO efficiency has greatly simplified analysis runs. A main limitation with the file format is that it is only supported by the very limited set of analysis tools developed in our own lab. This is somewhat alleviated...

  17. Genetic variants associated with Crohn's disease

    Directory of Open Access Journals (Sweden)

    Michail S

    2013-07-01

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

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

    OpenAIRE

    2016-01-01

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

  19. Genetic association study of TNFAIP3, IFIH1, IRF5 polymorphisms with polymyositis/dermatomyositis in Chinese Han population.

    Directory of Open Access Journals (Sweden)

    Si Chen

    Full Text Available BACKGROUND: Single-nucleotide polymorphisms (SNPs in the TNFAIP3, IFIH1, and IRF5 genes have been associated with several auto-inflammation diseases, while the susceptibility between these genes and idiopathic inflammatory myopathies (IIMs were not reported. This study aimed to investigate whether TNFAIP3, IFIH1, and IRF5 gene polymorphisms confer susceptibility for the IIMs in Chinese Han population. METHODS: A large case-control study of Chinese subjects with polymyositis (PM (n = 298 and dermatomyositis (DM (n = 530 was accomplished. 968 healthy and ethnically matched controls were available for comparison. Six SNPs in the TNFAIP3 region (rs2230926 and rs5029939, the IFIH1 gene (rs1990760 and rs3747517 and the IRF5 region (rs4728142 and rs729302 were assessed and genotyped using the Sequenom MassArray iPLEX platform. RESULTS: Our study indicated a strong allele association was observed in PM/DM and PM patients for rs2230926 (OR: 1.61, 95%CI: 1.20-2.16, P(c = 7.5×10(-3; OR: 1.88, 95%CI: 1.30-2.74, P(c = 4.0×10(-3, respectively and rs5029939 (OR: 1.64, 95%CI: 1.21-2.21, P(c = 6.0×10(-3; OR: 1.88, 95%CI: 1.28-2.76, P(c = 5.5×10(-3, respectively. And rs2230926 and rs5029939 were significantly associated with interstitial lung disease (ILD in PM/DM and PM patients (P(c = 0.04 and P(c = 0.016; P(c = 0.02 and P(c = 0.03, respectively. In addition, rs4728142 allele and genotype had significant association with PM/DM patients (P(c = 0.026 and P(c = 0.048, respectively. Further analysis with three logistic regression genetic models revealed statistically significant difference in the genotypic distribution in the PM/DM, PM or DM patients when the additive and dominant models were used. CONCLUSIONS: This was the first study to reveal TNFAIP3 and IRF5 polymorphisms were associated with PM/DM patients or these patients with ILD, indicating that TNFAIP3 and IRF5 might be the susceptibility gene for PM

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

    Directory of Open Access Journals (Sweden)

    Rozenn N Lemaitre

    2011-07-01

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

  1. Structural and Genetic Studies Demonstrate Neurologic Dysfunction in Triosephosphate Isomerase Deficiency Is Associated with Impaired Synaptic Vesicle Dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Roland, Bartholomew P.; Zeccola, Alison M.; Larsen, Samantha B.; Amrich, Christopher G.; Talsma, Aaron D.; Stuchul, Kimberly A.; Heroux, Annie; Levitan, Edwin S.; VanDemark, Andrew P.; Palladino, Michael J.; Pallanck, Leo J.

    2016-03-31

    Triosephosphate isomerase (TPI) deficiency is a poorly understood disease characterized by hemolytic anemia, cardiomyopathy, neurologic dysfunction, and early death. TPI deficiency is one of a group of diseases known as glycolytic enzymopathies, but is unique for its severe patient neuropathology and early mortality. The disease is caused by missense mutations and dysfunction in the glycolytic enzyme, TPI. Previous studies have detailed structural and catalytic changes elicited by disease-associated TPI substitutions, and samples of patient erythrocytes have yielded insight into patient hemolytic anemia; however, the neuropathophysiology of this disease remains a mystery. This study combines structural, biochemical, and genetic approaches to demonstrate that perturbations of the TPI dimer interface are sufficient to elicit TPI deficiency neuropathogenesis. The present study demonstrates that neurologic dysfunction resulting from TPI deficiency is characterized by synaptic vesicle dysfunction, and can be attenuated with catalytically inactive TPI. Collectively, our findings are the first to identify, to our knowledge, a functional synaptic defect in TPI deficiency derived from molecular changes in the TPI dimer interface.

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

    Science.gov (United States)

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

    2013-02-28

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

  3. Novel genetic loci associated with hippocampal volume

    Science.gov (United States)

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

    2017-01-01

    The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness. PMID:28098162

  4. Functional relevance for associations between osteoporosis and genetic variants

    Science.gov (United States)

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

    2017-01-01

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

  5. Genetic studies in alcohol research

    Energy Technology Data Exchange (ETDEWEB)

    Karp, R.W. [National Institute on Alcohol Abuse and Alcoholism, Rockville, MD (United States)

    1994-12-15

    The National Institute on Alcohol Abuse and Alcoholism (NIAAA) supports research to elucidate the specific genetic factors, now largely unknown, which underlie susceptibility to alcoholism and its medical complications (including fetal alcohol syndrome). Because of the genetic complexity and heterogeneity of alcoholism, identification of the multiple underlying factors will require the development of new study designs and methods of analysis of data from human families. While techniques of genetic analysis of animal behavioral traits (e.g., targeted gene disruption, quantitative trait locus (QTL) mapping) are more powerful that those applicable to humans (e.g., linkage and allelic association studies), the validation of animal behaviors as models of aspects of human alcoholism has been problematic. Newly developed methods for mapping QTL influencing animal behavioral traits can not only permit analyses of human family data to be directly informed by the results of animal studies, but can also serve as a novel means of validating animal models of aspects of alcoholism. 55 refs.

  6. Smoking and caffeine consumption: A genetic analysis of their association

    NARCIS (Netherlands)

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

    2017-01-01

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

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

    NARCIS (Netherlands)

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

    2011-01-01

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

  8. 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

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

    Science.gov (United States)

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

    2017-01-01

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

  10. Association of RET Genetic Polymorphisms and Haplotypes with Papillary Thyroid Carcinoma in the Portuguese Population: A Case-Control Study

    Science.gov (United States)

    Santos, Marina; Azevedo, Teresa; Martins, Teresa; Rodrigues, Fernando J.; Lemos, Manuel C.

    2014-01-01

    Thyroid cancer has a multifactorial aetiology resulting from the interaction of genetic and environmental factors. Several low penetrance susceptibility genes have been identified but their effects often vary between different populations. Somatic point mutations and translocations of the REarranged during Transfection (RET) proto-oncogene are frequently found in thyroid cancer. The aim of this case-control study was to determine the effect of four well known RET single nucleotide polymorphisms (SNPs) on the risk for differentiated thyroid carcinoma. A total of 545 Portuguese patients and 543 controls were genotyped by PCR and restriction enzyme analysis, for the following SNPs: G691S (exon 11, rs1799939 G/A), L769L (exon 13, rs1800861 T/G), S836S (exon 14, rs1800862 C/T), and S904S (exon 15, rs1800863 C/G). The minor allele of S836S was overrepresented in patients with papillary thyroid carcinoma (PTC) when compared to controls (OR 1.57; 95% CI 1.05–2.35; p = 0.026). The GGTC haplotype was also overrepresented in PTC (OR 2.51; 95% CI 1.07–5.91; p = 0.029). No associations were found in follicular thyroid carcinoma (FTC). Multivariate logistic regression analysis showed no differences regarding gender, age at diagnosis, lymph node or distant metastasis. However, a near significant overrepresentation of the minor alleles of G691S and S904S was found in patients with tumours greater than 10 mm of diameter at diagnosis. These data suggest that the RET S836S polymorphism in exon 14 and the GGTC haplotype are risk factors for PTC, but not FTC, and that the G691S/S904S polymorphisms might be associated with tumour behaviour. PMID:25330015

  11. Association between subjective memory complaints and depressive symptoms after adjustment for genetic and family environmental factors in a Japanese twin study.

    Science.gov (United States)

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

    2016-03-01

    The aim of this study was to investigate the association between subjective memory complaints (SMCs) and depressive symptoms, with and without adjustment for genetic and family environmental factors. We conducted a cross-sectional study using twins and measured SMCs and depressive symptoms as outcomes and explanatory variables, respectively. First, we performed regression analyses using generalized estimating equations to investigate the associations between SMCs and depressive symptoms without adjustment for genetic and family environmental factors (individual-level analyses). We then performed regression analyses for within-pair differences using monozygotic (MZ) and dizygotic (DZ) twin pairs and MZ twin pairs to investigate these associations with adjustment for genetic and family environmental factors by subtracting the values of one twin from those of co-twin variables (within-pair level analyses). Therefore, differences between the associations at individual- and within-pair level analyses suggested confounding by genetic factors. We included 556 twins aged ≥ 20 years. In the individual-level analyses, SMCs were significantly associated with depressive symptoms in both males and females [standardized coefficients: males, 0.23 (95% CI 0.08-0.38); females, 0.35 (95% CI 0.23-0.46)]. In the within-pair level analyses using MZ and same-sex DZ twin pairs, SMCs were significantly associated with depressive symptoms. In the within-pair level analyses using the MZ twin pairs, SMCs were significantly associated with depressive symptoms [standardized coefficients: males, 0.32 (95% CI 0.08-0.56); females, 0.24 (95% CI 0.13-0.42)]. This study suggested that SMCs were significantly associated with depressive symptoms after adjustment for genetic and family environmental factors.

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    Schizophrenia is a psychiatric disorder with large personal and social costs, and understanding the genetic etiology is important. Such knowledge can be obtained by testing the association between a disease phenotype and individual genetic markers; however, such single-marker methods have limited...... power to detect genetic markers with small effects. Instead, aggregating genetic markers based on biological information might increase the power to identify sets of genetic markers of etiological significance. Several set test methods have been proposed: Here we propose a new set test derived from...... genomic best linear unbiased prediction (GBLUP), the covariance association test (CVAT). We compared the performance of CVAT to other commonly used set tests. The comparison was conducted using a simulated study population having the same genetic parameters as for schizophrenia. We found that CVAT...

  13. Genetic variants in interleukin genes are associated with breast cancer risk and survival in a genetically admixed population: the Breast Cancer Health Disparities Study.

    Science.gov (United States)

    Slattery, Martha L; Herrick, Jennifer S; Torres-Mejia, Gabriella; John, Esther M; Giuliano, Anna R; Hines, Lisa M; Stern, Mariana C; Baumgartner, Kathy B; Presson, Angela P; Wolff, Roger K

    2014-08-01

    Interleukins (ILs) are key regulators of immune response. Genetic variation in IL genes may influence breast cancer risk and mortality given their role in cell growth, angiogenesis and regulation of inflammatory process. We examined 16 IL genes with breast cancer risk and mortality in an admixed population of Hispanic/Native American (NA) (2111 cases and 2597 controls) and non-Hispanic white (NHW) (1481 cases and 1585 controls) women. Adaptive Rank Truncated Product (ARTP) analysis was conducted to determine gene significance and lasso (least absolute shrinkage and selection operator) was used to identify potential gene by gene and gene by lifestyle interactions. The pathway was statistically significant for breast cancer risk overall (P ARTP = 0.0006), for women with low NA ancestry (P(ARTP) = 0.01), for premenopausal women (P(ARTP) = 0.02), for estrogen receptor (ER)+/progesterone receptor (PR)+ tumors (P(ARTP) = 0.03) and ER-/PR- tumors (P(ARTP) = 0.02). Eight of the 16 genes evaluated were associated with breast cancer risk (IL1A, IL1B, IL1RN, IL2, IL2RA, IL4, IL6 and IL10); four genes were associated with breast cancer risk among women with low NA ancestry (IL1B, IL6, IL6R and IL10), two were associated with breast cancer risk among women with high NA ancestry (IL2 and IL2RA) and four genes were associated with premenopausal breast cancer risk (IL1A, IL1B, IL2 and IL3). IL4, IL6R, IL8 and IL17A were associated with breast cancer-specific mortality. We confirmed associations with several functional polymorphisms previously associated with breast cancer risk and provide support that their combined effect influences the carcinogenic process.

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

    NARCIS (Netherlands)

    Winkler, T.; Justice, A.E.; Graff, M.; Barata, L.; Feitosa, M.F.; Groot, de C.P.G.M.

    2015-01-01

    Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially

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

    NARCIS (Netherlands)

    T.W. Winkler (Thomas W.); A.E. Justice (Anne); M.J. Graff (Maud J.L.); Barata, L. (Llilda); M.F. Feitosa (Mary Furlan); Chu, S. (Su); J. Czajkowski (Jacek); T. Esko (Tõnu); M. Fall (Magnus); T.O. Kilpeläinen (Tuomas); Y. Lu (Yingchang); R. Mägi (Reedik); E. Mihailov (Evelin); T.H. Pers (Tune); Rüeger, S. (Sina); A. Teumer (Alexander); G.B. Ehret (Georg); T. Ferreira (Teresa); N.L. Heard-Costa (Nancy); J. Karjalainen (Juha); V. Lagou (Vasiliki); A. Mahajan (Anubha); Neinast, M.D. (Michael D.); I. Prokopenko (Inga); J. Simino (Jeannette); T.M. Teslovich (Tanya M.); R. Jansen; H.J. Westra (Harm-Jan); C.C. White (Charles); D. Absher (Devin); T.S. Ahluwalia (Tarunveer Singh); S. Ahmad (Shafqat); E. Albrecht (Eva); A.C. Alves (Alexessander Couto); Bragg-Gresham, J.L. (Jennifer L.); A.J. de Craen (Anton); J.C. Bis (Joshua); A. Bonnefond (Amélie); G. Boucher (Gabrielle); G. Cadby (Gemma); Y.-C. Cheng (Yu-Ching); Chiang, C.W. (Charleston W K); G. Delgado; A. Demirkan (Ayşe); N. Dueker (Nicole); N. Eklund (Niina); G. Eiriksdottir (Gudny); J. Eriksson (Joel); B. Feenstra (Bjarke); K. Fischer (Krista); F. Frau (Francesca); T.E. Galesloot (Tessel); F. Geller (Frank); A. Goel (Anuj); M. Gorski (Mathias); T.B. Grammer (Tanja); S. Gustafsson (Stefan); Haitjema, S. (Saskia); J.J. Hottenga (Jouke Jan); J.E. Huffman (Jennifer); A.U. Jackson (Anne); K.B. Jacobs (Kevin); A. Johansson (Åsa); M. Kaakinen (Marika); M.E. Kleber (Marcus); J. Lahti (Jari); I.M. Leach (Irene Mateo); Lehne, B. (Benjamin); Liu, Y. (Youfang); K.S. Lo; M. Lorentzon (Mattias); J. Luan (Jian'An); P.A. Madden (Pamela); M. Mangino (Massimo); B. McKnight (Barbara); Medina-Gomez, C. (Carolina); K.L. Monda (Keri); M.E. Montasser (May E.); G. Müller (Gabriele); M. Müller-Nurasyid (Martina); I.M. Nolte (Ilja); Panoutsopoulou, K. (Kalliope); L. Pascoe (Laura); L. Paternoster (Lavinia); N.W. Rayner (Nigel William); F. Renström (Frida); Rizzi, F. (Federica); L.M. Rose (Lynda); Ryan, K.A. (Kathy A.); P. Salo (Perttu); S. Sanna (Serena); H. Scharnagl (Hubert); Shi, J. (Jianxin); A.V. Smith (Albert Vernon); L. Southam (Lorraine); A. Stancáková (Alena); V. Steinthorsdottir (Valgerdur); R.J. Strawbridge (Rona); Sung, Y.J. (Yun Ju); I. Tachmazidou (Ioanna); T. Tanaka (Toshiko); G. Thorleifsson (Gudmar); S. Trompet (Stella); N. Pervjakova (Natalia); J.P. Tyrer (Jonathan); L. Vandenput (Liesbeth); S.W. Van Der Laan (Sander W.); N. van der Velde (Nathalie); J. van Setten (Jessica); J.V. van Vliet-Ostaptchouk (Jana); N. Verweij (Niek); E. Vlachopoulou (Efthymia); L. Waite (Lindsay); S.R. Wang (Sophie); Z. Wang (Zhaoming); S.H. Wild (Sarah); C. Willenborg (Christina); J.F. Wilson (James); A. Wong (Andrew); Yang, J. (Jian); L. Yengo (Loic); L.M. Yerges-Armstrong (Laura); Yu, L. (Lei); W. Zhang (Weihua); Zhao, J.H. (Jing Hua); E.A. Andersson (Ehm Astrid); S.J.L. Bakker (Stephan); D. Baldassarre (Damiano); Banasik, K. (Karina); Barcella, M. (Matteo); Barlassina, C. (Cristina); C. Bellis (Claire); P. Benaglio (Paola); J. Blangero (John); M. Blüher (Matthias); Bonnet, F. (Fabrice); L.L. Bonnycastle (Lori); H.A. Boyd (Heather); M. Bruinenberg (M.); Buchman, A.S. (Aron S.); H. Campbell (Harry); Y.D. Chen (Y.); P.S. Chines (Peter); S. Claudi-Boehm (Simone); J.W. Cole (John W.); F.S. Collins (Francis); E.J.C. de Geus (Eco); L.C.P.G.M. de Groot (Lisette); M. Dimitriou (Maria); J. Duan (Jubao); S. Enroth (Stefan); E. Eury (Elodie); A.-E. Farmaki (Aliki-Eleni); N.G. Forouhi (Nita); N. Friedrich (Nele); P.V. Gejman (Pablo); B. Gigante (Bruna); N. Glorioso (Nicola); A. Go (Attie); R.F. Gottesman (Rebecca); J. Gräßler (Jürgen); H. Grallert (Harald); N. Grarup (Niels); Gu, Y.-M. (Yu-Mei); L. Broer (Linda); A.C. Ham (Annelies); T. Hansen (T.); T.B. Harris (Tamara); C.A. Hartman (Catharina A.); Hassinen, M. (Maija); N. Hastie (Nick); A.T. Hattersley (Andrew); A.C. Heath (Andrew); A.K. Henders (Anjali); D.G. Hernandez (Dena); H.L. Hillege (Hans); O.L. Holmen (Oddgeir); G.K. Hovingh (Kees); J. Hui (Jennie); Husemoen, L.L. (Lise L.); Hutri-Kähönen, N. (Nina); P.G. Hysi (Pirro); T. Illig (Thomas); P.L. de Jager (Philip); S. Jalilzadeh (Shapour); T. Jorgensen (Torben); J.W. Jukema (Jan Wouter); Juonala, M. (Markus); S. Kanoni (Stavroula); M. Karaleftheri (Maria); K.T. Khaw; L. Kinnunen (Leena); T. Kittner (Thomas); W. Koenig (Wolfgang); I. Kolcic (Ivana); P. Kovacs (Peter); Krarup, N.T. (Nikolaj T.); W. Kratzer (Wolfgang); Krüger, J. (Janine); Kuh, D. (Diana); M. Kumari (Meena); T. Kyriakou (Theodosios); C. Langenberg (Claudia); L. Lannfelt (Lars); C. Lanzani (Chiara); V. Lotay (Vaneet); L.J. Launer (Lenore); K. Leander (Karin); J. Lindström (Jaana); A. Linneberg (Allan); Liu, Y.-P. (Yan-Ping); S. Lobbens (Stéphane); R.N. Luben (Robert); V. Lyssenko (Valeriya); S. Männistö (Satu); P.K. Magnusson (Patrik); W.L. McArdle (Wendy); C. Menni (Cristina); S. Merger (Sigrun); L. Milani (Lili); Montgomery, G.W. (Grant W.); A.P. Morris (Andrew); N. Narisu (Narisu); M. Nelis (Mari); K.K. Ong (Ken); A. Palotie (Aarno); L. Perusse (Louis); I. Pichler (Irene); M.G. Pilia (Maria Grazia); A. Pouta (Anneli); Rheinberger, M. (Myriam); Ribel-Madsen, R. (Rasmus); Richards, M. (Marcus); K.M. Rice (Kenneth); T.K. Rice (Treva K.); C. Rivolta (Carlo); V. Salomaa (Veikko); A.R. Sanders (Alan); M.A. Sarzynski (Mark A.); S. Scholtens (Salome); R.A. Scott (Robert); W.R. Scott (William R.); S. Sebert (Sylvain); S. Sengupta (Sebanti); B. Sennblad (Bengt); T. Seufferlein (Thomas); A. Silveira (Angela); P.E. Slagboom (Eline); J.H. Smit (Jan); T. Sparsø (Thomas); K. Stirrups (Kathy); R.P. Stolk (Ronald); H.M. Stringham (Heather); Swertz, M.A. (Morris A.); A.J. Swift (Amy); A.C. Syvänen; S.-T. Tan (Sian-Tsung); B. Thorand (Barbara); A. Tönjes (Anke); Tremblay, A. (Angelo); E. Tsafantakis (Emmanouil); P.J. van der Most (Peter); U. Völker (Uwe); M.-C. Vohl (Marie-Claude); J.M. Vonk (Judith); M. Waldenberger (Melanie); Walker, R.W. (Ryan W.); R. Wennauer (Roman); E. Widen; G.A.H.M. Willemsen (Gonneke); T. Wilsgaard (Tom); A.F. Wright (Alan); M.C. Zillikens (Carola); S. Van Dijk (Suzanne); N.M. van Schoor (Natasja); F.W. Asselbergs (Folkert); P.I.W. de Bakker (Paul); J.S. Beckmann (Jacques); J.P. Beilby (John); D.A. Bennett (David A.); R.N. Bergman (Richard); S.M. Bergmann (Sven); C.A. Böger (Carsten); B.O. Boehm (Bernhard); E.A. Boerwinkle (Eric); D.I. Boomsma (Dorret); S.R. Bornstein (Stefan); E.P. Bottinger (Erwin); C. Bouchard (Claude); J.C. Chambers (John); S.J. Chanock (Stephen); D.I. Chasman (Daniel); F. Cucca (Francesco); D. Cusi (Daniele); G.V. Dedoussis (George); J. Erdmann (Jeanette); K. Hagen (Knut); D. Evans; U. de Faire (Ulf); M. Farrall (Martin); L. Ferrucci (Luigi); I. Ford (Ian); L. Franke (Lude); P.W. Franks (Paul); P. Froguel (Philippe); R.T. Gansevoort (Ron); C. Gieger (Christian); H. Grönberg (Henrik); V. Gudnason (Vilmundur); U. Gyllensten (Ulf); P. Hall (Per); A. Hamsten (Anders); P. van der Harst (Pim); C. Hayward (Caroline); M. Heliovaara (Markku); C. Hengstenberg (Christian); A.A. Hicks (Andrew); A. Hingorani (Aroon); A. Hofman (Albert); Hu, F. (Frank); H.V. Huikuri (Heikki); K. Hveem (Kristian); A. James (Alan); Jordan, J.M. (Joanne M.); A. Jula (Antti); M. Kähönen (Mika); E. Kajantie (Eero); S. Kathiresan (Sekar); L.A.L.M. Kiemeney (Bart); M. Kivimaki (Mika); P. Knekt; H. Koistinen (Heikki); J.S. Kooner (Jaspal S.); S. Koskinen (Seppo); J. Kuusisto (Johanna); W. Maerz (Winfried); N.G. Martin (Nicholas); M. Laakso (Markku); T.A. Lakka (Timo); T. Lehtimäki (Terho); G. Lettre (Guillaume); D.F. Levinson (Douglas); W.H.L. Kao (Wen); M.L. Lokki; Mäntyselkä, P. (Pekka); M. Melbye (Mads); A. Metspalu (Andres); B.D. Mitchell (Braxton); F.L. Moll (Frans); J.C. Murray (Jeffrey); A.W. Musk (Arthur); M.S. Nieminen (Markku); I. Njølstad (Inger); C. Ohlsson (Claes); A.J. Oldehinkel (Albertine); B.A. Oostra (Ben); C. Palmer (Cameron); J.S. Pankow (James); G. Pasterkamp (Gerard); N.L. Pedersen (Nancy); O. Pedersen (Oluf); B.W.J.H. Penninx (Brenda); M. Perola (Markus); A. Peters (Annette); O. Polasek (Ozren); P.P. Pramstaller (Peter Paul); Psaty, B.M. (Bruce M.); Qi, L. (Lu); T. Quertermous (Thomas); Raitakari, O.T. (Olli T.); T. Rankinen (Tuomo); R. Rauramaa (Rainer); P.M. Ridker (Paul); J.D. Rioux (John); F. Rivadeneira Ramirez (Fernando); J.I. Rotter (Jerome I.); I. Rudan (Igor); H.M. den Ruijter (Hester ); J. Saltevo (Juha); N. Sattar (Naveed); Schunkert, H. (Heribert); P.E.H. Schwarz (Peter); A.R. Shuldiner (Alan); J. Sinisalo (Juha); H. Snieder (Harold); T.I.A. Sørensen (Thorkild); T.D. Spector (Timothy); Staessen, J.A. (Jan A.); Stefania, B. (Bandinelli); U. Thorsteinsdottir (Unnur); M. Stumvoll (Michael); J.-C. Tardif (Jean-Claude); E. Tremoli (Elena); J. Tuomilehto (Jaakko); A.G. Uitterlinden (André); M. Uusitupa (Matti); A.L.M. Verbeek; S.H.H.M. Vermeulen (Sita); J. Viikari (Jorma); Vitart, V. (Veronique); H. Völzke (Henry); P. Vollenweider (Peter); G. Waeber (Gérard); M. Walker (Mark); H. Wallaschofski (Henri); N.J. Wareham (Nick); H. Watkins (Hugh); E. Zeggini (Eleftheria); A. Chakravarti (Aravinda); Clegg, D.J. (Deborah J.); L.A. Cupples (Adrienne); P. Gordon-Larsen (Penny); C.E. Jaquish (Cashell); D.C. Rao (Dabeeru C.); Abecasis, G.R. (Goncalo R.); T.L. Assimes (Themistocles); I. Barroso (Inês); S.I. Berndt (Sonja); M. Boehnke (Michael); P. Deloukas (Panagiotis); C.S. Fox (Caroline); L. Groop (Leif); D. Hunter (David); E. Ingelsson (Erik); R.C. Kaplan (Robert); McCarthy, M.I. (Mark I.); K.L. Mohlke (Karen); J.R. O´Connell; Schlessinger, D. (David); D.P. Strachan (David); J-A. Zwart (John-Anker); C.M. van Duijn (Cock); J.N. Hirschhorn (Joel); C.M. Lindgren (Cecilia M.); I.M. Heid (Iris); K.E. North (Kari); I.B. Borecki (Ingrid); Z. Kutalik (Zoltán); R.J.F. Loos (Ruth)

    2015-01-01

    textabstractGenome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ

  16. Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption

    NARCIS (Netherlands)

    G. Schumann (Gunter); L. Coin (Lachlan); A. Lourdusamy (Anbarasu); P. Charoen (Pimphen); K.H. Berger (Karen); D. Stacey (David); S. Desrivières (Sylvane); F.A. Aliev (Fazil); A.A. Khan (Anokhi); N. Amin (Najaf); G. Bakalkin (Georgy); B. Balkau (Beverley); J.W.J. Beulens (Joline); A. Bilbao (Ainhoa); R.A. de Boer (Rudolf); D. Beury (Delphine); M.L. Bots (Michiel); E.J. Breetvelt (Elemi); S. Cauchi (Stephane); C. Cavalcanti-Proença (Christine); J.C. Chambers (John); T.-K. Clarke; N. Dahmen (N.); E.J.C. de Geus (Eco); D. Dick (Danielle); F. Ducci (Francesca); A. Easton (Alanna); H.J. Edenberg (Howard); T. Esk (Tõnu); A. Fernández-Medarde (Alberto); T. Foroud (Tatiana); N.B. Freimer (Nelson); J.-A. Girault; D.E. Grobbee (Diederick); S. Guarrera (Simonetta); D.F. Gudbjartsson (Daniel); A.L. Hartikainen; A.C. Heath (Andrew); V. Hesselbrock (Victor); A. Hofman (Albert); J.J. Hottenga (Jouke Jan); M.K. Isohanni (Matti); J. Kaprio (Jaakko); K-T. Khaw (Kay-Tee); B. Kuehnel (Brigitte); J. Laitinen (Jaana); S. Lobbens (Stéphane); J. Luan; M. Mangino (Massimo); M. Maroteaux (Matthieu); G. Matullo (Giuseppe); M.I. McCarthy (Mark); C. Mueller (Christian); G. Navis (Gerjan); M.E. Numans (Mattijs); A.M. Núñez (Alejandro); D.R. Nyholt (Dale); C.N. Onland-Moret (Charlotte); B.A. Oostra (Ben); P.F. O'Reilly (Paul); M. Palkovits (Miklos); B.W.J.H. Penninx (Brenda); S. Polidoro (Silvia); A. Pouta (Anneli); I. Prokopenko (Inga); F. Ricceri (Fulvio); E. Santos (Eugenio); J.H. Smit (Johannes); N. Soranzo (Nicole); K. Song (Kijoung); U. Sovio (Ulla); M. Stumvoll (Michael); I. Surakk (Ida); T.E. Thorgeirsson (Thorgeir); U. Thorsteinsdottir (Unnur); C. Troakes (Claire); T. Tyrfingsson (Thorarinn); A. Tönjes (Anke); C.S.P.M. Uiterwaal (Cuno); A.G. Uitterlinden (André); P. van der Harst (Pim); Y.T. van der Schouw (Yvonne); O. Staehlin (Oliver); N. Vogelzangs (Nicole); P. Vollenweider (Peter); G. Waeber (Gérard); N.J. Wareham (Nick); D. Waterworth (Dawn); J.B. Whitfield (John); E.H. Wichmann (Erich); G.A.H.M. Willemsen (Gonneke); J.C.M. Witteman (Jacqueline); X. Yuan (Xin); G. Zhai (Guangju); J.H. Zhao (Jing); W. Zhang (Weihua); N.G. Martin (Nicholas); A. Metspalu (Andres); A. Doering (Angela); J. Scott (James); T.D. Spector (Timothy); R.J.F. Loos (Ruth); D.I. Boomsma (Dorret); V. Mooser (Vincent); L. Peltonen (Leena Johanna); K. Stefansson (Kari); P. Tikka-Kleemola (Päivi); P. Vineis (Paolo); W.H. Sommer (Wolfgang); J.S. Kooner (Jaspal); R. Spanagel (Rainer); U.A. Heberlein (Ulrike); M.R. Järvelin; P. Elliott (Paul); Y.S. Aulchenko (Yurii); S.J.L. Bakker (Stephan)

    2011-01-01

    textabstractAlcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram

  17. Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption

    NARCIS (Netherlands)

    Schumann, Gunter; Coin, Lachlan J.; Lourdusamy, Anbarasu; Charoen, Pimphen; Berger, Karen H.; Stacey, David; Desrivieres, Sylvane; Aliev, Fazil A.; Khan, Anokhi A.; Amin, Najaf; Aulchenko, Yurii S.; Bakalkin, Georgy; Bakker, Stephan J.; Balkau, Beverley; Beulens, Joline W.; Bilbao, Ainhoa; de Boer, Rudolf A.; Beury, Delphine; Bots, Michiel L.; Breetvelt, Elemi J.; Cauchi, Stephane; Cavalcanti-Proenca, Christine; Chambers, John C.; Clarke, Toni-Kim; Dahmen, Norbert; de Geus, Eco J.; Dick, Danielle; Ducci, Francesca; Easton, Alanna; Edenberg, Howard J.; Esk, Tonu; Fernandez-Medarde, Alberto; Foroud, Tatiana; Freimer, Nelson B.; Girault, Jean-Antoine; Grobbee, Diederick E.; Guarrera, Simonetta; Gudbjartsson, Daniel F.; Hartikainen, Anna-Liisa; Heath, Andrew C.; Hesselbrock, Victor; Hofman, Albert; Hottenga, Jouke-Jan; Isohanni, Matti K.; Kaprio, Jaakko; Khaw, Kay-Tee; Kuehnel, Brigitte; Laitinen, Jaana; Lobbens, Stephane; Luan, Jian'an; Mangino, Massimo; Maroteaux, Matthieu; Matullo, Giuseppe; McCarthy, Mark I.; Mueller, Christian; Navis, Gerjan; Numans, Mattijs E.; Nunez, Alejandro; Nyholt, Dale R.; Onland-Moret, Charlotte N.; Oostra, Ben A.; O'Reilly, Paul F.; Palkovits, Miklos; Penninx, Brenda W.; Polidoro, Silvia; Pouta, Anneli; Prokopenko, Inga; Ricceri, Fulvio; Santos, Eugenio; Smit, Johannes H.; Soranzo, Nicole; Song, Kijoung; Sovio, Ulla; Stumvoll, Michael; Surakk, Ida; Thorgeirsson, Thorgeir E.; Thorsteinsdottir, Unnur; Troakes, Claire; Tyrfingsson, Thorarinn; Toenjes, Anke; Uiterwaal, Cuno S.; Uitterlinden, Andre G.; van der Harst, Pim; van der Schouw, Yvonne T.; Staehlin, Oliver; Vogelzangs, Nicole; Vollenweider, Peter; Waeber, Gerard; Wareham, Nicholas J.; Waterworth, Dawn M.; Whitfield, John B.; Wichmann, Erich H.; Willemsen, Gonneke; Witteman, Jacqueline C.; Yuan, Xin; Zhai, Guangju; Zhao, Jing H.; Zhang, Weihua; Martin, Nicholas G.; Metspalu, Andres; Doering, Angela; Scott, James; Spector, Tim D.; Loos, Ruth J.; Boomsma, Dorret I.; Mooser, Vincent; Peltonen, Leena; Stefansson, Kari; van Duijn, Cornelia M.; Vineis, Paolo; Sommer, Wolfgang H.; Kooner, Jaspal S.; Spanagel, Rainer; Heberlein, Ulrike A.; Jarvelin, Marjo-Riitta; Elliott, Paul

    2011-01-01

    Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of similar to 2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram p

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

    NARCIS (Netherlands)

    Winkler, Thomas W.; Justice, Anne E.; Graff, Mariaelisa; Barata, Llilda; Feitosa, Mary F.; Chu, Su; Czajkowski, Jacek; Esko, Tonu; Fall, Tove; Kilpelainen, Tuomas O.; Lu, Yingchang; Magi, Reedik; Mihailov, Evelin; Pers, Tune H.; Rueeger, Sina; Teumer, Alexander; Ehret, Georg B.; Ferreira, Teresa; Heard-Costa, Nancy L.; Karjalainen, Juha; Lagou, Vasiliki; Mahajan, Anubha; Neinast, Michael D.; Prokopenko, Inga; Simino, Jeannette; Teslovich, Tanya M.; Jansen, Rick; Westra, Harm-Jan; White, Charles C.; Absher, Devin; Ahluwalia, Tarunveer S.; Ahmad, Shafqat; Albrecht, Eva; Alves, Alexessander Couto; Bragg-Gresham, Jennifer L.; de Craen, Anton J. M.; Bis, Joshua C.; Bonnefond, Amelie; Boucher, Gabrielle; Cadby, Gemma; Cheng, Yu-Ching; Chiang, Charleston W. K.; Delgado, Graciela; Demirkan, Ayse; Dueker, Nicole; Eklund, Niina; Eiriksdottir, Gudny; Eriksson, Joel; Feenstra, Bjarke; Fischer, Krista; Frau, Francesca; Galesloot, Tessel E.; Geller, Frank; Goel, Anuj; Gorski, Mathias; Grammer, Tanja B.; Gustafsson, Stefan; Haitjema, Saskia; Hottenga, Jouke-Jan; Huffman, Jennifer E.; Jackson, Anne U.; Jacobs, Kevin B.; Johansson, Asa; Kaakinen, Marika; Kleber, Marcus E.; Lahti, Jari; Leach, Irene Mateo; Lehne, Benjamin; Liu, Youfang; Lo, Ken Sin; Lorentzon, Mattias; Luan, Jian'an; Madden, Pamela A. F.; Mangino, Massimo; McKnight, Barbara; Medina-Gomez, Carolina; Monda, Keri L.; Montasser, May E.; Mueller, Gabriele; Mueller-Nurasyid, Martina; Nolte, Ilja M.; Panoutsopoulou, Kalliope; Pascoe, Laura; Paternoster, Lavinia; Rayner, Nigel W.; Renstrom, Frida; Rizzi, Federica; Rose, Lynda M.; Ryan, Kathy A.; Salo, Perttu; Sanna, Serena; Scharnagl, Hubert; Shi, Jianxin; Smith, Albert Vernon; Southam, Lorraine; Stancakova, Alena; Steinthorsdottir, Valgerdur; Strawbridge, Rona J.; Sung, Yun Ju; Tachmazidou, Ioanna; Tanaka, Toshiko; Thorleifsson, Gudmar; Trompet, Stella; Pervjakova, Natalia; Tyrer, Jonathan P.; Vandenput, Liesbeth; van der Laan, Sander W.; van der Velde, Nathalie; van Setten, Jessica; van Vliet-Ostaptchouk, Jana V.; Verweij, Niek; Vlachopoulou, Efthymia; Waite, Lindsay L.; Wang, Sophie R.; Wang, Zhaoming; Wild, Sarah H.; Willenborg, Christina; Wilson, James F.; Wong, Andrew; Yang, Jian; Yengo, Loic; Yerges-Armstrong, Laura M.; Yu, Lei; Zhang, Weihua; Zhao, Jing Hua; Andersson, Ehm A.; Bakker, Stephan J. L.; Baldassarre, Damiano; Banasik, Karina; Barcella, Matteo; Barlassina, Cristina; Bellis, Claire; Benaglio, Paola; Blangero, John; Blueher, Matthias; Bonnet, Fabrice; Bonnycastle, Lori L.; Boyd, Heather A.; Bruinenberg, Marcel; Buchman, Aron S.; Campbell, Harry; Chen, Yii-Der Ida; Chines, Peter S.; Claudi-Boehm, Simone; Cole, John; Collins, Francis S.; de Geus, Eco J. C.; de Groot, Lisette C. P. G. M.; Dimitriou, Maria; Duan, Jubao; Enroth, Stefan; Eury, Elodie; Farmaki, Aliki-Eleni; Forouhi, Nita G.; Friedrich, Nele; Gejman, Pablo V.; Gigante, Bruna; Glorioso, Nicola; Go, Alan S.; Gottesman, Omri; Graessler, Juergen; Grallert, Harald; Grarup, Niels; Gu, Yu-Mei; Broer, Linda; Ham, Annelies C.; Hansen, Torben; Harris, Tamara B.; Hartman, Catharina A.; Hassinen, Maija; Hastie, Nicholas; Hattersley, Andrew T.; Heath, Andrew C.; Henders, Anjali K.; Hernandez, Dena; Hillege, Hans; Holmen, Oddgeir; Hovingh, Kees G.; Hui, Jennie; Husemoen, Lise L.; Hutri-Kahonen, Nina; Hysi, Pirro G.; Illig, Thomas; De Jager, Philip L.; Jalilzadeh, Shapour; Jorgensen, Torben; Jukema, J. Wouter; Juonala, Markus; Kanoni, Stavroula; Karaleftheri, Maria; Khaw, Kay Tee; Kinnunen, Leena; Kittner, Steven J.; Koenig, Wolfgang; Kolcic, Ivana; Kovacs, Peter; Krarup, Nikolaj T.; Kratzer, Wolfgang; Krueger, Janine; Kuh, Diana; Kumari, Meena; Kyriakou, Theodosios; Langenberg, Claudia; Lannfelt, Lars; Lanzani, Chiara; Lotay, Vaneet; Launer, Lenore J.; Leander, Karin; Lindstrom, Jaana; Linneberg, Allan; Liu, Yan-Ping; Lobbens, Stephane; Luben, Robert; Lyssenko, Valeriya; Mannisto, Satu; Magnusson, Patrik K.; McArdle, Wendy L.; Menni, Cristina; Merger, Sigrun; Milani, Lili; Montgomery, Grant W.; Morris, Andrew P.; Narisu, Narisu; Nelis, Mari; Ong, Ken K.; Palotie, Aarno; Perusse, Louis; Pichler, Irene; Pilia, Maria G.; Pouta, Anneli; Rheinberger, Myriam; Ribel-Madsen, Rasmus; Richards, Marcus; Rice, Kenneth M.; Rice, Treva K.; Rivolta, Carlo; Salomaa, Veikko; Sanders, Alan R.; Sarzynski, Mark A.; Scholtens, Salome; Scott, Robert A.; Scott, William R.; Sebert, Sylvain; Sengupta, Sebanti; Sennblad, Bengt; Seufferlein, Thomas; Silveira, Angela; Slagboom, P. Eline; Smit, Jan H.; Sparso, Thomas H.; Stirrups, Kathleen; Stolk, Ronald P.; Stringham, Heather M.; Swertz, Morris A.; Swift, Amy J.; Syvanen, Ann-Christine; Tan, Sian-Tsung; Thorand, Barbara; Toenjes, Anke; Tremblay, Angelo; Tsafantakis, Emmanouil; van der Most, Peter J.; Voelker, Uwe; Vohl, Marie-Claude; Vonk, Judith M.; Waldenberger, Melanie; Walker, Ryan W.; Wennauer, Roman; Widen, Elisabeth; Willemsen, Gonneke; Wilsgaard, Tom; Wright, Alan F.; Zillikens, M. Carola; van Dijk, Suzanne C.; van Schoor, Natasja M.; Asselbergs, Folkert W.; de Bakker, Paul I. W.; Beckmann, Jacques S.; Beilby, John; Bennett, David A.; Bergman, Richard N.; Bergmann, Sven; Boeger, Carsten A.; Boehm, Bernhard O.; Boerwinkle, Eric; Boomsma, Dorret I.; Bornstein, Stefan R.; Bottinger, Erwin P.; Bouchard, Claude; Chambers, John C.; Chanock, Stephen J.; Chasman, Daniel I.; Cucca, Francesco; Cusi, Daniele; Dedoussis, George; Erdmann, Jeanette; Eriksson, Johan G.; Evans, Denis A.; de Faire, Ulf; Farrall, Martin; Ferrucci, Luigi; Ford, Ian; Franke, Lude; Franks, Paul W.; Froguel, Philippe; Gansevoort, Ron T.; Gieger, Christian; Gronberg, Henrik; Gudnason, Vilmundur; Gyllensten, Ulf; Hall, Per; Hamsten, Anders; van der Harst, Pim; Hayward, Caroline; Heliovaara, Markku; Hengstenberg, Christian; Hicks, Andrew A.; Hingorani, Aroon; Hofman, Albert; Hu, Frank; Huikuri, Heikki V.; Hveem, Kristian; James, Alan L.; Jordan, Joanne M.; Jula, Antti; Kaehoenen, Mika; Kajantie, Eero; Kathiresan, Sekar; Kiemeney, Lambertus A. L. M.; Kivimaki, Mika; Knekt, Paul B.; Koistinen, Heikki A.; Kooner, Jaspal S.; Koskinen, Seppo; Kuusisto, Johanna; Maerz, Winfried; Martin, Nicholas G.; Laakso, Markku; Lakka, Timo A.; Lehtimaki, Terho; Lettre, Guillaume; Levinson, Douglas F.; Lind, Lars; Lokki, Marja-Liisa; Mantyselka, Pekka; Melbye, Mads; Metspalu, Andres; Mitchell, Braxton D.; Moll, Frans L.; Murray, Jeffrey C.; Musk, Arthur W.; Nieminen, Markku S.; Njolstad, Inger; Ohlsson, Claes; Oldehinkel, Albertine J.; Oostra, Ben A.; Palmer, Lyle J.; Pankow, James S.; Pasterkamp, Gerard; Pedersen, Nancy L.; Pedersen, Oluf; Penninx, Brenda W.; Perola, Markus; Peters, Annette; Polasek, Ozren; Pramstaller, Peter P.; Psaty, Bruce M.; Qi, Lu; Quertermous, Thomas; Raitakari, Olli T.; Rankinen, Tuomo; Rauramaa, Rainer; Ridker, Paul M.; Rioux, John D.; Rivadeneira, Fernando; Rotter, Jerome I.; Rudan, Igor; den Ruijter, Hester M.; Saltevo, Juha; Sattar, Naveed; Schunkert, Heribert; Schwarz, Peter E. H.; Shuldiner, Alan R.; Sinisalo, Juha; Snieder, Harold; Sorensen, Thorkild I. A.; Spector, Tim D.; Staessen, Jan A.; Stefania, Bandinelli; Thorsteinsdottir, Unnur; Stumvoll, Michael; Tardif, Jean-Claude; Tremoli, Elena; Tuomilehto, Jaakko; Uitterlinden, Andre G.; Uusitupa, Matti; Verbeek, Andre L. M.; Vermeulen, Sita H.; Viikari, Jorma S.; Vitart, Veronique; Voelzke, Henry; Vollenweider, Peter; Waeber, Gerard; Walker, Mark; Wallaschofski, Henri; Wareham, Nicholas J.; Watkins, Hugh; Zeggini, Eleftheria; Chakravarti, Aravinda; Clegg, Deborah J.; Cupples, L. Adrienne; Gordon-Larsen, Penny; Jaquish, Cashell E.; Rao, D. C.; Abecasis, Goncalo R.; Assimes, Themistocles L.; Barroso, Ines; Berndt, Sonja I.; Boehnke, Michael; Deloukas, Panos; Fox, Caroline S.; Groop, Leif C.; Hunter, David J.; Ingelsson, Erik; Kaplan, Robert C.; McCarthy, Mark I.; Mohlke, Karen L.; O'Connell, Jeffrey R.; Schlessinger, David; Strachan, David P.; Stefansson, Kari; van Duijn, Cornelia M.; Hirschhorn, Joel N.; Lindgren, Cecilia M.; Heid, Iris M.; North, Kari E.; Borecki, Ingrid B.; Kutalik, Zoltan; Loos, Ruth J. F.

    2015-01-01

    Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially

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

    NARCIS (Netherlands)

    Winkler, Thomas W; Justice, Anne E; Graff, Mariaelisa; Barata, Llilda; Feitosa, Mary F; Chu, Su; Czajkowski, Jacek; Esko, Tõnu; Fall, Tove; Kilpeläinen, Tuomas O; Lu, Yingchang; Mägi, Reedik; Mihailov, Evelin; Pers, Tune H; Rüeger, Sina; Teumer, Alexander; Ehret, Georg B; Ferreira, Teresa; Heard-Costa, Nancy L; Karjalainen, Juha; Lagou, Vasiliki; Mahajan, Anubha; Neinast, Michael D; Prokopenko, Inga; Simino, Jeannette; Teslovich, Tanya M; Jansen, Rick; Westra, Harm-Jan; White, Charles C; Absher, Devin; Ahluwalia, Tarunveer S; Ahmad, Shafqat; Albrecht, Eva; Alves, Alexessander Couto; Bragg-Gresham, Jennifer L; de Craen, Anton J M; Bis, Joshua C; Bonnefond, Amélie; Boucher, Gabrielle; Cadby, Gemma; Cheng, Yu-Ching; Chiang, Charleston W K; Delgado, Graciela; Demirkan, Ayse; Dueker, Nicole; Eklund, Niina; Eiriksdottir, Gudny; Eriksson, Joel; Feenstra, Bjarke; Fischer, Krista; Frau, Francesca; Galesloot, Tessel E; Geller, Frank; Goel, Anuj; Gorski, Mathias; Grammer, Tanja B; Gustafsson, Stefan; Haitjema, Saskia; Hottenga, Jouke-Jan; Huffman, Jennifer E; Jackson, Anne U; Jacobs, Kevin B; Johansson, Åsa; Kaakinen, Marika; Kleber, Marcus E; Lahti, Jari; Leach, Irene Mateo; Lehne, Benjamin; Liu, Youfang; Lo, Ken Sin; Lorentzon, Mattias; Luan, Jian'an; Madden, Pamela A F; Mangino, Massimo; McKnight, Barbara; Medina-Gomez, Carolina; Monda, Keri L; Montasser, May E; Müller, Gabriele; Müller-Nurasyid, Martina; Nolte, Ilja M; Panoutsopoulou, Kalliope; Pascoe, Laura; Paternoster, Lavinia; Rayner, Nigel W; Renström, Frida; Rizzi, Federica; Rose, Lynda M; Ryan, Kathy A; Salo, Perttu; Sanna, Serena; Scharnagl, Hubert; Shi, Jianxin; Smith, Albert Vernon; Southam, Lorraine; Stančáková, Alena; Steinthorsdottir, Valgerdur; Strawbridge, Rona J; Sung, Yun Ju; Tachmazidou, Ioanna; Tanaka, Toshiko; Thorleifsson, Gudmar; Trompet, Stella; Pervjakova, Natalia; Tyrer, Jonathan P; Vandenput, Liesbeth; van der Laan, Sander W; van der Velde, Nathalie; van Setten, Jessica; van Vliet-Ostaptchouk, Jana V; Verweij, Niek; Vlachopoulou, Efthymia; Waite, Lindsay L; Wang, Sophie R; Wang, Zhaoming; Wild, Sarah H; Willenborg, Christina; Wilson, James F; Wong, Andrew; Yang, Jian; Yengo, Loïc; Yerges-Armstrong, Laura M; Yu, Lei; Zhang, Weihua; Zhao, Jing Hua; Andersson, Ehm A; Bakker, Stephan J L; Baldassarre, Damiano; Banasik, Karina; Barcella, Matteo; Barlassina, Cristina; Bellis, Claire; Benaglio, Paola; Blangero, John; Blüher, Matthias; Bonnet, Fabrice; Bonnycastle, Lori L; Boyd, Heather A; Bruinenberg, Marcel; Buchman, Aron S; Campbell, Harry; Chen, Yii-Der Ida; Chines, Peter S; Claudi-Boehm, Simone; Cole, John; Collins, Francis S; de Geus, Eco J C; de Groot, Lisette C P G M; Dimitriou, Maria; Duan, Jubao; Enroth, Stefan; Eury, Elodie; Farmaki, Aliki-Eleni; Forouhi, Nita G; Friedrich, Nele; Gejman, Pablo V; Gigante, Bruna; Glorioso, Nicola; Go, Alan S; Gottesman, Omri; Gräßler, Jürgen; Grallert, Harald; Grarup, Niels; Gu, Yu-Mei; Broer, Linda; Ham, Annelies C; Hansen, Torben; Harris, Tamara B; Hartman, Catharina A; Hassinen, Maija; Hastie, Nicholas; Hattersley, Andrew T; Heath, Andrew C; Henders, Anjali K; Hernandez, Dena; Hillege, Hans; Holmen, Oddgeir; Hovingh, Kees G; Hui, Jennie; Husemoen, Lise L; Hutri-Kähönen, Nina; Hysi, Pirro G; Illig, Thomas; De Jager, Philip L; Jalilzadeh, Shapour; Jørgensen, Torben; Jukema, J Wouter; Juonala, Markus; Kanoni, Stavroula; Karaleftheri, Maria; Khaw, Kay Tee; Kinnunen, Leena; Kittner, Steven J; Koenig, Wolfgang; Kolcic, Ivana; Kovacs, Peter; Krarup, Nikolaj T; Kratzer, Wolfgang; Krüger, Janine; Kuh, Diana; Kumari, Meena; Kyriakou, Theodosios; Langenberg, Claudia; Lannfelt, Lars; Lanzani, Chiara; Lotay, Vaneet; Launer, Lenore J; Leander, Karin; Lindström, Jaana; Linneberg, Allan; Liu, Yan-Ping; Lobbens, Stéphane; Luben, Robert; Lyssenko, Valeriya; Männistö, Satu; Magnusson, Patrik K; McArdle, Wendy L; Menni, Cristina; Merger, Sigrun; Milani, Lili; Montgomery, Grant W; Morris, Andrew P; Narisu, Narisu; Nelis, Mari; Ong, Ken K; Palotie, Aarno; Pérusse, Louis; Pichler, Irene; Pilia, Maria G; Pouta, Anneli; Rheinberger, Myriam; Ribel-Madsen, Rasmus; Richards, Marcus; Rice, Kenneth M; Rice, Treva K; Rivolta, Carlo; Salomaa, Veikko; Sanders, Alan R; Sarzynski, Mark A; Scholtens, Salome; Scott, Robert A; Scott, William R; Sebert, Sylvain; Sengupta, Sebanti; Sennblad, Bengt; Seufferlein, Thomas; Silveira, Angela; Slagboom, P Eline; Smit, Jan H; Sparsø, Thomas H; Stirrups, Kathleen; Stolk, Ronald P; Stringham, Heather M; Swertz, Morris A; Swift, Amy J; Syvänen, Ann-Christine; Tan, Sian-Tsung; Thorand, Barbara; Tönjes, Anke; Tremblay, Angelo; Tsafantakis, Emmanouil; van der Most, Peter J; Völker, Uwe; Vohl, Marie-Claude; Vonk, Judith M; Waldenberger, Melanie; Walker, Ryan W; Wennauer, Roman; Widén, Elisabeth; Willemsen, Gonneke; Wilsgaard, Tom; Wright, Alan F; Zillikens, M Carola; van Dijk, Suzanne C; van Schoor, Natasja M; Asselbergs, Folkert W; de Bakker, Paul I W; Beckmann, Jacques S; Beilby, John; Bennett, David A; Bergman, Richard N; Bergmann, Sven; Böger, Carsten A; Boehm, Bernhard O; Boerwinkle, Eric; Boomsma, Dorret I; Bornstein, Stefan R; Bottinger, Erwin P; Bouchard, Claude; Chambers, John C; Chanock, Stephen J; Chasman, Daniel I; Cucca, Francesco; Cusi, Daniele; Dedoussis, George; Erdmann, Jeanette; Eriksson, Johan G; Evans, Denis A; de Faire, Ulf; Farrall, Martin; Ferrucci, Luigi; Ford, Ian; Franke, Lude; Franks, Paul W; Froguel, Philippe; Gansevoort, Ron T; Gieger, Christian; Grönberg, Henrik; Gudnason, Vilmundur; Gyllensten, Ulf; Hall, Per; Hamsten, Anders; van der Harst, Pim; Hayward, Caroline; Heliövaara, Markku; Hengstenberg, Christian; Hicks, Andrew A; Hingorani, Aroon; Hofman, Albert; Hu, Frank; Huikuri, Heikki V; Hveem, Kristian; James, Alan L; Jordan, Joanne M; Jula, Antti; Kähönen, Mika; Kajantie, Eero; Kathiresan, Sekar; Kiemeney, Lambertus A L M; Kivimaki, Mika; Knekt, Paul B; Koistinen, Heikki A; Kooner, Jaspal S; Koskinen, Seppo; Kuusisto, Johanna; Maerz, Winfried; Martin, Nicholas G; Laakso, Markku; Lakka, Timo A; Lehtimäki, Terho; Lettre, Guillaume; Levinson, Douglas F; Lind, Lars; Lokki, Marja-Liisa; Mäntyselkä, Pekka; Melbye, Mads; Metspalu, Andres; Mitchell, Braxton D; Moll, Frans L; Murray, Jeffrey C; Musk, Arthur W; Nieminen, Markku S; Njølstad, Inger; Ohlsson, Claes; Oldehinkel, Albertine J; Oostra, Ben A; Palmer, Lyle J; Pankow, James S; Pasterkamp, Gerard; Pedersen, Nancy L; Pedersen, Oluf; Penninx, Brenda W; Perola, Markus; Peters, Annette; Polašek, Ozren; Pramstaller, Peter P; Psaty, Bruce M; Qi, Lu; Quertermous, Thomas; Raitakari, Olli T; Rankinen, Tuomo; Rauramaa, Rainer; Ridker, Paul M; Rioux, John D; Rivadeneira, Fernando; Rotter, Jerome I; Rudan, Igor; den Ruijter, Hester M; Saltevo, Juha; Sattar, Naveed; Schunkert, Heribert; Schwarz, Peter E H; Shuldiner, Alan R; Sinisalo, Juha; Snieder, Harold; Sørensen, Thorkild I A; Spector, Tim D; Staessen, Jan A; Stefania, Bandinelli; Thorsteinsdottir, Unnur; Stumvoll, Michael; Tardif, Jean-Claude; Tremoli, Elena; Tuomilehto, Jaakko; Uitterlinden, André G; Uusitupa, Matti; Verbeek, André L M; Vermeulen, Sita H; Viikari, Jorma S; Vitart, Veronique; Völzke, Henry; Vollenweider, Peter; Waeber, Gérard; Walker, Mark; Wallaschofski, Henri; Wareham, Nicholas J; Watkins, Hugh; Zeggini, Eleftheria; Chakravarti, Aravinda; Clegg, Deborah J; Cupples, L Adrienne; Gordon-Larsen, Penny; Jaquish, Cashell E; Rao, D C; Abecasis, Goncalo R; Assimes, Themistocles L; Barroso, Inês; Berndt, Sonja I; Boehnke, Michael; Deloukas, Panos; Fox, Caroline S; Groop, Leif C; Hunter, David J; Ingelsson, Erik; Kaplan, Robert C; McCarthy, Mark I; Mohlke, Karen L; O'Connell, Jeffrey R; Schlessinger, David; Strachan, David P; Stefansson, Kari; van Duijn, Cornelia M; Hirschhorn, Joel N; Lindgren, Cecilia M; Heid, Iris M; North, Kari E; Borecki, Ingrid B; Kutalik, Zoltán; Loos, Ruth J F

    2015-01-01

    Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially betw

  20. Common genetic variation in the type A endothelin-1 receptor is associated with ambulatory blood pressure: a family study.

    Science.gov (United States)

    Rahman, T; Baker, M; Hall, D H; Avery, P J; Keavney, B

    2008-04-01

    The endothelins are among the most potent vasoconstrictors known. Pharmacological inhibition of endothelin receptors lowers blood pressure (BP). It is unknown whether naturally occurring genetic variation in the endothelin receptors influences BP. We have evaluated the type A endothelin receptor (EDNRA) as a candidate gene for hypertension in a large family study. A total of 1425 members of 248 families selected via a proband with hypertension were studied. Ambulatory BP monitoring was conducted using the A&D TM2421 device. Four haplotype-tagging single nucleotide polymorphisms (SNPs) spanning the EDNRA gene were typed. There was evidence of association between genotype at the rs5335 (C+70G) SNP and night systolic blood pressure (+1.24% (s.e. 0.64) per G allele; P=0.05); night diastolic blood pressure (+1.64% (s.e. 0.71) per G allele; P=0.021) and night mean BP (+1.51% (s.e. 0.64) per G allele; P=0.017). Borderline significant trends in the same direction were seen for daytime BPs. Proportions of hypertensives in each of the three genotype groups were C/C 34.7%, C/G 37.9%, G/G 42.4% yielding an odds ratio for hypertension per G allele of 1.19 (95% confidence interval 1.00-1.41; P=0.05). In conclusion, the rs5335 (C+70G) polymorphism of the EDNRA gene has small effects on the risk of hypertension. Natural variation in other genes in the endothelin-signalling pathway should be explored to identify additional influences on BP regulation.

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

    OpenAIRE

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

    2010-01-01

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

  2. Multi-way association extraction and visualization from biological text documents using hyper-graphs: applications to genetic association studies for diseases.

    Science.gov (United States)

    Mukhopadhyay, Snehasis; Palakal, Mathew; Maddu, Kalyan

    2010-07-01

    Biological research literature, as in many other domains of human endeavor, represents a rich, ever growing source of knowledge. An important form of such biological knowledge constitutes associations among biological entities such as genes, proteins, diseases, drugs and chemicals, etc. There has been a considerable amount of recent research in extraction of various kinds of binary associations (e.g., gene-gene, gene-protein, protein-protein, etc.) using different text mining approaches. However, an important aspect of such associations (e.g., "gene A activates protein B") is identifying the context in which such associations occur (e.g., "gene A activates protein B in the context of disease C in organ D under the influence of chemical E"). Such contexts can be represented appropriately by a multi-way relationship involving more than two objects (e.g., objects A, B, C, D, E) rather than usual binary relationship (objects A and B). Such multi-way relations naturally lead to a hyper-graph representation of the knowledge rather than a binary graph. The hyper-graph based multi-way knowledge extraction from biological text literature represents a computationally difficult problem (due to its combinatorial nature) which has not received much attention from the Bioinformatics research community. In this paper, we describe and compare two different approaches to such multi-way hyper-graph extraction: one based on an exhaustive enumeration of all multi-way hyper-edges and the other based on an extension of the well-known A Priori algorithm for structured data to the case unstructured textual data. We also present a representative graph based approach towards visualizing these genetic association hyper-graphs. Two case studies are conducted for two biomedical problems (related to the diseases of lung cancer and colorectal cancer respectively), illustrating that the latter approach (using the text-based A Priori method) identifies the same hyper-edges as the former approach

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

    Science.gov (United States)

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

    2016-04-01

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

  4. Association of genetic variation in the tachykinin receptor 3 locus with hot flashes and night sweats in the Women's Health Initiative Study.

    Science.gov (United States)

    Crandall, Carolyn J; Manson, JoAnn E; Hohensee, Chancellor; Horvath, Steve; Wactawski-Wende, Jean; LeBlanc, Erin S; Vitolins, Mara Z; Nassir, Rami; Sinsheimer, Janet S

    2017-03-01

    Vasomotor symptoms (VMS, ie, hot flashes or night sweats) are reported by many, but not all, women. The extent to which VMS are genetically determined is unknown. We evaluated the relationship of genetic variation and VMS. In this observational study, we accessed data from three genome-wide association studies (GWAS) (SNP Health Association Resource cohort [SHARe], WHI Memory Study cohort [WHIMS+], and Genome-Wide Association Studies of Treatment Response in Randomized Clinical Trials [GARNET] studies, total n = 17,695) of European American, African American, and Hispanic American postmenopausal women aged 50 to 79 years at baseline in the Women's Health Initiative Study. We examined genetic variation in relation to VMS (yes/no) in each study and using trans-ethnic inverse variance fixed-effects meta-analysis. A total of 11,078,977 single-nucleotide polymorphisms (SNPs) met the quality criteria. After adjustment for covariates and population structure, three SNPs (on chromosomes 3 and 11) were associated with VMS at the genome-wide threshold of 5 × 10 in the African American SHARe GWAS, but were not associated in the other cohorts. In the meta-analysis, 14 SNPs, all located on chromosome 4 in the tachykinin receptor 3 (TACR3) locus, however, had P < 5 × 10. These SNPs' effect sizes were similar across studies/participants' ancestry (odds ratio ∼1.5). Genetic variation in TACR3 may contribute to the risk of VMS. To our knowledge, this is the first GWAS to examine SNPs associated with VMS. These results support the biological hypothesis of a role for TACR3 in VMS, which was previously hypothesized from animal and human studies. Further study of these variants may lead to new insights into the biological pathways involved in VMS, which are poorly understood.

  5. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study.

    Science.gov (United States)

    Healy, Daniel G; Falchi, Mario; O'Sullivan, Sean S; Bonifati, Vincenzo; Durr, Alexandra; Bressman, Susan; Brice, Alexis; Aasly, Jan; Zabetian, Cyrus P; Goldwurm, Stefano; Ferreira, Joaquim J; Tolosa, Eduardo; Kay, Denise M; Klein, Christine; Williams, David R; Marras, Connie; Lang, Anthony E; Wszolek, Zbigniew K; Berciano, Jose; Schapira, Anthony H V; Lynch, Timothy; Bhatia, Kailash P; Gasser, Thomas; Lees, Andrew J; Wood, Nicholas W

    2008-07-01

    Mutations in LRRK2, the gene that encodes leucine-rich repeat kinase 2, are a cause of Parkinson's disease (PD). The International LRRK2 Consortium was established to answer three key clinical questions: can LRRK2-associated PD be distinguished from idiopathic PD; which mutations in LRRK2 are pathogenic; and what is the age-specific cumulative risk of PD for individuals who inherit or are at risk of inheriting a deleterious mutation in LRRK2? Researchers from 21 centres across the world collaborated on this study. The frequency of the common LRRK2 Gly2019Ser mutation was estimated on the basis of data from 24 populations worldwide, and the penetrance of the mutation was defined in 1045 people with mutations in LRRK2 from 133 families. The LRRK2 phenotype was defined on the basis of 59 motor and non-motor symptoms in 356 patients with LRRK2-associated PD and compared with the symptoms of 543 patients with pathologically proven idiopathic PD. Six mutations met the consortium's criteria for being proven pathogenic. The frequency of the common LRRK2 Gly2019Ser mutation was 1% of patients with sporadic PD and 4% of patients with hereditary PD; the frequency was highest in the middle east and higher in southern Europe than in northern Europe. The risk of PD for a person who inherits the LRRK2 Gly2019Ser mutation was 28% at age 59 years, 51% at 69 years, and 74% at 79 years. The motor symptoms (eg, disease severity, rate of progression, occurrence of falls, and dyskinesia) and non-motor symptoms (eg, cognition and olfaction) of LRRK2-associated PD were more benign than those of idiopathic PD. Mutations in LRRK2 are a clinically relevant cause of PD that merit testing in patients with hereditary PD and in subgroups of patients with PD. However, this knowledge should be applied with caution in the diagnosis and counselling of patients. UK Medical Research Council; UK Parkinson's Disease Society; UK Brain Research Trust; Internationaal Parkinson Fonds; Volkswagen Foundation

  6. Pleiotropic meta-analyses of longitudinal studies discover novel genetic variants associated with age-related diseases

    Directory of Open Access Journals (Sweden)

    Liang He

    2016-10-01

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

  7. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

    DEFF Research Database (Denmark)

    Ehret, Georg B; Ferreira, Teresa; Chasman, Daniel I;

    2016-01-01

    To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66...... across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings...

  8. Role of 5-HTTLPR polymorphism in the development of the inward/outward personality organization: a genetic association study.

    Directory of Open Access Journals (Sweden)

    Bernardo Nardi

    Full Text Available Reciprocity with primary caregivers affects subjects' adaptive abilities toward the construction of the most useful personal meaning organization (PMO with respect to their developmental environment. Within cognitive theory the post-rationalist approach has outlined two basic categories of identity construction and of regulation of cognitive and emotional processes: the Outward and the Inward PMO. The presence of different, consistent clinical patterns in Inward and Outward subjects is paralleled by differences in cerebral activation during emotional tasks on fMRI and by different expression of some polymorphisms in serotonin pathways. Since several lines of evidence support a role for the 5-HTTLPR polymorphism in mediating individual susceptibility to environmental emotional stimuli, this study was conducted to investigate its influence in the development of the Inward/Outward PMO. PMO was assessed and the 5-HTTLPR polymorphism investigated in 124 healthy subjects who were subdivided into an Inward (n = 52 and an Outward (n = 72 group. Case-control comparisons of short allele (S frequencies showed significant differences between Inwards and Outwards (p = 0.036, χ2 test; p = 0.026, exact test. Genotype frequencies were not significantly different although values slightly exceeded p ≤ 0.05 (p = 0.056, χ2 test; p = 0.059, exact test. Analysis of the 5-HTTLPR genotypes according to the recessive inheritance model showed that the S/S genotype increased the likelihood of developing an Outward PMO (p = 0.0178, χ2 test; p = 0.0143, exact test; OR = 3.43, CI (95% = 1.188-9.925. A logistic regression analysis confirmed the association between short allele and S/S genotypes with the Outward PMO also when gender and age were considered. However none of the differences remained significant after correction for multiple testing, even though using the recessive model they approach significance. Overall our data seem to suggest a putative genetic basis

  9. Role of 5-HTTLPR polymorphism in the development of the inward/outward personality organization: a genetic association study.

    Science.gov (United States)

    Nardi, Bernardo; Marini, Alessandra; Turchi, Chiara; Arimatea, Emidio; Tagliabracci, Adriano; Bellantuono, Cesario

    2013-01-01

    Reciprocity with primary caregivers affects subjects' adaptive abilities toward the construction of the most useful personal meaning organization (PMO) with respect to their developmental environment. Within cognitive theory the post-rationalist approach has outlined two basic categories of identity construction and of regulation of cognitive and emotional processes: the Outward and the Inward PMO. The presence of different, consistent clinical patterns in Inward and Outward subjects is paralleled by differences in cerebral activation during emotional tasks on fMRI and by different expression of some polymorphisms in serotonin pathways. Since several lines of evidence support a role for the 5-HTTLPR polymorphism in mediating individual susceptibility to environmental emotional stimuli, this study was conducted to investigate its influence in the development of the Inward/Outward PMO. PMO was assessed and the 5-HTTLPR polymorphism investigated in 124 healthy subjects who were subdivided into an Inward (n = 52) and an Outward (n = 72) group. Case-control comparisons of short allele (S) frequencies showed significant differences between Inwards and Outwards (p = 0.036, χ2 test; p = 0.026, exact test). Genotype frequencies were not significantly different although values slightly exceeded p ≤ 0.05 (p = 0.056, χ2 test; p = 0.059, exact test). Analysis of the 5-HTTLPR genotypes according to the recessive inheritance model showed that the S/S genotype increased the likelihood of developing an Outward PMO (p = 0.0178, χ2 test; p = 0.0143, exact test; OR = 3.43, CI (95%) = 1.188-9.925). A logistic regression analysis confirmed the association between short allele and S/S genotypes with the Outward PMO also when gender and age were considered. However none of the differences remained significant after correction for multiple testing, even though using the recessive model they approach significance. Overall our data seem to suggest a putative genetic basis for

  10. Whole-genome association studies for multigenic diseases: ethical dilemmas arising from commercialization--the case of genetic testing for autism.

    Science.gov (United States)

    Jordan, Bertrand R; Tsai, Daniel Fu Chang

    2010-07-01

    This paper examines some ethical issues arising from whole-genome association studies for multigenic diseases, focusing on the case of autism. Events occurring following the announcement of a genetic test for autism in France (2005-2009) are described to exemplify the ethical controversies that can arise when genetic testing for autism is applied prematurely and inappropriately promoted by biotech companies. The authors argue that genetic tests assessing one or a few genes involved in highly multigenic disorders can only be useful if: (1) the genetic linkage found in the scientific study must be statistically convincing, reproducible and also applicable to the population to which the individual considered belongs (scientific validity); (2) the relative risk conferred by the 'high-risk' allele should be high enough to be significant to the patient (significant impact); (3) use of the test should lead to some improvement of outcome for the patient, resulting from adapted treatment if available, or at least from adjustment of lifestyle (or life goals) prompted by the new knowledge generated (clinical utility). Decisions concerning genetic testing for autism involve scientific judgement, value judgement and good knowledge of a constantly evolving therapeutic environment. The implementation of genetic tests for highly multigenic diseases thus requires strong mechanisms to ensure that they are used in a fashion that can benefit patients, and these mechanisms must be able to cope with rapid progress in scientific knowledge and therapeutic intervention.

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

    Directory of Open Access Journals (Sweden)

    Paul J McLaren

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

  12. 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.

  13. Genetic associations with lipoprotein subfraction measures differ by ethnicity in the multi-ethnic study of atherosclerosis (MESA)

    Science.gov (United States)

    A recent genome-wide association study associated 62 single nucleotide polymorphisms (SNPs) from 43 genomic loci, with fasting lipoprotein subfractions in European–Americans (EAs) at genome-wide levels of significance across three independent samples. Whether these associations are consistent across...

  14. A Common Genetic Variant Risk Score is Associated with Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study.

    Science.gov (United States)

    Strauss, David G; Vicente, Jose; Johannesen, Lars; Blinova, Ksenia; Mason, Jay W; Weeke, Peter; Behr, Elijah R; Roden, Dan M; Woosley, Raymond; Kosova, Gulum; Rosenberg, Michael A; Newton-Cheh, Christopher

    2017-02-17

    Background -Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known. Methods -We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs. Genetic analysis of 22 subjects was performed in a secondary analysis of a randomized, double-blind, placebo-controlled, cross-over trial of 3 QT-prolonging drugs with 15 time-matched QT and plasma drug concentration measurements. Subjects received single doses of dofetilide, quinidine, ranolazine and placebo. The outcome was the correlation between a genetic QT score comprising 61 common genetic variants and the slope of an individual subject's drug-induced increase in heart rate corrected QT (QTc) vs. drug concentration. Results -The genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide (r = 0.55 [95% CI, 0.09-0.81], P = 0.02), 23% in response to quinidine (r = 0.48 [95% CI, -0.03 to 0.79], P = 0.06) and 27% in response to ranolazine (r = 0.52 [95% CI, 0.05 to 0.80], P = 0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared to 771 controls (r(2) = 12%, P = 1x10(-7)). Conclusions -We demonstrate that a genetic QT score comprising 61 common genetic variants explains a significant proportion of the variability in drug-induced QT prolongation and is a significant predictor of drug-induced torsade de pointes. These findings highlight an opportunity for recent genetic discoveries to improve

  15. Genetic risk factors for cerebrovascular disease in children with sickle cell disease: design of a case-control association study and genomewide screen

    Directory of Open Access Journals (Sweden)

    Brambilla Donald

    2003-07-01

    Full Text Available Abstract Background The phenotypic heterogeneity of sickle cell disease is likely the result of multiple genetic factors and their interaction with the sickle mutation. High transcranial doppler (TCD velocities define a subgroup of children with sickle cell disease who are at increased risk for developing ischemic stroke. The genetic factors leading to the development of a high TCD velocity (i.e. cerebrovascular disease and ultimately to stroke are not well characterized. Methods We have designed a case-control association study to elucidate the role of genetic polymorphisms as risk factors for cerebrovascular disease as measured by a high TCD velocity in children with sickle cell disease. The study will consist of two parts: a candidate gene study and a genomewide screen and will be performed in 230 cases and 400 controls. Cases will include 130 patients (TCD ≥ 200 cm/s randomized in the Stroke Prevention Trial in Sickle Cell Anemia (STOP study as well as 100 other patients found to have high TCD in STOP II screening. Four hundred sickle cell disease patients with a normal TCD velocity (TCD Discussion It is expected that this study will yield important information on genetic risk factors for the cerebrovascular disease phenotype in sickle cell disease by clarifying the role of candidate genes in the development of high TCD. The genomewide screen for a large number of SNPs may uncover the association of novel polymorphisms with cerebrovascular disease and stroke in sickle cell disease.

  16. A genetic epidemiologic study of hemochromatosis

    NARCIS (Netherlands)

    O.T. Njajou (Omer)

    2002-01-01

    textabstractThe goal of genetic epidemiology is to study the genetic etiology of diseases. There were t\\vo main aims for the present thesis. The first aim was to study the effects of the hemochromatosis gene (HFE) mutations on serum iron levels and disease associated conditions. Secondly, we aimed a

  17. Genetic Study of the Manganese Use Efficiency Trait in Winter Barley (Hordeum vulgare L.) by Genome- Wide Association and Genomic Selection

    DEFF Research Database (Denmark)

    Leplat, Florian Jean Victor

    Manganese (Mn) deficiency remains an unsolved nutritional problem affecting crop production worldwide. The tolerance to Mn limiting conditions, known as Mn efficiency, is a quantitative abiotic stress trait, generally controlled by several genes. However the underlying genetic background of Mn...... efficiency remained elusive. This PhD study aimed to understand better the genetic determination of the trait and propose new insights for plant breeding purposes. Two genome-wide approaches were used in a winter barley collection to characterize the genetic control of the trait. First, a Genome......-wide association study (GWAS) and chlorophyll a fluorescence phenotyping allowed to identify several QTLs involved in the plant response to Mn deficiency. Multiple candidate coding genes were fund, among which, photosystem II PsbP subunit, germin-like proteins or Mn-Superoxide Dismutase. It supports the Mn...

  18. A large candidate-gene association study suggests genetic variants at IRF5 and PRDM1 to be associated with aggressive periodontitis

    NARCIS (Netherlands)

    Schaefer, Arne S.; Jochens, Arne; Dommisch, Henrik; Graetz, Christian; Jockel-Schneider, Yvonne; Harks, Inga; Staufenbiel, Ingmar; Meyle, Joerg; Eickholz, Peter; Folwaczny, Mathias; Laine, Marja; Noack, Barbara; Wijmenga, Cisca; Lieb, Wolfgang; Bruckmann, Corinna; Schreiber, Stefan; Jepsen, Soren; Loos, Bruno G.

    2014-01-01

    Aim: Epidemiological and clinical studies indicated a relationship of periodontitis with rheumatoid arthritis (RA). We aimed to identify shared genetic susceptibility loci of RA and periodontitis. Materials and Methods: Forty-seven risk genes of genome-wide significance of RA and SLE were genotyped

  19. A large candidate-gene association study suggests genetic variants at IRF5 and PRDM1 to be associated with aggressive periodontitis

    NARCIS (Netherlands)

    Schaefer, A.S.; Jochens, A.; Dommisch, H.; Graetz, C.; Jockel-Schneider, Y.; Harks, I.; Staufenbiel, I.; Meyle, J.; Eickholz, P.; Folwaczny, M.; Laine, M.; Noack, B.; Wijmenga, C.; Lieb, W.; Bruckmann, C.; Schreiber, S.; Jepsen, S.; Loos, B.G.

    2014-01-01

    Aim Epidemiological and clinical studies indicated a relationship of periodontitis with rheumatoid arthritis (RA). We aimed to identify shared genetic susceptibility loci of RA and periodontitis. Materials and Methods Forty-seven risk genes of genome-wide significance of RA and SLE were genotyped in

  20. Genetic modifiers of Hb E/β0 thalassemia identified by a two-stage genome-wide association study

    Directory of Open Access Journals (Sweden)

    Winichagoon Pranee

    2010-03-01

    Full Text Available Abstract Background Patients with Hb E/β0 thalassemia display remarkable variability in disease severity. To identify genetic modifiers influencing disease severity, we conducted a two-stage genome scan in groups of 207 mild and 305 severe unrelated patients from Thailand with Hb E/β0 thalassemia and normal α-globin genes. Methods First, we estimated and compared the allele frequencies of approximately 110,000 gene-based single nucleotide polymorphisms (SNPs in pooled DNAs from different severity groups. The 756 SNPs that showed reproducible allelic differences at P Results After adjustment for age, gender and geographic region, logistic regression models showed 50 SNPs significantly associated with disease severity (P P = 2.6 × 10-13. Seven SNPs in two distinct LD blocks within a region centromeric to the β-globin gene cluster that contains many olfactory receptor genes were also associated with disease severity; rs3886223 had the strongest association (OR = 3.03, P = 3.7 × 10-11. Several previously unreported SNPs were also significantly associated with disease severity. Conclusions These results suggest that there may be an additional regulatory region centromeric to the β-globin gene cluster that affects disease severity by modulating fetal hemoglobin expression.

  1. An Association Study Between Genetic Polymorphisms in Functional Regions of Five Genes and the Risk of Schizophrenia.

    Science.gov (United States)

    Yan, Peng; Qiao, Xiaomeng; Wu, Hua; Yin, Fangyuan; Zhang, Jing; Ji, Yuanyuan; Wei, Shuguang; Lai, Jianghua

    2016-07-01

    Schizophrenia is a severe mental disorder that is likely to be strongly determined by genetic factors. To identify markers of disks, large homolog 2 (DLG2), FAT atypical cadherin 3 (FAT3), kinectin1 (KTN1), deleted in colorectal carcinoma (DCC), and glycogen synthase kinase-3β (GSK3β) that contribute to the genetic susceptibility to schizophrenia, we systematically screened for polymorphisms in the functional regions of these genes. A total of 22 functional single-nucleotide polymorphisms (SNPs) in 940 Chinese subjects were genotyped using SNaPshot. The results first suggested that the allelic and genotypic frequencies of the DCC polymorphism rs2229080 were nominally associated with schizophrenia. The patients were significantly less likely to be CC homozygous (P = 0.005, odds ratio [OR] = 0.635, 95 % confidence interval [95 % CI] = 0.462-0.873), and the schizophrenia subjects exhibited lower frequency of the C allele (P = 0.024, OR = 0.811, 95 % CI = 0.676-0.972). Regarding GSK3β, there was a significant difference in genotype distribution of rs3755557 between schizophrenia and healthy control subjects (P = 0.009). The patients exhibited a significantly lower frequency of the T allele of rs3755557 (P = 0.002, OR = 0.654, 95 % CI = 0.498-0.860). Our results point to the polymorphisms of DCC and GSK3β as contributors to the genetic basis of individual differences in the susceptibility to schizophrenia.

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

    Energy Technology Data Exchange (ETDEWEB)

    Edvardsen, Hege, E-mail: hege.edvardsen@rr-research.no [Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet, Oslo (Norway); K. G. Jebsen Breast cancer centre, Institute for Clinical Medicine, University of Oslo, Oslo (Norway); Landmark-Høyvik, Hege [Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet, Oslo (Norway); K. G. Jebsen Breast cancer centre, Institute for Clinical Medicine, University of Oslo, Oslo (Norway); Reinertsen, Kristin V. [National Resource Centre for Late Effects after Cancer Treatment, OUS Radiumhospitalet, Oslo (Norway); Zhao, Xi [Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet, Oslo (Norway); K. G. Jebsen Breast cancer centre, Institute for Clinical Medicine, University of Oslo, Oslo (Norway); Grenaker-Alnæs, Grethe Irene; Nebdal, Daniel [Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet, Oslo (Norway); Syvänen, Ann-Christine [Department of Medical Sciences, Uppsala University, Uppsala (Sweden); Rødningen, Olaug [Department of Medical Genetics, OUS Ullevaal, Oslo (Norway); Alsner, Jan; Overgaard, Jens [Department of Experimental Clinical Oncology, Ahus University Hospital (Norway); Borresen-Dale, Anne-Lise [Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet, Oslo (Norway); K. G. Jebsen Breast cancer centre, Institute for Clinical Medicine, University of Oslo, Oslo (Norway); Fosså, Sophie D. [K. G. Jebsen Breast cancer centre, Institute for Clinical Medicine, University of Oslo, Oslo (Norway); National Resource Centre for Late Effects after Cancer Treatment, OUS Radiumhospitalet, Oslo (Norway); Kristensen, Vessela N. [Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet, Oslo (Norway); K. G. Jebsen Breast cancer centre, Institute for Clinical Medicine, University of Oslo, Oslo (Norway); Department of Clinical Molecular Biology (EpiGen), Division of Medicine, Ahus University Hospital (Norway)

    2013-07-15

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

  3. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals.

    Science.gov (United States)

    Ehret, Georg B; Ferreira, Teresa; Chasman, Daniel I; Jackson, Anne U; Schmidt, Ellen M; Johnson, Toby; Thorleifsson, Gudmar; Luan, Jian'an; Donnelly, Lousie A; Kanoni, Stavroula; Petersen, Ann-Kristin; Pihur, Vasyl; Strawbridge, Rona J; Shungin, Dmitry; Hughes, Maria F; Meirelles, Osorio; Kaakinen, Marika; Bouatia-Naji, Nabila; Kristiansson, Kati; Shah, Sonia; Kleber, Marcus E; Guo, Xiuqing; Lyytikäinen, Leo-Pekka; Fava, Cristiano; Eriksson, Niclas; Nolte, Ilja M; Magnusson, Patrik K; Salfati, Elias L; Rallidis, Loukianos S; Theusch, Elizabeth; Smith, Andrew J P; Folkersen, Lasse; Witkowska, Kate; Pers, Tune H; Joehanes, Roby; Kim, Stuart K; Lataniotis, Lazaros; Jansen, Rick; Johnson, Andrew D; Warren, Helen; Kim, Young Jin; Zhao, Wei; Wu, Ying; Tayo, Bamidele O; Bochud, Murielle; Absher, Devin; Adair, Linda S; Amin, Najaf; Arking, Dan E; Axelsson, Tomas; Baldassarre, Damiano; Balkau, Beverley; Bandinelli, Stefania; Barnes, Michael R; Barroso, Inês; Bevan, Stephen; Bis, Joshua C; Bjornsdottir, Gyda; Boehnke, Michael; Boerwinkle, Eric; Bonnycastle, Lori L; Boomsma, Dorret I; Bornstein, Stefan R; Brown, Morris J; Burnier, Michel; Cabrera, Claudia P; Chambers, John C; Chang, I-Shou; Cheng, Ching-Yu; Chines, Peter S; Chung, Ren-Hua; Collins, Francis S; Connell, John M; Döring, Angela; Dallongeville, Jean; Danesh, John; de Faire, Ulf; Delgado, Graciela; Dominiczak, Anna F; Doney, Alex S F; Drenos, Fotios; Edkins, Sarah; Eicher, John D; Elosua, Roberto; Enroth, Stefan; Erdmann, Jeanette; Eriksson, Per; Esko, Tonu; Evangelou, Evangelos; Evans, Alun; Fall, Tove; Farrall, Martin; Felix, Janine F; Ferrières, Jean; Ferrucci, Luigi; Fornage, Myriam; Forrester, Terrence; Franceschini, Nora; Duran, Oscar H Franco; Franco-Cereceda, Anders; Fraser, Ross M; Ganesh, Santhi K; Gao, He; Gertow, Karl; Gianfagna, Francesco; Gigante, Bruna; Giulianini, Franco; Goel, Anuj; Goodall, Alison H; Goodarzi, Mark O; Gorski, Mathias; Gräßler, Jürgen; Groves, Christopher; Gudnason, Vilmundur; Gyllensten, Ulf; Hallmans, Göran; Hartikainen, Anna-Liisa; Hassinen, Maija; Havulinna, Aki S; Hayward, Caroline; Hercberg, Serge; Herzig, Karl-Heinz; Hicks, Andrew A; Hingorani, Aroon D; Hirschhorn, Joel N; Hofman, Albert; Holmen, Jostein; Holmen, Oddgeir Lingaas; Hottenga, Jouke-Jan; Howard, Phil; Hsiung, Chao A; Hunt, Steven C; Ikram, M Arfan; Illig, Thomas; Iribarren, Carlos; Jensen, Richard A; Kähönen, Mika; Kang, Hyun; Kathiresan, Sekar; Keating, Brendan J; Khaw, Kay-Tee; Kim, Yun Kyoung; Kim, Eric; Kivimaki, Mika; Klopp, Norman; Kolovou, Genovefa; Komulainen, Pirjo; Kooner, Jaspal S; Kosova, Gulum; Krauss, Ronald M; Kuh, Diana; Kutalik, Zoltan; Kuusisto, Johanna; Kvaløy, Kirsti; Lakka, Timo A; Lee, Nanette R; Lee, I-Te; Lee, Wen-Jane; Levy, Daniel; Li, Xiaohui; Liang, Kae-Woei; Lin, Honghuang; Lin, Li; Lindström, Jaana; Lobbens, Stéphane; Männistö, Satu; Müller, Gabriele; Müller-Nurasyid, Martina; Mach, François; Markus, Hugh S; Marouli, Eirini; McCarthy, Mark I; McKenzie, Colin A; Meneton, Pierre; Menni, Cristina; Metspalu, Andres; Mijatovic, Vladan; Moilanen, Leena; Montasser, May E; Morris, Andrew D; Morrison, Alanna C; Mulas, Antonella; Nagaraja, Ramaiah; Narisu, Narisu; Nikus, Kjell; O'Donnell, Christopher J; O'Reilly, Paul F; Ong, Ken K; Paccaud, Fred; Palmer, Cameron D; Parsa, Afshin; Pedersen, Nancy L; Penninx, Brenda W; Perola, Markus; Peters, Annette; Poulter, Neil; Pramstaller, Peter P; Psaty, Bruce M; Quertermous, Thomas; Rao, Dabeeru C; Rasheed, Asif; Rayner, N William N W R; Renström, Frida; Rettig, Rainer; Rice, Kenneth M; Roberts, Robert; Rose, Lynda M; Rossouw, Jacques; Samani, Nilesh J; Sanna, Serena; Saramies, Jouko; Schunkert, Heribert; Sebert, Sylvain; Sheu, Wayne H-H; Shin, Young-Ah; Sim, Xueling; Smit, Johannes H; Smith, Albert V; Sosa, Maria X; Spector, Tim D; Stančáková, Alena; Stanton, Alice; Stirrups, Kathleen E; Stringham, Heather M; Sundstrom, Johan; Swift, Amy J; Syvänen, Ann-Christine; Tai, E-Shyong; Tanaka, Toshiko; Tarasov, Kirill V; Teumer, Alexander; Thorsteinsdottir, Unnur; Tobin, Martin D; Tremoli, Elena; Uitterlinden, Andre G; Uusitupa, Matti; Vaez, Ahmad; Vaidya, Dhananjay; van Duijn, Cornelia M; van Iperen, Erik P A; Vasan, Ramachandran S; Verwoert, Germaine C; Virtamo, Jarmo; Vitart, Veronique; Voight, Benjamin F; Vollenweider, Peter; Wagner, Aline; Wain, Louise V; Wareham, Nicholas J; Watkins, Hugh; Weder, Alan B; Westra, Harm-Jan; Wilks, Rainford; Wilsgaard, Tom; Wilson, James F; Wong, Tien Y; Yang, Tsun-Po; Yao, Jie; Yengo, Loic; Zhang, Weihua; Zhao, Jing Hua; Zhu, Xiaofeng; Bovet, Pascal; Cooper, Richard S; Mohlke, Karen L; Saleheen, Danish; Lee, Jong-Young; Elliott, Paul; Gierman, Hinco J; Willer, Cristen J; Franke, Lude; Hovingh, G Kees; Taylor, Kent D; Dedoussis, George; Sever, Peter; Wong, Andrew; Lind, Lars; Assimes, Themistocles L; Njølstad, Inger; Schwarz, Peter Eh; Langenberg, Claudia; Snieder, Harold; Caulfield, Mark J; Melander, Olle; Laakso, Markku; Saltevo, Juha; Rauramaa, Rainer; Tuomilehto, Jaakko; Ingelsson, Erik; Lehtimäki, Terho; Hveem, Kristian; Palmas, Walter; März, Winfried; Kumari, Meena; Salomaa, Veikko; Chen, Yii-Der I; Rotter, Jerome I; Froguel, Philippe; Jarvelin, Marjo-Riitta; Lakatta, Edward G; Kuulasmaa, Kari; Franks, Paul W; Hamsten, Anders; Wichmann, H-Erich; Palmer, Colin N A; Stefansson, Kari; Ridker, Paul M; Loos, Ruth J F; Chakravarti, Aravinda; Deloukas, Panos; Morris, Andrew P; Newton-Cheh, Christopher; Munroe, Patricia B

    2016-10-01

    To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.

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

    Science.gov (United States)

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

    2014-02-01

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

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

    OpenAIRE

    Randall, J. C.; Winkler, T.W.; Kutalik, Z.; Berndt, S.I.; Jackson, A.U.; Monda, K.L.; Kilpelainen, T.O.; Esko, T; Magi, R.; Li, S.; Workalemahu, T; Feitosa,M. F.; Croteau-Chonka, D.C.; Day, F. R.; Fall, T.

    2013-01-01

    Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previousl...

  6. HuGE Watch: tracking trends and patterns of published studies of genetic association and human genome epidemiology in near-real time.

    Science.gov (United States)

    Yu, Wei; Wulf, Anja; Yesupriya, Ajay; Clyne, Melinda; Khoury, Muin Joseph; Gwinn, Marta

    2008-09-01

    HuGE Watch is a web-based application for tracking the evolution of published studies on genetic association and human genome epidemiology in near-real time. The application allows users to display temporal trends and spatial distributions as line charts and google maps, providing a quick overview of progress in the field. http://www.hugenavigator.net/HuGENavigator/startPageWatch.do

  7. Genome-wide association study identifies GYS2 as a novel genetic factor for polycystic ovary syndrome through obesity-related condition.

    Science.gov (United States)

    Hwang, Joo-Yeon; Lee, Eun-Ju; Jin Go, Min; Sung, Yeon-Ah; Lee, Hye Jin; Heon Kwak, Soo; Jang, Hak C; Soo Park, Kyung; Lee, Hye-Ja; Byul Jang, Han; Song, Jihyun; Park, Kyung-Hee; Kim, Hyung-Lae; Cho, Myeong-Chan; Lee, Jong-Young

    2012-10-01

    To investigate the role of genetic predisposition in the pathogenesis of polycystic ovary syndrome (PCOS) in relation to obesity, we performed a genome-wide association study of PCOS in Koreans (n=1741). PCOS is a heterogeneous endocrinal disorder of uncertain etiology. Obesity is one of the well-known risk factors for PCOS. Genome-wide association study. Women with or without PCOS. A total of 1881 samples were genotyped using Illumina HumanOmni1 Quad v1 and processed by R packages. The PCOS patients were divided into two subgroups according to PCOS diagnostic criteria (Rotterdam and National Institutes of Health (NIH)). For PCOS-associated loci in the two definitions, we successfully confirmed significant associations of GYS2 for body mass index in the discovery stage. We further replicated pleiotropic associations of GYS2 in a childhood obesity study (n=482) and in a gestational diabetes study (n=1710), respectively. Our study provides a preliminary framework upon diverse genetic effects underlying PCOS in Korean women. A newly identified GYS2 gene as a predisposing factor of PCOS might expand understanding of the biological pathways in metabolic and endocrine regulation.

  8. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

    Science.gov (United States)

    Chasman, Daniel I.; Jackson, Anne U.; Schmidt, Ellen M.; Johnson, Toby; Thorleifsson, Gudmar; Luan, Jian'an; Donnelly, Lousie A.; Kanoni, Stavroula; Petersen, Ann-Kristin; Pihur, Vasyl; Strawbridge, Rona J.; Shungin, Dmitry; Hughes, Maria F.; Meirelles, Osorio; Kaakinen, Marika; Bouatia-Naji, Nabila; Kristiansson, Kati; Shah, Sonia; Kleber, Marcus E.; Guo, Xiuqing; Lyytikäinen, Leo-Pekka; Fava, Cristiano; Eriksson, Niclas; Nolte, Ilja M.; Magnusson, Patrik K.; Salfati, Elias L.; Rallidis, Loukianos S.; Theusch, Elizabeth; Smith, Andrew J.P.; Folkersen, Lasse; Witkowska, Kate; Pers, Tune H.; Joehanes, Roby; Kim, Stuart K.; Lataniotis, Lazaros; Jansen, Rick; Johnson, Andrew D.; Warren, Helen; Kim, Young Jin; Zhao, Wei; Wu, Ying; Tayo, Bamidele O.; Bochud, Murielle; Absher, Devin; Adair, Linda S.; Amin, Najaf; Arking, Dan E.; Axelsson, Tomas; Baldassarre, Damiano; Balkau, Beverley; Bandinelli, Stefania; Barnes, Michael R.; Barroso, Inês; Bevan, Stephen; Bis, Joshua C.; Bjornsdottir, Gyda; Boehnke, Michael; Boerwinkle, Eric; Bonnycastle, Lori L.; Boomsma, Dorret I.; Bornstein, Stefan R.; Brown, Morris J.; Burnier, Michel; Cabrera, Claudia P.; Chambers, John C.; Chang, I-Shou; Cheng, Ching-Yu; Chines, Peter S.; Chung, Ren-Hua; Collins, Francis S.; Connell, John M.; Döring, Angela; Dallongeville, Jean; Danesh, John; de Faire, Ulf; Delgado, Graciela; Dominiczak, Anna F.; Doney, Alex S.F.; Drenos, Fotios; Edkins, Sarah; Eicher, John D.; Elosua, Roberto; Enroth, Stefan; Erdmann, Jeanette; Eriksson, Per; Esko, Tonu; Evangelou, Evangelos; Evans, Alun; Fall, Tove; Farrall, Martin; Felix, Janine F.; Ferrières, Jean; Ferrucci, Luigi; Fornage, Myriam; Forrester, Terrence; Franceschini, Nora; Duran, Oscar H. Franco; Franco-Cereceda, Anders; Fraser, Ross M.; Ganesh, Santhi K.; Gao, He; Gertow, Karl; Gianfagna, Francesco; Gigante, Bruna; Giulianini, Franco; Goel, Anuj; Goodall, Alison H.; Goodarzi, Mark O.; Gorski, Mathias; Gräßler, Jürgen; Groves, Christopher; Gudnason, Vilmundur; Gyllensten, Ulf; Hallmans, Göran; Hartikainen, Anna-Liisa; Hassinen, Maija; Havulinna, Aki S.; Hayward, Caroline; Hercberg, Serge; Herzig, Karl-Heinz; Hicks, Andrew A.; Hingorani, Aroon D.; Hirschhorn, Joel N.; Hofman, Albert; Holmen, Jostein; Holmen, Oddgeir Lingaas; Hottenga, Jouke-Jan; Howard, Phil; Hsiung, Chao A.; Hunt, Steven C.; Ikram, M. Arfan; Illig, Thomas; Iribarren, Carlos; Jensen, Richard A.; Kähönen, Mika; Kang, Hyun; Kathiresan, Sekar; Keating, Brendan J.; Khaw, Kay-Tee; Kim, Yun Kyoung; Kim, Eric; Kivimaki, Mika; Klopp, Norman; Kolovou, Genovefa; Komulainen, Pirjo; Kooner, Jaspal S.; Kosova, Gulum; Krauss, Ronald M.; Kuh, Diana; Kutalik, Zoltan; Kuusisto, Johanna; Kvaløy, Kirsti; Lakka, Timo A; Lee, Nanette R.; Lee, I-Te; Lee, Wen-Jane; Levy, Daniel; Li, Xiaohui; Liang, Kae-Woei; Lin, Honghuang; Lin, Li; Lindström, Jaana; Lobbens, Stéphane; Männistö, Satu; Müller, Gabriele; Müller-Nurasyid, Martina; Mach, François; Markus, Hugh S.; Marouli, Eirini; McCarthy, Mark I.; McKenzie, Colin A.; Meneton, Pierre; Menni, Cristina; Metspalu, Andres; Mijatovic, Vladan; Moilanen, Leena; Montasser, May E.; Morris, Andrew D.; Morrison, Alanna C.; Mulas, Antonella; Nagaraja, Ramaiah; Narisu, Narisu; Nikus, Kjell; O'Donnell, Christopher J.; O'Reilly, Paul F.; Ong, Ken K.; Paccaud, Fred; Palmer, Cameron D.; Parsa, Afshin; Pedersen, Nancy L.; Penninx, Brenda W.; Perola, Markus; Peters, Annette; Poulter, Neil; Pramstaller, Peter P.; Psaty, Bruce M.; Quertermous, Thomas; Rao, Dabeeru C.; Rasheed, Asif; Rayner, N William N.W.R.; Renström, Frida; Rettig, Rainer; Rice, Kenneth M.; Roberts, Robert; Rose, Lynda M.; Rossouw, Jacques; Samani, Nilesh J.; Sanna, Serena; Saramies, Jouko; Schunkert, Heribert; Sebert, Sylvain; Sheu, Wayne H.-H.; Shin, Young-Ah; Sim, Xueling; Smit, Johannes H.; Smith, Albert V.; Sosa, Maria X.; Spector, Tim D.; Stančáková, Alena; Stanton, Alice; Stirrups, Kathleen E.; Stringham, Heather M.; Sundstrom, Johan; Swift, Amy J.; Syvänen, Ann-Christine; Tai, E-Shyong; Tanaka, Toshiko; Tarasov, Kirill V.; Teumer, Alexander; Thorsteinsdottir, Unnur; Tobin, Martin D.; Tremoli, Elena; Uitterlinden, Andre G.; Uusitupa, Matti; Vaez, Ahmad; Vaidya, Dhananjay; van Duijn, Cornelia M.; van Iperen, Erik P.A.; Vasan, Ramachandran S.; Verwoert, Germaine C.; Virtamo, Jarmo; Vitart, Veronique; Voight, Benjamin F.; Vollenweider, Peter; Wagner, Aline; Wain, Louise V.; Wareham, Nicholas J.; Watkins, Hugh; Weder, Alan B.; Westra, Harm-Jan; Wilks, Rainford; Wilsgaard, Tom; Wilson, James F.; Wong, Tien Y.; Yang, Tsun-Po; Yao, Jie; Yengo, Loic; Zhang, Weihua; Zhao, Jing Hua; Zhu, Xiaofeng; Bovet, Pascal; Cooper, Richard S.; Mohlke, Karen L.; Saleheen, Danish; Lee, Jong-Young; Elliott, Paul; Gierman, Hinco J.; Willer, Cristen J.; Franke, Lude; Hovingh, G Kees; Taylor, Kent D.; Dedoussis, George; Sever, Peter; Wong, Andrew; Lind, Lars; Assimes, Themistocles L.; Njølstad, Inger; Schwarz, Peter EH.; Langenberg, Claudia; Snieder, Harold; Caulfield, Mark J.; Melander, Olle; Laakso, Markku; Saltevo, Juha; Rauramaa, Rainer; Tuomilehto, Jaakko; Ingelsson, Erik; Lehtimäki, Terho; Hveem, Kristian; Palmas, Walter; März, Winfried; Kumari, Meena; Salomaa, Veikko; Chen, Yii-Der I.; Rotter, Jerome I.; Froguel, Philippe; Jarvelin, Marjo-Riitta; Lakatta, Edward G.; Kuulasmaa, Kari; Franks, Paul W.; Hamsten, Anders; Wichmann, H.-Erich; Palmer, Colin N.A.; Stefansson, Kari; Ridker, Paul M; Loos, Ruth J.F.; Chakravarti, Aravinda; Deloukas, Panos; Morris, Andrew P.; Newton-Cheh, Christopher; Munroe, Patricia B.

    2016-01-01

    To dissect the genetic architecture of blood pressure and assess effects on target-organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure loci, of which 17 were novel and 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our findings expand current knowledge of blood pressure pathways and highlight tissues beyond the classic renal system in blood pressure regulation. PMID:27618452

  9. Association of cytotoxic T-lymphocyte antigen 4 genetic polymorphism, hepatitis C viral infection and B-cell non-Hodgkin lymphoma: an Egyptian study.

    Science.gov (United States)

    Khorshied, Mervat Mamdooh; Gouda, Heba Mahmoud; Khorshid, Ola M Reda

    2014-05-01

    Abstract Genetic and environmental factors are involved in the pathogenesis of non-Hodgkin lymphoma (NHL). The present study aimed to investigate the association between cytotoxic T-lymphocyte antigen 4 (CTLA-4) genetic polymorphism, hepatitis C virus (HCV) infection and B-cell NHL risk in Egypt. Genotyping of CTLA-4 single nucleotide polymorphisms (SNPs) was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay for 181 adult patients with B-NHL and 200 controls. Our study revealed that CTLA-4 + 49 A/G polymorphism conferred increased risk of B-NHL (odds ratio [OR] = 1.7, 95% confidence interval [CI] = 1.36-2.565). The prevalence of HCV infection in individuals harboring the mutant genotype + 49 A/G and - 318 C/T SNPs was higher in patients with B-NHL and was associated with increased risk of B-NHL (OR = 2.79, 95% CI = 1.24-6.93 for + 49 A/G and OR = 3.9, 95% CI = 1.01-15.98 for - 318 C/T). In conclusion, some SNPs of CTLA-4 are genetic risk factors for B-NHL. Moreover, this study identified an association of CTLA-4 + 49 A/G and - 318 C/T promoter polymorphisms with HCV infection.

  10. Genetic variation in CD36, HBA, NOS3 and VCAM1 is associated with chronic haemolysis level in sickle cell anaemia: a longitudinal study.

    Science.gov (United States)

    Coelho, Andreia; Dias, Alexandra; Morais, Anabela; Nunes, Baltazar; Ferreira, Emanuel; Picanço, Isabel; Faustino, Paula; Lavinha, João

    2014-03-01

    Chronic haemolysis stands out as one of the hallmarks of sickle cell anaemia, a clinically heterogeneous autosomal recessive monogenic anaemia. However, the genetic architecture of this sub-phenotype is still poorly understood. Here, we report the results of an association study between haemolysis biomarkers (serum LDH, total bilirubin and reticulocyte count) and the inheritance of 41 genetic variants of ten candidate genes in a series of 99 paediatric SS patients (median current age of 9.9 yr) followed up in two general hospitals in Greater Lisboa area (median follow-up per patient of 5.0 yr). Although in a large number of tests a seemingly significant (i.e. P haplotype 7 within VCAM1 gene; (ii) a lower total bilirubin was associated with the 3.7-kb deletion at HBA gene, rs2070744_T allele at NOS3 gene, and haplotype 9 within VCAM1 promoter; and (iii) a diminished reticulocyte count was associated with the 3.7-kb deletion at HBA, whereas an increased count was associated with rs1984112_G allele at CD36 gene. On the whole, our findings suggest a complex genetic architecture for the sickle cell anaemia haemolysis process involving multiple pathways, namely control of vascular cell adhesion, NO synthesis and erythrocyte volume and haemoglobinisation.

  11. 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...

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry....... In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs...... × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23)

  13. GENETIC FACTORS ASSOCIATED WITH AMYOTROPHIC LATERAL SCLEROSIS

    Directory of Open Access Journals (Sweden)

    Katarina Vrabec

    2015-10-01

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

  14. Genetic association and gene-smoking interaction study of carotid intima-media thickness at five GWAS-indicated genes: the Bogalusa Heart Study.

    Science.gov (United States)

    Li, Changwei; Chen, Wei; Jiang, Fan; Simino, Jeannette; Srinivasan, Sathanur R; Berenson, Gerald S; Mei, Hao

    2015-05-15

    To examine the associations of five GWAS-identified genes with carotid intima-media thickness (IMT) in a biracial sample from the Bogalusa Heart Study, and evaluate their participation in gene-smoking interactions. Far wall IMTs of common carotid arteries were measured using high-resolution B-mode ultrasound. Both the gene-smoking interactions and single-marker associations were evaluated by linear models of carotid IMT levels, while the gene-based analyses were assessed through the truncated product method. A Bonferroni multiple testing correction was applied. Marker rs7840785 (PINX1) was significantly associated with right carotid IMT (p=0.0003) using all participants; mean levels for the CC, TC, and TT genotypes were 0.74 (0.73 to 0.75), 0.76 (0.75 to 0.78), and 0.78 (0.75, 0.81), respectively. Similar trends were observed in blacks (p=0.0031) and whites (p=0.0118). Marker rs7844465 (ZHX2) was significantly associated with left carotid IMT in whites (p=0.0005); mean IMT levels for the GG, TG, and TT genotypes were 0.73 (0.71 to 0.74), 0.75 (0.74 to 0.77) and 0.78 (0.75 to 0.81), respectively. Marker rs6841473 (EDNRA) modified the association between smoking and left carotid IMT in blacks (p=2.79×10(-5)). In addition, gene-based analysis demonstrated that EDNRA and ZHX2 were associated with left carotid IMT in the white and overall participants, respectively, while PINX1 was associated with right carotid IMT in both blacks and whites. We identified two novel markers that were associated with IMT in both blacks and whites. One gene-smoking interaction was identified in blacks only. Three genes showed gene-based associations with IMT levels. However, genetic markers with small effects may have been missed due to the limited number of black participants. Copyright © 2015 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2008-04-01

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

  16. Blood spots as an alternative to whole blood collection and the effect of a small monetary incentive to increase participation in genetic association studies

    Directory of Open Access Journals (Sweden)

    Ringer Danny

    2009-11-01

    Full Text Available Abstract Background Collection of buccal cells from saliva for DNA extraction offers a less invasive and convenient alternative to venipuncture blood collection that may increase participation in genetic epidemiologic studies. However, dried blood spot collection, which is also a convenient method, offers a means of collecting peripheral blood samples from which analytes in addition to DNA can be obtained. Methods To determine if offering blood spot collection would increase participation in genetic epidemiologic studies, we conducted a study of collecting dried blood spot cards by mail from a sample of female cancer cases (n = 134 and controls (n = 256 who were previously selected for a breast cancer genetics study and declined to provide a venipuncture blood sample. Participants were also randomized to receive either a $2.00 bill or no incentive with the blood spot collection kits. Results The average time between the venipuncture sample refusal and recruitment for the blood spot collection was 4.4 years. Thirty-seven percent of cases and 28% of controls provided a dried blood spot card. While the incentive was not associated with participation among controls (29% for $2.00 incentive vs. 26% for no incentive, p = 0.6, it was significantly associated with participation among the breast cancer cases (48% vs. 27%, respectively, p = 0.01. There did not appear to be any bias in response since no differences between cases and controls and incentive groups were observed when examining several demographic, work history and radiation exposure variables. Conclusion This study demonstrates that collection of dried blood spot cards in addition to venipuncture blood samples may be a feasible method to increase participation in genetic case-control studies.

  17. Comprehensive review of genetic association studies and meta-analyses on miRNA polymorphisms and cancer risk.

    Directory of Open Access Journals (Sweden)

    Kshitij Srivastava

    Full Text Available BACKGROUND: MicroRNAs (miRNAs are small RNA molecules that regulate the expression of corresponding messenger RNAs (mRNAs. Variations in the level of expression of distinct miRNAs have been observed in the genesis, progression and prognosis of multiple human malignancies. The present study was aimed to investigate the association between four highly studied miRNA polymorphisms (mir-146a rs2910164, mir-196a2 rs11614913, mir-149 rs2292832 and mir-499 rs3746444 and cancer risk by using a two-sided meta-analytic approach. METHODS: An updated meta-analysis based on 53 independent case-control studies consisting of 27573 cancer cases and 34791 controls was performed. Odds ratio (OR and 95% confidence interval (95% CI were used to investigate the strength of the association. RESULTS: Overall, the pooled analysis showed that mir-196a2 rs11614913 was associated with a decreased cancer risk (OR = 0.846, P = 0.004, TT vs. CC while other miRNA SNPs showed no association with overall cancer risk. Subgroup analyses based on type of cancer and ethnicity were also performed, and results indicated that there was a strong association between miR-146a rs2910164 and overall cancer risk in Caucasian population under recessive model (OR = 1.274, 95%CI = 1.096-1.481, P = 0.002. Stratified analysis by cancer type also associated mir-196a2 rs11614913 with lung and colorectal cancer at allelic and genotypic level. CONCLUSIONS: The present meta-analysis suggests an important role of mir-196a2 rs11614913 polymorphism with overall cancer risk especially in Asian population. Further studies with large sample size are needed to evaluate and confirm this association.

  18. A pilot study of the association between genetic polymorphisms involved in estrogen signaling and infant male genital phenotypes

    Institute of Scientific and Technical Information of China (English)

    Sheela Sathyanarayana; Shanna H Swan; Federico M Farin; Hui-Wen wilkerson; Michael Bamshad; Richard Grady; Chuan Zhou; Stephen M Schwartz

    2012-01-01

    Single nucleotide polymorphisms (SNPs) in genes that influence development of the male reproductive tract have been associated with male genitourinary abnormalities.However,no studies have tested the relationship between SNPs and intermediate phenotypes such as anogenital distance (AGD),anoscrotal distance (ASD) and penile width (PW).We tested whether 24 common SNPs in eight genes that influence male genital development were associated with intermediate phenotypes in 106 healthy male infants from the Study for Future Families.We used DNA from buccal smears and linear regression models to assess the relationship between anogenital measurements and SNP genotypes with adjustment for covariates.We found that the rs2077647 Gallele,located in the coding region of estrogen receptor alpha (ESR1),was associated with a shorter AGD (P=0.02; -7.3 mm,95% confidence interval (CI):-11.6 to -3.1),and the rs 10475 T allele,located in the 3' untranslated region of activating transcription factor 3 (ATF3),was associated with a shorter ASD (-4.3 mm,95% CI:- 7.2 to - 1.4),although this result was not significant (P=0.07) after controlling for multiple comparisons.We observed no association between PW and the SNPs tested.Minor alleles for two SNPs in genes that regulate estrogen signaling during male genital development were associated with AGD and ASD,although the significance of the association was marginal.Our findings suggest that AGD and ASD are influenced by heritable factors in genes known to be associated with frank male genital abnormalities such as hypospadias and cryptorchidism.

  19. 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

  20. Complement genetics, deficiencies, and disease associations.

    Science.gov (United States)

    Mayilyan, Karine R

    2012-07-01

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

  1. Biological insights from 108 schizophrenia-associated genetic loci

    NARCIS (Netherlands)

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

    2014-01-01

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

  2. Biological insights from 108 schizophrenia-associated genetic loci

    NARCIS (Netherlands)

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

    2014-01-01

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

  3. New genetic variants associated with prostate cancer

    Science.gov (United States)

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

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

    Science.gov (United States)

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

    2014-01-01

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

  5. Genetic association of deleted in colorectal carcinoma variants with breast cancer risk: A case-control study.

    Science.gov (United States)

    Liu, Xinghan; Wang, Xijing; Fu, Sidney W; Wang, Meng; Kang, Huafeng; Guan, Haitao; Zhang, Shuqun; Ma, Xiaobin; Lin, Shuai; Liu, Kang; Feng, Yanjing; Dai, Cong; Dai, Zhijun

    2016-05-31

    Deleted in colorectal carcinoma (DCC), a netrin-1 dependence receptor, is correlated with cell progression, migration, and adhesion. Evidence indicated that DCC was frequently down-regulated in many cancers. However, the association of DCC with breast cancer remains uncertain. We conducted a case-control study to investigate the impact of three DCC gene variants (rs2229080, rs7504990, and rs4078288) on breast cancer susceptibility in Chinese women. This study included 560 breast cancer patients and 583 age-matched healthy controls from Northwest China. The three gene variants were genotyped via Sequenom MassARRAY. Odds ratios (ORs) and 95% confidence intervals (CIs) were utilized to evaluate the associations. We found that individuals with the rs2229080 C/G, C/C, and C/G-CC genotypes had a higher breast cancer risk, and the minor allele C was associated with increased breast cancer risk in an allele model. We observed a significantly decreased breast cancer risk with the rs7504990 C/T, T/T, and C/T-T/T genotypes, and the minor allele T was protective against breast cancer in an allele model. In addition, rs2229080 was associated with the axillary lymph node (LN) metastasis status. An age-stratified analysis revealed an association between rs2229080 and reduced breast cancer risk among older patients (≥ 49 years). Furthermore, the haplotype analysis showed that the Crs2229080Crs7504990Ars4078288 haplotype was associated with a decreased breast cancer risk. However, the results indicated a lack of association between rs4078288 and breast cancer risk. These findings affirmed that rs2229080 and rs7504990 polymorphisms in DCC might be related with breast cancer susceptibility in Chinese women.

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

    DEFF Research Database (Denmark)

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

    2016-01-01

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

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

    Science.gov (United States)

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

    2012-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Joshua C Randall

    2013-06-01

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

  9. Genome-wide association reveals genetic effects on human Aβ42 and τ protein levels in cerebrospinal fluids: a case control study

    Directory of Open Access Journals (Sweden)

    Schellenberg Gerard D

    2010-10-01

    Full Text Available Abstract Background Alzheimer's disease (AD is common and highly heritable with many genes and gene variants associated with AD in one or more studies, including APOE ε2/ε3/ε4. However, the genetic backgrounds for normal cognition, mild cognitive impairment (MCI and AD in terms of changes in cerebrospinal fluid (CSF levels of Aβ1-42, T-tau, and P-tau181P, have not been clearly delineated. We carried out a genome-wide association study (GWAS in order to better define the genetic backgrounds to these three states in relation to CSF levels. Methods Subjects were participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI. The GWAS dataset consisted of 818 participants (mainly Caucasian genotyped using the Illumina Human Genome 610 Quad BeadChips. This sample included 410 subjects (119 Normal, 115 MCI and 176 AD with measurements of CSF Aβ1-42, T-tau, and P-tau181P Levels. We used PLINK to find genetic associations with the three CSF biomarker levels. Association of each of the 498,205 SNPs was tested using additive, dominant, and general association models while considering APOE genotype and age. Finally, an effort was made to better identify relevant biochemical pathways for associated genes using the ALIGATOR software. Results We found that there were some associations with APOE genotype although CSF levels were about the same for each subject group; CSF Aβ1-42 levels decreased with APOE gene dose for each subject group. T-tau levels tended to be higher among AD cases than among normal subjects. From adjusted result using APOE genotype and age as covariates, no SNP was associated with CSF levels among AD subjects. CYP19A1 'aromatase' (rs2899472, NCAM2, and multiple SNPs located on chromosome 10 near the ARL5B gene demonstrated the strongest associations with Aβ1-42 in normal subjects. Two genes found to be near the top SNPs, CYP19A1 (rs2899472, p = 1.90 × 10-7 and NCAM2 (rs1022442, p = 2.75 × 10-7 have been reported as genetic

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

    Directory of Open Access Journals (Sweden)

    Kastanis Alkibiadis

    2011-01-01

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

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

    NARCIS (Netherlands)

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

    2009-01-01

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

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

    NARCIS (Netherlands)

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

    2009-01-01

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

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

    NARCIS (Netherlands)

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

    2009-01-01

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

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

    NARCIS (Netherlands)

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

    2009-01-01

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

  15. Association studies in Populus tomentosa reveal the genetic interactions of Pto-MIR156c and its targets in wood formation

    Directory of Open Access Journals (Sweden)

    Mingyang Quan

    2016-08-01

    Full Text Available MicroRNAs (miRNAs regulate gene expression in many biological processes, but the significance of the interaction between a miRNA and its targets in perennial trees remains largely unknown. Here, we employed transcript profiling and association studies in Populus tomentosa (Pto to decipher the effect of genetic variation and interactions between Pto-miR156c and its potential targets (Pto-SPL15, Pto-SPL20, and Pto-SPL25 in 435 unrelated individuals from a natural population of P. tomentosa. Single-SNP (single-nucleotide polymorphism based association studies with analysis of the underlying additive and dominant effects identified 69 significant associations (P 0.05 from Pto-MIR156c and its three potential targets, with six wood and growth traits, revealing their common roles in wood formation. Epistasis analysis uncovered 129 significant SNP-SNP associations with ten traits, indicating the potential genetic interactions of Pto-MIR156c and its three putative targets. Interestingly, expression analysis in stem (phloem, cambium, and xylem revealed that Pto-miR156c expression showed strong negative correlations with Pto-SPL20 (r = -0.90, P < 0.01 and Pto-SPL25 (r = -0.65, P < 0.01, and a positive correlation with Pto-SPL15 (r = 0.40, P < 0.01, which also indicated the putative interactions of Pto-miR156c and its potential targets and their common roles in wood formation. Thus, our study provided an alternative approach to decipher the interaction between miRNAs and their targets and to dissect the genetic architecture of complex traits in trees.

  16. Distinct genetic loci control plasma HIV-RNA and cellular HIV-DNA levels in HIV-1 infection: the ANRS Genome Wide Association 01 study.

    Directory of Open Access Journals (Sweden)

    Cyril Dalmasso

    Full Text Available Previous studies of the HIV-1 disease have shown that HLA and Chemokine receptor genetic variants influence disease progression and early viral load. We performed a Genome Wide Association study in a cohort of 605 HIV-1-infected seroconverters for detection of novel genetic factors that influence plasma HIV-RNA and cellular HIV-DNA levels. Most of the SNPs strongly associated with HIV-RNA levels were localised in the 6p21 major histocompatibility complex (MHC region and were in the vicinity of class I and III genes. Moreover, protective alleles for four disease-associated SNPs in the MHC locus (rs2395029, rs13199524, rs12198173 and rs3093662 were strikingly over-represented among forty-five Long Term HIV controllers. Furthermore, we show that the HIV-DNA levels (reflecting the HIV reservoir are associated with the same four SNPs, but also with two additional SNPs on chromosome 17 (rs6503919; intergenic region flanked by the DDX40 and YPEL2 genes and chromosome 8 (rs2575735; within the Syndecan 2 gene. Our data provide evidence that the MHC controls both HIV replication and HIV reservoir. They also indicate that two additional genomic loci may influence the HIV reservoir.

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

    Directory of Open Access Journals (Sweden)

    Jojanneke A Bastiaansen

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

  18. 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.

  19. Stroke Genetics Network (SiGN) study: design and rationale for a genome-wide association study of ischemic stroke subtypes.

    Science.gov (United States)

    Meschia, James F; Arnett, Donna K; Ay, Hakan; Brown, Robert D; Benavente, Oscar R; Cole, John W; de Bakker, Paul I W; Dichgans, Martin; Doheny, Kimberly F; Fornage, Myriam; Grewal, Raji P; Gwinn, Katrina; Jern, Christina; Conde, Jordi Jimenez; Johnson, Julie A; Jood, Katarina; Laurie, Cathy C; Lee, Jin-Moo; Lindgren, Arne; Markus, Hugh S; McArdle, Patrick F; McClure, Leslie A; Mitchell, Braxton D; Schmidt, Reinhold; Rexrode, Kathryn M; Rich, Stephen S; Rosand, Jonathan; Rothwell, Peter M; Rundek, Tatjana; Sacco, Ralph L; Sharma, Pankaj; Shuldiner, Alan R; Slowik, Agnieszka; Wassertheil-Smoller, Sylvia; Sudlow, Cathie; Thijs, Vincent N S; Woo, Daniel; Worrall, Bradford B; Wu, Ona; Kittner, Steven J

    2013-10-01

    Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The National Institute of Neurological Disorders and Stroke SiGN (Stroke Genetics Network) contributes substantially to meta-analyses that focus on specific subtypes of stroke. The National Institute of Neurological Disorders and Stroke SiGN includes ischemic stroke cases from 24 genetic research centers: 13 from the United States and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the Web-based causative classification of stroke system, with data entered by trained and certified adjudicators at participating genetic research centers. Through the Center for Inherited Diseases Research, the Network plans to genotype 10,296 carefully phenotyped stroke cases using genome-wide single nucleotide polymorphism arrays and adds to these another 4253 previously genotyped cases, for a total of 14,549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. Center for Inherited Diseases Research-generated genotypes and corresponding phenotypes will be shared with the scientific community through the US National Center for Biotechnology Information database of Genotypes and Phenotypes, and brain MRI studies will be centrally archived. The Stroke Genetics Network, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.

  20. Genome-wide association study reveals genetic architecture of eating behavior in pigs and its implications for humans obesity by comparative mapping

    DEFF Research Database (Denmark)

    Do, Duy Ngoc; Strathe, Anders Bjerring; Ostersen, Tage

    2013-01-01

    are important for genetic improvement of pig feed efficiency. We have also conducted pig-human comparative gene mapping to reveal key genomic regions and/or genes on the human genome that may influence eating behavior in human beings and consequently affect the development of obesity and metabolic syndrome......This study was aimed at identifying genomic regions controlling feeding behavior in Danish Duroc boars and its potential implications for eating behavior in humans. Data regarding individual daily feed intake (DFI), total daily time spent in feeder (TPD), number of daily visits to feeder (NVD......1, PTPN4, MTMR4 and RNGTT) and positive regulation of peptide secretion genes (GHRH, NNAT and TCF7L2) were highly significantly associated with feeding behavior traits. This is the first GWAS to identify genetic variants and biological mechanisms for eating behavior in pigs and these results...

  1. Genome-wide association study reveals genetic architecture of eating behavior in pigs and its implications for humans obesity by comparative mapping

    DEFF Research Database (Denmark)

    Do, Duy Ngoc; Strathe, Anders Bjerring; Ostersen, Tage;

    2013-01-01

    are important for genetic improvement of pig feed efficiency. We have also conducted pig-human comparative gene mapping to reveal key genomic regions and/or genes on the human genome that may influence eating behavior in human beings and consequently affect the development of obesity and metabolic syndrome......This study was aimed at identifying genomic regions controlling feeding behavior in Danish Duroc boars and its potential implications for eating behavior in humans. Data regarding individual daily feed intake (DFI), total daily time spent in feeder (TPD), number of daily visits to feeder (NVD......1, PTPN4, MTMR4 and RNGTT) and positive regulation of peptide secretion genes (GHRH, NNAT and TCF7L2) were highly significantly associated with feeding behavior traits. This is the first GWAS to identify genetic variants and biological mechanisms for eating behavior in pigs and these results...

  2. 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

  3. Genetic contribution for non-syndromic cleft lip with or without cleft palate (NS CL/P) in different regions of Brazil and implications for association studies.

    Science.gov (United States)

    Brito, Luciano A; Cruz, Lucas A; Rocha, Kátia M; Barbara, Ligia K; Silva, Camila B F; Bueno, Daniela F; Aguena, Meire; Bertola, Débora R; Franco, Diogo; Costa, André M; Alonso, Nivaldo; Otto, Paulo A; Passos-Bueno, Maria Rita

    2011-07-01

    Non-syndromic cleft lip with or without cleft palate (NS CL/P) is a complex disease in which heritability estimates vary widely depending on the population studied. To evaluate the importance of genetic contribution to NS CL/P in the Brazilian population, we conducted a study with 1,042 families from five different locations (Santarém, Fortaleza, Barbalha, Maceió, and Rio de Janeiro). We also evaluated the role of consanguinity and ethnic background. The proportion of familial cases varied significantly across locations, with the highest values found in Santarém (44%) and the lowest in Maceió (23%). Heritability estimates showed a higher genetic contribution to NS CL/P in Barbalha (85%), followed by Santarém (71%), Rio de Janeiro (70%), Fortaleza (64%), and Maceió (45%). Ancestry was not correlated with the occurrence of NS CL/P or with the variability in heritability. Only in Rio de Janeiro was the coefficient of inbreeding significantly larger in NS CL/P families than in the local population. Recurrence risk for the total sample was approximately 1.5-1.6%, varying according to the location studied (0.6-0.7% in Maceió to 2.2-2.8% in Barbalha). Our findings show that the degree of genetic contribution to NS CL/P varies according to the geographic region studied, and this difference cannot be attributed to consanguinity or ancestry. These findings suggest that Barbalha is a promising region for genetic studies. The data presented here will be useful in interpreting results from molecular analyses and show that care must be taken when pooling samples from different populations for association studies.

  4. Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study.

    Science.gov (United States)

    Naj, Adam C; Jun, Gyungah; Reitz, Christiane; Kunkle, Brian W; Perry, William; Park, Yo Son; Beecham, Gary W; Rajbhandary, Ruchita A; Hamilton-Nelson, Kara L; Wang, Li-San; Kauwe, John S K; Huentelman, Matthew J; Myers, Amanda J; Bird, Thomas D; Boeve, Bradley F; Baldwin, Clinton T; Jarvik, Gail P; Crane, Paul K; Rogaeva, Ekaterina; Barmada, M Michael; Demirci, F Yesim; Cruchaga, Carlos; Kramer, Patricia L; Ertekin-Taner, Nilufer; Hardy, John; Graff-Radford, Neill R; Green, Robert C; Larson, Eric B; St George-Hyslop, Peter H; Buxbaum, Joseph D; Evans, Denis A; Schneider, Julie A; Lunetta, Kathryn L; Kamboh, M Ilyas; Saykin, Andrew J; Reiman, Eric M; De Jager, Philip L; Bennett, David A; Morris, John C; Montine, Thomas J; Goate, Alison M; Blacker, Deborah; Tsuang, Debby W; Hakonarson, Hakon; Kukull, Walter A; Foroud, Tatiana M; Martin, Eden R; Haines, Jonathan L; Mayeux, Richard P; Farrer, Lindsay A; Schellenberg, Gerard D; Pericak-Vance, Margaret A; Albert, Marilyn S; Albin, Roger L; Apostolova, Liana G; Arnold, Steven E; Barber, Robert; Barnes, Lisa L; Beach, Thomas G; Becker, James T; Beekly, Duane; Bigio, Eileen H; Bowen, James D; Boxer, Adam; Burke, James R; Cairns, Nigel J; Cantwell, Laura B; Cao, Chuanhai; Carlson, Chris S; Carney, Regina M; Carrasquillo, Minerva M; Carroll, Steven L; Chui, Helena C; Clark, David G; Corneveaux, Jason; Cribbs, David H; Crocco, Elizabeth A; DeCarli, Charles; DeKosky, Steven T; Dick, Malcolm; Dickson, Dennis W; Duara, Ranjan; Faber, Kelley M; Fallon, Kenneth B; Farlow, Martin R; Ferris, Steven; Frosch, Matthew P; Galasko, Douglas R; Ganguli, Mary; Gearing, Marla; Geschwind, Daniel H; Ghetti, Bernardino; Gilbert, John R; Glass, Jonathan D; Growdon, John H; Hamilton, Ronald L; Harrell, Lindy E; Head, Elizabeth; Honig, Lawrence S; Hulette, Christine M; Hyman, Bradley T; Jicha, Gregory A; Jin, Lee-Way; Karydas, Anna; Kaye, Jeffrey A; Kim, Ronald; Koo, Edward H; Kowall, Neil W; Kramer, Joel H; LaFerla, Frank M; Lah, James J; Leverenz, James B; Levey, Allan I; Li, Ge; Lieberman, Andrew P; Lin, Chiao-Feng; Lopez, Oscar L; Lyketsos, Constantine G; Mack, Wendy J; Martiniuk, Frank; Mash, Deborah C; Masliah, Eliezer; McCormick, Wayne C; McCurry, Susan M; McDavid, Andrew N; McKee, Ann C; Mesulam, Marsel; Miller, Bruce L; Miller, Carol A; Miller, Joshua W; Murrell, Jill R; Olichney, John M; Pankratz, Vernon S; Parisi, Joseph E; Paulson, Henry L; Peskind, Elaine; Petersen, Ronald C; Pierce, Aimee; Poon, Wayne W; Potter, Huntington; Quinn, Joseph F; Raj, Ashok; Raskind, Murray; Reisberg, Barry; Ringman, John M; Roberson, Erik D; Rosen, Howard J; Rosenberg, Roger N; Sano, Mary; Schneider, Lon S; Seeley, William W; Smith, Amanda G; Sonnen, Joshua A; Spina, Salvatore; Stern, Robert A; Tanzi, Rudolph E; Thornton-Wells, Tricia A; Trojanowski, John Q; Troncoso, Juan C; Valladares, Otto; Van Deerlin, Vivianna M; Van Eldik, Linda J; Vardarajan, Badri N; Vinters, Harry V; Vonsattel, Jean Paul; Weintraub, Sandra; Welsh-Bohmer, Kathleen A; Williamson, Jennifer; Wishnek, Sarah; Woltjer, Randall L; Wright, Clinton B; Younkin, Steven G; Yu, Chang-En; Yu, Lei

    2014-11-01

    Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants. To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium. The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes. Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria. Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10(-96)), with associations in CR1 (rs6701713, P = 7.2 × 10(-4)), BIN1 (rs7561528, P = 4.8 × 10(-4)), and PICALM (rs561655, P = 2.2 × 10(-3)) reaching statistical significance (P Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.

  5. Genetic variants of interleukin-10 gene promoter are associated with schizophrenia in Saudi patients: A case-control study

    Directory of Open Access Journals (Sweden)

    Saeed Mohammad Al-Asmary

    2014-01-01

    Full Text Available Background: Interleukin-10 (IL-10 gene is considered as a potential candidate gene in schizophrenia association studies. The polymorphisms on IL-10 gene have been reported to be linked with susceptibility to the development of schizophrenia within consistent results. Aims: The aim of this case-control study was to examine whether the -1082A/G, -819T/C, and -592A/C polymorphisms in IL-10 gene are implicated in schizophrenia development in the Saudi population. Materials and Methods: Molecular genotyping of IL-10 gene polymorphisms was performed to analyze the genotypes and alleles distribution of three single-nucleotide polymorphisms (SNPs in patients (n = 181 and healthy individuals as control group (n = 211. Results: The frequencies of GA genotype at -1082, and CC genotype at positions -592 and -819 were significantly higher in schizophrenia patients compared to healthy subjects suggesting that GA, CC, and CC genotypes are susceptible to schizophrenia. The ACC haplotype known to be associated with intermediate production of IL-10 are more prevalent in our schizophrenia patients. On the other hand, genotypes -1082 GG, -819 CT, and -592 CA of IL-10 were more prevalent in healthy controls suggesting protective effects of GA, CT, and CA genotypes against schizophrenia. There was no significant association of IL-10 polymorphisms with sex or positive or negative symptoms of schizophrenia. Conclusion: This study indicates that the IL-10 gene polymorphisms play a significant role in the etiology of schizophrenia in Saudi Arabians patients.

  6. 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.

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

    Science.gov (United States)

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

    2016-10-01

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

  8. Immunologic, genetic and social human risk factors associated to histoplasmosis: studies in the State of Guerrero, Mexico.

    Science.gov (United States)

    Taylor, M L; Pérez-Mejía, A; Yamamoto-Furusho, J K; Granados, J

    1997-01-01

    Immunologic and occupational aspects of the susceptible population exposed to Histoplasma capsulatum, the causative agent of histoplasmosis were analyzed in the Mexican State of Guerrero. Three areas were studied, Juxtlahuaca, Olinala, and Coyuca; in the first two, their populations refer contact with bat guano and/or avian excreta, which contain nutrients for fungal growth, while the Coyuca population referred no contact with the above mentioned excreta. Previous infection with H. capsulatum was determined by histoplasmin-skin test, and the response was higher in men than in women (93.87, 85.71, and 6.6% for men, and 78.94, 66.6, and 0% for women) in Juxtlahuaca, Olinala, and Coyuca, respectively. Labor activities related to a persistent contact with the fungus were considered as an occupational risk factor, histoplasmin-skin test reached 88.57 and 36.36% of positive response in individuals with high and low risk activities. A high percentage of histoplasmin responses was observed in subjects with constant contact with H. capsulatum, such as, cave-tourist guides, peasants, and game-cock handlers, and generally they developed the largest diameter of skin reactions. Genetic risk factor was determined by studying the gene frequency of the Major Histocompatibility Complex antigens in a sample of individuals and their degree relatives in Juxtlahuaca, Olinala, and Coyuca. Significant differences were found for HLA-B22 and B17 antigens in Juxtlahuaca, and for HLA-B22 in Olinala, in comparison to the usual gene frequency observed in the normal Mexican population. HLA results were important, considering that HLA-B22 was previously found to be possibly related to pulmonary histoplasmosis in Guerrero.

  9. Genetic Associations with Gestational Duration and Spontaneous Preterm Birth

    DEFF Research Database (Denmark)

    Zhang, Ge; Feenstra, Bjarke; Bacelis, Jonas

    2017-01-01

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

  10. Genetical Genomics for Evolutionary Studies

    NARCIS (Netherlands)

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

    2012-01-01

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

  11. Defining asthma in genetic studies

    NARCIS (Netherlands)

    Koppelman, GH; Postma, DS; Meijer, G.

    1999-01-01

    Genetic studies have been hampered by the lack of a gold standard to diagnose asthma. The complex nature of asthma makes it more difficult to identify asthma genes. Therefore, approaches to define phenotypes, which have been successful in other genetically complex diseases, may be applied to define

  12. Defining asthma in genetic studies

    NARCIS (Netherlands)

    Koppelman, GH; Postma, DS; Meijer, G.

    1999-01-01

    Genetic studies have been hampered by the lack of a gold standard to diagnose asthma. The complex nature of asthma makes it more difficult to identify asthma genes. Therefore, approaches to define phenotypes, which have been successful in other genetically complex diseases, may be applied to define

  13. Association study between the rs165599 catechol-O-methyltransferase genetic polymorphism and schizophrenia in a Brazilian sample

    Directory of Open Access Journals (Sweden)

    Quirino Cordeiro

    2012-12-01

    Full Text Available Schizophrenia is a severe psychiatric disorder with frequent recurrent psychotic relapses and progressive functional impairment. It results from a poorly understood gene-environment interaction. The gene encoding catechol-O-methyltransferase (COMT is a likely candidate for schizophrenia. Its rs165599 (A/G polymorphism has been shown to be associated with alteration of COMT gene expression. Therefore, the present study aimed to investigate a possible association between schizophrenia and this polymorphism. The distribution of the alleles and genotypes of this polymorphism was investigated in a Brazilian sample of 245 patients and 834 controls. The genotypic frequencies were in Hardy-Weinberg equilibrium and no statistically significant differences were found between cases and controls when analyzed according to gender or schizophrenia subtypes. There was also no difference in homozygosis between cases and controls. Thus, in the sample studied, there was no evidence of any association between schizophrenia and rs165599 (A/G polymorphism in the non-coding region 3' of the COMT gene.

  14. Genetic variants and clinical relevance associated with gestational diabetes mellitus in Chinese women: a case-control study.

    Science.gov (United States)

    Yan, Jie; Su, Rina; Ao, Deng; Wang, Yan; Wang, Haijun; Yang, Huixia

    2017-06-14

    Gestational diabetes mellitus (GDM) may share similar mechanisms with type 2 diabetes and obesity. In the current study, we aimed to verify twenty genes reported to be associated with type 2 diabetes and obesity in the Chinese GDM population. Pregnant women aged 20-49 years at 24-28 gestational weeks were recruited and 556 cases and 445 controls were enrolled in the study. The genotyping of single nucleotide polymorphisms (SNPs) was performed on peripheral blood samples. We discovered that GDM was associated with rs945508 (OR = 1.368, 95% CI = 1.080-1.732, p = .009), rs10804591 (OR = 1.446, 95% CI = 1.192-1.754, p diabetes and obesity may also increase the risk of developing GDM in the Chinese population. Among these SNPs, we report for the first time that rs945508 in ARHGEF11, rs10804591 in PLXND1 and rs10245353 in NFE2L3 were associated with GDM.

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

    Science.gov (United States)

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

    2011-03-01

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

  16. Genetic Associations with Gestational Length and Spontaneous Preterm Birth

    Science.gov (United States)

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

    2017-01-01

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

  17. Genetic variants of Complement factor H gene are not associated with premature coronary heart disease: a family-based study in the Irish population

    OpenAIRE

    Kee Frank; Horan Paul G; Kamaruddin Muhammad S; Belton Christine; Patterson Chris C; Hughes Anne; Meng Weihua; McKeown Pascal P

    2007-01-01

    Abstract Background The complement factor H (CFH) gene has been recently confirmed to play an essential role in the development of age-related macular degeneration (AMD). There are conflicting reports of its role in coronary heart disease. This study was designed to investigate if, using a family-based approach, there was an association between genetic variants of the CFH gene and risk of early-onset coronary heart disease. Methods We evaluated 6 SNPs and 5 common haplotypes in the CFH gene a...

  18. 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

  19. Association of novel genetic loci with circulating fibrinogen levels a genome-wide association study in 6 population-based cohorts

    NARCIS (Netherlands)

    A. Dehghan (Abbas); Q. Yang (Qiong Fang); A. Peters (Annette); S. Basu (Saonli); J.C. Bis (Joshua); A.R. Rudnicka (Alicja); M. Kavousi (Maryam); M-H. Chen (Ming-Huei); J. Baumert (Jens); G.D.O. Lowe (Gordon); B. McKnight (Barbara); W. Tang (Weihong); M.P.M. de Maat (Moniek); M.G. Larson (Martin); S. Eyhermendy (Susana); W.L. McArdle (Wendy); T. Lumley (Thomas); J.S. Pankow (James); A. Hofman (Albert); J. Massaro (Joseph); F. Rivadeneira Ramirez (Fernando); M. Kolz (Melanie); K.D. Taylor (Kent); P. Tikka-Kleemola (Päivi); S. Kathiresan (Sekar); T. Illig (Thomas); Y.S. Aulchenko (Yurii); K.A. Volcik (Kelly); A.D. Johnson (Andrew); A.G. Uitterlinden (André); G.H. Tofler (Geoffrey); C. Gieger (Christian); B.M. Psaty (Bruce); D.J. Couper (David); E.A. Boerwinkle (Eric); W. Koenig (Wolfgang); C.J. O'Donnell (Christopher); J.C.M. Witteman (Jacqueline); D.P. Strachan (David); N.L. Smith (Nicholas); A.R. Folsom (Aaron)

    2009-01-01

    textabstractBackground: Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels. Methods and Results: We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study

  20. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

    NARCIS (Netherlands)

    G.B. Ehret (Georg); T. Ferreira (Teresa); D.I. Chasman (Daniel); A.U. Jackson (Anne); E.M. Schmidt (Ellen); T. Johnson (Toby); G. Thorleifsson (Gudmar); J. Luan (Jian'An); L.A. Donnelly (Louise); S. Kanoni (Stavroula); A.K. Petersen; V. Pihur (Vasyl); R.J. Strawbridge (Rona); D. Shungin (Dmitry); Hughes, M.F. (Maria F.); O. Meirelles; M. Kaakinen (Marika); N. Bouatia-Naji (Nabila); K. Kristiansson (Kati); S. Shah (Sonia); M.E. Kleber (Marcus); X. Guo (Xiuqing); L.-P. Lyytikäinen (Leo-Pekka); C. Fava (Cristiano); N. Eriksson (Niclas); I.M. Nolte (Ilja); P.K. Magnusson (Patrik); E. Salfati (Elias); L.S. Rallidis (Loukianos); Theusch, E. (Elizabeth); A.J.P. Smith; L. Folkersen (Lasse); H.E. Witkowska (Ewa); T.H. Pers (Tune); R. Joehanes (Roby); Kim, S.K. (Stuart K.); L. Lataniotis (Lazaros); R. Jansen; A.D. Johnson (Andrew); H. Warren (Helen); Y.J. Kim; Zhao, W. (Wei); Y. Wu (Ying); B. Tayo (Bamidele); M. Bochud (Murielle); D. Absher (Devin); L.S. Adair (Linda); N. Amin (Najaf); D.E. Arking (Dan); T. Axelsson (Tomas); D. Baldassarre (Damiano); B. Balkau (Beverley); S. Bandinelli (Stefania); M. Barnes (Michael); I. Barroso (Inês); Bevan, S. (Stephen); J.C. Bis (Joshua); Bjornsdottir, G. (Gyda); M. Boehnke (Michael); E.A. Boerwinkle (Eric); L.L. Bonnycastle (Lori); D.I. Boomsma (Dorret); S.R. Bornstein (Stefan); M.J. Brown (Morris); M. Burnier (Michel); Cabrera, C.P. (Claudia P.); J.C. Chambers (John); Chang, I.-S. (I-Shou); Cheng, C.-Y. (Ching-Yu); P.S. Chines (Peter); Chung, R.-H. (Ren-Hua); F.S. Collins (Francis); Connell, J.M. (John M.); A. Döring (Angela); J. Dallongeville; J. Danesh (John); U. de Faire (Ulf); G. Delgado; A. Dominiczak (Anna); A.S.F. Doney (Alex); F. Drenos (Fotios); T. Edkins (Ted); Eicher, J.D. (John D.); R. Elosua (Roberto); S. Enroth (Stefan); J. Erdmann (Jeanette); P. Eriksson (Per); T. Esko (Tõnu); E. Evangelou (Evangelos); A. Evans (Alun); M. Fall (Magnus); M. Farrall (Martin); J.F. Felix (Janine); J. Ferrieres (Jean); L. Ferrucci (Luigi); M. Fornage (Myriam); T. Forrester (Terrence); N. Franceschini (Nora); O.H. Franco (Oscar); A. Franco-Cereceda (Anders); R.M. Fraser (Ross); S.K. Ganesh (Santhi); Gao, H. (He); K. Gertow (Karl); F. Gianfagna (Francesco); B. Gigante (Bruna); F. Giulianini (Franco); A. Goel (Anuj); A.H. Goodall (Alison); M. Goodarzi (Mark); M. Gorski (Mathias); J. Gräßler (Jürgen); C.J. Groves (Christopher); V. Gudnason (Vilmundur); U. Gyllensten (Ulf); G. Hallmans (Göran); A.L. Hartikainen; Hassinen, M. (Maija); A.S. Havulinna (Aki); C. Hayward (Caroline); S. Hercberg (Serge); K.H. Herzig; A.A. Hicks (Andrew); A. Hingorani (Aroon); J.N. Hirschhorn (Joel); Hofman, A. (Albert); Holmen, J. (Jostein); O.L. Holmen (Oddgeir); J.J. Hottenga (Jouke Jan); P. Howard (Philip); Hsiung, C.A. (Chao A.); S.C. Hunt (Steven); M.K. Ikram (Kamran); T. Illig (Thomas); C. Iribarren (Carlos); Jensen, R.A. (Richard A.); M. Kähönen (Mika); H.M. Kang (Hyun Min); S. Kathiresan (Sekar); J. Keating (John); K.T. Khaw; Y.K. Kim (Yun Kyoung); E. Kim (Eric); M. Kivimaki (Mika); N. Klopp (Norman); Kolovou, G. (Genovefa); P. Komulainen (Pirjo); J.S. Kooner (Jaspal S.); Kosova, G. (Gulum); R.M. Krauss (Ronald); D. Kuh (Diana); Z. Kutalik (Zoltán); J. Kuusisto (Johanna); K. Kvaløy (Kirsti); T.A. Lakka (Timo); N.R. Lee (Nanette); I.T. Lee; W.-J. Lee (Wen-Jane); D. Levy (Daniel); X. Li (Xiaohui); Liang, K.-W. (Kae-Woei); Lin, H. (Honghuang); Lin, L. (Li); J. Lindström (Jaana); S. Lobbens (Stéphane); S. Männistö (Satu); G. Müller (Gabriele); M. Müller-Nurasyid (Martina); F. MacH (François); H.S. Markus (Hugh); E. Marouli (Eirini); M.I. McCarthy (Mark); C.A. McKenzie (Colin); P. Meneton (Pierre); C. Menni (Cristina); A. Metspalu (Andres); Mijatovic, V. (Vladan); L. Moilanen (Leena); M.E. Montasser (May E.); A.D. Morris (Andrew); A.C. Morrison (Alanna); Mulas, A. (Antonella); R. Nagaraja (Ramaiah); N. Narisu (Narisu); K. Nikus (Kjell); C.J. O'Donnell (Christopher); P.F. O'Reilly (Paul); K.K. Ong (Ken); Paccaud, F. (Fred); C. Palmer (Cameron); A. Parsa (Afshin); N.L. Pedersen (Nancy); B.W.J.H. Penninx (Brenda); M. Perola (Markus); A. Peters (Annette); N.R. Poulter (Neil); P.P. Pramstaller (Peter Paul); B.M. Psaty (Bruce); T. Quertermous (Thomas); D.C. Rao (Dabeeru C.); A. Rasheed (Asif); N.W. Rayner (Nigel William); F. Renström (Frida); R. Rettig (Rainer); K.M. Rice (Kenneth); R. Roberts (Robert); L.M. Rose (Lynda); Rossouw, J. (Jacques); N.J. Samani (Nilesh); S. Sanna (Serena); J. Saramies (Jouko); H. Schunkert (Heribert); S. Sebert (Sylvain); Sheu, W.H.-H. (Wayne H.-H.); Shin, Y.-A. (Young-Ah); X. Sim (Xueling); G.D. Smith; A.V. Smith (Albert Vernon); M.X. Sosa (Maria X.); T.D. Spector (Timothy); A. Stancáková (Alena); A. Stanton (Alice); K. Stirrups (Kathy); H.M. Stringham (Heather); Sundstrom, J. (Johan); A.J. Swift (Amy); A.C. Syvänen; Tai, E.-S. (E-Shyong); T. Tanaka (Toshiko); K.V. Tarasov (Kirill); A. Teumer (Alexander); U. Thorsteinsdottir (Unnur); M.D. Tobin (Martin); E. Tremoli (Elena); Uitterlinden, A.G. (Andre G.); M. Uusitupa (Matti); A. Vaez (Ahmad); D. Vaidya (Dhananjay); Van Duijn, C.M. (Cornelia M.); E.P.A. van Iperen (Erik); Vasan, R.S. (Ramachandran S.); G.C. Verwoert (Germaine); J. Virtamo (Jarmo); Vitart, V. (Veronique); B.F. Voight (Benjamin); P. Vollenweider (Peter); Wagner, A. (Aline); Wain, L.V. (Louise V.); N.J. Wareham (Nick); H. Watkins (Hugh); A.B. Weder (Alan); H.J. Westra (Harm-Jan); Wilks, R. (Rainford); T. Wilsgaard (Tom); J.F. Wilson (James F.); Wong, T.Y. (Tien Y.); T.-P. Yang (Tsun-Po); J. Yao (Jiefen); L. Yengo (Loic); W. Zhang (Weihua); J.H. Zhao; X. Zhu (Xiaofeng); P. Bovet (Pascal); Cooper, R.S. (Richard S.); K.L. Mohlke (Karen); Saleheen, D. (Danish); J.-Y. Lee (Jong-Young); P. Elliott (Paul); L.M. Gierman (Lobke); C.J. Willer (Cristen); L. Franke (Lude); G. Kees Hovingh; K.D. Taylor (Kent); G.V. Dedoussis (George); P. Sever (Peter); A. Wong (Andrew); W.H.L. Kao (Wen); T.L. Assimes (Themistocles); I. Njølstad (Inger); P.E.H. Schwarz (Peter); C. Langenberg (Claudia); H. Snieder (Harold); M. Caulfield (Mark); O. Melander (Olle); M. Laakso (Markku); J. Saltevo (Juha); R. Rauramaa (Rainer); J. Tuomilehto (Jaakko); Ingelsson, E. (Erik); T. Lehtimäki (Terho); K. Hveem (Kristian); W. Palmas (Walter); W. März (Winfried); M. Kumari (Meena); V. Salomaa (Veikko); Y.D. Chen (Y.); Rotter, J.I. (Jerome I.); P. Froguel (Philippe); M.-R. Jarvelin (Marjo-Riitta); E. Lakatta (Edward); K. Kuulasmaa (Kari); P.W. Franks (Paul); A. Hamsten (Anders); H.E. Wichmann (Heinz Erich); C.N.A. Palmer (Colin); Stefansson, K. (Kari); P.M. Ridker (Paul); R.J.F. Loos (Ruth); A. Chakravarti (Aravinda); P. Deloukas (Panagiotis); A.P. Morris (Andrew); C. Newton-Cheh (C.); P. Munroe (Patricia)

    2016-01-01

    textabstractTo dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We

  1. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

    NARCIS (Netherlands)

    Ehret, Georg B.; Ferreira, Teresa; Chasman, Daniel I.; Jackson, Anne U.; Schmidt, Ellen M.; Johnson, Toby; Thorleifsson, Gudmar; Luan, Jian'an; Donnelly, Louise A.; Kanoni, Stavroula; Petersen, Ann -Kristin; Pihurl, Vasyl; Strawbridge, Rona J.; Shungin, Dmitry; Hughes, Maria F.; Meirelles, Osorio; Kaakinen, Marika; Bouatia-Naji, Nabila; Kristiansson, Kati; Shah, Sonia; Kleber, Marcus E.; Guo, Xiuqing; Lyytikainen, Leo-Pekka; Fava, Cristiano; Eriksson, Nidas; Nolte, Ilja M.; Magnusson, Patrik K.; Salfati, Elias L.; Rallidis, Loukianos S.; Theusch, Elizabeth; Smith, Andrew J. P.; Folkersen, Lasse; Witkowska, Kate; Pers, Tune H.; Joehanes, Roby; Kim, Stuart K.; Lataniotis, Lazaros; Jansen, Rick; Johnson, Andrew D.; Warren, Helen; Kim, Young Jin; Zhao, Wei; Wu, Ying; Tayo, Bamidele O.; Bochud, Murielle; Absher, Devin; Adair, Linda S.; Amin, Najaf; Arkingl, Dan E.; Axelsson, Tomas; Baldassarre, Damian; Balkau, Beverley; Bandinelli, Stefania; Barnes, Michael R.; Barroso, Ines; Bevan, Stephen; Bis, Joshua C.; Bjornsdottir, Gyda; Boehnke, Michael; Boerwinkle, Eric; Bonnycastle, Lori L.; Boomsma, Dorret I.; Bornstein, Stefan R.; Brown, Morris J.; Burnier, Michel; Cabrera, Claudia P.; Chambers, John C.; Chang, I-Shou; Cheng, Ching-Yu; Chines, Peter S.; Chung, Ren-Hua; Collins, Francis S.; Connell, John M.; Doring, Angela; Dallongeville, Jean; Danesh, John; de Faire, Ulf; Delgado, Graciela; Dominiczak, Anna F.; Doney, Alex S. F.; Drenos, Fotios; Edkins, Sarah; Eicher, John D.; Elosua, Roberto; Enroth, Stefan; Erdmann, Jeanette; Eriksson, Per; Esko, Tonu; Evangelou, Evangelos; Evans, Alun; Fai, Tove; Farra, Martin; Felixl, Janine F.; Ferrieres, Jean; Ferrucci, Luigi; Fornage, Myriam; Forrester, Terrence; Franceschinil, Nora; Franco, Oscar H.; Franco-Cereceda, Anders; Fraser, Ross M.; Ganesh, Santhi K.; Gao, He; Gertow, Karl; Gianfagna, Francesco; Gigante, Bruna; Giulianini, Franco; Goe, Anuj; Goodall, Alison H.; Goodarzi, Mark; Gorski, Mathias; Grassler, Jurgen; Groves, Christopher J.; Gudnason, Vilmundur; Gyllensten, Ulf; Hallmans, Goran; Hartikainen, Anna-Liisa; Hassinen, Maija; Havulinna, Aki S.; Hayward, Caroline; Hercberg, Serge; Herzig, Karl-Heinz; Hicks, Andrew A.; Hingorani, Aroon D.; Hirschhorn, Joel N.; Hofmanl, Albert; Holmen, Jostein; Holmen, Oddgeir Lingaas; Hottenga, Jouke-Jan; Howard, Phil; Hsiung, Chao A.; Hunt, Steven C.; Ikram, M. Arfan; Illig, Thomas; Iribarren, Carlos; Jensen, Richard A.; Kahonen, Mika; Kang, Hyun Min; Kathiresan, Sekar; Keating, Brendan J.; Khaw, Kay-Tee; Kim, Yun Kyoung; Kim, Eric; Kivimaki, Mika; Klopp, Norman; Kolovou, Genovefa; Komulainen, Pirjo; Kooner, Jaspal S.; Kosova, Gulum; Krauss, Ronald M.; Kuh, Diana; Kutalik, Zoltan; Kuusisto, Johanna; Kvaloy, Kirsti; Lakka, Timo A.; Lee, Nanette R.; Lee, I-Te; Lee, Wen-Jane; Levy, Daniel; Li, Xiaohui; Liang, Kae-Woei; Lin, Honghuang; Lin, Li; Lindstrom, Jaana; Lobbens, Stephane; Mannisto, Satu; Muller, Gabriele; Muller-Nurasyid, Martina; Mach, Francois; Markus, Hugh S.; Marouli, Eirini; McCarthy, Mark I.; McKenzie, Colin A.; Meneton, Pierre; Menni, Cristina; Metspalu, Andres; Mijatovic, Vladan; Moilanen, Leena; Montasser, May E.; Morris, Andrew D.; Morrison, Alanna C.; Mulas, Antonella; Nagaraja, Ramaiah; Narisu, Narisu; Nikus, Kjell; O'Donnell, Christopher J.; O'Reilly, Paul F.; Ong, Ken K.; Paccaud, Fred; Palmer, Cameron D.; Parsa, Afshin; Pedersen, Nancy L.; Penninx, Brenda W.; Perola, Markus; Peters, Annette; Poulter, Neil; Pramstaller, Peter P.; Psaty, Bruce M.; Quertermous, Thomas; Rao, Dabeeru C.; Rasheed, Asif; Rayner, N. William; Renstrom, Frida; Rettig, Rainer; Rice, Kenneth M.; Roberts, Robert; Rose, Lynda M.; Rossouw, Jacques; Samani, Nilesh J.; Sanna, Serena; Saramies, Jouko; Schunkert, Heribert; Sebert, Sylvain; Sheu, Wayne H-H; Shin, Young-Ah; Sim, Xueling; Smit, Johannes H.; Smith, Albert V.; Sosa, Maria X.; Spector, Tim D.; Stancakova, Alena; Stanton, Alice V.; Stirrups, Kathleen E.; Stringham, Heather M.; Sundstrom, Johan; Swift, Amy J.; Syvanen, Ann-Christine; Tai, E-Shyong; Tanaka, Toshiko; Tarasov, Kirill V.; Teumer, Alexander; Thorsteinsdottir, Unnur; Tobin, Martin D.; Tremoli, Elena; Uitterlinden, Andre G.; Uusitupa, Matti; Vaez, Ahmad; Vaidya, Dhananjay; van Duijn, Cornelia M.; van Iperen, Erik P. A.; Vasan, Ramachandran S.; Verwoert, Germaine C.; Virtamo, Jarmo; Vitart, Veronique; Voight, Benjamin F.; Vollenweider, Peter; Wagner, Aline; Wain, Louise V.; Wareham, Nicholas J.; Watldns, Hugh; Weder, Alan B.; Westra, Harm Jan; Wilks, Rainford; Wilsgaard, Tom; Wilson, James F.; Wong, Tien Y.; Yang, Tsun-Po; Yao, Jie; Yengo, Loic; Zhang, Weihua; Zhao, Jing Hua; Zhu, Xiaofeng; Bovet, Pascal; Cooper, Richard S.; Mohlke, Karen L.; Saleheen, Danish; Lee, Jong-Young; Elliott, Paul; Gierman, Hinco J.; Willer, Cristen J.; Franke, Lude; Hovingh, G. Kees; Taylor, Kent D.; Dedoussis, George; Sever, Peter; Wong, Andrew; Lind, Lars; Assimes, Themistocles L.; Njolstad, Inger; Schwarz, Peter E. H.; Langenberg, Claudia; Snieder, Harold; Caulfield, Mark J.; Melander, E.; Laakso, Markku; Saltevo, Juha; Rauramaa, Rainer; Tuomilehto, Jaakko; Ingelsson, Erik; Lehtimaki, Terho; Hveem, Kristian; Palmas, Walter; Marz, Winfried; Kumar, Meena; Salomaa, Veikko; Chen, Yii-Der I.; Rotter, Jerome I.; Froguel, Philippe; Jarvelin, Marjo-Riitta; Lakatta, Edward G.; Kuulasmaa, Kari; Franks, Paul W.; Hamsten, Anders; Wichmann, H-Erich; Palmer, Colin N. A.; Stefansson, Kari; Ridker, Paul M.; Loos, Ruth J. F.; Chalcravarti, Aravinda; Deloukas, Panos; Morris, Andrew P.; Newton-Cheh, Christopher; Munroe, Patricia B.

    2016-01-01

    To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66

  2. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study

    NARCIS (Netherlands)

    Rauch, A.; Wieczorek, D.; Graf, E.; Wieland, T.; Endele, S.; Schwarzmayr, T.; Albrecht, B.; Bartholdi, D.; Beygo, J.; Donato, N. di; Dufke, A.; Cremer, K.; Hempel, M.; Horn, D.; Hoyer, J.; Joset, P.; Ropke, A.; Moog, U.; Riess, A.; Thiel, C.T.; Tzschach, A.; Wiesener, A.; Wohlleber, E.; Zweier, C.; Ekici, A.B.; Zink, A.M.; Rump, A.; Meisinger, C.; Grallert, H.; Sticht, H.; Schenck, A.; Engels, H.; Rappold, G.; Schrock, E.; Wieacker, P.; Riess, O.; Meitinger, T.; Reis, A.; Strom, T.M.

    2012-01-01

    BACKGROUND: The genetic cause of intellectual disability in most patients is unclear because of the absence of morphological clues, information about the position of such genes, and suitable screening methods. Our aim was to identify de-novo variants in individuals with sporadic non-syndromic intell

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

    DEFF Research Database (Denmark)

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

    2007-01-01

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

  4. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

    DEFF Research Database (Denmark)

    Aung, Tin; Ozaki, Mineo; Lee, Mei Chin

    2017-01-01

    and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24...... (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology....

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

    NARCIS (Netherlands)

    Bastiaansen, Jojanneke A.; Cummins, Tarrant D. R.; Riese, Harriette; van Roon, Arie; Nolte, Ilja M.; Oldehinkel, Albertine J.; Bellgrove, Mark A.

    2015-01-01

    The catecholamines dopamine and noradrenaline have been implicated in spontaneous low-frequency fluctuations in reaction time, which are associated with attention deficit hyperactivity disorder (ADHD) and subclinical attentional problems. The molecular genetic substrates of these behavioral phenotyp

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

    Science.gov (United States)

    Feitosa, Mary F.; Chu, Su; Czajkowski, Jacek; Esko, Tõnu; Fall, Tove; Kilpeläinen, Tuomas O.; Lu, Yingchang; Mägi, Reedik; Mihailov, Evelin; Pers, Tune H.; Rüeger, Sina; Teumer, Alexander; Ehret, Georg B.; Ferreira, Teresa; Heard-Costa, Nancy L.; Karjalainen, Juha; Lagou, Vasiliki; Mahajan, Anubha; Neinast, Michael D.; Prokopenko, Inga; Simino, Jeannette; Teslovich, Tanya M.; Jansen, Rick; Westra, Harm-Jan; White, Charles C.; Absher, Devin; Ahluwalia, Tarunveer S.; Ahmad, Shafqat; Albrecht, Eva; Alves, Alexessander Couto; Bragg-Gresham, Jennifer L.; de Craen, Anton J. M.; Bis, Joshua C.; Bonnefond, Amélie; Boucher, Gabrielle; Cadby, Gemma; Cheng, Yu-Ching; Chiang, Charleston W. K.; Delgado, Graciela; Demirkan, Ayse; Dueker, Nicole; Eklund, Niina; Eiriksdottir, Gudny; Eriksson, Joel; Feenstra, Bjarke; Fischer, Krista; Frau, Francesca; Galesloot, Tessel E.; Geller, Frank; Goel, Anuj; Gorski, Mathias; Grammer, Tanja B.; Gustafsson, Stefan; Haitjema, Saskia; Hottenga, Jouke-Jan; Huffman, Jennifer E.; Jackson, Anne U.; Jacobs, Kevin B.; Johansson, Åsa; Kaakinen, Marika; Kleber, Marcus E.; Lahti, Jari; Leach, Irene Mateo; Lehne, Benjamin; Liu, Youfang; Lo, Ken Sin; Lorentzon, Mattias; Luan, Jian'an; Madden, Pamela A. F.; Mangino, Massimo; McKnight, Barbara; Medina-Gomez, Carolina; Monda, Keri L.; Montasser, May E.; Müller, Gabriele; Müller-Nurasyid, Martina; Nolte, Ilja M.; Panoutsopoulou, Kalliope; Pascoe, Laura; Paternoster, Lavinia; Rayner, Nigel W.; Renström, Frida; Rizzi, Federica; Rose, Lynda M.; Ryan, Kathy A.; Salo, Perttu; Sanna, Serena; Scharnagl, Hubert; Shi, Jianxin; Smith, Albert Vernon; Southam, Lorraine; Stančáková, Alena; Steinthorsdottir, Valgerdur; Strawbridge, Rona J.; Sung, Yun Ju; Tachmazidou, Ioanna; Tanaka, Toshiko; Thorleifsson, Gudmar; Trompet, Stella; Pervjakova, Natalia; Tyrer, Jonathan P.; Vandenput, Liesbeth; van der Laan, Sander W; van der Velde, Nathalie; van Setten, Jessica; van Vliet-Ostaptchouk, Jana V.; Verweij, Niek; Vlachopoulou, Efthymia; Waite, Lindsay L.; Wang, Sophie R.; Wang, Zhaoming; Wild, Sarah H.; Willenborg, Christina; Wilson, James F.; Wong, Andrew; Yang, Jian; Yengo, Loïc; Yerges-Armstrong, Laura M.; Yu, Lei; Zhang, Weihua; Zhao, Jing Hua; Andersson, Ehm A.; Bakker, Stephan J. L.; Baldassarre, Damiano; Banasik, Karina; Barcella, Matteo; Barlassina, Cristina; Bellis, Claire; Benaglio, Paola; Blangero, John; Blüher, Matthias; Bonnet, Fabrice; Bonnycastle, Lori L.; Boyd, Heather A.; Bruinenberg, Marcel; Buchman, Aron S; Campbell, Harry; Chen, Yii-Der Ida; Chines, Peter S.; Claudi-Boehm, Simone; Cole, John; Collins, Francis S.; de Geus, Eco J. C.; de Groot, Lisette C. P. G. M.; Dimitriou, Maria; Duan, Jubao; Enroth, Stefan; Eury, Elodie; Farmaki, Aliki-Eleni; Forouhi, Nita G.; Friedrich, Nele; Gejman, Pablo V.; Gigante, Bruna; Glorioso, Nicola; Go, Alan S.; Gottesman, Omri; Gräßler, Jürgen; Grallert, Harald; Grarup, Niels; Gu, Yu-Mei; Broer, Linda; Ham, Annelies C.; Hansen, Torben; Harris, Tamara B.; Hartman, Catharina A.; Hassinen, Maija; Hastie, Nicholas; Hattersley, Andrew T.; Heath, Andrew C.; Henders, Anjali K.; Hernandez, Dena; Hillege, Hans; Holmen, Oddgeir; Hovingh, Kees G; Hui, Jennie; Husemoen, Lise L.; Hutri-Kähönen, Nina; Hysi, Pirro G.; Illig, Thomas; De Jager, Philip L.; Jalilzadeh, Shapour; Jørgensen, Torben; Jukema, J. Wouter; Juonala, Markus; Kanoni, Stavroula; Karaleftheri, Maria; Khaw, Kay Tee; Kinnunen, Leena; Kittner, Steven J.; Koenig, Wolfgang; Kolcic, Ivana; Kovacs, Peter; Krarup, Nikolaj T.; Kratzer, Wolfgang; Krüger, Janine; Kuh, Diana; Kumari, Meena; Kyriakou, Theodosios; Langenberg, Claudia; Lannfelt, Lars; Lanzani, Chiara; Lotay, Vaneet; Launer, Lenore J.; Leander, Karin; Lindström, Jaana; Linneberg, Allan; Liu, Yan-Ping; Lobbens, Stéphane; Luben, Robert; Lyssenko, Valeriya; Männistö, Satu; Magnusson, Patrik K.; McArdle, Wendy L.; Menni, Cristina; Merger, Sigrun; Milani, Lili; Montgomery, Grant W.; Morris, Andrew P.; Narisu, Narisu; Nelis, Mari; Ong, Ken K.; Palotie, Aarno; Pérusse, Louis; Pichler, Irene; Pilia, Maria G.; Pouta, Anneli; Rheinberger, Myriam; Ribel-Madsen, Rasmus; Richards, Marcus; Rice, Kenneth M.; Rice, Treva K.; Rivolta, Carlo; Salomaa, Veikko; Sanders, Alan R.; Sarzynski, Mark A.; Scholtens, Salome; Scott, Robert A.; Scott, William R.; Sebert, Sylvain; Sengupta, Sebanti; Sennblad, Bengt; Seufferlein, Thomas; Silveira, Angela; Slagboom, P. Eline; Smit, Jan H.; Sparsø, Thomas H.; Stirrups, Kathleen; Stolk, Ronald P.; Stringham, Heather M.; Swertz, Morris A; Swift, Amy J.; Syvänen, Ann-Christine; Tan, Sian-Tsung; Thorand, Barbara; Tönjes, Anke; Tremblay, Angelo; Tsafantakis, Emmanouil; van der Most, Peter J.; Völker, Uwe; Vohl, Marie-Claude; Vonk, Judith M.; Waldenberger, Melanie; Walker, Ryan W.; Wennauer, Roman; Widén, Elisabeth; Willemsen, Gonneke; Wilsgaard, Tom; Wright, Alan F.; Zillikens, M. Carola; van Dijk, Suzanne C.; van Schoor, Natasja M.; Asselbergs, Folkert W.; de Bakker, Paul I. W.; Beckmann, Jacques S.; Beilby, John; Bennett, David A.; Bergman, Richard N.; Bergmann, Sven; Böger, Carsten A.; Boehm, Bernhard O.; Boerwinkle, Eric; Boomsma, Dorret I.; Bornstein, Stefan R.; Bottinger, Erwin P.; Bouchard, Claude; Chambers, John C.; Chanock, Stephen J.; Chasman, Daniel I.; Cucca, Francesco; Cusi, Daniele; Dedoussis, George; Erdmann, Jeanette; Eriksson, Johan G.; Evans, Denis A.; de Faire, Ulf; Farrall, Martin; Ferrucci, Luigi; Ford, Ian; Franke, Lude; Franks, Paul W.; Froguel, Philippe; Gansevoort, Ron T.; Gieger, Christian; Grönberg, Henrik; Gudnason, Vilmundur; Gyllensten, Ulf; Hall, Per; Hamsten, Anders; van der Harst, Pim; Hayward, Caroline; Heliövaara, Markku; Hengstenberg, Christian; Hicks, Andrew A; Hingorani, Aroon; Hofman, Albert; Hu, Frank; Huikuri, Heikki V.; Hveem, Kristian; James, Alan L.; Jordan, Joanne M.; Jula, Antti; Kähönen, Mika; Kajantie, Eero; Kathiresan, Sekar; Kiemeney, Lambertus A. L. M.; Kivimaki, Mika; Knekt, Paul B.; Koistinen, Heikki A.; Kooner, Jaspal S.; Koskinen, Seppo; Kuusisto, Johanna; Maerz, Winfried; Martin, Nicholas G; Laakso, Markku; Lakka, Timo A.; Lehtimäki, Terho; Lettre, Guillaume; Levinson, Douglas F.; Lind, Lars; Lokki, Marja-Liisa; Mäntyselkä, Pekka; Melbye, Mads; Metspalu, Andres; Mitchell, Braxton D.; Moll, Frans L.; Murray, Jeffrey C.; Musk, Arthur W.; Nieminen, Markku S.; Njølstad, Inger; Ohlsson, Claes; Oldehinkel, Albertine J.; Oostra, Ben A.; Palmer, Lyle J; Pankow, James S.; Pasterkamp, Gerard; Pedersen, Nancy L.; Pedersen, Oluf; Penninx, Brenda W.; Perola, Markus; Peters, Annette; Polašek, Ozren; Pramstaller, Peter P.; Psaty, Bruce M.; Qi, Lu; Quertermous, Thomas; Raitakari, Olli T.; Rankinen, Tuomo; Rauramaa, Rainer; Ridker, Paul M.; Rioux, John D.; Rivadeneira, Fernando; Rotter, Jerome I.; Rudan, Igor; den Ruijter, Hester M.; Saltevo, Juha; Sattar, Naveed; Schunkert, Heribert; Schwarz, Peter E. H.; Shuldiner, Alan R.; Sinisalo, Juha; Snieder, Harold; Sørensen, Thorkild I. A.; Spector, Tim D.; Staessen, Jan A.; Stefania, Bandinelli; Thorsteinsdottir, Unnur; Stumvoll, Michael; Tardif, Jean-Claude; Tremoli, Elena; Tuomilehto, Jaakko; Uitterlinden, André G.; Uusitupa, Matti; Verbeek, André L. M.; Vermeulen, Sita H.; Viikari, Jorma S.; Vitart, Veronique; Völzke, Henry; Vollenweider, Peter; Waeber, Gérard; Walker, Mark; Wallaschofski, Henri; Wareham, Nicholas J.; Watkins, Hugh; Zeggini, Eleftheria; Chakravarti, Aravinda; Clegg, Deborah J.; Cupples, L. Adrienne; Gordon-Larsen, Penny; Jaquish, Cashell E.; Rao, D. C.; Abecasis, Goncalo R.; Assimes, Themistocles L.; Barroso, Inês; Berndt, Sonja I.; Boehnke, Michael; Deloukas, Panos; Fox, Caroline S.; Groop, Leif C.; Hunter, David J.; Ingelsson, Erik; Kaplan, Robert C.; McCarthy, Mark I.; Mohlke, Karen L.; O'Connell, Jeffrey R.; Schlessinger, David; Strachan, David P.; Stefansson, Kari; van Duijn, Cornelia M.; Hirschhorn, Joel N.; Lindgren, Cecilia M.; Heid, Iris M.; North, Kari E.; Borecki, Ingrid B.; Kutalik, Zoltán; Loos, Ruth J. F.

    2015-01-01

    Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape. PMID:26426971

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

    Directory of Open Access Journals (Sweden)

    Thomas W Winkler

    2015-10-01

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

  8. A genetic association study of serum acute-phase C-reactive protein levels in rheumatoid arthritis: implications for clinical interpretation.

    Directory of Open Access Journals (Sweden)

    Benjamin Rhodes

    2010-09-01

    Full Text Available BACKGROUND: The acute-phase increase in serum C-reactive protein (CRP is used to diagnose and monitor infectious and inflammatory diseases. Little is known about the influence of genetics on acute-phase CRP, particularly in patients with chronic inflammation. METHODS AND FINDINGS: We studied two independent sets of patients with chronic inflammation due to rheumatoid arthritis (total 695 patients. A tagSNP approach captured common variation at the CRP locus and the relationship between genotype and serum CRP was explored by linear modelling. Erythrocyte sedimentation rate (ESR was incorporated as an independent marker of inflammation to adjust for the varying levels of inflammatory disease activity between patients. Common genetic variants at the CRP locus were associated with acute-phase serum CRP (for the most associated haplotype: p = 0.002, p<0.0005, p<0.0005 in patient sets 1, 2, and the combined sets, respectively, translating into an approximately 3.5-fold change in expected serum CRP concentrations between carriers of two common CRP haplotypes. For example, when ESR = 50 mm/h the expected geometric mean CRP (95% confidence interval concentration was 43.1 mg/l (32.1-50.0 for haplotype 1 and 14.2 mg/l (9.5-23.2 for haplotype 4. CONCLUSIONS: Our findings raise questions about the interpretation of acute-phase serum CRP. In particular, failure to take into account the potential for genetic effects may result in the inappropriate reassurance or suboptimal treatment of patients simply because they carry low-CRP-associated genetic variants. CRP is increasingly being incorporated into clinical algorithms to compare disease activity between patients and to predict future clinical events: our findings impact on the use of these algorithms. For example, where access to effective, but expensive, biological therapies in rheumatoid arthritis is rationed on the basis of a DAS28-CRP clinical activity score, then two patients with identical

  9. Genetic association study with metabolic syndrome and metabolic-related traits in a cross-sectional sample and a 10-year longitudinal sample of chinese elderly population.

    Directory of Open Access Journals (Sweden)

    Jinghui Yang

    Full Text Available BACKGROUND: The metabolic syndrome (MetS has been known as partly heritable, while the number of genetic studies on MetS and metabolic-related traits among Chinese elderly was limited. METHODS: A cross-sectional analysis was performed among 2 014 aged participants from September 2009 to June 2010 in Beijing, China. An additional longitudinal study was carried out among the same study population from 2001 to 2010. Biochemical profile and anthropometric parameters of all the participants were measured. The associations of 23 SNPs located within 17 candidate genes (MTHFR, PPARγ, LPL, INSIG, TCF7L2, FTO, KCNJ11, JAZF1, CDKN2A/B, ADIPOQ, WFS1, CDKAL1, IGF2BP2, KCNQ1, MTNR1B, IRS1, ACE with overweight and obesity, diabetes, metabolic phenotypes, and MetS were examined in both studies. RESULTS: In this Chinese elderly population, prevalence of overweight, central obesity, diabetes, dyslipidemia, hypertension, and MetS were 48.3%, 71.0%, 32.4%, 75.7%, 68.3% and 54.5%, respectively. In the cross-sectional analyses, no SNP was found to be associated with MetS. Genotype TT of SNP rs4402960 within the gene IGF2BP2 was associated with overweight (odds ratio (OR  = 0.479, 95% confidence interval (CI: 0.316-0.724, p = 0.001 and genotype CA of SNP rs1801131 within the gene MTHFR was associated with hypertension (OR = 1.560, 95% CI: 1.194-2.240, p = 0.001. However, these associations were not observed in the longitudinal analyses. CONCLUSIONS: The associations of SNP rs4402960 with overweight as well as the association of SNP rs1801131 with hypertension were found to be statistically significant. No SNP was identified to be associated with MetS in our study with statistical significance.

  10. GSTP1 and TNF Gene Variants and Associations between Air Pollution and Incident Childhood Asthma : The Traffic, Asthma and Genetics (TAG) Study

    NARCIS (Netherlands)

    MacIntyre, Elaina A.; Brauer, Michael; Melen, Erik; Bauer, Carl Peter; Bauer, Mario; Berdel, Dietrich; Bergstroem, Anna; Brunekreef, Bert; Chan-Yeung, Moira; Kluemper, Claudia; Fuertes, Elaine; Gehring, Ulrike; Gref, Anna; Heinrich, Joachim; Herbarth, Olf; Kerkhof, Marjan; Koppelman, Gerard H.; Kozyrskyj, Anita L.; Pershagen, Goran; Postma, Dirkje S.; Thiering, Elisabeth; Tiesler, Carla M. T.; Carlsten, Christopher

    2014-01-01

    Background: Genetics may partially explain observed heterogeneity in associations between traffic-related air pollution and incident asthma. Objective: Our aim was to investigate the impact of gene variants associated with oxidative stress and inflammation on associations between air pollution and i

  11. Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity.

    Science.gov (United States)

    Soerensen, Mette; Dato, Serena; Tan, Qihua; Thinggaard, Mikael; Kleindorp, Rabea; Beekman, Marian; Suchiman, H Eka D; Jacobsen, Rune; McGue, Matt; Stevnsner, Tinna; Bohr, Vilhelm A; de Craen, Anton J M; Westendorp, Rudi G J; Schreiber, Stefan; Slagboom, P Eline; Nebel, Almut; Vaupel, James W; Christensen, Kaare; Christiansen, Lene

    2013-04-01

    In this study, we investigated 102 single-nucleotide polymorphisms (SNPs) covering the common genetic variation in 16 genes recurrently regarded as candidates for human longevity: APOE; ACE; CETP; HFE; IL6; IL6R; MTHFR; TGFB1; APOA4; APOC3; SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. In a case-control study of 1,089 oldest-old (ages 92-93) and 736 middle-aged Danes, the minor allele frequency (MAF) of rs769449 (APOE) was significantly decreased in the oldest-old, while the MAF of rs9923854 (CETP) was significantly enriched. These effects were supported when investigating 1,613 oldest-old (ages 95-110) and 1,104 middle-aged Germans. rs769449 was in modest linkage equilibrium (R (2)=0.55) with rs429358 of the APOE-ε4 haplotype and adjusting for rs429358 eliminated the association of rs769449, indicating that the association likely reflects the well-known effect of rs429358. Gene-based analysis confirmed the effects of variation in APOE and CETP and furthermore pointed to HSPA14 as a longevity gene. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes, only one SNP, rs2069827 (IL6), was borderline significantly associated with survival from age 92 (P-corrected=0.064). This advantageous effect of the minor allele was supported when investigating a Dutch longitudinal cohort (N=563) of oldest-old (age 85+). Since rs2069827 was located in a putative transcription factor binding site, quantitative RNA expression studies were conducted. However, no difference in IL6 expression was observed between rs2069827 genotype groups. In conclusion, we here support and expand the evidence suggesting that genetic variation in APOE, CETP, and IL6, and possible HSPA14, is associated with human longevity.

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

    Science.gov (United States)

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

    2016-07-20

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

  13. Association of genetic variants with diabetic nephropathy

    Institute of Scientific and Technical Information of China (English)

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

    2014-01-01

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

  14. Association of genetic variants with diabetic nephropathy.

    Science.gov (United States)

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

    2014-12-15

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

  15. Association between genetic variants of the leukotriene biosynthesis pathway and the risk of stroke: a case-control study in the Chinese Han population

    Institute of Scientific and Technical Information of China (English)

    SUN Hao; ZHANG Jing; WANG Jun; SUN Tao; XIAO Hang; ZHANG Jin-song

    2013-01-01

    Background Leukotrienes are arachidonic acid derivatives long known for their inflammatory properties.Leukotrienebased inflammation has been demonstrated to play a crucial role in atherosclerosis,a major risk factor for several human diseases.Recently,human genetic studies from us and others suggest that single nucleotide polymorphisms (SNPs) in leukotriene pathway genes influence the risk of atherosclerotic diseases such as stroke.This study aimed to assess the role of additional leukotriene pathway genes as a stroke risk factor within the Chinese Han population.Methods We sequenced the promoter,exonic,and intronic regions of leukotriene A4 hydrolase (LTA4H) and arachidonate 5-lipoxygenase (ALOX5),and then genotyped five SNPs in LTA4H and four SNPs in ALOX5 among 691 cases with stroke and 732 controls from the Chinese population.Results We detected a significant association between an intronic SNP in LTA4H (rs6538697) and stroke in our subjects (adjusted odds ratio,recessive model,1.75; P=0.022); and the SNP rs2029253 in ALOX5 was associated with a decreased risk of stroke (adjusted odds ratio,0.76; 95% confidence interval,0.59-0.97).Conclusion Genetic variants in LTA4H and ALOX5 may modulate the risk of stroke in the Chinese Han population.

  16. The ABCA1 Gene R230C Variant Is Associated with Decreased Risk of Premature Coronary Artery Disease: The Genetics of Atherosclerotic Disease (GEA) Study

    Science.gov (United States)

    Villarreal-Molina, Teresa; Posadas-Romero, Carlos; Romero-Hidalgo, Sandra; Antúnez-Argüelles, Erika; Bautista-Grande, Araceli; Vargas-Alarcón, Gilberto; Kimura-Hayama, Eric; Canizales-Quinteros, Samuel; Juárez-Rojas, Juan Gabriel; Posadas-Sánchez, Rosalinda; Cardoso-Saldaña, Guillermo; Medina-Urrutia, Aída; González-Salazar, María del Carmen; Martínez-Alvarado, Rocío; Jorge-Galarza, Esteban; Carnevale, Alessandra

    2012-01-01

    Background ABCA1 genetic variation is known to play a role in HDL-C levels and various studies have also implicated ABCA1 variation in cardiovascular risk. The functional ABCA1/R230C variant is frequent in the Mexican population and has been consistently associated with low HDL-C concentrations. Although it has been associated with other cardiovascular risk factors such as obesity and type 2 diabetes mellitus, it is not known whether it is associated with coronary artery disease (CAD). Aim The purpose of the study was to analyze whether the ABCA1/R230C variant is associated with premature CAD in a case-control association study (GEA or Genetics of Atherosclerotic Disease), and to explore whether BMI modulates the effect of the C230 allele on other metabolic traits using a population-based design. Results The C230 allele was significantly associated with both lower HDL-C levels and a lower risk of premature CAD as compared to controls (OR = 0.566; Padd = 1.499×10−5). In addition, BMI modulated the effect of R230C on body fat distribution, as the correlation between BMI and visceral to subcutaneous adipose tissue (a metric of the propensity to store fat viscerally as compared to subcutaneously) was negative in RR homozygous individuals, but positive in premenopausal women bearing the C230 allele, with a statistically significant interaction (P = 0.005). BMI-R230C interaction was also significant for triglyceride levels in women regardless of their menopausal status (P = 0.036). Conclusion This is the first study assessing the effect of the R230C/ABCA1 variant in remature CAD. C230 was associated with both decreased HDL-C levels and a lower risk of premature CAD, and gender-specific BMI-R230C interactions were observed for different metabolic traits. These interactions may help explain inconsistencies in associations, and underscore the need to further analyze interactions of this functional and frequent variant with diet, exercise and other

  17. The ABCA1 gene R230C variant is associated with decreased risk of premature coronary artery disease: the genetics of atherosclerotic disease (GEA study.

    Directory of Open Access Journals (Sweden)

    Teresa Villarreal-Molina

    Full Text Available BACKGROUND: ABCA1 genetic variation is known to play a role in HDL-C levels and various studies have also implicated ABCA1 variation in cardiovascular risk. The functional ABCA1/R230C variant is frequent in the Mexican population and has been consistently associated with low HDL-C concentrations. Although it has been associated with other cardiovascular risk factors such as obesity and type 2 diabetes mellitus, it is not known whether it is associated with coronary artery disease (CAD. AIM: The purpose of the study was to analyze whether the ABCA1/R230C variant is associated with premature CAD in a case-control association study (GEA or Genetics of Atherosclerotic Disease, and to explore whether BMI modulates the effect of the C230 allele on other metabolic traits using a population-based design. RESULTS: The C230 allele was significantly associated with both lower HDL-C levels and a lower risk of premature CAD as compared to controls (OR = 0.566; P(add = 1.499×10(-5. In addition, BMI modulated the effect of R230C on body fat distribution, as the correlation between BMI and visceral to subcutaneous adipose tissue (a metric of the propensity to store fat viscerally as compared to subcutaneously was negative in RR homozygous individuals, but positive in premenopausal women bearing the C230 allele, with a statistically significant interaction (P = 0.005. BMI-R230C interaction was also significant for triglyceride levels in women regardless of their menopausal status (P = 0.036. CONCLUSION: This is the first study assessing the effect of the R230C/ABCA1 variant in remature CAD. C230 was associated with both decreased HDL-C levels and a lower risk of premature CAD, and gender-specific BMI-R230C interactions were observed for different metabolic traits. These interactions may help explain inconsistencies in associations, and underscore the need to further analyze interactions of this functional and frequent variant with diet, exercise

  18. Genetic Association Analysis of Drusen Progression

    NARCIS (Netherlands)

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

    2016-01-01

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

  19. The FTO gene is associated with an atherogenic lipid profile and myocardial infarction in patients with type 2 diabetes:A Genetics of Diabetes Audit and Research Study in Tayside Scotland (Go-DARTS) Study

    OpenAIRE

    2009-01-01

    Background-Common variation in the fat mass and obesity (FTO)-related gene is associated with increased body fat and susceptibility to type 2 diabetes. We hypothesized that this would also associate with metabolic phenotypes of insulin resistance and increased risk of cardiovascular morbidity and mortality. Methods and Results-FTO rs9939609 genotype was determined in 4897 patients with type 2 diabetes in the prospective Genetics of Diabetes Audit and Research Study in Tayside Scotland study. ...

  20. Original Research: A case-control genome-wide association study identifies genetic modifiers of fetal hemoglobin in sickle cell disease

    Science.gov (United States)

    Liu, Li; Pertsemlidis, Alexander; Ding, Liang-Hao; Story, Michael D; Steinberg, Martin H; Sebastiani, Paola; Hoppe, Carolyn; Ballas, Samir K

    2016-01-01

    Sickle cell disease (SCD) is a group of inherited blood disorders that have in common a mutation in the sixth codon of the β-globin (HBB) gene on chromosome 11. However, people with the same genetic mutation display a wide range of clinical phenotypes. Fetal hemoglobin (HbF) expression is an important genetic modifier of SCD complications leading to milder symptoms and improved long-term survival. Therefore, we performed a genome-wide association study (GWAS) using a case-control experimental design in 244 African Americans with SCD to discover genetic factors associated with HbF expression. The case group consisted of subjects with HbF≥8.6% (133 samples) and control group subjects with HbF≤£3.1% (111 samples). Our GWAS results replicated SNPs previously identified in an erythroid-specific enhancer region located in the second intron of the BCL11A gene associated with HbF expression. In addition, we identified SNPs in the SPARC, GJC1, EFTUD2 and JAZF1 genes as novel candidates associated with HbF levels. To gain insights into mechanisms of globin gene regulation in the HBB locus, linkage disequilibrium (LD) and haplotype analyses were conducted. We observed strong LD in the low HbF group in contrast to a loss of LD and greater number of haplotypes in the high HbF group. A search of known HBB locus regulatory elements identified SNPs 5′ of δ-globin located in an HbF silencing region. In particular, SNP rs4910736 created a binding site for a known transcription repressor GFi1 which is a candidate protein for further investigation. Another HbF-associated SNP, rs2855122 in the cAMP response element upstream of Gγ-globin, was analyzed for functional relevance. Studies performed with siRNA-mediated CREB binding protein (CBP) knockdown in primary erythroid cells demonstrated γ-globin activation and HbF induction, supporting a repressor role for CBP. This study identifies possible molecular determinants of HbF production. PMID:27022141

  1. Original Research: A case-control genome-wide association study identifies genetic modifiers of fetal hemoglobin in sickle cell disease.

    Science.gov (United States)

    Liu, Li; Pertsemlidis, Alexander; Ding, Liang-Hao; Story, Michael D; Steinberg, Martin H; Sebastiani, Paola; Hoppe, Carolyn; Ballas, Samir K; Pace, Betty S

    2016-04-01

    Sickle cell disease (SCD) is a group of inherited blood disorders that have in common a mutation in the sixth codon of the β-globin (HBB) gene on chromosome 11. However, people with the same genetic mutation display a wide range of clinical phenotypes. Fetal hemoglobin (HbF) expression is an important genetic modifier of SCD complications leading to milder symptoms and improved long-term survival. Therefore, we performed a genome-wide association study (GWAS) using a case-control experimental design in 244 African Americans with SCD to discover genetic factors associated with HbF expression. The case group consisted of subjects with HbF≥8.6% (133 samples) and control group subjects with HbF≤£3.1% (111 samples). Our GWAS results replicated SNPs previously identified in an erythroid-specific enhancer region located in the second intron of the BCL11A gene associated with HbF expression. In addition, we identified SNPs in the SPARC, GJC1, EFTUD2 and JAZF1 genes as novel candidates associated with HbF levels. To gain insights into mechanisms of globin gene regulation in the HBB locus, linkage disequilibrium (LD) and haplotype analyses were conducted. We observed strong LD in the low HbF group in contrast to a loss of LD and greater number of haplotypes in the high HbF group. A search of known HBB locus regulatory elements identified SNPs 5' of δ-globin located in an HbF silencing region. In particular, SNP rs4910736 created a binding site for a known transcription repressor GFi1 which is a candidate protein for further investigation. Another HbF-associated SNP, rs2855122 in the cAMP response element upstream of Gγ-globin, was analyzed for functional relevance. Studies performed with siRNA-mediated CREB binding protein (CBP) knockdown in primary erythroid cells demonstrated γ-globin activation and HbF induction, supporting a repressor role for CBP. This study identifies possible molecular determinants of HbF production.

  2. Genetic Variants Are Not Associated with Outcome in Patients with Coronary Artery Disease and Left Ventricular Dysfunction: Results of the Genetic Sub-study of the Surgical Treatment for Ischemic Heart Failure (STICH) Trials

    Science.gov (United States)

    Feldman, Arthur M.; She, Lilin; McNamara, Dennis M.; Mann, Douglas L.; Bristow, Michael R.; Maisel, Alan S.; Wagner, Daniel R.; Andersson, Bert; Chiariello, Luigi; Hayward, Christopher S.; Hendry, Paul; Parker, John D.; Racine, Normand; Selzman, Craig H.; Senni, Michele; Stepinska, Janina; Zembala, Marian; Rouleau, Jean; Velazquez, Eric J.; Lee, Kerry L.

    2015-01-01

    Objectives and Background We evaluated the ability of 23 genetic variants to provide prognostic information in patients enrolled in the Genotype Sub-studies of the Surgical Treatment for Ischemic Heart Failure (STICH) trials. Methods Patients in STICH Hypothesis 1 were randomized to medical therapy with or without CABG (Coronary Artery Bypass Grafting). Those in STICH Hypothesis 2 were randomized to CABG or CABG with left ventricular reconstruction. Results In patients assigned to STICH Hypothesis 2 (n=714), no genetic variant met the pre-specified Bonferroni-adjusted threshold for statistical significance (p<0.002); however, several met nominal prognostic significance: variants in the β2-adrenergic receptor gene (β2-AR Gln27Glu) and in the A1-adenosine receptor gene (A1-717 T/G) were associated with an increased risk of a subject dying or being hospitalized for a cardiac problem (p=0.027 and 0.031, respectively). These relationships remained nominally significant even after multivariable adjustment for prognostic clinical variables. However, none of the 23 genetic variants influenced all-cause mortality or the combination of death or cardiovascular hospitalization in the STICH Hypothesis 1 population (n=532) by either univariate or multivariable analysis. Conclusion We were unable to identify the predictive genotypes in optimally treated patients in these two ischemic heart failure populations. PMID:25592552

  3. Maternal and offspring fasting glucose and type 2 diabetes-associated genetic variants and cognitive function at age 8: a Mendelian randomization study in the Avon Longitudinal Study of Parents and Children

    Directory of Open Access Journals (Sweden)

    Bonilla Carolina

    2012-09-01

    Full Text Available Abstract Background In observational epidemiological studies type 2 diabetes (T2D and both low and high plasma concentrations of fasting glucose have been found to be associated with lower cognitive performance. These associations could be explained by confounding. Methods In this study we looked at the association between genetic variants, known to be robustly associated with fasting glucose and T2D risk, in the mother and her offspring to determine whether there is likely to be a causal link between early life exposure to glucose and child’s intelligence quotient (IQ scores in the Avon Longitudinal Study of Parents and Children (ALSPAC cohort. We generated a fasting glucose (FGGRS and a T2D (T2DGRS genetic risk score and used them in a Mendelian randomization approach. Results We found a strong correlation between the FGGRS and fasting glucose plasma measurements that were available for a subset of children, but no association of either the maternal or the offspring FGGRS with child’s IQ was observed. In contrast, the maternal T2DGRS was positively associated with offspring IQ. Conclusions Maternal and offspring genetic variants which are associated with glucose levels are not associated with offspring IQ, suggesting that there is unlikely to be a causal link between glucose exposure in utero and IQ in childhood. Further exploration in even larger cohorts is required to exclude the possibility that our null findings were due to a lack of statistical power.

  4. Maternal and offspring fasting glucose and type 2 diabetes-associated genetic variants and cognitive function at age 8: a Mendelian randomization study in the Avon Longitudinal Study of Parents and Children.

    Science.gov (United States)

    Bonilla, Carolina; Lawlor, Debbie A; Ben-Shlomo, Yoav; Ness, Andrew R; Gunnell, David; Ring, Susan M; Smith, George Davey; Lewis, Sarah J

    2012-09-27

    In observational epidemiological studies type 2 diabetes (T2D) and both low and high plasma concentrations of fasting glucose have been found to be associated with lower cognitive performance. These associations could be explained by confounding. In this study we looked at the association between genetic variants, known to be robustly associated with fasting glucose and T2D risk, in the mother and her offspring to determine whether there is likely to be a causal link between early life exposure to glucose and child's intelligence quotient (IQ) scores in the Avon Longitudin