scholarly journals Susceptibility variants for rheumatoid arthritis in the TRAF1-C5 and 6q23 loci: a meta-analysis

2009 ◽  
Vol 69 (3) ◽  
pp. 561-566 ◽  
Author(s):  
Nikolaos A Patsopoulos ◽  
John P A Ioannidis
Keyword(s):  
Rheumatoid Arthritis ◽  
Association Studies ◽  
Meta Analysis ◽  
Statistical Significance ◽  
Genome Wide Association Studies ◽  
Gene Environment ◽  
Genome Wide ◽  
Study Heterogeneity ◽  
Meta Analyses ◽  
Citrullinated Peptide

BackgroundGenome-wide association studies have proposed susceptibility variants for rheumatoid arthritis in the TRAF1-C5 locus and 6q23 region. Furthermore, additional independent studies have investigated the same or highly linked polymorphisms in the same regions.ObjectiveTo carry out a meta-analysis of the available evidence for the association of polymorphisms in the TRAF1-C5 locus and 6q23 region with rheumatoid arthritis.MethodsData were synthesised for four polymorphisms: rs3761847 (n=13 datasets) and rs2900180 (n=9 datasets) in the TRAF1-C5 locus, and rs10499194 (n=5 datasets) and rs6920220 (n=7 datasets) in the 6q23 region. Meta-analyses for subgroups defined by anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF) status were also performed.ResultsThe polymorphism rs6920220 reached genome-wide statistical significance with p=7.9×10−17 and an allelic odds ratio of 1.24 (95% CI 1.18 to 1.30) and no between-study heterogeneity (I2=0%). The risk was significantly stronger in patients with anti-CCP antibodies and in patients with RF. The other three variants showed large between-study heterogeneity across datasets (I2 range 74–82%); rs10499194 was nominally statistically significant after exclusion of the discovery data. Two variants had genome-wide statistical significance in subgroups defined by the presence of RF (rs3761847 and rs6920220) or anti-CCP (rs6920220).ConclusionsGenetic markers in the 6q23 region and TRAF1-C5 are associated with rheumatoid arthritis, in particular with positive anti-CCP and RF profile. With the exception of rs6920220, which shows highly consistent results, other proposed markers have high between-study heterogeneity that may reflect unrecognised phenotypic or genetic variability (eg, gene environment interactions) within rheumatoid arthritis. Furthermore, these markers may not be the true causative loci but rather be in linkage disequilibrium with the true ones.

Abstract P260: Large-scale Meta-analysis of Diverse Ancestry Genome-wide Association Studies to Identify Pharmacogenomic Interactions of Sulfonylureas and ECG Phenotypes

Circulation ◽  
2016 ◽  
Vol 133 (suppl_1) ◽  
Author(s):  
James S Floyd ◽  
Colleen Sitlani ◽  
Christy L Avery ◽  
Eric A Whitsel ◽  
Leslie Lange ◽  
...  
Keyword(s):  
Repeated Measures ◽  
Qt Interval ◽  
Association Studies ◽  
Meta Analysis ◽  
Small Sample ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Meta Analyses

Introduction: Sulfonylureas are a commonly-used class of diabetes medication that can prolong the QT-interval, which is a leading cause of drug withdrawals from the market given the possible risk of life-threatening arrhythmias. Previously, we conducted a meta-analysis of genome-wide association studies of sulfonylurea-genetic interactions on QT interval among 9 European-ancestry (EA) cohorts using cross-sectional data, with null results. To improve our power to identify novel drug-gene interactions, we have included repeated measures of medication use and QT interval and expanded our study to include several additional cohorts, including African-American (AA) and Hispanic-ancestry (HA) cohorts with a high prevalence of sulfonylurea use. To identify potentially differential effects on cardiac depolarization and repolarization, we have also added two phenotypes - the JT and QRS intervals, which together comprise the QT interval. Hypothesis: The use of repeated measures and expansion of our meta-analysis to include diverse ancestry populations will allow us to identify novel pharmacogenomic interactions for sulfonylureas on the ECG phenotypes QT, JT, and QRS. Methods: Cohorts with unrelated individuals used generalized estimating equations to estimate interactions; cohorts with related individuals used mixed effect models clustered on family. For each ECG phenotype (QT, JT, QRS), we conducted ancestry-specific (EA, AA, HA) inverse variance weighted meta-analyses using standard errors based on the t-distribution to correct for small sample inflation in the test statistic. Ancestry-specific summary estimates were combined using MANTRA, an analytic method that accounts for differences in local linkage disequilibrium between ethnic groups. Results: Our study included 65,997 participants from 21 cohorts, including 4,020 (6%) sulfonylurea users, a substantial increase from the 26,986 participants and 846 sulfonylureas users in the previous meta-analysis. Preliminary ancestry-specific meta-analyses have identified genome-wide significant associations (P < 5х10–8) for each ECG phenotype, and analyses with MANTRA are in progress. Conclusions: In the setting of the largest collection of pharmacogenomic studies to date, we used repeated measurements and leveraged diverse ancestry populations to identify new pharmacogenomic loci for ECG traits associated with cardiovascular risk.

scholarly journals A meta-analysis of genome-wide association studies of asthma in Puerto Ricans

2017 ◽  
Vol 49 (5) ◽  
pp. 1601505 ◽  
Author(s):  
Qi Yan ◽  
John Brehm ◽  
Maria Pino-Yanes ◽  
Erick Forno ◽  
Jerome Lin ◽  
...  
Keyword(s):  
Puerto Ricans ◽  
Association Studies ◽  
Meta Analysis ◽  
Linkage Disequilibrium Block ◽  
Genome Wide Association ◽  
Health Study ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
The Usa ◽  
Meta Analyses

Puerto Ricans are disproportionately affected with asthma in the USA. In this study, we aim to identify genetic variants that confer susceptibility to asthma in Puerto Ricans.We conducted a meta-analysis of genome-wide association studies (GWAS) of asthma in Puerto Ricans, including participants from: the Genetics of Asthma in Latino Americans (GALA) I-II, the Hartford–Puerto Rico Study and the Hispanic Community Health Study. Moreover, we examined whether susceptibility loci identified in previous meta-analyses of GWAS are associated with asthma in Puerto Ricans.The only locus to achieve genome-wide significance was chromosome 17q21, as evidenced by our top single nucleotide polymorphism (SNP), rs907092 (OR 0.71, p=1.2×10−12) at IKZF3. Similar to results in non-Puerto Ricans, SNPs in genes in the same linkage disequilibrium block as IKZF3 (e.g. ZPBP2, ORMDL3 and GSDMB) were significantly associated with asthma in Puerto Ricans. With regard to results from a meta-analysis in Europeans, we replicated findings for rs2305480 at GSDMB, but not for SNPs in any other genes. On the other hand, we replicated results from a meta-analysis of North American populations for SNPs at IL1RL1, TSLP and GSDMB but not for IL33.Our findings suggest that common variants on chromosome 17q21 have the greatest effects on asthma in Puerto Ricans.

scholarly journals Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci

PLoS Genetics ◽  
2011 ◽  
Vol 7 (2) ◽  
pp. e1002004 ◽  
Author(s):  
Alexandra Zhernakova ◽  
Eli A. Stahl ◽  
Gosia Trynka ◽  
Soumya Raychaudhuri ◽  
Eleanora A. Festen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Celiac Disease ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

scholarly journals Adipokines and risk of rheumatoid arthritis: a Mendelian randomization study

2020 ◽  
Author(s):  
Jiahao Zhu ◽  
Haiyan Zheng ◽  
Yasong Li ◽  
Tianle Wang ◽  
Yaohong Zhong ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Large Scale ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Statistical Significance ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Primary Analysis ◽  
Genome Wide

Abstract Background: Circulating adipokines levels have been reported to be associated with the risk of rheumatoid arthritis (RA). However, it is still unclear whether these associations are causal or biased by reverse causation or residual confounding. This study aimed to assess potential causal roles of five adipokines (namely, adiponectin, leptin, resistin, chemerin, and retinol-blinding protein 4 [RBP4]) in the occurrence of RA.Methods: We conducted a two-sample Mendelian randomization analysis to investigate these associations. We used summary-level data from genome-wide association studies (GWASs) for adipokines in individuals of European ancestry as the exposure, and a separate large-scale meta-analysis of a GWAS which included 14,361 RA cases and 43,923 controls of European ancestry as the outcome. Genetic variants were selected as instrumental variables if robustly genome-wide significant in their associations with adipokines. The causal effects were estimated using the inverse-variance weighted method in the primary analysis. Sensitivity analyses were performed to warrant that bias due to genetic pleiotropy was unlikely.Results: The circulating resistin was found to be the only adipokinetic factor having statistical significance, with higher levels causally associated with the risk of RA (odds ratio: 1.28; 95% confidence interval: [1.07, 1.53] per unit increase in the natural log-transformed resistin). In contrast, associations of adiponectin, leptin, chemerin, and RBP4 with risk of RA were not statistically significant. The MR assumptions did not seem to be violated. Sensitivity analyses yielded consistent findings.Conclusions: Genetically predicted circulating resistin levels were positively associated with RA risk. Our analysis suggested that resistin may play a notable causal role in RA pathogenesis. It would be beneficial for the development of clinical as well as public health strategies that target appropriate levels of resistin for future RA intervention.

scholarly journals Caring without sharing: Meta-analysis 2.0 for massive genome-wide association studies

2018 ◽  
Author(s):  
Armin Pourshafeie ◽  
Carlos D. Bustamante ◽  
Snehit Prabhu
Keyword(s):  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Large Sample Size ◽  
Genome Wide Association Studies ◽  
Raw Data ◽  
Structure Control ◽  
Genome Wide ◽  
Sufficient Power ◽  
Meta Analyses

AbstractGenome-wide association studies have been effective at revealing the genetic architecture of simple traits. Extending this approach to more complex phenotypes has necessitated a massive increase in cohort size. To achieve sufficient power, participants are recruited across multiple collaborating institutions, leaving researchers with two choices: either collect all the raw data at a single institution or rely on meta-analyses to test for association. In this work, we present a third alternative. Here, we implement an entire GWAS workflow (quality control, population structure control, and association) in a fully decentralized setting. Our iterative approach (a) does not rely on consolidating the raw data at a single coordination center, and (b) does not hinge upon large sample size assumptions at each silo. As we show, our approach overcomes challenges faced by meta-studies when it comes to associating rare alleles and when case/control proportions are wildly imbalanced at each silo. We demonstrate the feasibility of our method in cohorts ranging in size from 2K (small) to 500K (large), and recruited across 2 to 10 collaborating institutions.

scholarly journals Multiethnic meta-analysis identifies new loci for pulmonary function

2017 ◽  
Author(s):  
Annah B. Wyss ◽  
Tamar Sofer ◽  
Mi Kyeong Lee ◽  
Natalie Terzikhan ◽  
Jennifer N. Nguyen ◽  
...  
Keyword(s):  
Pulmonary Function ◽  
Drug Targets ◽  
Association Studies ◽  
Meta Analysis ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Causal Variants ◽  
Multiethnic Population ◽  
Meta Analyses

AbstractNearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N=60,552), African (N=8,429), Asian (N=9,959), and Hispanic/Latino (N=11,775) ethnicities. We identified over 50 novel loci at genome-wide significance in ancestry-specific and/or multiethnic meta-analyses. Recent fine mapping methods incorporating functional annotation, gene expression, and/or differences in linkage disequilibrium between ethnicities identified potential causal variants and genes at known and newly identified loci. Sixteen of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12.

scholarly journals The Genetics of Human DZ Twinning

2020 ◽  
Vol 23 (2) ◽  
pp. 74-76
Author(s):  
Dorret I. Boomsma
Keyword(s):  
Association Studies ◽  
Meta Analysis ◽  
Twin Studies ◽  
Reproductive Traits ◽  
Genome Wide Association Studies ◽  
Behavioral Traits ◽  
Genome Wide ◽  
Female Reproductive Traits ◽  
Genetic And Environmental Factors ◽  
Meta Analyses

AbstractIn the course of twin studies whose main focus was elucidation of genetic and environmental factors on behavioral traits, many twin researchers became aware of the strong tendency for dizygotic (DZ) twinning to run in families. Over four decades, Nick Martin and others initiated hormone and ultrasound studies, performed segregation and pedigree analyses, tested candidate genes, carried out linkage projects in sister pairs and formed large collaborations to illuminate the genetics of DZ twinning by genome-wide association studies and meta-analysis. This article summarizes the early work on hormone and genetic studies and describes the meta-analyses that have at last met with success in finding the first genes that predispose to DZ twinning, which also appear to influence many other female reproductive traits.

scholarly journals Trans-ethnic genome-wide meta-analysis of 35,732 cases and 34,424 controls identifies novel genomic cross-ancestry loci contributing to lung cancer susceptibility

2020 ◽  
Author(s):  
Jinyoung Byun ◽  
Younghun Han ◽  
Yafang Li ◽  
Jun Xia ◽  
Xiangjun Xiao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Large Scale ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Cancer Etiology ◽  
Genome Wide ◽  
Meta Analyses

SummaryLung cancer is the leading cause of cancer death worldwide. Genome-wide association studies have revealed genetic risk factors, highlighting the role of smoking, family history, telomere regulation, and DNA damage-repair in lung cancer etiology. Many studies have focused on a single ethnic group to avoid confounding from variability in allele frequencies across populations; however, comprehensive multi-ethnic analyses may identify variants that are more likely to be causal. This large-scale, multi- ethnic meta-analyses identified 28 novel risk loci achieving genome-wide significance. Leading candidates were further studied using single-cell methods for evaluating DNA-damage. DNA-damage promoting activities were confirmed for selected genes by knockdown genes and overexpression studies.

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