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

ABSTRACT: Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)

SUBMITTER: Ng MC

PROVIDER: S-EPMC4125087 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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

Ng Maggie C Y MC Shriner Daniel D Chen Brian H BH Li Jiang J Chen Wei-Min WM Guo Xiuqing X Liu Jiankang J Bielinski Suzette J SJ Yanek Lisa R LR Nalls Michael A MA Comeau Mary E ME Rasmussen-Torvik Laura J LJ Jensen Richard A RA Evans Daniel S DS Sun Yan V YV An Ping P Patel Sanjay R SR Lu Yingchang Y Long Jirong J Armstrong Loren L LL Wagenknecht Lynne L Yang Lingyao L Snively Beverly M BM Palmer Nicholette D ND Mudgal Poorva P Langefeld Carl D CD Keene Keith L KL Freedman Barry I BI Mychaleckyj Josyf C JC Nayak Uma U Raffel Leslie J LJ Goodarzi Mark O MO Chen Y-D Ida YD Taylor Herman A HA Correa Adolfo A Sims Mario M Couper David D Pankow James S JS Boerwinkle Eric E Adeyemo Adebowale A Doumatey Ayo A Chen Guanjie G Mathias Rasika A RA Vaidya Dhananjay D Singleton Andrew B AB Zonderman Alan B AB Igo Robert P RP Sedor John R JR Kabagambe Edmond K EK Siscovick David S DS McKnight Barbara B Rice Kenneth K Liu Yongmei Y Hsueh Wen-Chi WC Zhao Wei W Bielak Lawrence F LF Kraja Aldi A Province Michael A MA Bottinger Erwin P EP Gottesman Omri O Cai Qiuyin Q Zheng Wei W Blot William J WJ Lowe William L WL Pacheco Jennifer A JA Crawford Dana C DC Grundberg Elin E Rich Stephen S SS Hayes M Geoffrey MG Shu Xiao-Ou XO Loos Ruth J F RJ Borecki Ingrid B IB Peyser Patricia A PA Cummings Steven R SR Psaty Bruce M BM Fornage Myriam M Iyengar Sudha K SK Evans Michele K MK Becker Diane M DM Kao W H Linda WH Wilson James G JG Rotter Jerome I JI Sale Michèle M MM Liu Simin S Rotimi Charles N CN Bowden Donald W DW

PLoS genetics 20140807 8

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 a ...[more]

PMID: 25102180

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Project description:The PR interval on the electrocardiogram reflects atrial and atrioventricular nodal conduction time. The PR interval is heritable, provides important information about arrhythmia risk, and has been suggested to differ among human races. Genome-wide association (GWA) studies have identified common genetic determinants of the PR interval in individuals of European and Asian ancestry, but there is a general paucity of GWA studies in individuals of African ancestry. We performed GWA studies in African American individuals from four cohorts (n?=?6,247) to identify genetic variants associated with PR interval duration. Genotyping was performed using the Affymetrix 6.0 microarray. Imputation was performed for 2.8 million single nucleotide polymorphisms (SNPs) using combined YRI and CEU HapMap phase II panels. We observed a strong signal (rs3922844) within the gene encoding the cardiac sodium channel (SCN5A) with genome-wide significant association (p<2.5 x 10??) in two of the four cohorts and in the meta-analysis. The signal explained 2% of PR interval variability in African Americans (beta ?=?5.1 msec per minor allele, 95% CI ?=?4.1-6.1, p?=?3 x 10?²³). This SNP was also associated with PR interval (beta?=?2.4 msec per minor allele, 95% CI?=?1.8-3.0, p?=?3 x 10?¹?) in individuals of European ancestry (n?=?14,042), but with a smaller effect size (p for heterogeneity <0.001) and variability explained (0.5%). Further meta-analysis of the four cohorts identified genome-wide significant associations with SNPs in SCN10A (rs6798015), MEIS1 (rs10865355), and TBX5 (rs7312625) that were highly correlated with SNPs identified in European and Asian GWA studies. African ancestry was associated with increased PR duration (13.3 msec, p?=?0.009) in one but not the other three cohorts. Our findings demonstrate the relevance of common variants to African Americans at four loci previously associated with PR interval in European and Asian samples and identify an association signal at one of these loci that is more strongly associated with PR interval in African Americans than in Europeans.

Dataset Information

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

Publications

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

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