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

Maggie C. Y. Ng, Daniel Shriner, Brian H. Chen, Jiang Li, Wei-Min Chen, Xiuqing Guo, Jiankang Liu, Suzette J. Bielinski, Lisa R. Yanek, Michael A. Nalls, Mary E. Comeau, Laura J. Rasmussen-Torvik, Richard A. Jensen, Daniel S. Evans, Yan V. Sun, Ping An, Sanjay R. Patel, Yingchang Lu, Jirong Long, Loren L. Armstrong, Lynne Wagenknecht, Lingyao Yang, Beverly M. Snively, Nicholette D. Palmer, Poorva Mudgal, Carl D. Langefeld, Keith L. Keene, Barry I. Freedman, Josyf C. Mychaleckyj, Uma Nayak, Leslie J. Raffel, Mark O. Goodarzi, Y-D Ida Chen, Herman A. Taylor, Adolfo Correa, Mario Sims, David Couper, James S. Pankow, Eric Boerwinkle, Adebowale Adeyemo, Ayo Doumatey, Guanjie Chen, Rasika A. Mathias, Dhananjay Vaidya, Andrew B. Singleton, Alan B. Zonderman, Robert P. Igo, John R. Sedor, Edmond K. Kabagambe, David S. Siscovick, Barbara McKnight, Kenneth Rice, Yongmei Liu, Wen-Chi Hsueh, Wei Zhao, Lawrence F. Bielak, Aldi Kraja, Michael A. Province, Erwin P. Bottinger, Omri Gottesman, Qiuyin Cai, Wei Zheng, William J. Blot, William L. Lowe, Jennifer A. Pacheco, Dana C. Crawford, Elin Grundberg, Stephen S. Rich, M. Geoffrey Hayes, Xiao-Ou Shu, Ruth J. F. Loos, Ingrid B. Borecki, Patricia A. Peyser, Steven R. Cummings, Bruce M. Psaty, Myriam Fornage, Sudha K. Iyengar, Michele K. Evans, Diane M. Becker, W. H. Linda Kao, James G. Wilson, Jerome I. Rotter, Michèle M. Sale, Simin Liu, Charles N. Rotimi, Donald W. Bowden

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)<P<5 × 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) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.