Ng, Maggie C Y2; Shriner, Daniel2; Chen, Brian H2; Li, Jiang2; Chen, Wei-Min2; Guo, Xiuqing2; Liu, Jiankang2; Bielinski, Suzette J2; Yanek, Lisa R2; Nalls, Michael A2; Comeau, Mary E2; Rasmussen-Torvik, Laura J2; Jensen, Richard A2; Evans, Daniel S2; Sun, Hong Yan2; An, Ping2; Patel, Sanjay R2; Lu, Yingchang2; Long, Jirong2; Armstrong, Loren L2; Wagenknecht, Lynne2; Yang, Lingyao2; Snively, Beverly M2; Palmer, Nicholette D2; Mudgal, Poorva2; Langefeld, Carl D2; Keene, Keith L2; Freedman, Barry I2; Mychaleckyj, Josyf C2; Nayak, Uma2; Raffel, Leslie J2; Goodarzi, Mark O2; Chen, Y-D Ida2; Taylor, Herman A2; Correa, Adolfo2; Sims, Mario2; Couper, David2; Pankow, James S2; Boerwinkle, Eric2; Adeyemo, Adebowale2; Doumatey, Ayo2; Chen, Guanjie2; Mathias, Rasika A2; Vaidya, Dhananjay2; Singleton, Andrew B2; Zonderman, Alan B2; Igo, Robert P2; Sedor, John R2; Kabagambe, Edmond K2; Siscovick, David S2; McKnight, Barbara2; Rice, Kenneth2; Liu, Yongmei2; Hsueh, Wen-Chi2; Zhao, Wei2; Bielak, Lawrence F2; Kraja, Aldi2; Province, Michael A2; Bottinger, Erwin P2; Gottesman, Omri2; Cai, Qiuyin2; Zheng, Wei2; Blot, William J2; Lowe, William L2; Pacheco, Jennifer A2; Crawford, Dana C2; Grundberg, Elin2; Rich, Stephen S2; Hayes, M Geoffrey2; Shu, Xiao-Ou2; Loos, Ruth J F2; Borecki, Ingrid B2; Peyser, Patricia A2; Cummings, Steven R2; Psaty, Bruce M2; Fornage, Myriam2; Iyengar, Sudha K2; Evans, Michele K2; Becker, Diane M2; Kao, W H Linda2; Wilson, James2; Rotter, Jerome I2; Sale, Michèle M2; Liu, Simin2; Rotimi, Charles N2; Bowden, Donald W2
1 Research Centre for Prevention and Health, FCFS, The Capital Region of Denmark2 unknown
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.