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<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.
Highlights
The prevalence of type 2 diabetes (T2D) among adults in the USA is currently 11.3%, with substantially higher prevalence in African Americans (18.7%) than in European Americans (10.2%) [1]
From stage 1 meta-analysis, 49 single nucleotide polymorphism (SNP) moderately associated with T2D (P,161025) and two candidate SNPs near the p value threshold totaling 51 SNPs in 21 loci were followed up for replication. rs231356 is 14 kb downstream of the reported T2D index SNP, rs231362, in Europeans [3]
Associations at previously reported T2D and glucose homeostasis loci We investigated index SNPs from 158 independent loci associated with T2D and/or glucose homeostasis from prior genome-wide and candidate gene studies in individuals of European, East Asian, South Asian, or African American ancestry (Table S5)
Summary
The prevalence of type 2 diabetes (T2D) among adults in the USA is currently 11.3%, with substantially higher prevalence in African Americans (18.7%) than in European Americans (10.2%) [1]. Genome-wide association studies (GWAS) have identified .70 susceptibility loci for T2D [2,3,4,5,6,7,8]. While it is known that T2D is heritable in African Americans [9], it is unclear how much heritability is explained by the known genetic associations discovered primarily from European ancestry populations and whether there are risk loci specific to African Americans. Given that individuals of African ancestry tend to harbor more genetic diversity than individuals of other ancestries [10], we hypothesized that large-scale association analyses in African Americans could shed light on the genetic architecture of T2D and the risk attributable to cosmopolitan vs population-specific variants
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