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)<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.

Figure 1. Association results of stage 1 meta-analysis in African Americans in a model adjusted for age, sex, study sites and study-specific principle components.

(A) Manhattan plot. Previously identified loci are denoted in red. Novel loci identified in this study are denoted in blue. (B) Quantile-quantile plot. The observed P values (y axis) were compared with the expected P values under the null distribution (x axis).

Figure 2. Regional plots of five previously and newly identified T2D loci in African Americans.

Association P values (on a −log₁₀ scale) of genotyped and imputed SNPs from stage 1 meta-analysis are plotted as a function of genomic position (NCBI Build 36). Plots for HLA-B, TCF7L2, KCNQ1, and HMGA2 used the model without BMI adjustment whereas plots for INS-IGF2 used the model with BMI adjustment. In each panel, the most strongly associated SNP from stage 1 and stage 1+2a+2b meta-analysis is denoted by a purple circle and a purple diamond, respectively. The color of all other SNPs indicates LD with the most strongly associated SNP based on the HapMap 2 YRI data. At KCNQ1, two independent signals are shown.