Meta-analysis of type 2 Diabetes in African Americans Consortium

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.Peer reviewe

Power and false positive rate over thresholds and by population samples.

<p>The empirical power (dashed) and false positive rate (solid) are shown for a range of sibling versus unrelated LCL decision thresholds. In each plot, the indicated population sample is assumed in the calculations. Within each plot, the colored curves indicate the true population sample allele frequencies used to simulate individuals. Red signifies Vietnamese, orange African American, purple European American, blue Latino, and green Navajo. Similarly color-coded crosses indicate for each population sample pair.</p

LCL distributions for siblings and unrelated individuals by population samples.

<p>Each individual plot shows the distribution of LCLs for unrelated individuals (solid) and siblings (dashed). The dotted vertical lines indicate . The horizontal lines show the central 95% of observed values over genotypes. The true and assumed population samples are listed on the column and row headings, respectively. Plot coloring indicates distinguishability where red represents low and blue represents high .</p

<b> versus </b><b>.</b>

<p>The empirical distinguishability () for siblings and unrelated individuals is plotted against average gene diversity () for each population sample. Points are colored according to the true population sample where red signifies Vietnamese, orange African American, purple European American, blue Latino, and green Navajo.</p