A Genome-Wide Association Search for Type 2 Diabetes Genes in African Americans

Abstract

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10−8). SNP rs7560163 (P = 7.0×10−9, OR (95% CI) = 0.75 (0.67–0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10−5) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.

Calcium release channel RyR2 regulates insulin release and glucose homeostasis

“…GWAS have identified components of the genetic architecture of T2DM susceptibility (56)(57)(58). Notably, a GWAS focused on African Americans revealed an association between T2DM and a single nucleotide polymorphism located intergenically between RYR2 and 5-methyltetrahydrofolate-homocysteine (59). Previously, the association between RYR2 and T2DM was Figure 6.…”

High-Resolution Genetic Maps Identify Multiple Type 2 Diabetes Loci at Regulatory Hotspots in African Americans and Europeans

“…The AA GWA sample for a population of predominantly African ancestry was obtained from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). 13 Analyzing ''one-SNP-at-a-time'' ignores LD structure when testing for association with disease or gene expression.…”

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

“…We manually curated a list of SNPs that both passed genome-wide significance and were associated with kidney disease traits (Table S7). [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] To acquire independent loci, we removed any SNPs having r 2 R 0.2. In total, we analyzed 110 leading SNPs and 2,357 tagging SNPs with r 2 R 0.8 (Table S7).…”