Consistent Association of Type 2 Diabetes Risk Variants Found in Europeans in Diverse Racial and Ethnic Groups

Abstract

It has been recently hypothesized that many of the signals detected in genome-wide association studies (GWAS) to T2D and other diseases, despite being observed to common variants, might in fact result from causal mutations that are rare. One prediction of this hypothesis is that the allelic associations should be population-specific, as the causal mutations arose after the migrations that established different populations around the world. We selected 19 common variants found to be reproducibly associated to T2D risk in European populations and studied them in a large multiethnic case-control study (6,142 cases and 7,403 controls) among men and women from 5 racial/ethnic groups (European Americans, African Americans, Latinos, Japanese Americans, and Native Hawaiians). In analysis pooled across ethnic groups, the allelic associations were in the same direction as the original report for all 19 variants, and 14 of the 19 were significantly associated with risk. In summing the number of risk alleles for each individual, the per-allele associations were highly statistically significant (P<10 ⁻⁴) and similar in all populations (odds ratios 1.09–1.12) except in Japanese Americans the estimated effect per allele was larger than in the other populations (1.20; P _het = 3.8×10 ⁻⁴). We did not observe ethnic differences in the distribution of risk that would explain the increased prevalence of type 2 diabetes in these groups as compared to European Americans. The consistency of allelic associations in diverse racial/ethnic groups is not predicted under the hypothesis of Goldstein regarding “synthetic associations” of rare mutations in T2D.

Author Summary

Single rare causal alleles and/or collections of multiple rare alleles have been suggested to create “synthetic associations” with common variants in genome-wide association studies (GWAS). This model predicts that associations with common variants will not be consistent across populations. In this study, we examined 19 T2D variants for association with T2D risk in 6,142 cases and 7,403 controls from five racial/ethnic populations in the Multiethnic Cohort (European Americans, African Americans, Latinos, Japanese Americans, and Native Hawaiians). In racial/ethnic pooled analysis, all 19 variants were associated with T2D risk in the same direction as previous reports in Europeans, and the sum total of risk variants was significantly associated with T2D risk in each racial/ethnic group. The consistent associations across populations do not support the Goldstein hypothesis that rare causal alleles underlie GWAS signals. We also did not find evidence that these markers underlie racial/ethnic disparities in T2D prevalence. Large-scale GWAS and sequencing studies in these populations are necessary in order to both improve the current set of markers at these risk loci and identify new risk variants for T2D that may be difficult, or impossible, to detect in European populations.