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; Phet = 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.

10 Years of GWAS Discovery: Biology, Function, and Translation

“…78,79 In keeping with the age of these common risk alleles (which predates the diaspora of modern humans out of Africa), most common variant associations for T2D are replicated across major ethnic groups. 75,80 However, as increasingly diverse populations are genotyped and sequenced, more ethnic-specific alleles 82 From GWAS to Biology. Regulatory information on the key tissues of insulin action (fat, muscle, and liver) 82,83 and equivalent data from pancreatic islet material 67,84 have provided compelling evidence that the variants most strongly associated with T2D (as well as fasting glucose and other related quantitative traits) are preferentially located at active enhancers (particularly stretch enhancers) in pancreatic islets 67,84 and, to a lesser extent, at enhancers active in fat, muscle, and liver.…”

Progress and Promise of Genome-Wide Association Studies for Human Complex Trait Genetics

“…Fine mapping across ethnicities is based on the idea that a SNP associated in multiple populations must be in LD with the causal variant in all populations (e.g., Udler et al 2009) and assumes a single causal variant across populations and no population differences in disease etiology. Most GWAS signals have replicated across populations of different ethnicity (Waters et al 2009(Waters et al , 2010Teslovich et al 2010), but in some cases differences between populations have been observed due to extreme allele frequency differences or lack of effect in one population vs. another (Kochi et al 2009). Recently, it has been shown that under some circumstances, mapping in multiethnic cohorts can significantly increase power to detect associations, as genetic drift may elevate allele frequencies of some variants in different populations, thereby boosting statistical power to detect an association (Pulit et al 2010).…”

Understanding Genetic Heterogeneity in Type 2 Diabetes by Delineating Physiological Phenotypes:SIRT1and its Gene Network in Impaired Insulin Secretion

“…Variations of these genes have been described, and correlations between genotype and disease phenotype have been drawn. These studies have provided strong evidence of an association of the genes involved in β-cell development, proliferation, function, and apoptosis [5][6][7][8][9][10][11][12][13]. Other associated genes are involved in glucose homeostasis [5,7,14], insulin secretion, resistance, and function [5,7,[12][13][14][15][16][17][18][19][20][21][22][23], membrane transporters [5,24], transcription factors (TFs) [25][26][27], and energy sensing and fat metabolism [7,8,10,12,24,[28][29][30].…”