Transferability of Type 2 Diabetes Implicated Loci in Multi-Ethnic Cohorts from Southeast Asia

Xueling Sim,Yik-Ying Teo,Wan-Ting Tay,Mark Seielstad,Kee-Seng Chia,E-Shyong Tai,Rick Twee-Hee Ong,Daniel Peng-Keat Ng,Michael Boehnke,Tien-Yin Wong,Jianjun Liu,Chen Suo,Greg Gibson

doi:10.1371/journal.pgen.1001363

Abstract

Recent large genome-wide association studies (GWAS) have identified multiple loci which harbor genetic variants associated with type 2 diabetes mellitus (T2D), many of which encode proteins not previously suspected to be involved in the pathogenesis of T2D. Most GWAS for T2D have focused on populations of European descent, and GWAS conducted in other populations with different ancestry offer a unique opportunity to study the genetic architecture of T2D. We performed genome-wide association scans for T2D in 3,955 Chinese (2,010 cases, 1,945 controls), 2,034 Malays (794 cases, 1,240 controls), and 2,146 Asian Indians (977 cases, 1,169 controls). In addition to the search for novel variants implicated in T2D, these multi-ethnic cohorts serve to assess the transferability and relevance of the previous findings from European descent populations in the three major ethnic populations of Asia, comprising half of the world's population. Of the SNPs associated with T2D in previous GWAS, only variants at CDKAL1 and HHEX/IDE/KIF11 showed the strongest association with T2D in the meta-analysis including all three ethnic groups. However, consistent direction of effect was observed for many of the other SNPs in our study and in those carried out in European populations. Close examination of the associations at both the CDKAL1 and HHEX/IDE/KIF11 loci provided some evidence of locus and allelic heterogeneity in relation to the associations with T2D. We also detected variation in linkage disequilibrium between populations for most of these loci that have been previously identified. These factors, combined with limited statistical power, may contribute to the failure to detect associations across populations of diverse ethnicity. These findings highlight the value of surveying across diverse racial/ethnic groups towards the fine-mapping efforts for the casual variants and also of the search for variants, which may be population-specific.

Highlights

Type 2 diabetes mellitus (T2D) is a major chronic disease worldwide, affecting more than 300 million people
These genome-wide association studies (GWAS) have identified a number of novel loci harboring common variants that are associated with an increased risk of T2D [4,5,6,7,8,9,10,11], adding to the loci previously identified by candidate gene studies (PPARG [12], KCNJ11 [13,14], WFS1 [15,16]) and linkage studies TCF7L2 [17,18,19])
Type 2 diabetes mellitus (T2D) is a chronic disease which can lead to complications such as heart disease, stroke, hypertension, blindness due to diabetic retinopathy, amputations from peripheral vascular diseases, and kidney disease from diabetic nephropathy

Summary

Introduction

Type 2 diabetes mellitus (T2D) is a major chronic disease worldwide, affecting more than 300 million people. T2D has been one of the major human diseases to benefit from the advent of large-scale genetic studies that survey the entire genomic landscape for variants correlating with disease onset or severity These genome-wide association studies (GWAS) have identified a number of novel loci harboring common variants that are associated with an increased risk of T2D [4,5,6,7,8,9,10,11], adding to the loci previously identified by candidate gene studies (PPARG [12], KCNJ11 [13,14], WFS1 [15,16]) and linkage studies TCF7L2 [17,18,19]).

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