Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci

Abstract

We carried out a genome wide association study of type-2 diabetes (T2D) amongst 20,119 people of South Asian ancestry (5,561 with T2D); we identified 20 independent SNPs associated with T2D at P<10−4 for testing amongst a further 38,568 South Asians (13,170 with T2D). In combined analysis, common genetic variants at six novel loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) were associated with T2D (P=4.1×10−8 to P=1.9×10−11); SNPs at GRB14 were also associated with insulin sensitivity, and at ST6GAL1 and HNF4A with pancreatic beta-cell function respectively. Our findings provide additional insight into mechanisms underlying T2D, and demonstrate the potential for new discovery from genetic association studies in South Asians who have increased susceptibility to T2D.

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

“…87 These approaches have generated some notable advances, for example, cis-expression mapping has highlighted KLF14 (MIM: 609393) as the mediator of a chromosome 7 T2D signal that is associated with insulin resistance and hyperlipidemia (appropriately, this expression signal is specific to adipose tissue). 85 90,91 or data from animal models (CDKAL1 [MIM: 611259]). 92 Finally, the accumulation of data on coding variants (via exome sequencing and/or exome array genotyping) has highlighted several instances where GWAS signals previously attributed to non-coding variants can be reassigned to causal coding variants (e.g., TM6SF2 [MIM: 606563] 74 ).…”

Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits

“…The coincidence is supported by reciprocal conditional analysis: after conditioning was performed on each lead eSNP, no GWAS variant remained significant (FDR < 1%), and after conditioning on each GWAS variant, 124 eSNP signals were no longer significant, and 16 were strongly attenuated (Dlog 10 (p) of 8.5 to 112 ) (Table S8). Of the 140 cis-eQTLs at GWAS loci, 93 (66.4%) were not previously reported by large-scale GWASs that interrogated available cis-eQTLs [14][15][16][17]38,45,48,[57][58][59][60][61][62][63][64][65][66][67][68] and 50 showed consistent direction of allelic effect at p < 0.05 in the MuTHER study. Table 1 shows 29 eQTLs for glycemic, obesity, and lipid traits at the LD threshold of r 2 > 0.9 between the GWAS variant and lead eSNP; three of these eQTLs were also identified with the SMR method.…”

Efficiency of trans-ethnic genome-wide meta-analysis and fine-mapping

“…7 Conversely, the other spectrum of low regional F ST and haplotype entropy included loci like CDKAL1, SLC30A8 and IRS1 where the associations are consistently reproduced across East and South Asians. 5,7 For a higher chance of success in identifying the causal variants, adopting a trans-ethnic approach to T2D loci like THADA, IRS1, PRC1 and CDKAL1 may be useful as they are found in genomic regions with either a lower degree of haplotype similarity or a higher extent of LD variation between populations (Figure 5b). …”

“…1,2 Early phases of GWAS and genome-wide meta-analyses (GWMA) have predominantly been performed in the Caucasian populations, although increasingly there are reports of GWAS and GWMA involving non-Caucasian communities from Africa, 3,4 East and South Asia, [5][6][7] and admixed African-Americans. 8,9 These have validated many previous discoveries made in the Caucasian populations, as well as identified and even guided the discovery of previously unsuspected loci that are either likely to be ancestry specific or are present at higher frequencies in the non-Caucasian populations.…”