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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) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10(-4) for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10(-8) to P = 1.9 × 10(-11)). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10(-4)), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D.

SUBMITTER: Kooner JS

PROVIDER: S-EPMC3773920 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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

Kooner Jaspal S JS Saleheen Danish D Sim Xueling X Sehmi Joban J Zhang Weihua W Frossard Philippe P Been Latonya F LF Chia Kee-Seng KS Dimas Antigone S AS Hassanali Neelam N Jafar Tazeen T Jowett Jeremy B M JB Li Xinzhong X Radha Venkatesan V Rees Simon D SD Takeuchi Fumihiko F Young Robin R Aung Tin T Basit Abdul A Chidambaram Manickam M Das Debashish D Grundberg Elin E Hedman Asa K AK Hydrie Zafar I ZI Islam Muhammed M Khor Chiea-Chuen CC Kowlessur Sudhir S Kristensen Malene M MM Liju Samuel S Lim Wei-Yen WY Matthews David R DR Liu Jianjun J Morris Andrew P AP Nica Alexandra C AC Pinidiyapathirage Janani M JM Prokopenko Inga I Rasheed Asif A Samuel Maria M Shah Nabi N Shera A Samad AS Small Kerrin S KS Suo Chen C Wickremasinghe Ananda R AR Wong Tien Yin TY Yang Mingyu M Zhang Fan F Abecasis Goncalo R GR Barnett Anthony H AH Caulfield Mark M Deloukas Panos P Frayling Timothy M TM Froguel Philippe P Kato Norihiro N Katulanda Prasad P Kelly M Ann MA Liang Junbin J Mohan Viswanathan V Sanghera Dharambir K DK Scott James J Seielstad Mark M Zimmet Paul Z PZ Elliott Paul P Teo Yik Ying YY McCarthy Mark I MI Danesh John J Tai E Shyong ES Chambers John C JC

Nature genetics 20110828 10

We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10(-4) for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci ( ...[more]

PMID: 21874001

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Project description:Abstract Population stratification, or systematic differences in allele frequencies between subpopulations, can distort the results from genome-wide association studies (GWAS). While GWAS are usually conducted within continental (e.g. European) ancestry groups, sub-groups may have specific population histories that result in enrichment for risk or protective alleles for complex disease. In this analysis, we examined genetic risk for glioma in a US population with predominantly Ashkenazi Jewish (AJ) ancestry. Genotyping data were obtained from three prior glioma case-control studies. Best-guess assignment to one of seven subcontinental European ancestry groups was performed using AIPS (https://github.com/biomedicaldatascience/AIPS). Out of a total of 6,416 cases and 7,441 controls across all three studies, 202 cases (3% of all cases, 63% GBM) and 403 controls (5% of all controls) were assigned to the AJ ancestry group. Unconditional logistic regression was performed for by study (adjusted for age and first two principal components) and then studies were combined using fixed effects meta-analysis. No associations reached genome-wide significance (p< 5x10-8), including those detected in prior pan-European GWAS. A nominally significant association was detected on chromosome 17 in ASPA (rs9904040, MAF=20%, p=2.61x10-6, Odds ratio=2.22 [95% confidence interval=1.59–3.09]) which is in linkage equilibrium (r2=0.0013) with the previously detected glioma risk SNP in TP53 (MAF=0.3% in this analysis, p=0.8801) in the European population. In our prior pan-European meta-analysis (Melin et al., 2017, this SNP was non-significant (p=0.0620). This study failed to replicate many previously identified glioma risk alleles, likely due to diminished power due to small sample size. We did identify a novel risk allele on chromosome 17 in ASPA, which encodes for aspartoacylase (which catalyzes deacylation of N-acetyl_L-aspartic acid). Larger sample sizes identified via targeted recruitment are necessary in order to fully characterize genetic risk for glioma in this population, including assessment of rare (MAF< 5%) risk allele associations.

Dataset Information

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

Publications

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

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