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Kooner J.S.,Imperial College London | Saleheen D.,Center for Non Communicable Diseases Pakistan | Saleheen D.,University of Cambridge | Sim X.,National University of Singapore | And 80 more authors.
Nature Genetics | Year: 2011

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. © 2011 Nature America, Inc. All rights reserved. Source


Chambers J.C.,Imperial College London | Zhao J.,University College London | Terracciano C.M.N.,Imperial College London | Bezzina C.R.,Heart Failure Research Center | And 27 more authors.
Nature Genetics | Year: 2010

To identify genetic factors influencing cardiac conduction, we carried out a genome-wide association study of electrocardiographic time intervals in 6,543 Indian Asians. We identified association of a nonsynonymous SNP, rs6795970, in SCN10A (P = 2.8 × 10 15) with PR interval, a marker of cardiac atrioventricular conduction. Replication testing among 6,243 Indian Asians and 5,370 Europeans confirmed that rs6795970 (GA) is associated with prolonged cardiac conduction (longer P-wave duration, PR interval and QRS duration, P = 10 5 to 10 20). SCN10A encodes Na V 1.8, a sodium channel. We show that SCN10A is expressed in mouse and human heart tissue and that PR interval is shorter in Scn10a / mice than in wild-type mice. We also find that rs6795970 is associated with a higher risk of heart block (P 0.05) and a lower risk of ventricular fibrillation (P = 0.01). Our findings provide new insight into the pathogenesis of cardiac conduction, heart block and ventricular fibrillation. © 2010 Nature America, Inc. All rights reserved. Source


Nikpay M.,University of Ottawa | Goel A.,University of Oxford | Won H.-H.,The Broad Institute of MIT and Harvard | Won H.-H.,Massachusetts General Hospital | And 207 more authors.
Nature Genetics | Year: 2015

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size. © 2015 Nature America, Inc. Source

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