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A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.

ABSTRACT: Identifying the genetic variants that increase the risk of type 2 diabetes (T2D) in humans has been a formidable challenge. Adopting a genome-wide association strategy, we genotyped 1161 Finnish T2D cases and 1174 Finnish normal glucose-tolerant (NGT) controls with >315,000 single-nucleotide polymorphisms (SNPs) and imputed genotypes for an additional >2 million autosomal SNPs. We carried out association analysis with these SNPs to identify genetic variants that predispose to T2D, compared our T2D association results with the results of two similar studies, and genotyped 80 SNPs in an additional 1215 Finnish T2D cases and 1258 Finnish NGT controls. We identify T2D-associated variants in an intergenic region of chromosome 11p12, contribute to the identification of T2D-associated variants near the genes IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings the number of T2D loci now confidently identified to at least 10.

SUBMITTER: Scott LJ

PROVIDER: S-EPMC3214617 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.

Scott Laura J LJ Mohlke Karen L KL Bonnycastle Lori L LL Willer Cristen J CJ Li Yun Y Duren William L WL Erdos Michael R MR Stringham Heather M HM Chines Peter S PS Jackson Anne U AU Prokunina-Olsson Ludmila L Ding Chia-Jen CJ Swift Amy J AJ Narisu Narisu N Hu Tianle T Pruim Randall R Xiao Rui R Li Xiao-Yi XY Conneely Karen N KN Riebow Nancy L NL Sprau Andrew G AG Tong Maurine M White Peggy P PP Hetrick Kurt N KN Barnhart Michael W MW Bark Craig W CW Goldstein Janet L JL Watkins Lee L Xiang Fang F Saramies Jouko J Buchanan Thomas A TA Watanabe Richard M RM Valle Timo T TT Kinnunen Leena L Abecasis Gonçalo R GR Pugh Elizabeth W EW Doheny Kimberly F KF Bergman Richard N RN Tuomilehto Jaakko J Collins Francis S FS Boehnke Michael M

Science (New York, N.Y.) 20070426 5829

Identifying the genetic variants that increase the risk of type 2 diabetes (T2D) in humans has been a formidable challenge. Adopting a genome-wide association strategy, we genotyped 1161 Finnish T2D cases and 1174 Finnish normal glucose-tolerant (NGT) controls with >315,000 single-nucleotide polymorphisms (SNPs) and imputed genotypes for an additional >2 million autosomal SNPs. We carried out association analysis with these SNPs to identify genetic variants that predispose to T2D, compared our T ...[more]

PMID: 17463248

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Project description:This study examined how differences in the BMI distribution of type 2 diabetic case subjects affected genome-wide patterns of type 2 diabetes association and considered the implications for the etiological heterogeneity of type 2 diabetes.We reanalyzed data from the Wellcome Trust Case Control Consortium genome-wide association scan (1,924 case subjects, 2,938 control subjects: 393,453 single-nucleotide polymorphisms [SNPs]) after stratifying case subjects (into "obese" and "nonobese") according to median BMI (30.2 kg/m(2)). Replication of signals in which alternative case-ascertainment strategies generated marked effect size heterogeneity in type 2 diabetes association signal was sought in additional samples.In the "obese-type 2 diabetes" scan, FTO variants had the strongest type 2 diabetes effect (rs8050136: relative risk [RR] 1.49 [95% CI 1.34-1.66], P = 1.3 x 10(-13)), with only weak evidence for TCF7L2 (rs7901695 RR 1.21 [1.09-1.35], P = 0.001). This situation was reversed in the "nonobese" scan, with FTO association undetectable (RR 1.07 [0.97-1.19], P = 0.19) and TCF7L2 predominant (RR 1.53 [1.37-1.71], P = 1.3 x 10(-14)). These patterns, confirmed by replication, generated strong combined evidence for between-stratum effect size heterogeneity (FTO: P(DIFF) = 1.4 x 10(-7); TCF7L2: P(DIFF) = 4.0 x 10(-6)). Other signals displaying evidence of effect size heterogeneity in the genome-wide analyses (on chromosomes 3, 12, 15, and 18) did not replicate. Analysis of the current list of type 2 diabetes susceptibility variants revealed nominal evidence for effect size heterogeneity for the SLC30A8 locus alone (RR(obese) 1.08 [1.01-1.15]; RR(nonobese) 1.18 [1.10-1.27]: P(DIFF) = 0.04).This study demonstrates the impact of differences in case ascertainment on the power to detect and replicate genetic associations in genome-wide association studies. These data reinforce the notion that there is substantial etiological heterogeneity within type 2 diabetes.

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A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.

Publications

A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.

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