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Adiposity-Related Heterogeneity in Patterns of Type 2 Diabetes Susceptibility Observed in Genome-Wide Association Data

Lookup NU author(s): Professor Mark Walker

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Abstract

OBJECTIVE-This study examined how differences in the BMI distribution of type 2 diabetic case subjects affected genome-wide patterns of type 2 diabetes, association mid considered the implications for the etiological heterogeneity of type 2 diabetes. RESEARCH DESIGN AND METHODS-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. RESULTS-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). reversed in the "nonobese" scan, with FTO This situation was 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 gencome-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 (RRobese 1.08 [1.01-1.15]; RRnonobese 1.18 [1.10-1.27]: P-DIFF = 0.04). CONCLUSIONs-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. Diabetes 58:505-510, 2009

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Author(s): Timpson NJ, Lindgren CM, Weedon MN, Randall J, Ouwehand WH, Strachan DP, Rayner NW, Walker M, Hitman GA, Doney ASF, Palmer CNA, Morris AD, Hattersley AT, Zeggini E, Frayling TM, McCarthy MI

Publication type: Article

Publication status: Published

Journal: Diabetes

Year: 2009

Volume: 58

Issue: 2

Pages: 505-510

ISSN (print): 0012-1797

ISSN (electronic): 1939-327X

Publisher: American Diabetes Association

URL: http://dx.doi.org/10.2337/db08-0906

DOI: 10.2337/db08-0906

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