Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data

Nicholas J. Timpson, Cecilia M. Lindgren, Michael N. Weedon, Joshua Randall, Willem H. Ouwehand, David P. Strachan, N. William Rayner, Mark Walker, Graham A. Hitman, Alex S F Doney, Colin N A Palmer, Andrew D. Morris, Andrew T. Hattersley, Eleftheria Zeggini, Timothy M. Frayling, Mark I. McCarthy

Research output: Contribution to journalArticlepeer-review


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 and 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/m2). 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 × 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 × 10-14). These patterns, confimed by replication, generated strong combined evidence for between-stratum effect size heterogeneity (FTO: PDIFF = 1.4 × 10-7; TCF7L2: PDIFF = 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 [1.011.15]; RRnonobese 1.18 [1.10-1.27]: PdiFF = 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.

Original languageEnglish
Pages (from-to)505-510
Number of pages6
Issue number2
Publication statusPublished - 1 Feb 2009

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