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

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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 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
JournalDiabetes
Volume58
Issue number2
DOIs
StatePublished - Feb 2009
Externally publishedYes

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