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