TY - JOUR
T1 - Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data
AU - Timpson, Nicholas J.
AU - Lindgren, Cecilia M.
AU - Weedon, Michael N.
AU - Randall, Joshua
AU - Ouwehand, Willem H.
AU - Strachan, David P.
AU - Rayner, N. William
AU - Walker, Mark
AU - Hitman, Graham A.
AU - Doney, Alex S.F.
AU - Palmer, Colin N.A.
AU - Morris, Andrew D.
AU - Hattersley, Andrew T.
AU - Zeggini, Eleftheria
AU - Frayling, Timothy M.
AU - McCarthy, Mark I.
PY - 2009/2
Y1 - 2009/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=63249135474&partnerID=8YFLogxK
U2 - 10.2337/db08-0906
DO - 10.2337/db08-0906
M3 - Article
C2 - 19056611
AN - SCOPUS:63249135474
SN - 0012-1797
VL - 58
SP - 505
EP - 510
JO - Diabetes
JF - Diabetes
IS - 2
ER -
