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

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 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

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 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

KW - COMMON VARIANTS

KW - EUROPEAN POPULATIONS

KW - INSULIN-RELEASE

KW - RISK LOCI

KW - REPLICATION

KW - GENES

KW - OBESITY

KW - CDKAL1

KW - HHEX

KW - MASS

U2 - 10.2337/db08-0906

DO - 10.2337/db08-0906

M3 - Article

C2 - 19056611

SN - 0012-1797

VL - 58

SP - 505

EP - 510

JO - Diabetes

JF - Diabetes

IS - 2

ER -