title: Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data.
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.
  
  
  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). 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 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 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 [1.01-1.15]; RR(nonobese) 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.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lindgren
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.forename: Joshua
authors.initials: J
authors.lastname: Randall
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.forename: David P
authors.initials: DP
authors.lastname: Strachan
authors.forename: N William
authors.initials: NW
authors.lastname: Rayner
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
authors.forename: Graham A
authors.initials: GA
authors.lastname: Hitman
authors.forename: Alex S F
authors.initials: AS
authors.lastname: Doney
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Morris
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
mesh_terms: D050154:Adiposity / Q000235:genetics*; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics*; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D009765:Obesity / Q000150:complications / Q000235:genetics; D020641:Polymorphism, Single Nucleotide