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Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data.

ABSTRACT: 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.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.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).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.

SUBMITTER: Timpson NJ

PROVIDER: S-EPMC2628627 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data.

Timpson Nicholas J NJ Lindgren Cecilia M CM Weedon Michael N MN Randall Joshua J Ouwehand Willem H WH Strachan David P DP Rayner N William NW Walker Mark M Hitman Graham A GA Doney Alex S F AS Palmer Colin N A CN Morris Andrew D AD Hattersley Andrew T AT Zeggini Eleftheria E Frayling Timothy M TM McCarthy Mark I MI

Diabetes 20081203 2

<h4>Objective</h4>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.<h4>Research design and methods</h4>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 ...[more]

PMID: 19056611

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Project description:Susceptibility to type 2 diabetes may be conferred by genetic variants having modest effects on risk. Genome-wide fixed marker arrays offer a novel approach to detect these variants.We used the Affymetrix 100K SNP array in 1,087 Framingham Offspring Study family members to examine genetic associations with three diabetes-related quantitative glucose traits (fasting plasma glucose (FPG), hemoglobin A1c, 28-yr time-averaged FPG (tFPG)), three insulin traits (fasting insulin, HOMA-insulin resistance, and 0-120 min insulin sensitivity index); and with risk for diabetes. We used additive generalized estimating equations (GEE) and family-based association test (FBAT) models to test associations of SNP genotypes with sex-age-age2-adjusted residual trait values, and Cox survival models to test incident diabetes.We found 415 SNPs associated (at p < 0.001) with at least one of the six quantitative traits in GEE, 242 in FBAT (18 overlapped with GEE for 639 non-overlapping SNPs), and 128 associated with incident diabetes (31 overlapped with the 639) giving 736 non-overlapping SNPs. Of these 736 SNPs, 439 were within 60 kb of a known gene. Additionally, 53 SNPs (of which 42 had r2 < 0.80 with each other) had p < 0.01 for incident diabetes AND (all 3 glucose traits OR all 3 insulin traits, OR 2 glucose traits and 2 insulin traits); of these, 36 overlapped with the 736 other SNPs. Of 100K SNPs, one (rs7100927) was in moderate LD (r2 = 0.50) with TCF7L2 (rs7903146), and was associated with risk of diabetes (Cox p-value 0.007, additive hazard ratio for diabetes = 1.56) and with tFPG (GEE p-value 0.03). There were no common (MAF > 1%) 100K SNPs in LD (r2 > 0.05) with ABCC8 A1369S (rs757110), KCNJ11 E23K (rs5219), or SNPs in CAPN10 or HNFa. PPARG P12A (rs1801282) was not significantly associated with diabetes or related traits.Framingham 100K SNP data is a resource for association tests of known and novel genes with diabetes and related traits posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite. Framingham 100K data replicate the TCF7L2 association with diabetes.

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Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data.

Publications

Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data.

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