Adiposity-Related Heterogeneity in Patterns of Type 2 Diabetes Susceptibility Observed in Genome-Wide Association Data-Reference-Cited by-同舟云学术

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

Published:2009-02-01 Issue:2 Volume:58 Page:505-510
ISSN:0012-1797
Container-title:Diabetes
language:en
Short-container-title:

Author:

Timpson Nicholas J.¹²,Lindgren Cecilia M.¹³,Weedon Michael N.⁴⁵,Randall Joshua¹,Ouwehand Willem H.⁶⁷,Strachan David P.⁸,Rayner N. William¹³,Walker Mark⁹,Hitman Graham A.¹⁰,Doney Alex S.F.¹¹,Palmer Colin N.A.¹²,Morris Andrew D.¹¹,Hattersley Andrew T.⁴⁵,Zeggini Eleftheria¹,Frayling Timothy M.⁴⁵,McCarthy Mark I.¹³

Affiliation:

1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K

2. The Medical Research Council Centre for Causal Analyses in Translational Epidemiology, Bristol University, Bristol, U.K

3. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K

4. Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K

5. Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K

6. Department of Haematology, University of Cambridge, Cambridge, U.K

7. National Health Service Blood and Transplant, Cambridge Centre, Cambridge, U.K

8. Division of Community Health Services, St. George's University of London, London, U.K

9. Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K

10. Centre for Diabetes and Metabolic Medicine, Barts, and The London, Royal London Hospital, Whitechapel, London, U.K

11. Diabetes Research Centre, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee, U.K

12. Population Pharmacogenetics Group, Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, U.K

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. 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, confirmed by replication, generated strong combined evidence for between-stratum effect size heterogeneity (FTO: PDIFF = 1.4 × 10−7; TCF7L2: PDIFF = 4.0 × 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 (RRobese 1.08 [1.01–1.15]; 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.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

Link

https://journals.org/diabetes/diabetes/article-pdf/58/2/505/507723/zdb00209000505.pdf

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