Advertisement

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

  1. Nicholas J. Timpson12,
  2. Cecilia M. Lindgren13,
  3. Michael N. Weedon45,
  4. Joshua Randall1,
  5. Willem H. Ouwehand67,
  6. David P. Strachan8,
  7. N. William Rayner13,
  8. Mark Walker9,
  9. Graham A. Hitman10,
  10. Alex S.F. Doney11,
  11. Colin N.A. Palmer12,
  12. Andrew D. Morris11,
  13. Andrew T. Hattersley45,
  14. Eleftheria Zeggini1,
  15. Timothy M. Frayling45 and
  16. Mark I. McCarthy13
  1. 1Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K
  2. 2The Medical Research Council Centre for Causal Analyses in Translational Epidemiology, Bristol University, Bristol, U.K
  3. 3Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K
  4. 4Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K
  5. 5Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K
  6. 6Department of Haematology, University of Cambridge, Cambridge, U.K
  7. 7National Health Service Blood and Transplant, Cambridge Centre, Cambridge, U.K
  8. 8Division of Community Health Services, St. George's University of London, London, U.K
  9. 9Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K
  10. 10Centre for Diabetes and Metabolic Medicine, Barts, and The London, Royal London Hospital, Whitechapel, London, U.K
  11. 11Diabetes Research Centre, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee, U.K
  12. 12Population Pharmacogenetics Group, Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, U.K
  1. Corresponding author: Mark I. McCarthy, mark.mccarthy{at}drl.ox.ac.uk

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.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 3 December 2008.

    Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

    • Accepted November 19, 2008.
    • Received July 7, 2008.
| Table of Contents

This Article

  1. Published online before print December 3, 2008, doi: 10.2337/db08-0906 Diabetes February 2009 vol. 58 no. 2 505-510
  1. » Abstract
  2. Full Text
  3. Full Text (PDF)
  4. Online-Only Appendix
  5. All Versions of this Article:
    1. db08-0906v1
    2. 58/2/505 most recent

Social Bookmarking

Current Issue

  1. February 2012, 61 (2)
  1. Current Issue
  1. Alert me to new issues of Diabetes
Advertisement