Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome wide association data.
- Nicholas J Timpson1,2,
- Cecilia M Lindgren1,3,
- Michael N Weedon4,5,
- Joshua Randall1,
- Willem H Ouwehand6,7,
- David P Strachan8,
- William N Rayner1,3,
- Mark Walker9,
- Graham A Hitman10,
- Alex SF Doney11,
- Colin NA Palmer12,
- Andrew D Morris11,
- Andrew T Hattersley4,5,
- Eleftheria Zeggini1,
- Timothy M Frayling4,5 and
- Mark I McCarthy (mark.mccarthy{at}drl.ox.ac.uk)1,3
- 1Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 2BN UK
- 2The MRC Centre for Causal Analyses in Translational Epidemiology, Bristol University, Canynge Hall, Whiteladies Rd, Bristol BS2 8PR, UK
- 3Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, OX3 7LJ, UK
- 4Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Magdalen Road, Exeter EX1 2LU UK
- 5Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5DU, UK
- 6Department of Haematology, University of Cambridge, Long Road, Cambridge, CB2 2PT, UK
- 7National Health Service Blood and Transplant, Cambridge Centre, Long Road, Cambridge, CB2 2PT, UK
- 8Division of Community Health Services, St George's University of London, Cranmer Terrace, London SW17 0RE, UK
- 9Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
- 10Centre for Diabetes and Metabolic Medicine, Barts and The London, Royal London Hospital, Whitechapel, London, E1 1BB, UK
- 11Diabetes Research Centre, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, DD1 9SY
- 12Population Pharmacogenetics Group, Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, UK
Abstract
OBJECTIVE: This study examined how differences in the BMI distribution of type 2 diabetes (T2D) cases impacted on genome-wide patterns of T2D association and considered the implications for the aetiological heterogeneity of T2D.
RESEARCH DESIGN and METHODS: We reanalysed data from the Wellcome Trust Case Control Consortium genome-wide association scan (1924 cases, 2938 controls: 393,453 SNPs) after stratifying cases (into “obese” and “nonobese”) according to median BMI (30.2kgm-2). Replication of signals in which alternative case-ascertainment strategies generated marked effect-size heterogeneity in T2D-association signal was sought in additional samples.
RESULTS: In the “obese-T2D” scan, FTO variants had the strongest T2D effect (rs8050136: RR=1.49, [1.34, 1.66], p=1.3x10-13), with only weak evidence for TCF7L2 (rs7901695 RR=1.21 [1.09, 1.35], p=0.001). This situation was reversed in the “non-obese” 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=1.3x10-14). These patterns, confirmed by replication, generated strong combined evidence for between-stratum effect-size heterogeneity (FTO: Pdiff=1.4x10-7; TCF7L2: pdiff=4.0x10-6). 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 T2D-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 aetiological heterogeneity within T2D.
Footnotes
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- Received July 7, 2008.
- Accepted November 19, 2008.
- Copyright © American Diabetes Association
