Genome-Wide Association Scan Allowing for Epistasis in Type 2 Diabetes

Authors

  • Jordana T. Bell,

    Corresponding author
    1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
    2. Department of Twin Research, King's College London, UK
      Corresponding author: Dr. Jordana Bell, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. Tel: 01865-287828; Fax: 01865-287501; E-mail: jordana@well.ox.ac.uk
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  • Nicholas J. Timpson,

    1. MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, Bristol University, Bristol
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  • N. William Rayner,

    1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
    2. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
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  • Eleftheria Zeggini,

    1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
    2. Wellcome Trust Sanger Institute, Hinxton, UK
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  • Timothy M. Frayling,

    1. Peninsula Medical School, Exeter, UK
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  • Andrew T. Hattersley,

    1. Peninsula Medical School, Exeter, UK
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  • Andrew P. Morris,

    1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
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  • Mark I. McCarthy

    1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
    2. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
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Corresponding author: Dr. Jordana Bell, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. Tel: 01865-287828; Fax: 01865-287501; E-mail: jordana@well.ox.ac.uk

Summary

In the presence of epistasis multilocus association tests of human complex traits can provide powerful methods to detect susceptibility variants. We undertook multilocus analyses in 1924 type 2 diabetes cases and 2938 controls from the Wellcome Trust Case Control Consortium (WTCCC). We performed a two-dimensional genome-wide association (GWA) scan using joint two-locus tests of association including main and epistatic effects in 70,236 markers tagging common variants. We found two-locus association at 79 SNP-pairs at a Bonferroni-corrected P-value = 0.05 (uncorrected P-value = 2.14 × 10−11). The 79 pair-wise results always contained rs11196205 in TCF7L2 paired with 79 variants including confirmed variants in FTO, TSPAN8, and CDKAL1, which are associated in the absence of epistasis. However, the majority (82%) of the 79 variants did not have compelling single-locus association signals (P-value = 5 × 10−4). Analyses conditional on the single-locus effects at TCF7L2 established that the joint two-locus results could be attributed to single-locus association at TCF7L2 alone. Interaction analyses among the peak 80 regions and among 23 previously established diabetes candidate genes identified five SNP-pairs with case-control and case-only epistatic signals. Our results demonstrate the feasibility of systematic scans in GWA data, but confirm that single-locus association can underlie and obscure multilocus findings.

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