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Population structure, differential bias and genomic control in a large-scale, case-control association study

Nature Genetics volume 37, pages 1243–1246 (2005)Cite this article

Abstract

The main problems in drawing causal inferences from epidemiological case-control studies are confounding by unmeasured extraneous factors, selection bias and differential misclassification of exposure1. In genetics the first of these, in the form of population structure, has dominated recent debate2,3,4. Population structure explained part of the significant +11.2% inflation of test statistics we observed in an analysis of 6,322 nonsynonymous SNPs in 816 cases of type 1 diabetes and 877 population-based controls from Great Britain. The remainder of the inflation resulted from differential bias in genotype scoring between case and control DNA samples, which originated from two laboratories, causing false-positive associations. To avoid excluding SNPs and losing valuable information, we extended the genomic control method2,3,4,5 by applying a variable downweighting to each SNP.

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Figure 1: Signal intensity plots.
Figure 2: Quantile-quantile plots of Cochran-Armitage test statistics.
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Acknowledgements

We thank the individuals with T1D and control individuals for their participation; G. Coleman, S. Field, T. Mistry, K. Bourget, S. Clayton, M. Hardy, P. Lauder, M. Maisuria, W. Meadows and S. Wood for preparing DNA samples; D. Strachan, R. Jones, S. Ring and W. McArdle for providing DNA from the 1958 British Birth Cohort collection; and A. Long, N. Naclerio, T. Cormier, K. Tran, C. Bruckner and S. Picton for genotyping and technical assistance. We acknowledge use of DNA from the 1958 British Birth Cohort collection, funded by the Medical Research Council and the Wellcome Trust. We thank the Juvenile Diabetes Research Foundation, the Wellcome Trust, Diabetes UK and the Medical Research Council for financial support. D.G.C. is a Juvenile Diabetes Research Foundation and Wellcome Trust Principal Research Fellow.

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Authors and Affiliations

  1. Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge, CB2 2XY, UK

    David G Clayton, Neil M Walker, Deborah J Smyth, Rebecca Pask, Jason D Cooper, Lisa M Maier, Luc J Smink, Alex C Lam, Nigel R Ovington, Helen E Stevens, Sarah Nutland, Joanna M M Howson & John A Todd

  2. ParAllele BioScience, 7300 Shoreline Court, South San Francisco, California, 94080, USA

    Malek Faham, Martin Moorhead, Hywel B Jones, Matthew Falkowski, Paul Hardenbol & Thomas D Willis

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  1. David G Clayton
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  2. Neil M Walker
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Corresponding authors

Correspondence to David G Clayton or John A Todd.

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Competing interests

M. Faham, M.M., H.B.J., M. Falkowski, P.H. and T.D.W. are currently employed by ParAllele Bioscience.

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Clayton, D., Walker, N., Smyth, D. et al. Population structure, differential bias and genomic control in a large-scale, case-control association study. Nat Genet 37, 1243–1246 (2005). https://doi.org/10.1038/ng1653

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