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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References
Breslow, N.E. & Day, N.E. Statistical Methods in Cancer Research Vol. I. The Analysis of Case-Control Studies (International Agency for Research on Cancer, Lyon, 1980).
Devlin, B., Bacanu, S.A. & Roeder, K. Genomic control to the extreme. Nat. Genet. 36, 1129–1130; author reply 1131 (2004).
Freedman, M.L. et al. Assessing the impact of population stratification on genetic association studies. Nat. Genet. 36, 388–393 (2004).
Marchini, J., Cardon, L.R., Phillips, M.S. & Donnelly, P. The effects of human population structure on large genetic association studies. Nat. Genet. 36, 512–517 (2004).
Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).
Vella, A. et al. Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am. J. Hum. Genet. 76, 773–779 (2005).
Lowe, C.E. et al. Cost-effective analysis of candidate genes using htSNPs: a staged approach. Genes Immun. 5, 301–305 (2004).
Wang, W.Y., Barratt, B.J., Clayton, D.G. & Todd, J.A. Genome-wide association studies: theoretical and practical concerns. Nat. Rev. Genet. 6, 109–118 (2005).
Hardenbol, P. et al. Multiplexed genotyping with sequence-tagged molecular inversion probes. Nat. Biotechnol. 21, 673–678 (2003).
Hardenbol, P. et al. Highly multiplexed molecular inversion probe genotyping: over 10,000 targeted SNPs genotyped in a single tube assay. Genome Res. 15, 269–275 (2005).
Ueda, H. et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506–511 (2003).
The International HapMap Consortium. The International HapMap Project. Nature 426, 789–796 (2003).
Armitage, P. Test for linear trend in proportions and frequencies. Biometrics II, 375–386 (1955).
Mantel, N. Chi-square tests with one degree of freedom: extensions of the Mantel-Haenszel procedure. J. Am. Stat. Assoc. 58, 690–700 (1963).
Nelder, J. & Wedderburn, R. Generalised linear models. J. R. Statist. Soc. A 135, 370–384 (1972).
Moorhead, M. et al. Optimal genotype determination in highly multiplexed SNP data. Eur. J. Hum. Genet. (in the press).
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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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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DOI: https://doi.org/10.1038/ng1653
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