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The effects of human population structure on large genetic association studies

Nature Genetics volume 36, pages 512–517 (2004)Cite this article

Abstract

Large-scale association studies hold substantial promise for unraveling the genetic basis of common human diseases. A well-known problem with such studies is the presence of undetected population structure, which can lead to both false positive results and failures to detect genuine associations. Here we examine ∼15,000 genome-wide single-nucleotide polymorphisms typed in three population groups to assess the consequences of population structure on the coming generation of association studies. The consequences of population structure on association outcomes increase markedly with sample size. For the size of study needed to detect typical genetic effects in common diseases, even the modest levels of population structure within population groups cannot safely be ignored. We also examine one method for correcting for population structure (Genomic Control). Although it often performs well, it may not correct for structure if too few loci are used and may overcorrect in other settings, leading to substantial loss of power. The results of our analysis can guide the design of large-scale association studies.

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Figure 1: The effects of population structure at a SNP locus.
Figure 2: Differences between actual and predicted values (residuals) in data set II (the Asian sample).
Figure 3: Multiplicative change in P values due to population structure in small samples.
Figure 4: Multiplicative change in P values due to population structure in large samples (shown on log10 scale).
Figure 5: Multiplicative change in P values due to population structure after Genomic Control correction for scenario A2.
Figure 6: Multiplicative change in P values due to population structure after Genomic Control correction for scenarios B1 (a–c), B2 (d–f) and B3 (g–i).

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Acknowledgements

L.R.C. and J.M. thank The Wellcome Trust for support. L.R.C. and P.D. acknowledge the US National Institutes of Health and The SNP Consortium.

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Authors and Affiliations

  1. Department of Statistics, University of Oxford, 1 South Parks Road, Oxford, OX1 3TG, UK

    Jonathan Marchini & Peter Donnelly

  2. Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK

    Lon R Cardon

  3. Genome Quebec and McGill University Genome Center, Montreal, H3A 1A4, Canada

    Michael S Phillips

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  1. Jonathan Marchini
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  2. Lon R Cardon
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  4. Peter Donnelly
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Correspondence to Peter Donnelly.

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Marchini, J., Cardon, L., Phillips, M. et al. The effects of human population structure on large genetic association studies. Nat Genet 36, 512–517 (2004). https://doi.org/10.1038/ng1337

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