Abstract
Population stratification refers to differences in allele frequencies between cases and controls due to systematic differences in ancestry rather than association of genes with disease. It has been proposed that false positive associations due to stratification can be controlled by genotyping a few dozen unlinked genetic markers. To assess stratification empirically, we analyzed data from 11 case-control and case-cohort association studies. We did not detect statistically significant evidence for stratification but did observe that assessments based on a few dozen markers lack power to rule out moderate levels of stratification that could cause false positive associations in studies designed to detect modest genetic risk factors. After increasing the number of markers and samples in a case-cohort study (the design most immune to stratification), we found that stratification was in fact present. Our results suggest that modest amounts of stratification can exist even in well designed studies.
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Acknowledgements
We thank A. Villapakkam for assistance in genotyping and data checking and K. Ardlie, D. Goldstein and C. Haiman for discussions. M.L.F. is supported by a Department of Defense Health Disparity training grant and a Postdoctoral Fellowship for Physicians from the Howard Hughes Medical Institute. D.A. is a Clinical Scholar in Translational Research from the Burroughs Wellcome Fund, as well as a Charles E. Culpeper Medical Scholar. J.N.H. and D.R. are recipients of Career Development Awards from the Burroughs Welcome Fund. T.L.P. is supported by a Canadian Institutes of Health Research Postdoctoral Fellowship and is a NARSAD Young Investigator. This work was supported in part by a grant from the Functional Genomics Program at the Whitehead Institute/MIT Center for Genome Research (supported by Affymetrix, Millennium Pharmaceuticals and Bristol Myers Squibb) and by a grant from the US National Institutes of Health to B.H. and L.K.
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D.A. is a paid consultant to Genomics Collaborative, which provided the previously published data set (Am. J. Hum. Genet. 71, 304–311; 2002) that was reanalyzed in this paper.
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Freedman, M., Reich, D., Penney, K. et al. Assessing the impact of population stratification on genetic association studies. Nat Genet 36, 388–393 (2004). https://doi.org/10.1038/ng1333
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DOI: https://doi.org/10.1038/ng1333
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