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Chunk #57 — Discussion

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Population substructure and control selection in genome-wide association studies.
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We used empirical data from two GWAS within the CGEMS project to assess the extent and impact of PS in studies with two distinct control selection strategies. We also evaluated our proposed procedures for choosing structural inference SNPs as well as for selecting the PCs for correction of PS. In the two original GWAS based on the nested case-control design, we observed only minor confounding effect by PS with over-dispersion factors of 1.025 and 1.005 for prostate and breast cancer studies, respectively. These small inflations, which in practice may not raise major concern, can be further reduced by adjustment for a single PC. In the two reconstructed studies where cases and controls were collected independently using different designs, we observed more extensive confounding effect by PS with over-dispersion factors of 1.090 and 1.062. In these studies with external controls, three principal components were required to optimally correct for the confounding effect of PS, resulting in the reduction of the inflation factor to a level comparable to that in the original nested case-control studies. Our conclusions are based on two actual