Correcting for Population Stratification in Genomewide Association Studies

Genomewide association studies have become the primary tool for discovering the genetic basis of complex human diseases. Such studies are susceptible to the confounding effects of population stratification, in that the combination of allele-frequency heterogeneity with disease-risk heterogeneity among different ancestral subpopulations can induce spurious associations between genetic variants and disease. This article provides a statistically rigorous and computationally feasible solution to this challenging problem of unmeasured confounders. We show that the odds ratio of disease with a genetic variant is identifiable if and only if the genotype is independent of the unknown population substructure conditional on a set of observed ancestry-informative markers in the disease-free population. Under this condition, the odds ratio of interest can be estimated by fitting a semiparametric logistic regression model with an arbitrary function of a propensity score relating the genotype probability to ancestry-informative markers. Approximating the unknown function of the propensity score by B-splines, we derive a consistent and asymptotically normal estimator for the odds ratio of interest with a consistent variance estimator. Simulation studies demonstrate that the proposed inference procedures perform well in realistic settings. An application to the well-known Wellcome Trust Case-Control Study is presented. Supplemental materials are available online.