Testing for differences in polygenic scores in the presence of confounding

Polygenic scores have become an important tool in human genetics, enabling the prediction of individuals’ phenotypes from their genotypes. Understanding how the pattern of differences in polygenic score predictions across individuals intersects with variation in ancestry can provide insights into the evolutionary forces acting on the trait in question, and is important for understanding health disparities. However, because most polygenic scores are computed using effect estimates from population samples, they are susceptible to confounding by both genetic and environmental effects that are correlated with ancestry. The extent to which this confounding drives patterns in the distribution of polygenic scores depends on patterns of population structure in both the original estimation panel and in the prediction/test panel. Here, we use theory from population and statistical genetics, together with simulations, to study the procedure of testing for an association between polygenic scores and axes of ancestry variation in the presence of confounding. We use a general model of genetic relatedness to describe how confounding in the estimation panel biases the distribution of polygenic scores in a way that depends on the degree of overlap in population structure between panels. We then show how this confounding can bias tests for associations between polygenic scores and important axes of ancestry variation in the test panel. Finally, we use the understanding gained from this analysis to develop a method that uses patterns of genetic similarity between the two panels to guard against these biases, and show that this method can provide better protection against confounding than the standard PCA-based approach.