Differential confounding of rare and common variants in spatially structured populations

Well-powered genome-wide association studies, now possible through advances in technology and large-scale collaborative projects, promise to reveal the contribution of rare variants to complex traits and disease. However, while population structure is a known confounder of association studies, it is unknown whether methods developed to control stratification are equally effective for rare variants. Here we demonstrate that rare variants can show a systematically different and typically stronger stratification than common variants, and that this is not necessarily corrected by existing methods. We show that the same process leads to inflation for load-based tests and can obscure signals at truly associated variants. We show that populations can display spatial structure in rare variants even when F(ST) is low, but that allele-frequency dependent metrics of allele sharing can reveal localized stratification. These results underscore the importance of collecting and integrating spatial information in the genetic analysis of complex traits.