Abstract
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 FST 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.
Accepted Version
Published Version
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