Evaluating Confounding in Rare Variant Genome Wide Association Studies

The theorised risk that confounded rare variant associations will emerge from population-based genetic studies has not been investigated empirically. Using 306,991 sequenced exomes from the UK Biobank, we demonstrate that recent demography is poorly captured by common and rare variant principal components (PCs), and accounting for haplotype sharing does not eliminate false-positive rare variant associations with non-heritable spatially structured traits. Through re-analysis of 155 phenotypes in siblings, we show a trend of higher effect estimates bias for non-uniformly distributed traits, suggesting population stratification is most pervasive in these settings. Despite its spatial structure, bias of rare variant associations with height appeared most strongly influenced by assortative mating. We explore the risk of elevated false discovery rates for recent variants private to extended families sharing polygenic liability to extreme phenotypes, as well as through local linkage with common causal variants. Overall, we consider the complex confounding mechanisms that can impact rare variant studies and demonstrate family-based approaches enabling critical sensitivity analyses.