A frequentist test of proportional colocalization after selecting relevant genetic variants

Colocalization analyses assess whether two traits are affected by the same or distinct causal genetic variants in a single gene region. A class of Bayesian enumeration colocalization tests are now routinely used in practice; for example, for genetic analyses in drug development pipelines. In this work, we consider an alternative frequentist approach to colocalization testing that examines the proportionality of genetic associations with each trait. The proportional colocalization approach uses markedly different assumptions to enumeration colocalization tests, and therefore can provide valuable complementary evidence in cases where enumeration colocalization results are inconclusive or sensitive to priors. We propose a novel conditional test of proportional colocalization, prop-coloc-cond, that aims to account for the uncertainty in variant selection, in order to recover accurate type I error control. The test can be implemented straightforwardly, requiring only summary data on genetic associations. Simulation evidence and an empirical investigation into GLP1R gene expression demonstrates how tests of proportional colocalization can offer important insights in conjunction with enumeration colocalization tests.