In this study, we performed a phenome-wide association study (PheWAS) using exome sequence data from 269,171 UKB participants of European ancestry to evaluate the association between protein-coding variants and 17,361 binary and 1,419 quantitative phenotypes. We first report the diversity of phenotypes and sequence variation present in this cohort. We then performed variant-level and gene-level association tests to identify risk factors across the allele frequency spectrum. Finally, we performed additional collapsing analyses in 11,933 individuals of African, East Asian or South Asian genetic ancestry. Using these results, we implemented a pan-ancestry analysis of 281,104 UKB participants. Altogether, this study comprehensively examines the contribution of rare protein-coding variation to the genetic architecture of complex human diseases and quantitative traits.
