ABSTRACT Background Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes Coronavirus disease-19 (COVID-19), a respiratory illness with influenza-like symptoms that can result in hospitalization or death. We investigated human genetic determinants of COVID-19 risk and severity in 455,838 UK Biobank participants, including 2,003 with COVID-19.Methods We defined eight COVID-19 phenotypes (including risks of infection, hospitalization and severe disease) and tested these for association with imputed and exome sequencing variants.Results We replicated prior COVID-19 genetic associations with common variants in the 3p21.31 (in LZTFL1) and 9q34.2 (in ABO) loci. The 3p21.31 locus (rs11385942) was associated with disease severity amongst COVID-19 cases (OR=2.2, P=3×10−5), but not risk of SARS-CoV-2 infection without hospitalization (OR=0.89, P=0.25). We identified two loci associated with risk of infection at P<5×10−8, including a missense variant that tags the ε4 haplotype in APOE (rs429358; OR=1.29, P=9×10−9). The association with rs429358 was attenuated after adjusting for cardiovascular disease and Alzheimer’s disease status (OR=1.15, P=0.005). Analyses of rare coding variants identified no significant associations overall, either exome-wide or with (i) 14 genes related to interferon signaling and reported to contain rare deleterious variants in severe COVID-19 patients; (ii) 36 genes located in the 3p21.31 and 9q34.2 GWAS risk loci; and (iii) 31 additional genes of immunologic relevance and/or therapeutic potential.Conclusions Our analyses corroborate the association with the 3p21.31 locus and highlight that there are no rare protein-coding variant associations with effect sizes detectable at current sample sizes. Our full analysis results are publicly available, providing a substrate for meta-analysis with results from other sequenced COVID-19 cases as they become available. Association results are available at https://rgc-covid19.regeneron.com.