We tested single pLOF, nonsense, frameshift and essential splice-site variants85,86 for association with 1,419 PheCodes constructed from composites of ICD-10 (International Classification of Diseases 10th revision) codes to define cases and controls. Construction of the PheCodes has been previously described114. We performed the association analysis in the ‘white British’ individuals, which resulted in 408,008 individuals after the following quality control metrics were applied: (1) samples did not withdraw consent from the UK Biobank study as of the end of 2019; (2) ‘submitted gender’ matches ‘inferred sex’; (3) phased autosomal data available; (4) outliers for the number of missing genotypes or heterozygosity removed; (5) no putative sex chromosome aneuploidy; (6) no excess of relatives; (7) not excluded from kinship inference; and (8) in the UK Biobank defined the ‘white British’ ancestry subset. To perform the association analyses, we used a logistic mixed model test implemented in SAIGE114 with birth year and the top four principal components (computed from the white British subset) as covariates. For the pLOF burden tests, for each autosomal gene with at least two rare pLOF variants (n
