Rare variant contribution to human disease in 281,104 UK Biobank exomes.

Summary of variant-level exome-wide association study results.a, The number of genes (y axis) with at least the number of PTV carriers (x axis) in 287,917 UKB participants of any ancestry. The dashed line corresponds to the minimum number of carriers typically required to detect individual PTVs with a MAF > 0.5%, that is, 2,873 carriers. Colours represent heterozygous (het.), putative compound heterozygous (comp. het.) and homozygous/hemizygous carriers (recessive). b, The MAF distribution of 632 genome-wide significant ExWAS variants associated with binary traits. The inset plot represents the same data limited to variants with MAF < 0.5%. c, The distribution of effect sizes for 509 common versus 123 rare (MAF < 0.5%) significant ExWAS variants. The plots in b and c include variants with the largest effect sizes achieved per gene. d, Percentage of ExWAS study-wide significant PTVs (n = 24) and missense variants (n = 326) that reflect known or novel gene–phenotype relationships. Variants capturing known gene–phenotype relationships were partitioned into those validated in (1) at least one but not all, or (2) all four publicly available databases: FinnGen release r5, OMIM, the GWAS Catalog (including GWAS Catalog variants within a 50-kb flanking sequence either side of the index variant), and the ClinVar pathogenic/likely pathogenic variant collection.

Summary of gene-level collapsing analysis results.a, Gene–phenotype associations for binary traits. For gene–phenotype associations that appear in multiple collapsing models, we display only the association with the strongest effect size. The dashed line represents the genome-wide significant P value threshold (2 × 10−9). The y axis is capped at −log10(P) = 50 and only associations with P < 10−5 were plotted (n = 94,208). b, Enrichment of FDA-approved drug targets6,46 among significant binary traits, quantitative traits, OMIM genes and GWAS signals. P values were generated via two-sided Fisher’s exact test (*P < 10−5, **P < 10−20, ***P < 10−70). Exact statistics: binary odds ratio (OR) = 7.38, 95% CI: 3.71–13.59, P = 1.5 × 10−7; quantitative OR = 3.71, 95% CI: 2.28–5.76, P = 4.5 × 10−7; OMIM OR = 5.95, 95% CI: 4.90–7.23, P = 1.1 × 10−75; GWAS OR = 2.68, 95% CI: 2.12–3.32, P = 3.6 × 10−23). Error bars represent 95% CIs. Contingency tables were created using each of the binary (n = 195), quantitative (n = 395), OMIM (n = 3,875) and GWAS (n = 10,692) categories, alongside approved targets from Informa Pharmaprojects (n = 463). P values were generated via a two-tailed Fisher’s exact test. c, Effect sizes for select gene associations per disease area. Genes with the highest OR for a chapter or with OR > 100 are labelled. d, Illustration of large effect gene–phenotype associations for select disease-related quantitative traits. FEV1/FVC, forced expiratory volume in 1 s/forced vital capacity ratio; HDL, high-density lipoprotein; LDL, low-density lipoprotein. Dashed line corresponds to a beta of 0.

Pan-ancestry collapsing analysis.a, b, The change in Phred scores between the pan-ancestry and European-only analyses for 46,769 binary associations (a) and 39,541 quantitative associations (b) stratified by chapter. For gene–phenotype associations that appear in multiple collapsing models, we display only those with the lowest P value. The green dots indicate associations that were not significant in the European analysis but were significant in the combined analysis. The orange dots represent associations that were originally significant in the European-only analysis but became not significant in the combined analysis. In both figures, the y axis is capped at ΔPhred = 40 (equivalent to a P value change of 0.0001).