Barton, Alison R.Sherman, Maxwell A.Mukamel, Ronen E.Loh, Po-Ru2023-02-082020-07-05Barton, Alison R, Maxwell A Sherman, Ronen E Mukamel, and Po-Ru Loh. 2021. “Whole-Exome Imputation Within UK Biobank Powers Rare Coding Variant Association and Fine-Mapping Analyses.” Nature Genetics 53 (8): 1260–69.https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37374291Exome association studies to date have generally been underpowered to systematically evaluate the phenotypic impact of very rare coding variants. We leveraged extensive haplotype sharing between 49,960 exome-sequenced UK Biobank participants and the remainder of the cohort (total N~500K) to impute exome-wide variants with accuracy (R2>0.5) down to minor allele frequency (MAF) ~0.00005. Association and fine-mapping analyses of 54 quantitative traits identified 1,189 significant associations (P<5 x 10-8) involving 675 distinct rare protein-altering variants (MAF<0.01) that passed stringent filters for likely causality. Across all traits, 49% of associations (578/1,189) occurred in genes with two or more hits; follow-up analyses of these genes identified allelic series containing up to 45 distinct likely-causal variants. Our results demonstrate the utility of within-cohort imputation in population-scale GWAS cohorts, provide a catalog of likely-causal, large-effect coding variant associations, and foreshadow the insights that will be revealed as genetic biobank studies continue to grow.en-USGenetic and Genomic MedicineJournal Article2023-02-0810.1101/2020.08.28.20180414