Title: Whole-exome imputation within UK Biobank powers rare coding variant association and fine-mapping analyses.
Authors: Barton, Alison R; Sherman, Maxwell A; Mukamel, Ronen E; Loh, Po-Ru
Published In Nat Genet, (2021 08)
Abstract: Exome 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 ≈ 500,000) 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 × 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 genome-wide association studies, 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.
PubMed ID: 34226706
MeSH Terms: Biological Specimen Banks*; Blood Pressure/genetics; Chromosome Mapping/methods; Chromosome Mapping/statistics & numerical data; Gene Frequency*; Genetic Markers; Genome-Wide Association Study/statistics & numerical data; Humans; Linkage Disequilibrium; Membrane Proteins/genetics; Models, Genetic; Phenotype; Polymorphism, Single Nucleotide; Proteins/genetics*; Proteins/metabolism; Receptors, Atrial Natriuretic Factor/genetics; United Kingdom; Whole Exome Sequencing/methods; Whole Exome Sequencing/statistics & numerical data*