Investigating the contribution of rare coding variants to human complex traits

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 50K exome-sequenced UK Biobank participants and the remainder of the cohort (total N~500K) to impute exome-wide variants with accuracy down to minor allele frequency (MAF) ~0.00005. Association and fine-mapping analyses of 54 quantitative traits identified 1,189 significant associations involving 675 distinct rare protein-altering variants (MAF.01) that passed stringent filters for likely causality. Follow-up analyses of recurrently-hit genes identified long allelic series containing up to 45 distinct likely-causal variants within the same gene. Using these imputed rare variants, we further examined evidence of mitigated, incompletely penetrant phenotypes in heterozygous carriers of recessive Mendelian disease variants. Testing a subset of these variants curated from ClinVar and OMIM for association with 58 quantitative traits yielded 102 significant associations involving variants previously implicated in 34 different diseases. 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, show that many disease-associated recessive variants can produce mitigated phenotypes in heterozygous carriers, and foreshadow the insights that will be revealed as genetic biobank studies continue to grow.