Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity

Genes & Health (G&H) is a biomedical study of adult British Pakistani and Bangladeshi research volunteers enriched for autozygosity. Here we performed whole-exome sequencing in 44,028 G&H participants, establishing a large publicly available South Asian exome resource linked to longitudinal electronic health records. We performed exome-wide association analyses for 645 electronic health record-derived traits under additive and recessive models, and meta-analyses of 33 cardiometabolic traits with UK Biobank, finding more than 100 novel gene–phenotype associations. We identified 2,991 genes with rare biallelic predicted loss-of-function (‘knockout’) genotypes, 546 of which had not been previously reported. We show that drugs targeting genes with knockouts in adults are associated with a 2.2-fold higher likelihood of progressing beyond phase 1 clinical trials. We further illustrate how phenotypic profiles associated with knockout genotypes can enhance efficacy and safety assessment of drug targets and aid in the interpretation of variants with ambiguous clinical significance in autosomal recessive disease genes.