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

Abstract Genes and Health (G&H) is a biomedical study of adult British-Pakistani and -Bangladeshi research volunteers enriched for autozygosity. We performed whole exome sequencing in 44,028 G&H participants, establishing the largest publicly available South Asian exome resource linked to longitudinal electronic health records. We performed association analyses for 646 traits under additive and recessive models, and meta-analysis of 33 cardiometabolic traits with UK Biobank, finding more than 100 novel gene-phenotype associations such as ADAM15 with pulmonary oedema and ADCY6 with intracerebral haemorrhage. 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 the presence of knockouts in adults is associated with 2.2-times higher likelihood of drugs progressing beyond…