Studying individuals who are complete knockouts for a gene can be informative about its function. We exome-sequenced 3222 British Pakistani adults with high parental relatedness from Birmingham and the Born-in-Bradford study, and discovered rare homozygous loss-of-function (rhLOF) mutations in 781 genes, a substantial enrichment compared to discovery rates in outbred populations. We observed a 13.7% depletion of homozygous knockout genotypes, implying selection against deleterious recessive variants, and estimated that each adult has an average load of 1.6 recessive loss-of-function lethal-equivalent variants. We also observed a much smaller but significant depletion of homozygous missense variants predicted to be highly deleterious. Our findings emphasize the value of cataloguing human knockouts in healthy adults; we found 52 genes with rhLOFs which are lethal when knocked out in mice, and 32 which have been reported to cause Mendelian disease but for which the carriers of the rhLOF do not fit the reported phenotype. Additionally, the discovery of a healthy PRDM9-knockout mother demonstrated unexpected redundancy of this gene in humans, highlighting how the discovery of natural LoF variants can help characterise gene function. We found individual gene knockouts significantly associated with lipid and glycaemic traits. If validated in a larger cohort, these associations could point to potential new drug targets. Finally, we are expanding this study as part of the East London Genes and Health project. We aim to exome-sequence 25,000 healthy British South Asian adults (enriched for consanguinity) with linked electronic health records, in whom we expect to find ~4,800 unique genes with rhLOFs if the individuals all have an inbreeding coefficient of 0.0625. Additionally, we are identifying individuals with high autozygosity in the UK Biobank for sequencing. We will present preliminary results from these projects, which are expected to greatly expand the catalogue of human knockouts, shedding light on gene essentiality.