Proteomic and clinical impact of human knockouts in British South Asians

Abstract Human loss-of-function (LoF) variants affecting both copies of a gene (“human knockouts”) provide a unique opportunity to directly study function and clinical impact of genes but are very rare in most populations sequenced to date. Here we study 1,569 British Bangladeshi and -Pakistani adults who were recalled for plasma sampling for proteomic profiling using three distinct technologies (covering >12,000 proteins) from 55k whole exome sequenced Genes & Health adults – a cohort enriched for rare, biallelic (homozygous) variants due to high autozygosity. We identified 199 individuals with rare homozygous predicted LoF genotypes (pLoF) for which the respective cis- protein was measured by at least one technology, and observed extreme (> 3SDs) cis- protein underexpression in 41 individuals (median z-score…