Testing the role of predicted gene knockouts in human anthropometric trait variation

摘要: Although the role of complete gene inactivation by two loss-of-function mutations inherited in trans is well-established recessive Mendelian diseases, we have not yet explored how such knockouts (KOs) could influence complex human phenotypes. Here, developed a statistical framework to test association between KOs and quantitative traits. Our method flexible, publicly available, compatible with common genotype format files (e.g. PLINK vcf). We characterized 4498 participants from NHLBI Exome Sequence Project (ESP) sequenced at high coverage (>100×), 1976 French Canadians Montreal Heart Institute Biobank low (5.7×), >100 000 Genetic Investigation ANthropometric Traits (GIANT) Consortium genotyped on an exome array. tested associations three anthropometric traits: body mass index (BMI), height BMI-adjusted waist-to-hip ratio (WHR). Despite our large sample size multiple datasets detect robust specific results highlight several limitations challenges for future KO studies humans, particular when there no prior knowledge phenotypes that might be affected KOs. They also suggest identified current DNA sequencing methodologies probably do strongly normal variation BMI, height, WHR general population.