Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study

• Published in: Nature communications Vol. 9; no. 1; pp. 1612 - 10
• Main Authors: DeBoever, Christopher, Tanigawa, Yosuke, Lindholm, Malene E., McInnes, Greg, Lavertu, Adam, Ingelsson, Erik, Chang, Chris, Ashley, Euan A., Bustamante, Carlos D., Daly, Mark J., Rivas, Manuel A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.04.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 45/43; 631/208/205/2138; 631/208/212/2301; 631/208/726/649/2219; 631/208/727/2000; Databases, Nucleic Acid - statistics & numerical data; Genes; Genome-Wide Association Study; Genomes; Humanities and Social Sciences; Humans; Major histocompatibility complex; multidisciplinary; Phenotype; Phenotypes; Proteins; Proteins - genetics; Science; Science (multidisciplinary); Sequence Deletion; United Kingdom; United Kingdom; United Kingdom > UK
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03910-9

Protein-truncating variants can have profound effects on gene function and are critical for clinical genome interpretation and generating therapeutic hypotheses, but their relevance to medical phenotypes has not been systematically assessed. Here, we characterize the effect of 18,228 protein-truncating variants across 135 phenotypes from the UK Biobank and find 27 associations between medical phenotypes and protein-truncating variants in genes outside the major histocompatibility complex. We perform phenome-wide analyses and directly measure the effect in homozygous carriers, commonly referred to as “human knockouts,” across medical phenotypes for genes implicated as being protective against disease or associated with at least one phenotype in our study. We find several genes with strong pleiotropic or non-additive effects. Our results illustrate the importance of protein-truncating variants in a variety of diseases. Protein-truncating variants (PTVs) are predicted to significantly affect a gene’s function and, thus, human traits. Here, DeBoever et al. systematically analyze PTVs in more than 300,000 individuals across 135 phenotypes and identify 27 associations between PTVs and medical conditions.