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

By Christopher M. DeBoever, Yosuke Tanigawa, M. Lindholm, G. McInnes, A. Lavertu, E. Ingelsson, Christopher J. Chang, Euan A. Ashley, Carlos D. Bustamante, Mark J. Daly and 1 more. 2017

115 citations recorded by the source corpus.

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.

Subfields: Genetics

Citations in the corpus

• Evaluating drug targets through human loss-of-function genetic variation (2019, unknown): “%) without known human disease association have two-hit pLoF genotypes reported in gnomAD 7 , ELGH 26 , PROMIS 27 , DeCODE 28 , or UK BioBank 29 , suggesting this genotype may be tolerated.”