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

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-truncat...

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Bibliographic Details
Published in:Nature communications 2018-04, Vol.9 (1), p.1612-10, Article 1612
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: Article
Language:English
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
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Summary: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.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-018-03910-9