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

Christopher DeBoever, Yosuke Tanigawa, Malene E. Lindholm, Greg McInnes, Adam Lavertu, Erik Ingelsson, Chris Chang, Euan A. Ashley, Carlos D. Bustamante, Mark J. Daly and Manuel A. Rivas ()
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Christopher DeBoever: Stanford University
Yosuke Tanigawa: Stanford University
Malene E. Lindholm: Grail, Inc.
Greg McInnes: Stanford University
Adam Lavertu: Stanford University
Erik Ingelsson: Stanford University School of Medicine
Chris Chang: Grail, Inc.
Euan A. Ashley: Stanford University
Carlos D. Bustamante: Stanford University
Mark J. Daly: Analytical and Translational Genetics Unit
Manuel A. Rivas: Stanford University

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03910-9

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