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Nat Commun. 2018 Apr 24;9(1):1612. doi: 10.1038/s41467-018-03910-9.

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

Author information

1
Department of Biomedical Data Science, Stanford University, Stanford, CA, 94305, USA.
2
Department of Genetics, Stanford University, Stanford, CA, 94305, USA.
3
Grail, Inc., 1525 O'Brien Drive, Menlo Park, CA, 94025, USA.
4
Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
5
Department of Medicine, School of Medicine, Stanford University, Stanford, CA, 94305, USA.
6
Analytical and Translational Genetics Unit, Boston, MA, 02114, USA.
7
Broad Institute of MIT and Harvard, Cambridge, 02142, MA, USA.
8
Department of Biomedical Data Science, Stanford University, Stanford, CA, 94305, USA. mrivas@stanford.edu.

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.

PMID:
29691392
PMCID:
PMC5915386
DOI:
10.1038/s41467-018-03910-9
[Indexed for MEDLINE]
Free PMC Article

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