Medical Relevance of Protein-truncating Variants Across 337,205 Individuals in the UK Biobank Study

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Apr 26

PMID 29691392

Citations 66

Authors

Christopher DeBoever

Yosuke Tanigawa

Malene E Lindholm

Greg McInnes

Adam Lavertu

Erik Ingelsson

Chris Chang

Euan A Ashley

Carlos D Bustamante

Mark J Daly

Manuel A Rivas

Affiliations

Soon will be listed here.

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.

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