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

Christopher Deboever,Chris Chang,Euan A Ashley,Greg Mcinnes,Erik Ingelsson,Carlos D Bustamante,Adam Lavertu,Mark J Daly,Yosuke Tanigawa,Malene E Lindholm,Manuel A Rivas

doi:10.1038/s41467-018-03910-9

Christopher Deboever, Chris Chang + Show 9 more

Open Access

https://doi.org/10.1038/s41467-018-03910-9

Copy DOI

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.

Highlights

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
We identified 18,228 predicted Protein-truncating variants (PTVs) in the UK Biobank array that were polymorphic across 8750 genes after filtering (Methods, Supplementary Fig. 1)
For PTVs with minor allele frequency (MAF) < 1%, we found that only the association between a PTV in HEATR6 and retinal detachment was explained by a nearby variant rs3744375 (Supplementary Data 3)

Summary

Introduction

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. 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. Protein-truncating variants (PTVs), genetic variants predicted to shorten the coding sequence of genes, are a promising set of variants for drug discovery since identification of PTVs that protect against human disease provides in vivo validation of therapeutic targets[1,2,3,4]. We perform phenome-wide association analyses across 206 medical phenotypes for these PTVs as well as PTVs with previously identified associations and find PTVs with pleiotropic effects. The associations reported here indicate new disease-causing genes that may be promising therapeutic targets

Methods

Results

Conclusion