Abstract
A major goal in human genetics is to use natural variation to understand the phenotypic consequences of altering each protein-coding gene in the genome. Here we used exome sequencing1 to explore protein-altering variants and their consequences in 454,787 participants in the UK Biobank study2. We identified 12 million coding variants, including around 1 million loss-of-function and around 1.8 million deleterious missense variants. When these were tested for association with 3,994 health-related traits, we found 564 genes with trait associations at P ≤ 2.18 × 10−11. Rare variant associations were enriched in loci from genome-wide association studies (GWAS), but most (91%) were independent of common variant signals. We discovered several risk-increasing associations with traits related to liver disease, eye disease and cancer, among others, as well as risk-lowering associations for hypertension (SLC9A3R2), diabetes (MAP3K15, FAM234A) and asthma (SLC27A3). Six genes were associated with brain imaging phenotypes, including two involved in neural development (GBE1, PLD1). Of the signals available and powered for replication in an independent cohort, 81% were confirmed; furthermore, association signals were generally consistent across individuals of European, Asian and African ancestry. We illustrate the ability of exome sequencing to identify gene–trait associations, elucidate gene function and pinpoint effector genes that underlie GWAS signals at scale.
Highlights
This is a PDF file of a peer-reviewed paper that has been accepted for publication
To illustrate the potential to elucidate gene function through analysis of WES data, we tested the association between rare pLOF and deleterious missense variants and 3,994 health-related traits measured in UK Biobank (UKB) study participants (Supplementary Data 1)
We demonstrate that a burden of rare pLOFs and deleterious missense variants in SLC9A3R2, as well as Arg171Trp, remain highly associated with systolic blood pressure (SBP), diastolic blood pressure (DBP) and hypertension after conditioning on Arg2200Cys in PKD1 (Supplementary Table 8)
Summary
E Cite this article as Backman, J. P coding variants, including ~1 million loss-of-function and ~1.8 million deleterious missense variants When these were tested for association with 3,994 health-related. To illustrate the potential to elucidate gene function through analysis of WES data, we tested the association between rare pLOF and deleterious missense variants and 3,994 health-related traits measured in UKB study participants (Supplementary Data 1). This included 3,702 binary traits with at least 100 cases and 292 quantitative traits from a variety of domains, including anthropometry, biochemistry and hematology (Supplementary Table 4). All 8,865 associations are provided in Supplementary Data 2, as well as two non-redundant sets obtained by retaining only the most
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