Protein-altering Variants at Copy Number-variable Regions Influence Diverse Human Phenotypes

Overview

Journal Nat Genet

Specialty Genetics

Date 2024 Mar 29

PMID 38548989

Authors

Margaux L A Hujoel

Robert E Handsaker

Maxwell A Sherman

Nolan Kamitaki

Alison R Barton

Ronen E Mukamel

Chikashi Terao

Steven A McCarroll

Po-Ru Loh

Affiliations

Soon will be listed here.

Abstract

Copy number variants (CNVs) are among the largest genetic variants, yet CNVs have not been effectively ascertained in most genetic association studies. Here we ascertained protein-altering CNVs from UK Biobank whole-exome sequencing data (n = 468,570) using haplotype-informed methods capable of detecting subexonic CNVs and variation within segmental duplications. Incorporating CNVs into analyses of rare variants predicted to cause gene loss of function (LOF) identified 100 associations of predicted LOF variants with 41 quantitative traits. A low-frequency partial deletion of RGL3 exon 6 conferred one of the strongest protective effects of gene LOF on hypertension risk (odds ratio = 0.86 (0.82-0.90)). Protein-coding variation in rapidly evolving gene families within segmental duplications-previously invisible to most analysis methods-generated some of the human genome's largest contributions to variation in type 2 diabetes risk, chronotype and blood cell traits. These results illustrate the potential for new genetic insights from genomic variation that has escaped large-scale analysis to date.

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