| Title: | Phenome-wide analysis of copy number variants in 470,727 UK Biobank genomes |
| Journal: | Nature |
| Published: | 4 Feb 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41639462/ |
| DOI: | https://doi.org/10.1038/s41586-025-10087-x |
Publication 18367
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Abstract
Copy number variants (CNVs) are key drivers of human diversity and disease risk1. Here we evaluate the role of CNVs across a broad range of human phenotypes and diseases by analysing CNVs from 470,727 UK Biobank whole-genome sequences and conducting a variant- and gene-level phenome-wide association study (PheWAS) with 2,941 plasma protein abundance measurements, 13,336 binary clinical phenotypes and 1,911 quantitative traits. Proteomic analyses validated functional associations of CNVs with nearby genes (cis-protein quantitative trait loci; cis-pQTLs) - with deletions and duplications typically associated with reduced and increased protein levels, respectively - and uncovered previously unknown protein-protein interactions (trans-pQTLs). Our PheWAS recapitulated known associations and uncovered associations in both coding and non-coding regions. Notably, we identified a rare deletion in ZNF451 associated with increased leukocyte telomere length and a non-coding deletion of a SLC2A9 enhancer associated with reduced gout risk. In addition, by combining CNVs with protein-coding single nucleotide variants and indels, we enhanced the power of our study to detect gene-disease associations. Finally, we leveraged this multiomics dataset to identify several pQTLs that constitute candidate biomarkers, including TMPRSS5 for Charcot-Marie-Tooth disease type 1A. This multiancestry whole-genome-sequence CNV PheWAS offers insights into the roles of CNVs in human health outcomes and could serve as a valuable resource for therapeutic development.</p>
33 Authors
- Xueqing Zoe Zou
- Fengyuan Hu
- Haiyi Lou
- Oliver S. Burren
- Xiaoyin Li
- Karyn Megy
- Eleanor Wheeler
- Qiang Wu
- Santosh S. Atanur
- Marcin Karpinski
- Douglas Loesch
- Zammy Fairhurst-Hunter
- Sri V. V. Deevi
- Erin Oerton
- Sean Wen
- Xiao Jiang
- Cecilia Salvoro
- Jonathan Mitchell
- Abhishek Nag
- Ben Hollis
- Amanda O'Neill
- Jen Harrow
- Stewart MacArthur
- Sebastian Wasilewski
- Sean O'Dell
- Lifeng Tian
- Katherine R. Smith
- Guillermo del Angel
- Margarete Fabre
- Ryan S. Dhindsa
- Quanli Wang
- Slavé Petrovski
- Keren Carss
Enabling scientific discoveries that improve human health