Phenome-wide analysis of copy number variants in 470,727 UK Biobank genomes
Copy number variants (CNVs) are key drivers of human diversity and disease risk<sup>1</sup>. 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.
Authors
- Erin Oerton (ORCID: https://orcid.org/0000-0002-7367-4263)
- C. Haefliger
- Satbhai Santosh
- Benjamin Challis (ORCID: https://orcid.org/0000-0002-1130-2851)
- Kieren Lythgow
- Dorota Matelska (ORCID: https://orcid.org/0000-0003-0798-3479)
- Xavier Romero Ros (ORCID: https://orcid.org/0000-0002-5755-1693)
- Q. Wang
- Mark Lal (ORCID: https://orcid.org/0000-0002-2885-3633)
- Stewart MacArthur (ORCID: https://orcid.org/0000-0003-0201-7044)
- Marcin Karpiński
- Haiyi Lou
- James D. Garnett
- Ken Smith (ORCID: https://orcid.org/0000-0002-4861-7048)
- Xiao Jiang (ORCID: https://orcid.org/0000-0002-1442-8927)
- Cecilia Salvoro (ORCID: https://orcid.org/0000-0003-1070-3220)
- Ryan S. Dhindsa (ORCID: https://orcid.org/0000-0002-8965-0813)
- Arwa Bin Raies (ORCID: https://orcid.org/0000-0003-3952-7363)
- Andrew Harper (ORCID: https://orcid.org/0000-0003-3599-1679)
- Margarida Lopes
- Anna Maria Tsakiroglou (ORCID: https://orcid.org/0000-0001-6500-5898)
- Anna S. E. Cuomo (ORCID: https://orcid.org/0000-0001-5168-6979)
- Tatiana Ort
- Guillermo del Angel (ORCID: https://orcid.org/0000-0002-0104-1563)
- Ruth Karen March
- Sebastian Wasilewski
- Ben Hollis
- Anish Konkar
- Richard N. Hanna
- Brian Dougherty (ORCID: https://orcid.org/0000-0002-0093-1142)
- Gabrielle Cass Baumberg
- Xiaoyin Li
- Wei Ding
- Abhishek Nag (ORCID: https://orcid.org/0000-0003-2129-8873)
- Zhongwu Lai
- Sean Wen
- Andrew Davis
- Anna Reznichenko
- Xueqing Zoe Zou
- Adam Platt
- Fengyuan Hu
- Oliver S. Burren
- Kousik Kundu
- Zammy Fairhurst-Hunter
- Glenda Lassi
- Eleanor Wheeler
- Jen Harrow
- Yoichiro Ohne
- Douglas Loesch
- Slavé Petrovski
- Sonja Hess
- Ioanna Tachmazidou
- Lily Wang
- Amanda O’Neill
- Regina F. Danielson
- Sophia Cameron-Christie
- Karyn Megy
- Margarete Fabre
- Mohammad Bohlooly-Y
- Jonathan Mitchell
- Meeta Maisuria-Armer
- Rob Menzies
- Xiao-Rong Peng
- Bram Prins
- Anna Szymaniak
- Daniel Elias Martin Herranz
- AstraZeneca Genomics Initiative
- Lisa Buvall
- Qiang Wu
- Manik Garg
- Sri V. V. Deevi
- Coralie Viollet
- Lauren Anderson-Dring
- Lifeng Tian
- Jorge L. Del-Aguila
- Keren Carss
- Ian Henry
- Sean O’Dell
- Natalia Frydrych
- Mårten Hammar
- Helen Stevens
- Bill Mowrey
- Rahul Sharma
- Daniel Muthas
- Suzanne Cohen
- Benjamin Pullman
- Benjamin Georgi
Institutions
- AstraZeneca (United Kingdom) (GB)
- Baylor College of Medicine (US)
- University of Cambridge (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- AstraZeneca (Australia) (AU)
- AstraZeneca (Singapore) (SG)
- Neurological Research Institute (US)
- Alexion Pharmaceuticals (United States) (US)
- AstraZeneca (Switzerland) (CH)
- AstraZeneca (Japan) (JP)
- AstraZeneca (Poland) (PL)
- AstraZeneca (Finland) (FI)
- AstraZeneca (Sweden) (SE)
- Texas Children's Hospital (US)
- AstraZeneca (Spain) (ES)
- AstraZeneca (United States) (US)
- Austin Health (AU)
- University of Tennessee at Knoxville (US)
Publication Details
- Journal
- Nature
- Published
- 2026-02-04
- DOI
- https://doi.org/10.1038/s41586-025-10087-x
- Primary Topic
- Genomic variations and chromosomal abnormalities
- Type
- article
- Field-Weighted Citation Impact
- 0.00