GWAS for primary angle-closure glaucoma identifies loci related to ocular biometry and morphology
GWAS of primary angle-closure glaucoma have identified eight loci conferring risk in Asian populations. However, it remains unclear whether the genetic risk factors for the disease are consistent across different populations. Here, we present a discovery GWAS for primary angle-closure glaucoma in Europeans using the UK Biobank. We replicate our findings in six independent European populations and compare these results with results from 14 Asian cohorts. Five genomic regions in the discovery cohort are associated at genome-wide significance, including two loci previously identified in Asian cohorts. We next meta-analyse the discovery and replication cohorts to identify six additional novel loci, all previously associated with refractive error. Mendelian randomisation provides evidence for a causal role of shorter axial length and hypermetropic refractive error on primary angle-closure glaucoma. A polygenic risk score derived from the European ancestry meta-analysis demonstrates significant associations with quantitative ocular traits - including a shallower anterior chamber and higher intraocular pressure - in the independent EPIC-Norfolk cohort. Finally, a multi-ancestry meta-analysis of all 21 European and Asian cohorts identifies 12 further novel loci. This work shows that genetic factors associated with a darker iris and hypermetropia confer risk for primary angle-closure glaucoma.
Authors
- Ahmad Tajudin Liza-Sharmini (ORCID: https://orcid.org/0000-0001-8144-8816)
- José Paulo Cabral de Vasconcellos (ORCID: https://orcid.org/0000-0001-8220-6675)
- Shamira Perera (ORCID: https://orcid.org/0000-0002-1404-5096)
- Edgar U. Leuenberger
- Masami Tanaka
- Y. Tokuda (ORCID: https://orcid.org/0009-0000-2725-106X)
- Pirro G. Hysi (ORCID: https://orcid.org/0000-0001-5752-2510)
- Antonia Kolovos (ORCID: https://orcid.org/0000-0001-6618-0137)
- Masakazu Nakano (ORCID: https://orcid.org/0000-0001-6720-2158)
- Tin Aung (ORCID: https://orcid.org/0000-0002-7916-0589)
- Shigeru Kinoshita (ORCID: https://orcid.org/0000-0002-6839-251X)
- Ronnie George (ORCID: https://orcid.org/0000-0001-7368-0252)
- Jamie E. Craig (ORCID: https://orcid.org/0000-0001-9955-9696)
- Kelsey V. Stuart (ORCID: https://orcid.org/0000-0001-7353-8774)
- Naris Kitnarong (ORCID: https://orcid.org/0000-0002-6041-4868)
- Ching Lin Ho (ORCID: https://orcid.org/0000-0001-9899-7635)
- Anthony P. Khawaja (ORCID: https://orcid.org/0000-0001-6802-8585)
- Robert Luben (ORCID: https://orcid.org/0000-0002-5088-6343)
- Paul J. Foster (ORCID: https://orcid.org/0000-0002-4755-177X)
- Ruiqi Hu (ORCID: https://orcid.org/0009-0003-9989-5042)
- Kei Tashiro
- Chi Pui Pang (ORCID: https://orcid.org/0000-0002-7764-6382)
- Mahantesh I. Biradar (ORCID: https://orcid.org/0000-0002-4114-6255)
- Chie Sotozono
- Monisha E. Nongpiur (ORCID: https://orcid.org/0000-0003-2372-8523)
- Chiea Chuen Khor
- Mônica Barbosa de Melo (ORCID: https://orcid.org/0000-0002-1801-5441)
- Zihan Sun (ORCID: https://orcid.org/0000-0002-5001-7113)
- Ningli Wang (ORCID: https://orcid.org/0000-0002-8933-4482)
- Zheng Li (ORCID: https://orcid.org/0000-0002-7060-2213)
- Ki Ho Park (ORCID: https://orcid.org/0000-0002-8137-8843)
- Morio Ueno (ORCID: https://orcid.org/0000-0002-8137-5730)
- Tan Do
- Antonio Maria Fea (ORCID: https://orcid.org/0000-0002-6551-6054)
- Yoko Ikeda (ORCID: https://orcid.org/0000-0003-3131-9156)
- Kazuhiko Mori (ORCID: https://orcid.org/0000-0002-5505-4917)
- Lingam Vijaya
- V P Costa (ORCID: https://orcid.org/0000-0002-8617-8066)
- Natsue Omi
Institutions
- Agency for Science, Technology and Research (SG)
- Sankara Nethralaya (IN)
- Beijing Tongren Hospital (CN)
- Moorfields Eye Hospital NHS Foundation Trust (GB)
- Siriraj Hospital (TH)
- Vietnam National University, Hanoi (VN)
- Chinese University of Hong Kong (HK)
- Universidade Estadual de Campinas (UNICAMP) (BR)
- Capital Medical University (CN)
- King's College London (GB)
- University of Cambridge (GB)
- Mahidol University (TH)
- Singapore National Eye Center (SG)
- Seoul National University Hospital (KR)
- Flinders Medical Centre (AU)
- President Ramon Magsaysay State University (PH)
- Kyoto Prefectural University of Medicine (JP)
- Hospital Universiti Sains Malaysia (MY)
- Sørlandet Hospital Arendal (NO)
- University of the East Ramon Magsaysay Memorial Medical Center (PH)
- Singapore Eye Research Institute (SG)
- Asian Eye Institute (PH)
- Duke-NUS Medical School (SG)
- Vietnam National Children's Hospital (VN)
- MRC Epidemiology Unit (GB)
- University College London (GB)
- University of Turin (IT)
- Genome Institute of Singapore (SG)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-14
- DOI
- https://doi.org/10.1038/s41467-025-64949-z
- Citations
- 1
- Primary Topic
- Glaucoma and retinal disorders
- Type
- article
- Field-Weighted Citation Impact
- 1.71
Funders
- Wellcome Trust
- UK Research and Innovation
- Cancer Research UK
- National Institute for Health and Care Research
- University College London
- Lister Institute of Preventive Medicine
- Northwest Regional Development Agency
- Moorfields Eye Hospital NHS Foundation Trust
- Medical Research Council
- Alcon Research Institute