GWAS for primary angle-closure glaucoma identifies loci related to ocular biometry and morphology

Robert N. Luben (), Mahantesh I. Biradar, Kelsey V. Stuart, Ruiqi Hu, Zihan Sun, Zheng Li, Ningli Wang, Tan Do, Chi Pui Pang, Masakazu Nakano, Kei Tashiro, Yoko Ikeda, Yuichi Tokuda, Masami Tanaka, Natsue Omi, Morio Ueno, Chie Sotozono, Shigeru Kinoshita, Kazuhiko Mori, Naris Kitnarong, Antonio Fea, Mônica B. Melo, José Paulo C. Vasconcellos, Vital P. Costa, Monisha E. Nongpiur, Ching Lin Ho, Shamira A. Perera, Jamie E. Craig, Antonia Kolovos, Ahmad Tajudin Liza-Sharmini, Edgar U. Leuenberger, Ki Ho Park, Lingam Vijaya, Ronnie George, Tin Aung, C. C. Khor, Paul J. Foster, Pirro Hysi and Anthony P. Khawaja
Additional contact information
Robert N. Luben: Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology
Mahantesh I. Biradar: Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology
Kelsey V. Stuart: Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology
Ruiqi Hu: Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology
Zihan Sun: Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology
Zheng Li: Technology and Research
Ningli Wang: Beijing Ophthalmology & Visual Science Key Lab
Tan Do: Vietnam National Eye Hospital
Chi Pui Pang: The Chinese University of Hong Kong
Masakazu Nakano: Kyoto Prefectural University of Medicine
Kei Tashiro: Kyoto Prefectural University of Medicine
Yoko Ikeda: Kyoto Prefectural University of Medicine
Yuichi Tokuda: Kyoto Prefectural University of Medicine
Masami Tanaka: Kyoto Prefectural University of Medicine
Natsue Omi: Kyoto Prefectural University of Medicine
Morio Ueno: Kyoto Prefectural University of Medicine
Chie Sotozono: Kyoto Prefectural University of Medicine
Shigeru Kinoshita: Kyoto Prefectural University of Medicine
Kazuhiko Mori: Kyoto Prefectural University of Medicine
Naris Kitnarong: Mahidol University
Antonio Fea: Università di Torino
Mônica B. Melo: Universidade Estadual de Campinas
José Paulo C. Vasconcellos: Universidade Estadual de Campinas
Vital P. Costa: Universidade Estadual de Campinas
Monisha E. Nongpiur: Duke-NUS Medical School
Ching Lin Ho: Duke-NUS Medical School
Shamira A. Perera: Duke-NUS Medical School
Jamie E. Craig: Flinders Health and Medical Research Institute
Antonia Kolovos: Flinders Health and Medical Research Institute
Ahmad Tajudin Liza-Sharmini: Universiti Sains Malaysia
Edgar U. Leuenberger: Asian Eye Institute and University of the East Ramon Magsaysay College of Medicine
Ki Ho Park: Seoul National University Hospital
Lingam Vijaya: Medical Research Foundation
Ronnie George: Medical Research Foundation
Tin Aung: Duke-NUS Medical School
C. C. Khor: Technology and Research
Paul J. Foster: Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology
Pirro Hysi: King’s College London
Anthony P. Khawaja: Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-64949-z

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