Genome-wide meta-analysis identifies 22 loci for normal tension glaucoma with significant overlap with high tension glaucoma

Santiago Diaz-Torres (), Weixiong He, Regina Yu, Anthony P. Khawaja, Christopher J. Hammond, Pirro G. Hysi, Louis R. Pasquale, Yeda Wu, Michiaki Kubo, Masato Akiyama, Tin Aung, Ching-Yu Cheng, Chiea Chuen Khor, Peter Kraft, Jae H. Kang, Alex W. Hewitt, David A. Mackey, Jamie E. Craig, Janey L. Wiggs, Jue-Sheng Ong, Stuart MacGregor and Puya Gharahkhani ()
Additional contact information
Santiago Diaz-Torres: QIMR Berghofer Medical Research Institute
Weixiong He: QIMR Berghofer Medical Research Institute
Regina Yu: QIMR Berghofer Medical Research Institute
Anthony P. Khawaja: Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology
Christopher J. Hammond: King’s College London
Pirro G. Hysi: King’s College London
Louis R. Pasquale: Icahn School of Medicine at Mount Sinai
Yeda Wu: QIMR Berghofer Medical Research Institute
Michiaki Kubo: RIKEN Center for Integrative Medical Sciences
Masato Akiyama: RIKEN Center for Integrative Medical Sciences
Tin Aung: Duke-NUS Medical School
Ching-Yu Cheng: Duke-NUS Medical School
Chiea Chuen Khor: Genome Institute of Singapore
Peter Kraft: Harvard School of Public Health
Jae H. Kang: Harvard Medical School
Alex W. Hewitt: University of Tasmania
David A. Mackey: Lions Eye Institute
Jamie E. Craig: Flinders Medical Centre
Janey L. Wiggs: Harvard Medical School
Jue-Sheng Ong: QIMR Berghofer Medical Research Institute
Stuart MacGregor: QIMR Berghofer Medical Research Institute
Puya Gharahkhani: QIMR Berghofer Medical Research Institute

Nature Communications, 2024, vol. 15, issue 1, 1-9

Abstract: Abstract Primary open-angle glaucoma typically presents as two subtypes. This study aimed to elucidate the shared and distinct genetic architectures of normal-tension (NTG) and high-tension glaucoma (HTG), motivated by the need to develop intraocular pressure (IOP)-independent drug targets for the disease. We conducted a comprehensive multi-ethnic meta-analysis, prioritized variants based on functional annotation, and explored drug-gene interactions. We further assessed the genetic overlap between NTG and HTG using pairwise GWAS analysis. We identified 22 risk loci associated with NTG, 17 of which have not previously been reported for NTG. Two loci, BMP4 and TBKBP1, have not previously been associated with glaucoma at the genome-wide significance level. Our results indicate that while there is a significant overlap in risk loci between tension subtypes, the magnitude of the effect tends to be lower in NTG compared to HTG, particularly for IOP-related loci. Additionally, we identified a potential role for biologic immunomodulatory treatments as neuroprotective agents.

Date: 2024
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DOI: 10.1038/s41467-024-54301-2

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