Disentangling the genetic overlap and causal relationships between primary open-angle glaucoma, brain morphology and four major neurodegenerative disorders

Santiago Diaz-Torres*, Weixiong He, IGGC International Glaucoma Genetics Consortium, Jackson Thorp, Sahba Seddighi, Sean Mullany, Christopher J. Hammond, Pirro G. Hysi, Louis R. Pasquale, Anthony P. Khawaja, Alex W. Hewitt, Jamie E. Craig, David A. Mackey, Janey L. Wiggs, Cornelia van Duijn, Michelle K. Lupton, Jue Sheng Ong, Stuart MacGregor, Puya Gharahkhani*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Background: Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by progressive degeneration of the optic nerve that leads to irreversible visual impairment. Multiple epidemiological studies suggest an association between POAG and major neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Parkinson's disease). However, the nature of the overlap between neurodegenerative disorders, brain morphology and glaucoma remains inconclusive. Method: In this study, we performed a comprehensive assessment of the genetic and causal relationship between POAG and neurodegenerative disorders, leveraging genome-wide association data from studies of magnetic resonance imaging of the brain, POAG, and four major neurodegenerative disorders. Findings: This study found a genetic overlap and causal relationship between POAG and its related phenotypes (i.e., intraocular pressure and optic nerve morphology traits) and brain morphology in 19 regions. We also identified 11 loci with a significant local genetic correlation and a high probability of sharing the same causal variant between neurodegenerative disorders and POAG or its related phenotypes. Of interest, a region on chromosome 17 corresponding to MAPT, a well-known risk locus for Alzheimer's and Parkinson's disease, was shared between POAG, optic nerve degeneration traits, and Alzheimer's and Parkinson's diseases. Despite these local genetic overlaps, we did not identify strong evidence of a causal association between these neurodegenerative disorders and glaucoma. Interpretation: Our findings indicate a distinctive and likely independent neurodegenerative process for POAG involving several brain regions although several POAG or optic nerve degeneration risk loci are shared with neurodegenerative disorders, consistent with a pleiotropic effect rather than a causal relationship between these traits. Funding: PG was supported by an NHMRC Investigator Grant (# 1173390), SM by an NHMRC Senior Research Fellowship and an NHMRC Program Grant (APP1150144), DM by an NHMRC Fellowship, LP is funded by the NEI EY015473 and EY032559 grants, SS is supported by an NIH-Oxford Cambridge Fellowship and NIH T32 grant ( GM136577), APK is supported by a UK Research and Innovation Future Leaders Fellowship, an Alcon Research Institute Young Investigator Award and a Lister Institute for Preventive Medicine Award.

Original languageEnglish
Article number104615
JournalEBioMedicine
Volume92
DOIs
Publication statusPublished - Jun 2023

Bibliographical note

Acknowledgments:
This work was conducted using the UK Biobank Resource (application number 25331). The UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council United Kingdom, Department of Health United Kingdom, Scottish Government, and Northwest Regional Development Agency. It also had funding from the Welsh Assembly Government , British Heart Foundation , and Diabetes United Kingdom. The eye and vision dataset has been developed with additional funding from The NIHR Biomedical Research Centre at Moorfields Eye Hospital and the UCL Institute of Ophthalmology , Fight for Sight charity United Kingdom , Moorfields Eye Charity United Kingdom , the Macula Society United Kingdom , the International Glaucoma Association United Kingdom and Alcon Research Institute (USA).

Publisher Copyright:
© 2023 The Author(s)

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