Disentangling the genetic overlap and causal relationships between primary open-angle glaucoma, brain morphology and four major neurodegenerative disordersResearch in context
Santiago Diaz-Torres,
Weixiong He,
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
Affiliations
Santiago Diaz-Torres
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Faculty of Medicine, University of Queensland (UQ), Brisbane, QLD, Australia; Corresponding author. Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Weixiong He
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
Jackson Thorp
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
Sahba Seddighi
Nuffield Department of Population Health, Oxford University, Oxford, UK; Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Sean Mullany
Department of Ophthalmology, Flinders University, Flinders Medical Centre, Bedford Park, Australia
Christopher J. Hammond
Departments of Ophthalmology & Twin Research and Genetic Epidemiology, King's College London, London, UK
Pirro G. Hysi
Departments of Ophthalmology & Twin Research and Genetic Epidemiology, King's College London, London, UK
Louis R. Pasquale
Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
Anthony P. Khawaja
NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
Alex W. Hewitt
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
Jamie E. Craig
Department of Ophthalmology, Flinders University, Flinders Medical Centre, Bedford Park, Australia
David A. Mackey
Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, Australia
Janey L. Wiggs
Department of Ophthalmology, Harvard Medical School, Boston, 02114, MA, USA
Cornelia van Duijn
Department of Epidemiology, Erasmus MC Rotterdam, the Netherlands
Michelle K. Lupton
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
Jue-Sheng Ong
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
Stuart MacGregor
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Faculty of Medicine, University of Queensland (UQ), Brisbane, QLD, Australia
Puya Gharahkhani
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Faculty of Medicine, University of Queensland (UQ), Brisbane, QLD, Australia; School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, Australia; Corresponding author. Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Summary: 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.
