Genetic discovery using deep learning-derived optic nerve integrity phenotypes
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: The peripapillary retinal nerve fibre layer (pRNFL) thickness and Bruch's membrane opening-minimum rim width (BMO-MRW) are three-dimensional retinal biomarkers for glaucoma. We aimed to demonstrate that AI-derived thickness from two-dimensional fundus images can act as proxies, enabling the discovery of novel neurodegenerative loci. AI-derived pRNFL and BMO-MRW strongly correlated with OCT-derived thickness (r: 0.69 and 0.79, respectively). After validation, these phenotypes were predicted in two cohorts lacking disc-centred OCT: the UK Biobank and the Canadian Longitudinal Study on Aging. The predicted phenotypes showed strong genetic correlations with directly measured phenotypes from a previous study for both phenotypes (0.70 and 0.96, respectively). This data increased statistical power, identifying 29 loci for pRNFL thickness and 122 loci for BMO-MRW, including 14 loci that were independent of VCDR. We observed shared and sector-specific thickness loci overlapping glaucoma loci and revealed loci independent of known risk factors. Together, these results emphasise that multidimensional inferences can be drawn from 2D imaging, enabling downstream genetic analyses.
Source: medRxiv
Authors: Asma M. Aman, Eslam Zaher, Santiago Diaz-Torres, Sjoerd J. Driessen, Victor A. de Vries, Frank CT. van der Heide, Antonia Kolovos, Joshua M. Schmidt, Henry N. Marshall, Lania Saleh, Alicia Schulze, Gabriëlla A. Blokland, Carroll A. Webers, Carla J. van der Kallen, Anke Wesselius, Ilja Arts, Freekje van Asten, Mathias Gorski, Martina E. Zimmermann, Klaus J. Stark, Iris M. Heid, Terri L. Young, Louis R. Pasquale, Ayellet V. Segrè, Janey L. Wiggs, Anthony P. Khawaja, Donald J. Zack, Raymond C. Wong, Alex W. Hewitt, Alexander K. Schuster, Tos T. Berendschot, Alberta A. Thiadens, Karin A. van Garderen, Caroline C.W. Klaver, Pirro G. Hysi, Christopher J. Hammond, Caroline Brandl, Jamie E. Craig, Wishal D. Ramdas, Ya Xing Wang, Jost B. Jonas, Fred Roosta, Michael L. Hunter, Stuart MacGregor, Samantha S. Lee, David A. Mackey, Maciej Trzaskowski, Puya Gharahkhani
Institutions: The University of Queensland, QIMR Berghofer Medical Research Institute, Erasmus MC, Inserm, Université Paris Cité, Maastricht University Medical Centre, Maastricht University, Hôpital Rothschild, Equipe de Recherche en Epidémiologie Nutritionnelle, Centre de Recherche Épidémiologie et Statistique, Flinders University, King's College London, University Medical Center of the Johannes Gutenberg University Mainz, University of Regensburg, University of Wisconsin–Madison, Icahn School of Medicine at Mount Sinai, Broad Institute, Massachusetts Eye and Ear Infirmary, Harvard University, Massachusetts Institute of Technology, Moorfields Eye Hospital NHS Foundation Trust, NIHR Moorfields Biomedical Research Centre, University College London, Johns Hopkins University, The University of Melbourne, The Royal Victorian Eye & Ear Hospital, Centre for Eye Research Australia, University of Tasmania, Menzies Institute for Medical Research, Radboud University Nijmegen, Radboud University Medical Center, Institute of Molecular and Clinical Ophthalmology Basel, University of Pittsburgh, Sørlandet Hospital Arendal, University Hospital Regensburg, Beijing Tsinghua Chang Gung Hospital, Tsinghua University, Beijing Tongren Hospital, Capital Medical University, The University of Western Australia, Sir Charles Gairdner Hospital, Lions Eye Institute, UNSW Sydney, Institute for Molecular Bioscience, Queensland University of Technology
Language: English
Subfield: Ophthalmology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Research to Prevent Blindness, Glaucoma Foundation, Sanofi, Health Foundation Limburg, Government of Canada, National Institute for Health and Care Research, Raine Medical Research Foundation, Lister Institute of Preventive Medicine, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Novo Nordisk, Oogfonds, Stichting De Weijerhorst, Moorfields Eye Hospital NHS Foundation Trust, Stan Perron Charitable Foundation, National Institutes of Health, Canadian Institutes of Health Research, National Health and Medical Research Council, European Regional Development Fund, CARIM School for Cardiovascular Diseases, Universiteit Maastricht, Care and Public Health Research Institute, Universiteit Maastricht, NUTRIM School of Nutrition and Translational Research in Metabolism, Alcon Research Institute, Cilag
Awards: G1111942589, Identifizierung und Charakterisierung der genetischen Basis von altersbedingter Makuladegeneration unter spezieller Berücksichtigung von geschlechtsspezifischen Effekten, G1551914075, G2408266837, Enabling genetics-based disease risk prediction in Australia, Expanding the indications for polygenic risk testing in glaucoma., G3036254274, Identifying the contribution of phenotypic and genetic risk factors for complex traits, with implication to risk prediction and causal inference, Identifizierung und Charakterisierung der genetischen Basis von altersbedingter Makuladegeneration unter spezieller Berücksichtigung von geschlechtsspezifischen und anderen nicht-genetischen Effekten (2. Förderphase), G4575545625, G558402791, G5997867284, G6227940160, Translating genetic determinants of glaucoma into better diagnosis and treatment, G7521026280, G8059889987, G8738466114, G9000349160, Multiomic Framework for Glaucoma, Understanding the clinical impact of cumulative genetic risk to glaucoma
OpenAlex ID: W7212249258