{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T15:58:43Z","timestamp":1792511923796,"version":"4.5.0"},"posted":{"date-parts":[[2025,11,6]]},"group-title":"Ophthalmology","reference-count":54,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The genetic architecture of primary open-angle glaucoma (POAG), a leading cause of irreversible blindness, remains largely unexplained due to the reliance of previous genome-wide association studies (GWAS) on imprecise phenotypes from electronic health records. Here, we overcome this with a disease-trained, task-transfer machine learning (ML) framework that learns glaucoma-related damage patterns from a large clinical repository of 8,323 glaucoma patients. We showed that ML optical coherence tomography (OCT)-derived endophenotypes trained on 18,985 OCT scans from these patients identified novel loci associated with POAG. By applying the derived endophenotypes to 47,908 UK Biobank participants, we performed GWAS in European, African, and Asian ancestral groups followed by cross-ancestry meta-analyses. In total, we identified 36 and 43 LD-independent GWAS loci that passed genome-wide significance in the EUR and cross-ancestry meta-analysis, respectively. About two thirds of the identified loci overlapped with previously reported POAG related associations, demonstrating the validity of our approach. Importantly, more than a third (21) of the loci were novel to glaucoma. Extensive functional analyses, including Bayesian colocalization analysis, gene-based association tests, Mendelian randomization, and single-cell enrichment analysis, converged on 11 high-confidence gene effectors, five of which are novel to glaucoma. These genes support Wnt-mediated outflow dysfunction and retinal ganglion cell vulnerability in POAG pathogenesis and are potential actionable drug targets. Our findings expanded POAG genetic associations, provided mechanistic insights at cell-type resolution, and proposed plausible putative causal genes. This study provides a powerful, generalizable ML-driven strategy for accelerating the discovery of disease mechanisms and therapeutic targets for complex diseases.<\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>A ML framework that bridged clinical eye scans with biobank genetics found 21 new genetic loci and 11 putative causal genes for glaucoma<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.04.25339517","type":"posted-content","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T21:10:12Z","timestamp":1762463412000},"source":"Crossref","is-referenced-by-count":3,"title":["Deep-learning-derived glaucoma-related endophenotypes enable novel genome-wide genetic and functional discovery"],"prefix":"10.64898","author":[{"given":"Liyin","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saber Kazeminasab","family":"Hashemabad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Elze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Eslami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janey L.","family":"Wiggs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayellet V.","family":"Segre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazlee","family":"Zebardast","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025110903101048000_2025.11.04.25339517v1.1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1167\/tvst.12.10.18","article-title":"Identifying, Understanding, and Addressing Disparities in Glaucoma Care in the United States","volume":"12","year":"2023","journal-title":"Transl Vis Sci Technol"},{"key":"2025110903101048000_2025.11.04.25339517v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2014.05.013"},{"key":"2025110903101048000_2025.11.04.25339517v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3482"},{"key":"2025110903101048000_2025.11.04.25339517v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3079"},{"key":"2025110903101048000_2025.11.04.25339517v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20851-4"},{"key":"2025110903101048000_2025.11.04.25339517v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.05.005"},{"key":"2025110903101048000_2025.11.04.25339517v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3087"},{"key":"2025110903101048000_2025.11.04.25339517v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajo.2012.07.023"},{"key":"2025110903101048000_2025.11.04.25339517v1.9","first-page":"438","article-title":"New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics","volume":"26","author":"NEIGHBORHOOD Consortium","year":"2017","journal-title":"Hum Mol Genet"},{"key":"2025110903101048000_2025.11.04.25339517v1.10","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr382"},{"key":"2025110903101048000_2025.11.04.25339517v1.11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002654"},{"key":"2025110903101048000_2025.11.04.25339517v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-023-01428-5"},{"key":"2025110903101048000_2025.11.04.25339517v1.13","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12884"},{"key":"2025110903101048000_2025.11.04.25339517v1.14","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1109\/JBHI.2017.2767063","article-title":"Deep EHR: A Survey of Recent Advances in Deep Learning Techniques for Electronic Health Record (EHR) Analysis","volume":"22","year":"2018","journal-title":"IEEE J Biomed Health Inform"},{"key":"2025110903101048000_2025.11.04.25339517v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0126-8"},{"key":"2025110903101048000_2025.11.04.25339517v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.05.005"},{"key":"2025110903101048000_2025.11.04.25339517v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.survophthal.2006.10.002"},{"key":"2025110903101048000_2025.11.04.25339517v1.18","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2014.3192"},{"key":"2025110903101048000_2025.11.04.25339517v1.19","doi-asserted-by":"crossref","first-page":"33","DOI":"10.2147\/EB.S226319","article-title":"nglion Cell Complex Analysis in Glaucoma Patients: What Can It Tell Us?","volume":"12","year":"2020","journal-title":"EB"},{"key":"2025110903101048000_2025.11.04.25339517v1.20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009497"},{"key":"2025110903101048000_2025.11.04.25339517v1.21","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy422"},{"key":"2025110903101048000_2025.11.04.25339517v1.22","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adg4517"},{"key":"2025110903101048000_2025.11.04.25339517v1.23","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btac369"},{"key":"2025110903101048000_2025.11.04.25339517v1.24","doi-asserted-by":"crossref","first-page":"e1011273","DOI":"10.1371\/journal.pgen.1011273","article-title":"iGWAS: Image-based genome-wide association of self-supervised deep phenotyping of retina fundus images","volume":"20","year":"2024","journal-title":"PLoS Genet"},{"key":"2025110903101048000_2025.11.04.25339517v1.25","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1038\/s41551-018-0195-0","article-title":"Prediction of cardiovascular risk factors from retinal fundus photographs via deep learning","volume":"2","year":"2018","journal-title":"Nat Biomed Eng"},{"key":"2025110903101048000_2025.11.04.25339517v1.26","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1186\/s12864-024-11112-5","article-title":"DeepMoIC: multi-omics data integration via deep graph convolutional networks for cancer subtype classification","volume":"25","year":"2024","journal-title":"BMC Genomics"},{"key":"2025110903101048000_2025.11.04.25339517v1.27","doi-asserted-by":"crossref","unstructured":"L. Chen , Can classical statistics and deep learning converge on explainable, causally driven target discovery? DNA Research, dsaf024 (2025).","DOI":"10.1093\/dnares\/dsaf024"},{"key":"2025110903101048000_2025.11.04.25339517v1.28","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1038\/s41467-024-55635-7","article-title":"Multi-omic spatial effects on high-resolution AI-derived retinal thickness","volume":"16","year":"2025","journal-title":"Nat Commun"},{"key":"2025110903101048000_2025.11.04.25339517v1.29","doi-asserted-by":"crossref","first-page":"btae732","DOI":"10.1093\/bioinformatics\/btae732","article-title":"Autoencoder-based phenotyping of ophthalmic images highlights genetic loci influencing retinal morphology and provides informative biomarkers","volume":"41","year":"2024","journal-title":"Bioinformatics"},{"key":"2025110903101048000_2025.11.04.25339517v1.30","doi-asserted-by":"publisher","DOI":"10.1007\/s10278-025-01539-x"},{"key":"2025110903101048000_2025.11.04.25339517v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2653"},{"key":"2025110903101048000_2025.11.04.25339517v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/S41588-019-0351-9"},{"key":"2025110903101048000_2025.11.04.25339517v1.33","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl4290"},{"key":"2025110903101048000_2025.11.04.25339517v1.34","doi-asserted-by":"publisher","DOI":"10.1101\/2021.11.24.469720"},{"key":"2025110903101048000_2025.11.04.25339517v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-44380-y"},{"key":"2025110903101048000_2025.11.04.25339517v1.36","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1007\/s00439-018-1942-8","article-title":"Genome-wide association studies for corneal and refractive astigmatism in UK Biobank demonstrate a shared role for myopia susceptibility loci","volume":"137","year":"2018","journal-title":"Hum Genet"},{"key":"2025110903101048000_2025.11.04.25339517v1.37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000978"},{"key":"2025110903101048000_2025.11.04.25339517v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2011.05.040"},{"key":"2025110903101048000_2025.11.04.25339517v1.39","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1016\/j.gendis.2023.01.013","article-title":"RSPO2 as Wnt signaling enabler: Important roles in cancer development and therapeutic opportunities","volume":"11","year":"2024","journal-title":"Genes Dis"},{"key":"2025110903101048000_2025.11.04.25339517v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601765"},{"key":"2025110903101048000_2025.11.04.25339517v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2005.11.025"},{"key":"2025110903101048000_2025.11.04.25339517v1.42","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae1128"},{"key":"2025110903101048000_2025.11.04.25339517v1.43","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20851-4"},{"key":"2025110903101048000_2025.11.04.25339517v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-023-01428-5"},{"key":"2025110903101048000_2025.11.04.25339517v1.45","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz1776"},{"key":"2025110903101048000_2025.11.04.25339517v1.46","doi-asserted-by":"publisher","DOI":"10.1038\/S41588-019-0351-9"},{"key":"2025110903101048000_2025.11.04.25339517v1.47","doi-asserted-by":"publisher","DOI":"10.1093\/NAR\/GKZ836"},{"key":"2025110903101048000_2025.11.04.25339517v1.48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2200914119"},{"key":"2025110903101048000_2025.11.04.25339517v1.49","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2306153120"},{"key":"2025110903101048000_2025.11.04.25339517v1.50","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06638-9"},{"key":"2025110903101048000_2025.11.04.25339517v1.51","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2200914119"},{"key":"2025110903101048000_2025.11.04.25339517v1.52","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2200914119"},{"key":"2025110903101048000_2025.11.04.25339517v1.53","doi-asserted-by":"crossref","first-page":"100298","DOI":"10.1016\/j.xgen.2023.100298","article-title":"A multi-omics atlas of the human retina at single-cell resolution","volume":"3","year":"2023","journal-title":"Cell Genom"},{"key":"2025110903101048000_2025.11.04.25339517v1.54","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2306153120"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.11.04.25339517","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:50:34Z","timestamp":1768510234000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.11.04.25339517"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,6]]},"references-count":54,"URL":"https:\/\/doi.org\/10.1101\/2025.11.04.25339517","relation":{},"subject":[],"published":{"date-parts":[[2025,11,6]]},"subtype":"preprint"}}