{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T10:58:46Z","timestamp":1785927526808,"version":"3.56.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","award":["P30EY032857"],"award-info":[{"award-number":["P30EY032857"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Primary open-angle glaucoma (POAG) remains a leading cause of irreversible blindness worldwide, with early detection crucial for preventing vision loss. Current polygenic risk scores (PRS) for POAG, however, demonstrate limited predictive power.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Here, we present a multi-trait polygenic probability risk score (PPRS) approach that integrates PRSs of multiple glaucoma-related traits, including POAG, intraocular pressure (IOP), vertical cup-to-disc ratio (VCDR), and retinal nerve fiber layer thickness, while leveraging functional genomic annotations and extensive genomic coverage (&amp;gt;7 million variants) to enhance POAG prediction across diverse ancestries. We evaluated the PPRS in the UK Biobank (n = 324,713, European ancestry) and the Mexican American Glaucoma Genetic Study (MAGGS, n = 4,549, Latino ancestry).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The PPRS improved prediction compared with conventional approaches, achieving area under the receiver operating characteristic curve (AUC) values of 0.814 in Europeans and 0.802 in Latinos, versus 0.721 and 0.753 for baseline models with age and sex alone. Genetic contributions varied by ancestry: IOP PRS showed the strongest association in Europeans (OR = 1.63, P = 5.37 \u00d7 10\n                      <jats:sup>\u221289<\/jats:sup>\n                      ), whereas VCDR PRS predominated in Latinos (OR = 1.64, P = 2.04 \u00d7 10\n                      <jats:sup>\u221211<\/jats:sup>\n                      ). Risk stratification was substantial, with the highest PPRS decile showing 74.4-fold and 49.3-fold greater POAG risk compared with the lowest decile in Europeans and Latinos, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings show that integrating multiple disease-relevant PRSs and functional annotations significantly improves genetic prediction of POAG across diverse populations, supporting applications in targeted screening and early intervention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1842316","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T05:42:18Z","timestamp":1778132538000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Enhancing glaucoma prediction across ancestries: integrating functional annotation into multi-trait polygenic risk scores"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiaoyi Raymond","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, The Ohio State University","place":["Columbus, OH, United States"]},{"name":"Department of Biomedical Informatics, The Ohio State University","place":["Columbus, OH, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"224ed4","DOI":"10.1126\/scitranslmed.3008601","article-title":"UK biobank data: come and get it","volume":"6","author":"Allen","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e144","DOI":"10.1016\/S2214-109X(20)30489-7","article-title":"Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: the right to sight: an analysis for the global burden of disease study","volume":"9","author":"Blindness","year":"2021","journal-title":"Lancet Glob. Health"},{"key":"B3","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/s41586-018-0579-z","article-title":"The UK Biobank resource with deep phenotyping and genomic data","volume":"562","author":"Bycroft","year":"2018","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/s13742-015-0047-8","article-title":"Second-generation PLINK: rising to the challenge of larger and richer datasets","volume":"4","author":"Chang","year":"2015","journal-title":"Gigascience"},{"key":"B5","doi-asserted-by":"crossref","DOI":"10.1145\/2939672.2939785","article-title":"XGBoost: a scalable tree boosting system","volume-title":"Proceedings of the 22nd ACM SIGKDD international conference on knowledge discovery and data mining","author":"Chen","year":"2016"},{"key":"B6","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1038\/s41588-019-0556-y","article-title":"Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression","volume":"52","author":"Craig","year":"2020","journal-title":"Nat. Genet."},{"key":"B7","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.ophtha.2024.08.005","article-title":"The clinical usefulness of a glaucoma polygenic risk score in 4 population-based European ancestry cohorts","volume":"132","author":"de Vries","year":"2025","journal-title":"Ophthalmology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"837","DOI":"10.2307\/2531595","article-title":"Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach","volume":"44","author":"DeLong","year":"1988","journal-title":"Biometrics"},{"key":"B9","doi-asserted-by":"publisher","first-page":"3064","DOI":"10.1172\/JCI43085","article-title":"Glaucoma: genes, phenotypes, and new directions for therapy","volume":"120","author":"Fan","year":"2010","journal-title":"J. Clin. Invest."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2205","DOI":"10.1093\/hmg\/ddy111","article-title":"Genome-wide association analyses identify new loci influencing intraocular pressure","volume":"27","author":"Gao","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"B11","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1167\/tvst.8.2.10","article-title":"Polygenic risk score is associated with intraocular pressure and improves glaucoma prediction in the UK biobank cohort","volume":"8","author":"Gao","year":"2019","journal-title":"Transl. Vis. Sci. Technol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"7376","DOI":"10.1038\/s41467-022-35188-3","article-title":"Whole-exome sequencing study identifies rare variants and genes associated with intraocular pressure and glaucoma","volume":"13","author":"Gao","year":"2022","journal-title":"Nat. Commun."},{"key":"B13","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1038\/s41598-023-27551-1","article-title":"Explainable machine learning aggregates polygenic risk scores and electronic health records for Alzheimer\u2019s disease prediction","volume":"13","author":"Gao","year":"2023","journal-title":"Sci. Rep."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1038\/ng.3954","article-title":"Linkage disequilibrium-dependent architecture of human complex traits shows action of negative selection","volume":"49","author":"Gazal","year":"2017","journal-title":"Nat. Genet."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1258","DOI":"10.1038\/s41467-020-20851-4","article-title":"Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries","volume":"12","author":"Gharahkhani","year":"2021","journal-title":"Nat. Commun."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1204","DOI":"10.1016\/j.ajhg.2021.05.005","article-title":"Automated AI labeling of optic nerve head enables insights into cross-ancestry glaucoma risk and genetic discovery in >280,000 images from UKB and CLSA","volume":"108","author":"Han","year":"2021","journal-title":"Am. J. Hum. Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1038\/s41588-023-01428-5","article-title":"Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci","volume":"55","author":"Han","year":"2023","journal-title":"Nat. Genet."},{"key":"B18","first-page":"426","volume-title":"An introduction to statistical learning with applications in R","author":"James","year":"2009"},{"key":"B19","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1038\/s41576-023-00637-2","article-title":"Principles and methods for transferring polygenic risk scores across global populations","volume":"25","author":"Kachuri","year":"2024","journal-title":"Nat. Rev. Genet."},{"key":"B20","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.ophtha.2016.07.033","article-title":"Associations with retinal pigment epithelium thickness measures in a large cohort: results from the UK biobank","volume":"124","author":"Ko","year":"2017","journal-title":"Ophthalmology"},{"key":"B21","volume-title":"Ophthalmology: a pocket textbook Atlas","author":"Lang","year":"2007"},{"key":"B22","article-title":"Mach 1.0: rapid haplotype reconstruction and missing genotype inference","author":"Li","year":"2006"},{"key":"B23","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/s42256-019-0138-9","article-title":"From local explanations to global understanding with explainable AI for trees","volume":"2","author":"Lundberg","year":"2020","journal-title":"Nat. Mach. Intell."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1038\/s41588-018-0176-y","article-title":"Genome-wide association study of intraocular pressure uncovers new pathways to glaucoma","volume":"50","author":"MacGregor","year":"2018","journal-title":"Nat. Genet."},{"key":"B25","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1038\/s41588-023-01394-y","article-title":"Including multiracial individuals is crucial for race, ethnicity and ancestry frameworks in genetics and genomics","volume":"55","author":"Martschenko","year":"2023","journal-title":"Nat. Genet."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1038\/s41588-021-00870-7","article-title":"Computationally efficient whole-genome regression for quantitative and binary traits","volume":"53","author":"Mbatchou","year":"2021","journal-title":"Nat. Genet."},{"key":"B27","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.ophtha.2015.08.042","article-title":"African ancestry is associated with higher intraocular pressure in latinos","volume":"123","author":"Nannini","year":"2016","journal-title":"Ophthalmology"},{"key":"B28","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1167\/iovs.16-19891","article-title":"A genome-wide association study of vertical cup-disc ratio in a Latino population","volume":"58","author":"Nannini","year":"2017","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"2825","DOI":"10.5555\/1953048.2078195","article-title":"Scikit-learn: machine learning in python","volume":"12","author":"Pedregosa","year":"2011","journal-title":"J. Mach. Learn Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1016\/j.ajhg.2019.11.001","article-title":"Making the Most of clumping and thresholding for polygenic scores","volume":"105","author":"Prive","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"B31","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: a tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"B32","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1038\/nature08185","article-title":"Common polygenic variation contributes to risk of schizophrenia and bipolar disorder","volume":"460","author":"Purcell","year":"2009","journal-title":"Nature"},{"key":"B33","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1136\/jmg.2010.083337","article-title":"Genetic architecture of open angle glaucoma and related determinants","volume":"48","author":"Ramdas","year":"2011","journal-title":"J. Med. Genet."},{"key":"B34","doi-asserted-by":"publisher","first-page":"e1001779","DOI":"10.1371\/journal.pmed.1001779","article-title":"UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age","volume":"12","author":"Sudlow","year":"2015","journal-title":"PLoS Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"2081","DOI":"10.1016\/j.ophtha.2014.05.013","article-title":"Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis","volume":"121","author":"Tham","year":"2014","journal-title":"Ophthalmology"},{"key":"B36","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/s41576-018-0018-x","article-title":"The personal and clinical utility of polygenic risk scores","volume":"19","author":"Torkamani","year":"2018","journal-title":"Nat. Rev. Genet."},{"key":"B37","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1038\/s41588-017-0009-4","article-title":"Multi-trait analysis of genome-wide association summary statistics using MTAG","volume":"50","author":"Turley","year":"2018","journal-title":"Nat. Genet."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1016\/j.ophtha.2004.02.001","article-title":"The Los Angeles Latino eye study: design, methods, and baseline data","volume":"111","author":"Varma","year":"","journal-title":"Ophthalmology"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1016\/j.ophtha.2004.01.025","article-title":"Prevalence of open-angle glaucoma and ocular hypertension in Latinos: the Los Angeles Latino eye study","volume":"111","author":"Varma","year":"","journal-title":"Ophthalmology"},{"key":"B40","doi-asserted-by":"publisher","first-page":"16067","DOI":"10.1038\/nrdp.2016.67","article-title":"Primary open-angle glaucoma","volume":"2","author":"Weinreb","year":"2016","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B41","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1038\/s41588-024-01704-y","article-title":"Leveraging functional genomic annotations and genome coverage to improve polygenic prediction of complex traits within and between ancestries","volume":"56","author":"Zheng","year":"2024","journal-title":"Nat. Genet."}],"updated-by":[{"DOI":"10.3389\/fgene.2026.1942473","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000}}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1842316\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T06:10:54Z","timestamp":1785737454000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1842316\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,7]]},"references-count":41,"alternative-id":["10.3389\/fgene.2026.1842316"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2026.1842316","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,7]]},"article-number":"1842316"}}