{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T19:08:35Z","timestamp":1789672115490,"version":"4.0.1"},"posted":{"date-parts":[[2026,9,14]]},"group-title":"Ophthalmology","reference-count":23,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["GNT1150144"],"award-info":[{"award-number":["GNT1150144"]}],"id":[{"id":"https:\/\/ror.org\/011kf5r70","id-type":"ROR","asserted-by":"publisher"}]},{"award":["GNT2016545"],"award-info":[{"award-number":["GNT2016545"]}],"id":[{"id":"https:\/\/ror.org\/011kf5r70","id-type":"ROR","asserted-by":"publisher"}]},{"award":["GNT2026787"],"award-info":[{"award-number":["GNT2026787"]}],"id":[{"id":"https:\/\/ror.org\/011kf5r70","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01 EY031820"],"award-info":[{"award-number":["R01 EY031820"]}],"id":[{"id":"https:\/\/ror.org\/03wkg3b53","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Snow Medical Research Foundation","award":["PF2019-040"],"award-info":[{"award-number":["PF2019-040"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Purpose<\/jats:title>\n                  <jats:p>To test whether juvenile open-angle glaucoma (JOAG) and primary congenital glaucoma (PCG) are polygenically continuous with primary open-angle glaucoma (POAG), using a multi-trait POAG polygenic risk score (PRS).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Design<\/jats:title>\n                  <jats:p>Retrospective cohort study.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Participants<\/jats:title>\n                  <jats:p>3,102 open-angle glaucoma index cases, of whom 2,836 had a recorded age at diagnosis (52 PCG, 226 JOAG, and 2,558 POAG) and 999 European-ancestry controls from a glaucoma disease registry and a population-based cohort. Two replication cohorts comprised 70 JOAG and 31 PCG probands with 230 controls (MEE), and 9 PCG and 120 POAG cases (GOGS).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>One index case per family was analysed. PRS were calculated from weighted SNPs and adjusted for ancestry. Cases were stratified by age at diagnosis (PCG \u22643 years, JOAG \u22654 and &lt;40 years, POAG \u226540 years) and presence of pathogenic\/likely pathogenic variants (\u201cMendelian\u201d). Groups were compared by Kruskal-Wallis test, with logistic regression and area under the curve for per-SD effects.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Main Outcome Measures<\/jats:title>\n                  <jats:p>PRS centile values compared across glaucoma subtypes and Mendelian and non-Mendelian subgroups.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Mean PRS was highest in cases diagnosed in the fourth decade of life. Among subgroups, it was highest in non-Mendelian JOAG (84.1%), exceeding controls (53.3%), Mendelian JOAG (68.9%), and non-Mendelian POAG (79.3%) (all P \u2264 0.003). Non-Mendelian JOAG was also the best discriminated from controls (OR 3.66 per SD increase, 95% CI 3.02-4.49; AUC 0.814, 95% CI 0.782-0.845). Neither PCG subgroup differed from controls. Among Mendelian cases, only\n                    <jats:italic>MYOC<\/jats:italic>\n                    p.Gln368Ter showed significantly elevated PRS (OR 2.49 per SD, 95% CI 1.89-3.34). In the MEE replication cohort, JOAG was associated with higher PRS (OR 2.12 per SD, 95% CI 1.50-3.07) while PCG was not (OR 0.90, P = 0.73). In GOGS, mean PRS was higher in POAG than PCG (84.8 vs 59.7 centile; P = 0.026).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>A POAG PRS predicts JOAG risk with discrimination comparable to or greater than POAG itself, supporting a shared polygenic architecture across juvenile and adult open-angle glaucoma. PCG showed no PRS elevation regardless of Mendelian status, indicating a distinct architecture for which rare-variant sequencing remains appropriate.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.13.26361381","type":"posted-content","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T04:10:19Z","timestamp":1789445419000},"source":"Crossref","is-referenced-by-count":0,"title":["Juvenile and adult open-angle glaucoma form a single polygenic continuum"],"prefix":"10.64898","author":[{"given":"Joshua","family":"Schmidt","sequence":"first","affiliation":[{"name":"Garvan Institute of Medical Research, Sydney, New South Wales, Australia"},{"name":"Department of Ophthalmology, Flinders Health and Medical Research Institute, Flinders University, Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma. 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