{
  "abstract": "PurposeTo 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).\n\nDesignRetrospective cohort study.\n\nParticipants3,102 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).\n\nMethodsOne index case per family was analysed. PRS were calculated from weighted SNPs and adjusted for ancestry. Cases were stratified by age at diagnosis (PCG [≤]3 years, JOAG [≥]4 and <40 years, POAG [≥]40 years) and presence of pathogenic/likely pathogenic variants (\"Mendelian\"). Groups were compared by Kruskal-Wallis test, with logistic regression and area under the curve for per-SD effects.\n\nMain Outcome MeasuresPRS centile values compared across glaucoma subtypes and Mendelian and non-Mendelian subgroups.\n\nResultsMean 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 [≤] 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 MYOC 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\nConclusionsA 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.",
  "abstract_shown": true,
  "affiliations": [
    "Garvan Institute of Medical Research, Sydney, New South Wales, Australia"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 21,
  "authors": [
    {
      "name": "J. Schmidt"
    },
    {
      "name": "M. C. B. Guevarra"
    },
    {
      "name": "G. Ni"
    },
    {
      "name": "T. A. D. Hassall"
    },
    {
      "name": "S. Ji"
    },
    {
      "name": "T. T. Nguyen"
    },
    {
      "name": "G. L. Hollitt"
    },
    {
      "name": "A. Kolovos"
    },
    {
      "name": "E. Souzeau"
    },
    {
      "name": "N. Q. Le"
    },
    {
      "name": "P. Gharahkhani"
    },
    {
      "name": "J. Turner-Maier"
    },
    {
      "name": "E. R. A. Collantes"
    },
    {
      "name": "I. F. Aboobakar"
    },
    {
      "name": "A. V. Segre"
    },
    {
      "name": "A. W. Hewitt"
    },
    {
      "name": "N. Haan"
    },
    {
      "name": "S. MacGregor"
    },
    {
      "name": "J. L. Wiggs"
    },
    {
      "name": "J. E. Craig"
    },
    {
      "affs": [
        0
      ],
      "name": "O. M. Siggs"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/c9cyj9ha3vw0k.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.13.26361381",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.09.13.26361381v1.full",
  "id": "c9cyj9ha3vw0k",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.09.13.26361381v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "ophthalmology"
    ],
    [
      "openalex",
      "2731|Glaucoma and retinal disorders"
    ]
  ],
  "openalex": "W7213341183",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.09.13.26361381v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-13",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/c9cyj9ha3vw0k.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:33Z",
      "native_id": "10.64898/2026.09.13.26361381",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.09.13.26361381v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:ophthalmology",
      "subfield": "general"
    }
  ],
  "title": "Juvenile and adult open-angle glaucoma form a single polygenic continuum",
  "title_text": "Juvenile and adult open-angle glaucoma form a single polygenic continuum",
  "type": "preprint",
  "updated_at": "2026-10-30T12:18:33Z",
  "url": "https://research.draconitic.com/paper/c9cyj9ha3vw0k",
  "venue": "medRxiv",
  "versions": []
}