Juvenile and adult open-angle glaucoma form a single polygenic continuum
- 1Garvan Institute of Medical Research, Sydney, New South Wales, Australia
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).
DesignRetrospective cohort study.
Participants3,102 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).
MethodsOne 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.
Main Outcome MeasuresPRS centile values compared across glaucoma subtypes and Mendelian and non-Mendelian subgroups.
ResultsMean 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).
ConclusionsA 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.
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BibTeX
@misc{schmidt2026juvenile,
title = {{Juvenile and adult open-angle glaucoma form a single polygenic continuum}},
author = {J. Schmidt and M. C. B. Guevarra and G. Ni and T. A. D. Hassall and S. Ji and T. T. Nguyen and G. L. Hollitt and A. Kolovos and E. Souzeau and N. Q. Le and P. Gharahkhani and J. Turner-Maier and E. R. A. Collantes and I. F. Aboobakar and A. V. Segre and A. W. Hewitt and N. Haan and S. MacGregor and J. L. Wiggs and J. E. Craig and O. M. Siggs},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.13.26361381},
url = {https://www.medrxiv.org/content/10.64898/2026.09.13.26361381v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Juvenile and adult open-angle glaucoma form a single polygenic continuum
AU - J. Schmidt
AU - M. C. B. Guevarra
AU - G. Ni
AU - T. A. D. Hassall
AU - S. Ji
AU - T. T. Nguyen
AU - G. L. Hollitt
AU - A. Kolovos
AU - E. Souzeau
AU - N. Q. Le
AU - P. Gharahkhani
AU - J. Turner-Maier
AU - E. R. A. Collantes
AU - I. F. Aboobakar
AU - A. V. Segre
AU - A. W. Hewitt
AU - N. Haan
AU - S. MacGregor
AU - J. L. Wiggs
AU - J. E. Craig
AU - O. M. Siggs
PY - 2026
DA - 2026/09/13
PB - medRxiv
DO - 10.64898/2026.09.13.26361381
UR - https://www.medrxiv.org/content/10.64898/2026.09.13.26361381v1
AB - 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). DesignRetrospective cohort study. Participants3,102 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). MethodsOne 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. Main Outcome MeasuresPRS centile values compared across glaucoma subtypes and Mendelian and non-Mendelian subgroups. ResultsMean 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). ConclusionsA 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.
ER -