Childhood Amblyopia as a Sex-Specific Risk Factor for Primary Open-Angle Glaucoma: A Prospective Study

Background: Amblyopia is a common childhood visual developmental disorder, but whether it is associated with the long-term risk of primary open-angle glaucoma (POAG) is unknown. We investigated the association between childhood amblyopia and incident POAG in adulthood and explored potential sex-specific genetic links between the two conditions.<br><br>Methods: In this prospective cohort study, we analysed 102,253 UK Biobank participants who underwent ocular examination and were free of glaucoma at baseline. Childhood amblyopia was identified from self-report and linked medical records and further classified into refractive, strabismic, and deprivation subtypes. Incident POAG was ascertained using linked health records. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Subtype-specific, sex-stratified, and competing-risk analyses were performed. Shared biological architecture was explored using Mendelian randomization, pleiotropic analysis under the composite null hypothesis (PLACO), Bayesian colocalization, and pathway enrichment analyses.<br><br>Findings: Over a mean follow-up of 10.55 years, 2,312 participants developed POAG. In the fully adjusted model, childhood amblyopia was associated with a higher risk of incident POAG (HR=1.50, 95%CI=1.31–1.72; P&lt;0.001). Deprivation amblyopia showed the strongest association (HR=1.86, 95%CI=1.47–2.36; P&lt;0.001), followed by refractive amblyopia (HR=1.40, 95%CI=1.17–1.68; P&lt;0.001) and strabismic amblyopia (HR=1.35, 95%CI=1.01–1.82; P=0.04). The association was present in both women (HR=1.63, 95%CI=1.29–2.07; P&lt;0.001) and men (HR 1.36, 95% CI 1.01–1.84; p=0.046), with stronger estimates in women; a significant sex interaction was observed for refractive amblyopia. Findings were robust in competing-risk analyses. Mendelian randomization did not support a significant overall causal effect, but pleiotropic and colocalization analyses identified sex-specific shared loci, with pathway enrichment indicating divergent biological processes in women and men.<br><br>Interpretation: Childhood amblyopia is associated with an increased long-term risk of POAG in adulthood. The observed sex differences in epidemiological association and shared genetic architecture suggest that the amblyopia–POAG relationship may involve distinct biological pathways in females and males. Amblyopia history may be a useful life-course marker for glaucoma risk stratification and warrants consideration in future mechanistic and translational studies.