Shared Genetic Architecture and Multidimensional Modifiable Correlates between Myopia and Retinal-Optic Nerve Diseases.

Purpose: This study aimed to characterize the shared genetic architecture and modifiable correlates between myopia and retinal-optic nerve diseases (RONDs). Design: Genetic pleiotropy analysis and population-based cohort study. Participants: A total of 81 491 UK Biobank participants and summary statistics from large-scale genome-wide association studies were included. Methods: We examined associations between myopia and 5 common RONDs using population-based analyses of prevalent and incident outcomes, followed by cross-trait genetic analyses, locus-level annotation, colocalization, and enrichment analyses. Among myopic individuals, modifiable correlates and gene-environment interactions were evaluated, and Mendelian randomization was used as complementary evidence for selected associations. Main Outcome Measures: Myopia and RONDs. Results: The primary findings were that, in baseline prevalent analyses, myopia was associated with higher risks of retinal detachment (RD) and primary open-angle glaucoma (POAG), but a lower risk of primary angle-closure glaucoma (PACG), with evident risk gradients across myopia severity, especially for RD. Diabetic retinopathy (DR) risk estimates were <1.0 across myopia severity categories but were not statistically significant. A U-shaped association was observed between refractive status and age-related macular degeneration, with elevated risk in both high myopia and hyperopia. Incident analyses during follow-up showed broadly consistent patterns. As supportive genetic evidence, cross-trait analyses revealed significant genetic correlations and overlaps between myopia and RONDs, identifying 66 pleiotropic loci and 115 candidate genes, with enrichment in immune-inflammatory, receptor-mediated signaling, and retinal developmental pathways. Among myopic individuals, exploratory analyses further showed that prevalent myopia-ROND comorbidity was associated with various modifiable correlates spanning health status, lifestyle, diet, mental health, sleep patterns, and medication use, and that 7 environmental factors interacted with 5 pleiotropic variants. Mendelian randomization analyses provided complementary and hypothesis-supporting evidence consistent with a positive association of myopia with RD and an inverse association with PACG, whereas findings for DR and POAG required more cautious interpretation because of pleiotropy or heterogeneity. Conclusions: This study reveals a shared genetic architecture and identifies modifiable correlates linking myopia to five common RONDs. These findings provide new insights into shared susceptibility patterns and offer a framework for future mechanistic, validation, and prevention-oriented research in myopic populations. Financial Disclosures: The author has no/the authors have no proprietary or commercial interest in any materials discussed in this article.