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

This study aimed to characterize the shared genetic architecture and modifiable correlates between myopia and retinal-optic nerve diseases (RONDs).

Genetic pleiotropy analysis and population-based cohort study.

A total of 81 491 UK Biobank participants and summary statistics from large-scale genome-wide association studies were included.

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.

Myopia and RONDs.

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.

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.

The author has no/the authors have no proprietary or commercial interest in any materials discussed in this article.