Mendelian Randomization Implicates Bidirectional Association between Myopia and Primary Open-Angle Glaucoma or Intraocular Pressure

Abstract

Purpose: Observational studies suggest that myopic eyes carry a greater risk of primary open-angle glaucoma (POAG); however, the evidence for this association is inconsistent. This may be the result of confounding factors that arise from myopia that complicate clinical tests for glaucoma. This study used Mendelian randomization (MR) analysis to determine genetic causal associations among myopia, glaucoma, and glaucoma-related traits that overcome the effects of external confounders. Design: Bidirectional genetic associations between myopia and refractive spherical equivalent (RSE), POAG, and POAG endophenotypes were investigated. Participants: Data from the largest publicly available genetic banks (n = 216,257–542,934) were analyzed. Methods: Multiple MR models and multivariate genomic structural modeling to identify significant mediators for the relationship between myopia and POAG. Main Outcome Measures: Genetic causal associations between myopia and POAG and POAG endophenotypes. Results: We found consistent bidirectional genetic associations between myopia and POAG and between myopia and intraocular pressure (IOP) using multiple MR models at Bonferroni-corrected levels of significance. Intraocular pressure showed the most significant mediation effect on RSE and POAG (Sobel test, 0.13; 95% confidence interval, 0.09–0.17; P = 1.37 × 10–8). Conclusions: A strong bidirectional genetic causal link exists between myopia and POAG that is mediated mainly by IOP. Our findings suggest that IOP-lowering treatment for glaucoma may be beneficial in myopic eyes, despite the challenges of establishing a clear clinical diagnosis. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.