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

Background: 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 due to confounding factors that arise from myopia, which complicate clinical tests for glaucoma. This study uses Mendelian randomization (MR) analysis to determine genetic causal associations between myopia, glaucoma and glaucoma-related traits, which overcomes the effects of external confounders.Methods: Bi-directional genetic associations between myopia or refractive spherical equivalent (RSE), POAG and POAG-endophenotypes were investigated using six MR models, based on data from the largest publicly-available genetic banks (N=216,257 to 542,934). We also performed multivariate genomic structural modeling to identify significant mediators for the relationship between myopia and POAG.Findings: We found consistent bi-directional genetic associations between myopia and POAG, and between myopia and intraocular pressure (IOP) using multiple MR models at Bonferroni-corrected levels of significance. IOP had the most significant mediation effect on RSE and POAG (Sobel test: 0.13, 95% confidence interval: 0.09 – 0.17; p= ).Interpretation: There is a strong bi-directional genetic causal link between myopia and POAG, which is mainly mediated 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.Funding Information: This study was supported by the National Medical Research Council of the Ministry of Health, Singapore.Declaration of Interests: We declare no competing interests. Ethics Approval Statement: Specific ethical approval was not required for this study, as all data were obtained from sources available to the public. This research adhered to the Declaration of Helsinki.