A Comprehensive Assessment of the Shared Genetic Architecture between Myopia and Open-Angle Glaucoma

Objective: Individuals with high myopia have an increased prevalence of open-angle glaucoma (OAG). We aim to clarify the possibly shared genetic architecture of myopia and OAG, in particular in high myopes with myopic macular degeneration (MMD), where OAG screening is highly challenging. Design: Individual participant data meta-analysis of one-sample Mendelian randomization analyses and pleiotropic analysis under a composite null hypothesis. Participants: A total of 34 825 participants from 6 population-based cohort studies and 1 high myopia case–control study, including 708 OAG and 1953 high-myopia cases. Methods: First, we calculated and validated genetic risk scores (GRSs) for OAG and myopia in each cohort. We subsequently meta-analyzed linear and logistic regression models for the association of a myopia GRS with OAG, intraocular pressure (IOP), and vertical cup-to-disc ratio (VCDR), and the association of an OAG-GRS with high myopia, axial length, and spherical equivalent. We stratified the analysis of OAG in different stages of axial elongation, and in high myopes with or without MMD. Pleiotropic analysis under a composite null hypothesis was applied to genome-wide association study summary statistics. Main Outcome Measures: Odds ratio (OR) of OAG and high myopia, and mean difference in IOP, VCDR, axial length, and spherical equivalent. Results: One standard deviation (SD) increase in myopia GRS was associated with an OR (95% CI) of 1.18 (1.09, 1.28) for OAG, a beta (95% CI) of 0.04 (0.00, 0.08) mmHg in IOP, and of 0.005 (0.003, 0.007) in VCDR. The OAG-GRS was not significantly associated with high myopia compared to emmetropes, but a 1 SD increase was associated with a beta (95% CI) of 0.05 (0.01, 0.08) mm in axial length and of –0.05 (–0.10, –0.00) diopters in spherical equivalent. One SD increase in OAG-GRS had a substantially larger effect on OAG in high myopes with MMD, with an OR (95% CI) of 3.83 (1.89, 7.78) compared to 1.55 (1.24, 1.94) in emmetropes. Finally, we identified 95 independent pleiotropic single-nucleotide polymorphisms (SNPs). Conclusions: There is strong evidence for pleiotropy between myopia and OAG. Further research into the biological mechanisms of the identified pleiotropic SNPs is needed. An OAG-GRS might help to clinically estimate OAG risk, in particular in individuals with MMD. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.