Myopia and glaucoma: is IOP the missing link?

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

Authors: Chong RS (1,2), Li H (1), Cheong AJY (3), Fan Q (4), Koh V (4,5), Raghavan L (1), Nongpiur ME (1,2), Cheng C-Y (1,2,4,5)

1. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Republic of Singapore
2. Ophthalmology & Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore, Republic of Singapore
3. Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
4. Centre for Innovation and Precision Eye Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
5. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore

Date: Published online December 6, 2022

Reference: Chong RS, Li H, Cheong AJY, Fan Q, Koh V, Raghavan L, Nongpiur ME, Cheng C-Y. Mendelian Randomization Implicates Bidirectional Association between Myopia and Primary Open-Angle Glaucoma or Intraocular Pressure. Ophthalmology. 2023 Apr;130(4):394-403.

[Link to open access paper]

Myopia has been linked to an increased risk of primary open-angle glaucoma (POAG).^1,2 In contrast, there does not appear to be a definitive relationship between myopia and intraocular pressure (IOP)—a known risk factor for glaucoma.^3,4 Conflicting evidence on this relationship between myopia and glaucoma may be due to difficulties in diagnosing glaucoma in the presence of structural and functional changes in highly myopic eyes.⁵ Traditional observational studies are limited by confounding variables, making it difficult to establish causality between myopia and glaucoma progression.^6–8

This study aimed to overcome these limitations by using Mendelian randomization (MR), a genetic analysis technique, to determine whether a causal relationship exists between myopia, POAG, and IOP. By using genetic variants as instrumental variables, MR helps infer causality between myopia and glaucoma, minimizing confounding factors inherent in observational studies.⁹

The researchers sampled from existing large-scale genetic data (n = 216,257–542,934) from genome-wide association studies (GWAS) in both European and Asian populations. Various MR models and multivariate genomic structural equation modelling (SEM) were used to reveal consistent mediators in the relationship between myopia and POAG.

Key findings were as follows.

• A causal link between myopia and POAG was identified in most models, with some also suggesting a reverse association. This relationship achieved statistical significance in European populations, and while Asian populations exhibited similar trends, they did not reach the same level of significance.
• IOP had a significant bidirectional genetic causal association with myopia. No such association was observed with other factors tested such as RNFL thickness, vertical cup-to-disc ratio, and optic cup area.
• Genetic SEM indicated that IOP was the key mediator in the causal association between myopia and POAG.

The study's findings highlight a complex, bidirectional relationship between myopia and POAG, suggesting that elevated IOP may contribute to myopia progression, and myopia may increase the risk of POAG through its effect on IOP. 

These insights have implications for the clinical management of patients who are both a glaucoma suspect and have high myopia. Research shows that 10.8% of highly myopic individuals exhibit glaucoma-like visual field defects,¹⁰ but only a minority of these individuals had elevated IOP and neuroretinal rim changes corresponding to their visual field test results. 

For highly myopic eyes with visual field defects yet normal IOP, diagnosing glaucoma is complicated as myopic disc changes can confuse interpretation. In this case, the authors suggested early glaucoma treatment for highly myopic, glaucoma suspects – to potentially delay glaucoma onset and also slow myopia progression.   It is unclear whether this referred to adults or children. 

These findings reconcile the notion that minimizing the final level of myopia in adulthood also reduce the risk of glaucoma. Past research has established that higher levels of myopia and longer axial lengths are correlated with a higher risk of ocular pathologies such as glaucoma¹¹ It stands to reason that interventions to slow the progression of myopia, particularly in children, may reduce the eye’s future susceptibility to IOP-mediated progressive optic neuropathy.

While this study provides important insights into the genetic links between myopia, IOP, and POAG, there are some limitations to consider. 

• Mendelian randomization relies on genetic data and does not fully account for environmental or lifestyle factors that may influence these conditions.
• Most participants were of European and Asian descent, so the findings may not apply equally to other ethnic groups. 
• Use of cross-sectional data prevented the ability to track how myopia, IOP, and glaucoma developed and interacted over time.

Future research should include more diverse populations to improve how broadly these results apply. Long-term studies that follow how myopia progresses and how IOP changes over time could help clarify whether controlling IOP in myopic patients can actually reduce their risk of developing glaucoma. Further understanding is needed about how environmental factors (such as screen time, reading habits, and outdoor activity) might interact with genetic risk factors for both myopia and glaucoma. Filling these gaps will help eye care professionals develop better prevention and treatment strategies for at-risk patients. 

Title: Mendelian randomization implicates bidirectional association between myopia and primary-open angle glaucoma or intraocular pressure

Authors: Rachel S Chong, Hengtong Li, Alex J Y Cheong, Qiao Fan, Victor Koh, Lavanya Raghavan, Monisha E Nongpiur, Ching-Yu Cheng

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.

Methods: Multiple MR models and multivariate genomic structural modeling to identify significant mediators for the relationship between myopia and POAG.

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.

[Link to open access paper]