Inside genetics and glaucoma

The primary benefit of this knowledge is the opportunity to better study the biology and mechanisms behind this complex disease to improve early glaucoma detection and allow for personalized treatment. Image credit: AdobeStock/immimagery

Glaucoma is a general term for a diverse group of complex disorders characterized by progressive degeneration of the optic nerve, leading to irreversible vision loss. It is the leading cause of irreversible blindness worldwide. As the global population ages, the number of people affected by the disease will increase dramatically; the number of people with glaucoma who are aged 40 to 80 years is expected to reach 112 million by 2040. Glaucoma disproportionately affects people of African and Asian descent and those living in urban areas. Men are also more likely to have primary open-angle glaucoma than women.¹ The economic and social burden of this reality is immeasurable; however, recent advances in genetic research show great promise in improving our ability to diagnose and treat glaucoma. Genome-wide association studies (GWAS) are rapidly identifying myriad genetic loci that play a role in the pathophysiology of the disease. This knowledge allows for further research into its biology and promotes the development of personalized glaucoma management, including risk prediction and targeted therapies.² The following is a brief overview of the scientific basis behind these discoveries and some of the major genetic loci that are emerging as contributors to glaucoma.

GWAS examine genetic variants and detect those that are more frequent in a disease group than in a control group. The most commonly studied genetic variants are single-nucleotide polymorphisms (SNPs) in which a single nucleotide at a specific location in a genome differs from the expected. GWAS use SNP arrays containing a large number (hundreds of thousands to millions) of SNPs to identify specific genetic loci associated with a particular disease state.³ This does not indicate a direct relationship between a genetic locus and a disease trait; however, it allows for further study into the function of the gene and how it might play a role in the biology of complex diseases. A better understanding of disease biology and variation between individuals can lead to more targeted and personalized therapies. Most clinically relevant at this time is the emergence of polygenic risk screenings for complex diseases such as glaucoma.

It is useful to separate the glaucoma types when examining the major genetic discoveries contributing to heritability. Early-onset glaucoma (onset earlier than 40 years of age) shows mendelian inheritance, while adult-onset glaucoma shows much more complex inheritance patterns.⁴ Early-onset glaucoma with developmentally normal ocular structures includes juvenile open-angle glaucoma (JOAG) and familial normal-tension glaucoma (NTG). Adult-onset glaucoma includes primary open-angle glaucoma (POAG), primary angle closure glaucoma (PACG), and pseudoexfoliation glaucoma (XFG). Genetic mutations associated with early-onset forms are rarer and have a larger biological impact, whereas those associated with adult-onset forms are more common and tend to have a smaller phenotypic effect.²

JOAG

JOAG shows an autosomal dominant inheritance pattern. Mutations in MYOC (a gene that encodes the protein myocilin found in the trabecular meshwork and ciliary body of the eye) are an important cause—MYOC mutations account for an estimated 8% to 36% of JOAG cases. These genetic loci are also associated with POAG.⁴ In an excellent example of how identifying these loci furthers our knowledge of the underlying disease process, studies have shown that the complete absence of MYOC function does not result in disease. Therefore, it is not the loss of gene function but a change in gene function that is associated with glaucoma. This presents an opportunity to eliminate or reduce MYOC expression as a potential therapeutic tool.⁴ Recent studies have shown that removing myocilin using CRISPR/Cas gene editing lowers IOP in mice carrying a MYOC gene mutation.²

Familial NTG

Familial NTG also shows an autosomal dominant inheritance pattern. OPTN and TBK1 mutations are associated with this form of glaucoma. These genes play an important role in autophagy and NF-kB signaling, which regulates inflammation and cell survival.⁴

POAG

POAG is the most common form of glaucoma and shows a complex inheritance pattern. Many genetic loci have been identified to be associated with POAG, especially in Asian and European Caucasian populations, which have been studied more often than African American and Hispanic populations.⁴ Recent GWAS have shown that genetic risk factors can be specific to ethnicity. For example, 3 novel loci identified in a Japanese population to be associated with POAG are not replicated in European or African population studies.² A few common variants to highlight include FNDC3B and FMNL2, which are associated with IOP and MYOF, which is associated with refractive error.² Other loci are responsible for a diverse array of cellular processes, including lipid metabolism, membrane biology, extracellular matrix development and maintenance, cell division, and ocular development.⁴ About half of the loci identified thus far have a role in the formation and maintenance of the extracellular matrix.⁵ Interestingly, some genetic loci are associated with an increased risk of multiple ocular diseases; C9 is associated with both POAG and age-related macular degeneration. Other loci are associated with both POAG and systemic diseases, including diabetes and cardiovascular disease.²

PACG

Eight genes have been identified in association with PACG. Not surprisingly, some of these genes are related to anterior chamber depth and choroidal thickness. Some genes are involved in acetylcholine metabolism, which may be a potential target for custom therapies.²

XFG

LOXL1 plays an important role in XFG; the gene has a role in extracellular matrix stability and alters elastin and collagen properties throughout the body. Population disease levels do not correlate well with population LOXL1 mutation frequencies; this has prompted research into environmental risk factors for XFG.⁴

The primary benefit of this knowledge is the opportunity to better study the biology and mechanisms behind this complex disease to improve early glaucoma detection and allow for personalized treatment. An exciting new development is the launch of SightScore (Seonix Bio), the first clinically available polygenic risk score test for glaucoma. The test uses a saliva sample and analyzes millions of genetic variants to create a personalized risk score. The research behind the test is based on GWAS of more than 400,000 individuals with and without glaucoma.⁶ This is a true breakthrough in glaucoma risk assessment: Not only does it indicate individuals at risk of glaucoma development, but it could also help determine previously diagnosed patients at the highest risk of fast progression. For example, a recent study found that a higher risk score was associated with early trabeculectomy in patients with POAG.⁷

However, there are limitations to these recent breakthroughs; it is estimated that glaucoma has an overall heritability of about 26%, and the currently identified SNPs only explain about 3% of the genetic contribution to glaucoma.² The concept of “missing heritability” is used to describe the gap between the heritability attributed to the loci that have been identified and the remaining unexplained heritability of the disease.³ Additionally, identifying these SNPs is only the first step in the extensive research it takes to determine a gene’s function and how possible manipulation of gene function could be used as a therapeutic tool. Despite limitations, this area of research is an exciting breakthrough and will play an important role in how we diagnose and treat glaucoma in the future.

References:

1. Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 2014;121(11):2081-2090. doi:10.1016/j.ophtha.2014.05.013

2. Choquet H, Wiggs JL, Khawaja AP. Clinical implications of recent advances in primary open-angle glaucoma genetics. Eye (Lond). 2020;34(1):29-39. doi:10.1038/s41433-019-0632-7

3. Visscher PM, Wray NR, Zhang Q, et al. 10 years of GWAS discovery: biology, function, and translation. Am J Hum Genet. 2017;101(1):5-22. doi:10.1016/j.ajhg.2017.06.005

4. Wiggs JL, Pasquale LR. Genetics of glaucoma. Hum Mol Genet. 2017;26(R1):R21-R27. doi:10.1093/hmg/ddx184

5. Wiggs JL. Glaucoma genes and mechanisms. Prog Mol Biol Transl Sci. 2015;134:315-342. doi:10.1016/bs.pmbts.2015.04.008

6. Seonix Bio announces US launch of SightScore, the first commercially available clinical polygenic risk score testing service for glaucoma. Businesswire.com. February 20, 2025. Accessed July 17, 2025.https://www.businesswire.com/news/home/20250220762988/en/Seonix-Bio-Announces-US-Launch-of-SightScore-the-First-Commercially-Available-Clinical-Polygenic-Risk-Score-Testing-Service-for-Glaucoma

7. Marshall HN, Hollitt GL, Wilckens K, et al. High polygenic risk is associated with earlier trabeculectomy in patients with primary open-angle glaucoma. Ophthalmol Glaucoma. 2023;6(1):54-57. doi:10.1016/j.ogla.2022.06.009