Understanding the Genetics Behind Glaucoma

Glaucoma is a leading cause of irreversible blindness worldwide.¹ The prevalence of its subtypes varies among different ethnicities, prompting the consideration of a genetic contribution, a topic gaining interest among researchers. This article outlines the better-understood genetic factors that influence the risk of adult-onset glaucoma subtypes.

PRIMARY OPEN-ANGLE GLAUCOMA

Primary open-angle glaucoma (POAG) constitutes approximately 75% of glaucoma cases.¹ To date, 127 genetic loci have been linked to POAG.² Much of these data have been uncovered through genome-wide association studies (GWAS), which analyze the entire genomes of large groups of individuals to identify genetic variations associated with a particular trait or disease. The majority of all GWAS data come from European and Asian populations, leading to a gap in data on individuals of African descent, who are disproportionately affected by POAG.³

The most common gene associated with POAG is the MYOC gene, which encodes the myocilin protein primarily located in the trabecular meshwork (TM). Although mutations in the MYOC gene are typically linked to severe juvenile open-angle glaucoma (JOAG), MYOC-associated POAG represents 3% to 5% of POAG cases.⁴ Several mechanisms have been suggested regarding the roles of various MYOC mutations in both POAG and JOAG. Most simply, it is thought that the accumulation of abnormal proteins within the TM may cause apoptosis in TM cells and/or structural changes in the TM, contributing to elevated IOP. The inheritance of the MYOC gene follows an autosomal dominant pattern, potentially influencing decisions related to family planning. Not all individuals with MYOC mutations will develop POAG; however, those with MYOC mutations should be monitored closely for POAG and JOAG, as glaucoma associated with MYOC mutations is typically severe.² As understanding of the MYOC gene improves, it has become a target for genetic therapies for glaucoma, with researchers focused on exploring ways to modulate myocilin’s function and reduce IOP in patients with MYOC mutations.⁵

NORMAL-TENSION GLAUCOMA

Several systemic associations have been described with normal-tension glaucoma (NTG), including obstructive sleep apnea, vascular risk factors, and low cerebrospinal fluid pressure. Known Mendelian (ie, single gene) causes for NTG account for only 2% of cases, but their autosomal dominant inheritance pattern makes them important targets for research.⁶ Additionally, existing literature indicates that up to 21% of patients with NTG report a positive family history of glaucoma, suggesting the likelihood of undiscovered genetic factors contributing to the disease.⁷

Like POAG, Mendelian causes for NTG involve mutations in the MYOC gene. Alterations in optineurin (OPTN) and TANK-binding kinase 1 (TBK1) have also been associated with NTG. Overexpression of OPTN in mice has been shown to be involved with retinal ganglion cell loss, providing insight into the pathogenesis of OPTN mutations in NTG.⁷ TBK1 copy number variations have been identified in NTG cohorts across the world, including India, South Korea, Australia, the United States, Japan, and a large African American pedigree, with a detection rate of 0.4% to 1.3% of patients with NTG.⁶ Still, the role of TBK1 in the development of NTG has yet to be further elucidated.

NTG linked to OPTN mutations and TBK1 duplications follows the average progression rate determined by the Collaborative Normal-Tension Glaucoma study; however, individuals with these gene mutations are typically diagnosed with NTG in their third to fourth decade of life, potentially resulting in more severe cases due to additional years for damage to accumulate.^6,8 Genetic testing may facilitate early identification and intervention, reducing the likelihood of substantial vision loss.

Although TBK1 and OPTN mutations are associated with various other neurodegenerative diseases, the category of mutations often differs. Notably, there is a single OPTN variant connected to both amyotrophic lateral sclerosis (ALS) and NTG.⁹ This highlights the importance of using genetic counselors when employing genetic testing for patients.

PRIMARY ANGLE-CLOSURE GLAUCOMA

Primary angle-closure glaucoma (PACG) carries a threefold higher risk of severe visual impairment than POAG.¹⁰ Globally, more than 75% of PACG cases are found in Asian populations, with a 60% to 65% heritability rate in this group.^11,12 Although GWAS have identified eight genes associated with PACG, widescale genetic risk scoring still holds poor clinical value, as these genes account for just 1.8% of PACG cases.¹³ All eight genes are expressed in the iridocorneal angle. They are thought to affect extracellular remodeling, cellular adhesion within the blood-aqueous barrier, anterior chamber depth, and IOP homeostasis. Not surprisingly, researchers have uncovered genetic overlap between POAG and PACG in relation to genes that are associated with IOP regulation.¹³

PSEUDOEXFOLIATION GLAUCOMA

Pseudoexfoliation glaucoma (PXG) occurs in conjunction with the age-related systemic disorder pseudoexfoliation syndrome (PXF), which is characterized by the accumulation of fibrillar extracellular material in the eyes and other organs. When this protein-like material accumulates in the TM, it can obstruct aqueous humor outflow.

Glaucoma occurs in up to half of patients with PXF.³ A correlation has been identified between single-nucleotide polymorphisms of the lysyl oxidase-like protein 1 (LOXL1) and PXF; however, there is variability in risk between ethnicities, with Scandinavian, Eastern Mediterranean, and Navajo Nation Indian populations carrying the highest risk.¹⁴ For Icelandic and Swedish populations over 60 years of age, PXF has a prevalence of upwards of 10% and 20%, respectively.³ The prevalence of PXF in Navajo Nation Indians has been reported to be as high as 38%.¹⁴

The variability in PXF risk across ethnicities prompts investigation into environmental effects on LOXL1 expression. Research suggests UV radiation plays a role in upregulation of LOXL1.^15,16 Interestingly, geomedical studies reveal that the incidence of PXF increases with distance from the equator and high altitude.¹⁵ Pasquale et al made the argument that although overall UV exposure increases with proximity to the equator, when accounting for factors including ground reflectance and solar altitude, ocular UV exposure may increase with distance from the equator.¹⁵

Furthermore, a data review of nearly 500,000 participants explored the influence of UV protection and the propensity for skin tanning on the risk of PXG in European populations. The team found genetic evidence to support a causal association between both UV protection and propensity for skin tanning and reduction in risk of PXG.¹⁷ This emphasizes the significance of eye care providers engaging in discussions about UV protection, especially with patient populations at higher risk for PXG.

THE QUEST FOR ANSWERS CONTINUES

Most glaucoma cases are not attributed to a single gene, making it challenging to unveil the complete array of genes involved. With advances in understanding of glaucoma-related genes, polygenic risk scores (PRS) arise as a potential method to assess for increased glaucoma risk.

Presently, PRS for glaucoma have limited clinical relevance due to their reliance on biobanks, which frequently include self-reported data that often lack specificity of glaucoma subtypes. Additionally, PRS algorithms face limitations due to insufficient data pertaining to certain ethnic groups.⁶

Overall, analysis of a diverse range of ethnic groups is essential for both enhancing the clinical usefulness of glaucoma PRS and deepening our understanding of the genetic components of this disease. With improved understanding of glaucoma genetics, the world moves ever closer to the possibility of routine screenings for glaucoma risk, earlier diagnosis and intervention, and novel genetic therapies.