The Genetics & Genomic Studies of Glaucoma

The Genetics & Genomic Studies of Glaucoma

September 13, 2022

Glaucoma can occur at all ages, with early onset disease (before the age of 40) exhibiting Mendelian inheritance and adult onset forms (developing after age 40) inherited as complex traits.

Generally, mutations in genes causing early onset glaucoma are rare with large biological effects, while variants contributing to the adult-onset glaucomas are common with smaller effects

Glaucoma is a term used to describe a group of disorders that have in common progressive degeneration of the optic nerve causing visual compromise and eventually blindness. Collectively, glaucoma is the leading cause of irreversible blindness world-wide.

Elevated intraocular pressure (IOP) is a major risk factor for most types of glaucoma. Fluid formed by the ciliary body (aqueous humor) is removed by the trabecular meshwork and Schlemm’s canal located in the ocular ‘angle’ that forms at the junction of the cornea and iris.

The IOP level is dependent on the rate of fluid removal, which is decreased in all types of glaucoma with elevated IOP. Glaucoma subgroups are defined as ‘open-angle’ or ‘closed-angle’ depending on the position of the ocular lens and iris relative to the trabecular meshwork.

Genetic and genomic studies, including genome-wide association studies (GWAS) have accelerated the discovery of genes contributing to glaucoma, the leading cause of irreversible blindness world-wide.

Glaucoma can occur at all ages, with Mendelian inheritance typical for the rare early onset disease (before age 40) and complex inheritance evident in common adult-onset forms of disease.

Primary open-angle glaucoma (POAG) is the most common type of glaucoma and has no obvious abnormality in the eye that points to a cause.

Although mutations in several genes, including myocilin, optineurin, and CYP1B1, have been reported to cause POAG, these genes account for less than 10% of cases worldwide.

In the past 2 years, large scale genetic studies that have examined the blood samples of thousands of glaucoma patients have been instrumental in the discovery of more common genetic risk factors for POAG.

Many genes and polymorphisms have been identified as being associated with glaucoma, predicting progression, identifying those at increased risk, and allowing treatment to be optimized.

During the past few years, we have witnessed great progress in the field of molecular genetics, mainly due to significant advancements and cost reductions in genotyping technology.

As a result, the number of genetic studies being undertaken in many fields of medicine, including ophthalmology, is rapidly increasing, leading to the discovery of new disease-related genes and genetic loci.

Identifying the genetic background of a disease is of great importance for improving our knowledge about biological pathways that contribute to disease pathogenesis and developing new DNA-based methods of diagnosis, risk assessment, and treatment.


Glaucoma, which is the leading global cause of irreversible blindness, is a multifactorial disorder resulting from a combination of genetic and environmental factors. A series of genes and polymorphisms has been associated with the disease and the pattern of inheritance may vary.

For instance, Mendelian inheritance is typical for rare early-onset disease, whereas complex inheritance is responsible for the common adult-onset forms.

The most common Mendelian forms of primary open-angle glaucoma (POAG) are caused by mutations in the myocilin (MYOC) gene, which have a prevalence of 2% to 4% in POAG patients.

Over 100 genomic regions (eg, SIX1/SIX6, TXNRD2, ATXN2, FOXC1, TMCO1, CDKN2B-AS1, ABCA1, AFAP1, GMDS) are known to be associated with POAG susceptibility at a genomewide level of significance: in 2017 this number was only 16.

However, the effect size of each one may be minor and collectively they explain only a small fraction of POAG heritability.

Apart from variants directly linked to the disease, many genetic loci have been associated with risk factors for POAG, such as IOP and cup-to-disc ratio. It remains unclear what role these loci play in the disease, because many of them do not demonstrate an association with POAG.

Regarding exfoliation glaucoma, it is highly prevalent in some populations, which could imply a specific genetic background.

The LOXL1 gene has an important role in exfoliation pathogenesis and recent studies have identified additional genetic loci (CACNA1A, FLT1-POMP, TLCD5, ARHGEF12, AGPAT1, RBMS3, SEMA6A) associated with increased risk of exfoliation syndrome.

However, as an analysis in the Thessaloniki Eye Study showed, gene variants of LOXL1 do not help to identify those with exfoliation who are at increased risk for glaucoma development, because they are similarly and strongly associated with both exfoliation syndrome and glaucoma.


Adopting genetic factors for risk assessment in clinical practice is challenging and probably not feasible for most of our patients.

Therefore, family history is often used as a surrogate for genetic risk. In the Rotterdam population-based study, first-degree relatives of patients with glaucoma and controls underwent standardized examination, including perimetry, and results demonstrated that the risk of developing glaucoma was 9.2 times increased in relatives of patients with glaucoma.

Risk calculators are useful tools for clinicians because they can provide more personalized risk estimations.

Genetic factors are already included in some calculators for age-related macular degeneration (AMD) but are not really used in clinical practice because no preventive intervention has been established for early AMD.

In glaucoma, preventive measures can be taken only for patients with ocular hypertension: the risk calculator developed by the Ocular Hypertension Treatment Study and European Glaucoma Prevention Study groups has helped clinicians treat patients at high risk of developing glaucoma.


Early detection of glaucomatous damage is of paramount importance to patients and great efforts have been made to develop effective screening methods. However, it has been suggested that the additional yield of periodic POAG screening is lower than expected from published prevalence data.

Likewise, genetic testing for POAG at a population level is not currently justified. However, for selected cases such as inherited early-onset disease, genetic testing is of clear benefit. There may be drawbacks related to the use of genetics as a screening approach for evaluating the risk of developing a disease.

We should be cautious about counseling patients who are at risk but not currently affected, because socioeconomic, psychological, and ethical issues may arise. Applying genetics to risk assessment of glaucoma progression could contribute to the improvement of patient management.

A 2015 study investigated whether known genetic loci for POAG are associated with visual field (VF) progression in patients from a Singaporean Chinese population.

A variant in the TGFBR3-CDC7 region was associated with 6.7 times increased chance of VF progression in POAG patients with 5 or more reliable VF measurements. However, the results need to be replicated in other independent cohorts.

Overall, it appears that genetics may be more relevant to manifest glaucoma management, having a role in predicting progression or rate of progression, identifying those at increased risk of becoming visually impaired, and optimizing treatment with targeted therapy.

This contribution would meet the aim of glaucoma management, which is to maintain the patient’s VF and related quality of life at a sustainable cost.


Progress in the field of genetic discoveries is remarkable and new data are emerging constantly.

Recently, in a large-scale multitrait analysis of glaucoma, investigators developed a polygenic risk score that could be predictive of increased risk of advanced glaucoma, glaucoma status beyond traditional risk factors, earlier age of glaucoma diagnosis, increased probability of disease progression in early-stage disease, and increased probability of incisional glaucoma surgery in advanced disease.

These developments are clearly promising and lead the way to personalized patient management.

However, at present, clinical application of genetic testing for glaucoma is justified only for selected cases and further research is needed before comprehensive genetic risk assessment and targeted genebased therapy can be achieved.