Understanding the genetics of glaucoma

Over 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 genetics

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.¹

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 2–4% in POAG patients.² Recently, genetic studies—and especially genome-wide association studies—have greatly contributed to the identification of new disease-related loci.

Currently, over 100 genomic regions (e.g., SIX1/SIX6, TXNRD2, ATXN2, FOXC1, TMCO1, CDKN2B-AS1, ABCA1, AFAP1, GMDS) are known to be associated with POAGsusceptibility at a genome-wide level of significance: in 2017 this number was only 16.1,³ However, the effect size of each one may be minor and collectively they explain only a small fraction of POAG heritability.⁴

Apart from variants directly linked to the disease, a large number of genetic loci have been associated with risk factors for POAG, such as intraocular pressure (IOP)and cup-to-disc ratio. It remains unclear what role these loci play in the disease, as many of them do not demonstrate an association with POAG.⁴

Regarding exfoliation glaucoma, we know that 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, TMEM136-ARHGEF12, AGPAT1, RBMS3, SEMA6A) associated with increased risk of exfoliation syndrome.⁵ 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.⁶

Risk assessment in clinical practice

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 glaucoma patients and controls underwent standardised examination, including perimetry, and results demonstrated that the risk of developing glaucoma was 9.2 times increased in relatives of glaucoma patients.⁷ Risk calculators are useful tools for clinicians as they can provide more personalised risk estimations. Genetic factors are already included in some calculators for age-related macular degeneration (AMD)^8,9 but they 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 to treat patients who are at high risk of developing glaucoma.¹⁰ An interesting question would be whether the addition of genetic parameters could further refine this risk calculator.

Genetic screening for glaucoma

Early detection of glaucomatous damage is of paramount importance for 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.¹¹

Likewise, genetic testing for POAG at a population level is not currently justified.4 However, for selected cases such as inherited early-onset disease, genetic testing is of clear benefit. For example, if a patient does not carry the mutation that causes POAG in their family then their risk of developing glaucoma will be similar to that in the general population so they could be discharged from frequent ophthalmic examinations.

We should also consider that 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 counselling patients who are at risk but not currently affected, as 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 a 6.7 times increased chance of VF progression in POAG patients with five or more reliable VF measurements.¹² 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 optimising 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.²

Recent developments

Progress in the field of genetic discoveries is remarkable and new data are emerging constantly. Recently, in a large-scale multi-trait analysis of glaucoma,³ 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 personalised 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 gene-based therapy can be achieved.

---

Fotis Topouzis, MD, PhD
E: ftopou12@otenet.gr
Prof. Topouzis is chair of the Department of Ophthalmology, Aristotle University of Thessaloniki, Greece, and current president of the European Glaucoma Society. He is principal investigator of two large population-based studies (Thessaloniki Eye Study, EUREYE Study). He reports grant support from Thea, Pfizer, Novartis, Alcon, Bausch & Lomb and Bayer and personal fees from Thea, Pfizer, Alcon, Bayer, Allergan, Novartis, Omikron and Santen.

Dimitrios Giannoulis, MD
E: dimitrisgian@gmail.com
Dr Giannoulis is university associate in the 1st Department of Ophthalmology at Aristotle University of Thessaloniki, Greece. He has no financial disclosures to report.

References

1. Wiggs JL, Pasquale LR. Genetics of glaucoma. Hum Mol Genet. 2017;26:R21-R27.
2. European Glaucoma Society. Terminology and Guidelines for Glaucoma. 4th ed. 2014.
3. Craig JE, Han X, Qassim A, et al. Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression. Nat Genet. 2020;52:160-166.
4. Khawaja AP, Viswanathan AC. Are we ready for genetic testing for primary open-angle glaucoma? Eye (Lond). 2018;32:877-883.
5. Aung T, Chan AS, Khor CC. Genetics of exfoliation syndrome. J Glaucoma. 2018;27 (suppl 1): S12-S14.
6. Anastasopoulos E, Coleman AL, Wilson MR, et al. Association of LOXL1 polymorphisms with pseudoexfoliation, glaucoma, intraocular pressure, and systemic diseases in a Greek population. The Thessaloniki eye study. Invest Ophthalmol Vis Sci. 2014;55:4238-4243.
7. Wolfs RCW, Klaver CC, Ramrattan RS, et al. Genetic risk of primary open-angle glaucoma.Population-based familial aggregation study. Arch Ophthalmol. 1998;116:1640-1645.
8. Seddon JM, Rosner B. Validated prediction models for macular degeneration progression and predictors of visual acuity loss identify high-risk individuals. Am J Ophthalmol. 2019;198:223-261.
9. Klein ML, Francis PJ, Ferris FL, et al. Risk assessment model for development of advanced age-related macular degeneration. Arch Ophthalmol. 2011;129:1543-1550.
10. Gordon MO, Torri V, Miglior S, et al. Validated prediction model for the development of primary open-angle glaucoma in individuals with ocular hypertension. Ophthalmology. 2007;114:10-19.
11. Stoutenbeek R, de Voogd S, Wolfs RCW, et al. The additional yield of a periodic screening programme for open-angle glaucoma: a population-based comparison of incident glaucoma cases detected in regular ophthalmic care with cases detected during screening. Br J Ophthalmol. 2008;92.1222-1226.
12. Trikha S, Saffari E, Nongpiur M, et al. A genetic variant in TGFBR3-CDC7 is associated with visual field progression in primary open-angle glaucoma patients from Singapore. Ophthalmology. 2015;122:2416-2422.