Studies over the past decade produced a more sophisticated understanding of many of the complex genetic factors that underlie glaucoma. These studies build on our previous understanding of familial inheritance in glaucoma and specific genetic defects associated with a small percentage of glaucoma cases. The ongoing challenge is to determine intersection points between our understanding of the genetics of glaucoma and the recognized clinical needs for improved methods in screening, risk stratification, and therapeutic development.

The role of family history is well established in glaucoma; however, an accurate family history is not always possible, and glaucoma inheritance is a complex, multifactorial process. In recent years, genetic alterations associated with glaucoma development and glaucoma endophenotypes — traits associated with glaucoma, such as elevated IOP and increased vertical cup-to-disc ratio — have been identified. But how will these exciting findings translate to patient care? Here we review the role of familial inheritance and glaucoma genetics as it relates to glaucoma treatment and diagnosis.

A Foundation of Knowledge

A mainstay of current clinical practice is assessing whether there is a family history of glaucoma in first-degree relatives; this practice is built on strong evidence. Studies across multiple populations and types of glaucoma have demonstrated increased risk of glaucoma in patients with first-degree relatives who have glaucoma.^1-4 In clinical practice, learning of a first-degree relative of a glaucoma suspect or glaucoma patient can lead to more aggressive monitoring or treatment of the patient. It is also good clinical practice to advise glaucoma patients of familial inheritance in glaucoma, recommend that they discuss their diagnosis with family, and recommend that our patients' siblings and grown children undergo an ophthalmic exam to assess risk for glaucoma. This recommendation is particularly relevant in patients who are diagnosed with advanced stages of glaucoma at a relatively young age (at risk for vision loss) or who have experienced an acute angle-closure event.

Genetic Contribution to Glaucoma Development

Simple genetic mutations (mutations of a single gene that cause glaucoma development) that are inherited in a Mendelian manner cause a small percentage of total glaucoma cases. Mutations in the optineurin (OPTN) and tank binding kinase genes cause early onset familial normal tension glaucoma (NTG) and are inherited in an autosomal dominant manner.^5,6 Mutations in myocilin (MYOC) are associated with a significant percentage of cases of juvenile open-angle glaucoma and to a lesser extent early-onset primary open-angle glaucoma (POAG).⁷ These mutations, however, only account for 2% to 3% of NTG glaucoma cases and 2% to 4% of POAG cases.^8-11 Complex genetic inheritance patterns, which involve the interaction of multiple genetic factors, contribute to a much greater percentage of glaucoma cases. Multiple approaches have been employed to assess to what degree complex genetic factors influence glaucoma development. Twin studies found heritability — the portion of a trait that is not due to random variation or environmental influence — of POAG ranging from 17% to 81% with a significant genetic component of glaucoma endophenotypes, such as elevated IOP, cup-to-disc ratio, and retinal nerve fiber thickness.¹²

By looking at single nucleotide polymorphisms (SNPs), researchers have quantified the SNP heritability of glaucoma in a UK-based population and a non-Hispanic white ethnic group and have found the genetic contribution to glaucoma to be approximately 26%.^8,13 To date, SNPs explain approximately 3% of glaucoma heritability.⁸ Taken together, these findings reveal the potential for identification of additional components of the genetic contribution to glaucoma with further study in the coming years. These findings additionally support the long-held notion that glaucoma is an “umbrella” diagnosis with many different clinical presentations and causes.

Rapid Increase in Understanding

Genome-wide association studies (GWAS) have accelerated the discovery of genetic determinants of glaucoma over the past decade.¹⁴ In GWAS studies, scientists look for SNPs that are enriched in patients with a specific disease or trait. A convergence of developments in modern gene sequencing techniques, sequence analysis methods, and biobanks of genetic material from large patient cohorts have made GWAS studies possible in the last few decades and have enabled rapid discovery of genetic variations associated with glaucoma in different populations. These studies have taken a variety of approaches to understand the genetic contributions to glaucoma. There have been multiple excellent reviews published over the past few years.

Studies that have compared populations of glaucomatous patients to controls have been conducted across different population cohorts and different types of glaucoma, including POAG, primary angle-closure glaucoma, and pseudoexfoliation glaucoma. To date, more than 70 genetic loci that contribute to POAG susceptibility,¹⁴ at least 8 loci associated with primary angle-closure glaucoma,¹⁵ and 3 associated with pseudoexfoliation have been identified.¹⁶ Overlap of genetic loci identified in studies of different populations validates the importance of some of these loci.

Interestingly, there are specific loci that seem to be population specific. For example, a variant of amyloid-β A4 precursor protein-binding family B member 2 was present to a significant level only in POAG patients with African ancestry and not individuals of European or Asian ancestry.¹⁷ This and other similar findings suggests that there could be population-specific genetic causes that may have implications in clinical management.

Genome-wide association studies have also been used to look for genetic contributions to glaucoma endophenotypes such as IOP, vertical cup-to-disc ratio (VCDR), and central corneal thickness (CCT). More than 100 genetic loci have been associated with IOP, and this explains approximately 17% of IOP variance.¹⁸ A recent study of the UK Biobank and other available population biobanks looked at 101 SNPs associated with IOP and found approximately half were associated with a diagnosis of glaucoma.¹⁹ These findings belie the close association of IOP level and glaucoma development. In contrast, a meta-analysis of VCDR GWAS identified more than 50 loci associated with VCDR, but only 9 were associated with POAG.²⁰ Three separate GWAS for CCT uncovered a number of loci, none of which were associated significantly with POAG.^21-23 While it is known that there is significant variation in VCDR independent from glaucoma development, and the limited overlap of genetic loci with POAG was not necessarily surprising, the lack of overlap between CCT and POAG was unexpected.

The role of some genetic loci in glaucoma development or elevated IOP has been established in animal models of glaucoma. Mutations in myocilin and angiopoietin signaling cause IOP elevation and retinal ganglion cell death in mouse models.^24,25 Analysis of the known roles of the genes that were identified in GWAS implicate biologic processes, such as epidermal growth factor signaling, abnormal retinal morphology, vascular development, and mitochondrial function.^19,26 The mechanisms by which the majority of identified variations cause glaucoma are not known. A future challenge will be to investigate how these genetic variations lead to glaucoma development.

Identification of genetic loci in GWAS has not only informed possible mechanisms of glaucoma pathogenesis but also identified potential therapeutic targets for glaucoma treatment. Two examples of therapeutic targets are found in studies of the genetic contributions to IOP elevation. Genetic variants in adenosine and angiopoietin-Tie2 signaling proteins were associated with IOP elevation. Each of these signaling pathways was a known potential therapeutic target for IOP reduction and could be targeted by currently available therapies. Their identification in GWAS further validates the therapeutic potential of targeting these pathways. Additionally, the mitochondrial protein thioredoxin reductase 2 was implicated in POAG development. This finding suggests that strategies to restore mitochondrial function could prevent glaucoma. Lastly, an ultimate goal in therapeutic development is to tailor treatment to the characteristics of each individual patient — precision medicine. Understanding the relevant therapeutic targets in each patient is a first step to accomplishing precision medicine in glaucoma treatment.

There is considerable promise is using variants identified in GWAS to risk stratify patients as likely or unlikely to develop progressive disease. A glaucoma risk score (GRS) utilizing 12 POAG genetic risk variants demonstrated earlier (5.2 years) POAG development in individuals with the highest GRS than in those with the lowest scores.²⁷ Additional studies have found similar predictive value of GRSs using glaucoma endophenotype-associated loci.^19,28 Genome-wide association study findings have been additionally combined with longitudinal clinical data to identify genetic contributions to glaucoma development and progression. A study of Singaporean POAG patients identified a locus that imparted a 6.7-fold increased chance of visual field progression.²⁹ To date, risk stratification of glaucoma development or progression through genetic GRS is not yet clinically available. The promise of this approach for the future is exciting.

Clinical Practice

Many of the topics discussed here have not yet reached clinical care; however, there are times when genetic testing could impact surveillance or therapy.^30,31 Currently, useful testing in glaucoma is limited, however, to 2 genes — MYOC and OPTN. Relatives of patients with MYOC-associated glaucoma could have a 50% risk of carrying a mutation, and testing could influence care. Relatives carrying the mutation would benefit from increased surveillance, while those not carrying the mutation would presumably not have an increased risk of glaucoma development. MYOC testing could also be indicated in patients with juvenile open-angle glaucoma or POAG with early onset disease and a strong family history indicating potential for dominant inheritance. Similar recommendations could be made for OPTN testing of people with family members with known OPTN-associated glaucoma or patients with early onset of NTG with a strong family history. Prior to discussing genetic testing, it is important to ensure that you have a reputable, CLIA-certified lab (genetests.org ) to conduct the test and genetic counseling services available for your patient. GP

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Ian Pitha, MD, is an assistant professor of ophthalmology in the Department of Ophthalmology, Center for Nanomedicine, and Glaucoma Center of Excellence at the Johns Hopkins University School of Medicine in Baltimore, Maryland. Dr. Pitha reports consultancy to W. L. Gore. Reach him at ipitha1@jhmi.edu.