Identifying individuals at risk of glaucoma via genetics studies

Ophthalmology Times EuropeOphthalmology Times Europe December 2021
Volume 17
Issue 10

Polygenic risk score allows multiple variants to be tested simultaneously.

Genetic investigations have garnered a wealth of information about glaucoma. The findings have pinpointed specific genes involved in early-onset familial disease with autosomal dominant or recessive inheritance, as well as genetic risk factors for common glaucoma types with complex inheritance patterns.

Speaking at a recent ophthalmology conference, Dr Janey Wiggs, the Paul Austin Chandler Professor of Ophthalmology, Harvard Medical School, Massachusetts, United States, defined the major goals of genetic research as being to identify at-risk individuals and to use knowledge about disease-causing genes to develop novel therapies.

She reported how current studies have set out to evaluate the risk and clinical outcomes in primary open-angle glaucoma (POAG) based on development of a polygenic risk score (PRS) applied to data in genome-wide association studies (GWASs).

POAG genetics and risks

The contribution of any single genetic variant to POAG is only small; multiple gene variants are needed to increase both the risk of disease and adverse outcomes. According to Dr Wiggs, to assess the risk, multiple variants must be tested simultaneously using a tool such as the recently developed PRS.

The PRS score determines the total number of genetic risk variants for each person, and individuals in a population are scored according to the number of DNA risk variants they have. Those with the highest number of variants have the highest genetic burden, which is likely to have the greatest impact on the risk of developing POAG and the outcome.

In analyses, the outcomes of individuals with the highest PRS (highest percentile) are often compared with the overall population distribution or with individuals who have the lowest genetic burden. Dr Wiggs said that to develop this valuable tool, two requirements must be met: a GWAS that is large enough to facilitate identifying all potential variants to be included in the PRS, and use of computational methods that can manage large data sets and create the score.


Individuals in the top 10% of the PRS had a 15 times greater risk of developing disease

The International Glaucoma Genetics Consortium (IGGC), which comprises investigators from around the world, was formed to complete the GWASs to identify all genetic risk variants for POAG. Each research group contributed their clinical and genetic data from POAG cases and controls.

A trans-ancestry meta-analysis1 was performed using all data sets; this resulted in the identification of 127 different chromosomal regions significantly associated with the risk for POAG. Dr Wiggs said that each region contains hundreds to thousands of genetic variants individually associated with disease risk.

Dr Wiggs reported that all the information from the participating groups worldwide was used to create a POAG PRS, which was applied to different populations and data sets to evaluate the clinical outcomes. When the investigators evaluated the impact of the PRS on disease risk, they found that individuals in the uppermost decile (the top 10% of the PRS) had a 15 times greater risk of developing disease compared with those in the lowest decile.

Dr Wiggs said: “This supported the concept that the PRS is associated with greatly increased risk.” The results also showed that individuals with the highest genetic burden as defined by the PRS experienced the onset of disease 5–10 years earlier than individuals in the bottom PRS distribution.

Further applications

A high genetic burden defined by the primary open-angle glaucoma polygenic risk score is associated with earlier disease onset, higher IOP, thinner nerve fibre layer and a greater need for surgery.

An association has been identified between PRS and increased intraocular pressure (IOP). A recent Australian study2 showed that individuals with the highest PRS had higher IOP throughout the day, which was especially true in the morning, and those individuals with the highest PRS had increased IOP spikes.

“These results suggested that home tonometry would be useful in patients with high PRS to accurately assess the IOP burden,” Dr Wiggs said. The highest PRS is also associated with ageing, thinner retinal nerve fibre layers and the proportion of patients requiring trabeculectomy to control IOP.3

One recent study into myocilin-related glaucoma4, conducted on individuals belonging to the UK Biobank, reported that mutations in the MYOC gene can cause juvenile OAG and early POAG, and that the most common mutation in carriers was found to be MYOC p.Gln368Ter.

The study identified 200 carriers of this gene who had IOP measurements and fundus photographs. The goal was to determine the disease rate (penetrance), diagnosis rate and effect of the POAG PRS among mutation carriers.

Dr Wiggs reported that the PRS reflected both the disease penetrance and disease severity; this finding supported the use of PRS in optimising risk stratification among MYOC p.Gln368Ter mutation carriers. “People who were mutation carriers were much more likely to have evidence of disease as defined by elevated IOP and disc-defined glaucoma if they were also in the high PRS percentiles,” she said.

Moreover, among patients with glaucoma who were mutation carriers, those in the highest percentiles were far more likely to have received a diagnosis, suggesting that having the myocilin mutation and a high PRS causes more severe disease that is evident to the patient.

Another study involving the UK Biobank, to assess the association of increased caffeine consumption5 and the PRS interaction with IOP and the risk of POAG, found that caffeine only caused IOP elevations in patients who had the highest PRS. The individuals who had raised IOP levels resulting from higher caffeine intake also had a greater risk of glaucoma.

The main takeaways from this line of research are that a large GWAS made the development of a PRS for POAG possible. A high genetic burden defined by the POAG PRS is associated with disease onset that is earlier by 10 to 15 years, higher IOP, thinner nerve fibre layer and a greater need for surgery. As Dr Wiggs noted, the PRS can modify disease outcomes due to other genes, such as MYOC, and can interact with environmental factors to influence the level of disease risk.

Janey Wiggs, MD, PhD
This article was adapted from Dr Wiggs’ presentation at the Women In Ophthalmology 2021 Summer Symposium. She has no financial interest in this subject matter.


1. Gharahkhani P, Jorgenson E, Hysi P, et al. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries. Nat Commun. 2021;12:1258.
2. Qassim A, Mullany S, Awadalla MS, et al. A polygenic risk score predicts intraocular pressure readings outside office hours and early morning spikes as measured by home tonometry. Ophthalmol Glaucoma. 2021;4:411-420.
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. Zebardast N, Sekimitsu S, Wang J, et al. Characteristics of p.Gln368Ter myocilin variant and influence of polygenic risk on glaucoma penetrance in the UK Biobank. Ophthalmology.2021;128:1300-1311.
5. Kim J, Aschard H, Kang JH, et al. Intraocular pressure, glaucoma, and dietary caffeine consumption: a gene–diet interaction study from the UK Biobank. Ophthalmology.2021;128:866-876.

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