NEW YORK – An international team of researchers has developed a polygenic risk score for glaucoma that could help identify people who are at risk of developing the condition at an earlier age and may benefit from earlier screening and treatment.
Glaucoma is the leading cause of blindness across the globe, and though there is no cure, there are treatments to slow or stop vision loss. But once vision is gone, it cannot be restored, meaning that early detection is important to prevent disease progression.
The researchers started out by conducting a genome-wide association study of glaucoma based on two key symptoms of the condition to identify about four dozen previously unknown loci. As they reported Monday in Nature Genetics, they then coupled these and other loci into a polygenic risk score (PRS) that they said could differentiate people with an increased risk of developing glaucoma and predict disease progression.
"Importantly, unlike existing eye health checks that are based on eye pressure or optic nerve damage, the genetic test can be done before damage begins, so regular screening can be put in place," senior author Stuart MacGregor, an associate professor at QIMR Berghofer Medical Research Institute in Australia, said in a statement. "Having a high risk score doesn't mean you will definitely get glaucoma, but knowing you could be at future risk allows people to take the necessary precautions."
For their study, the researchers characterized the optic nerves from 67,040 UK Biobank participants, as optic nerve degeneration is a sign of glaucoma, and used those results and intraocular pressure data, another sign of glaucoma, from 103,914 UK Biobank participants to conduct two GWAS. Through these, they identified 49 novel genetic loci associated with glaucoma.
Nine of the previously unknown SNPs could be replicated in two independent glaucoma cohorts — one from Australia and New Zealand and one from the US — and a further 26 were associated at a nominally significant level.
Based on their GWAS findings, the researchers developed a PRS for glaucoma. In the Australian and New Zealand cohort, individuals in the top PRS decile had a nearly 15-fold higher glaucoma risk than those in the bottom decile. Similarly, in a smaller UK cohort, the top decile had nearly a 12-fold higher risk than the bottom decile.
Some glaucoma cases are associated with pathogenic variants in the MYOC gene, especially Gln368Ter. The researchers identified 965 MYOC Gln368Ter carriers in the UK Biobank and stratified them by their PRS to find that the highest tertile still had an increased risk of early diagnosis, as compared to the lowest tertile.
This suggested that the PRS could be used as a screening tool in the general population. In a small Australian eye study cohort, screening those between 50 years and 60 years old with a top decile PRS identified 40 percent of cases. Similarly, in the UK Biobank cohort, screening the top 10 percent PRS scores found 29 percent of the cases between the ages of 50 and 60.
Within the larger Australian and New Zealand cohort of 1,336 advanced glaucoma cases, the PRS was significantly associated with age at diagnosis. People in the top decile were diagnosed with glaucoma an average seven years earlier than those in the bottom decile.
This score, the researchers said, could help identify people who are at an increased risk of developing glaucoma and who could benefit from additional disease screening.
"Early detection is paramount because existing treatments can't restore vision that has been lost, and late detection of glaucoma is a major risk factor for blindness," first author Jamie Craig, an ophthalmologist at Flinders University, said in a statement. "Glaucoma can arise at any age, but most of those affected are in their 50s or older, so our ultimate aim is to be able to offer blood tests to people when they turn 50 so they can find out if they are at risk, and then hopefully act on it."