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Glaucoma Polygenic Risk Score Appears Similarly Informative to Monogenic Risk Assessment

NEW YORK – An Australian team has developed a polygenic risk score and related genetic test for open-angle glaucoma that may eventually complement risk prediction tools based on monogenic glaucoma contributors, family history, age, and other factors.

"[E]arly detection can lead to vision-saving treatment, and genetic information can potentially give us an edge in making earlier diagnoses, and better treatment decisions," first and corresponding author Owen Siggs, an ophthalmology researcher affiliated with Flinders University and the Garvan Institute of Medical Research, explained in an email, noting that members of the team are in the process of developing an accredited polygenic risk test to address this genetic risk prediction approach in a clinical trial.

For their study in JAMA Ophthalmology on Thursday, the researchers tested a glaucoma PRS in hundreds of thousands of individuals with or without open-angle glaucoma from the Australian and New Zealand Registry of Advanced Glaucoma, or ANZRAG, UK Biobank, and other large studies to get a better look at genetic contributors to the disease that might be used for early detection and treatment.

"Current glaucoma screening guidelines target high-risk groups, including first-degree relatives or individuals of a certain age or ancestry," the authors noted. "The use of genetic risk stratification may be a valuable screening adjunct, allowing higher-risk individuals to be monitored earlier and more frequently, and lower-risk individuals later and less frequently."

The team established a polygenic open-angle glaucoma score based on almost 2,700-unrelated variants identified in several genome-wide association studies that they assessed using data for 2,507 individuals from ANZRAG and more than 411,300 individuals from other studies. The latter group included more than 7,900 UK Biobank participants with glaucoma and 119,318 without.

Siggs noted that previous studies have defined hundreds of common and rare genetic variants contributing to glaucoma risk, "although currently only rare variant testing is performed in certain clinical settings."

The team's results suggested that individuals with PRS scores in the top 5 percent risk group had a glaucoma odds ratio approaching 2.8, making them roughly as likely to develop open-angle glaucoma as individuals with established monogenic risk factors such as heterogeneous variants in the primary open-angle glaucoma gene MYOC. Moreover, the high PRS score appears to be far more common than carriage of a risky MYOC variant.

"Monogenic and high polygenic risk were each associated with a more than 2.5-fold increased odds of developing glaucoma and an equivalent mean age at glaucoma diagnosis," the authors reported, "with high polygenic risk more than 15 times more common in the general population."

Within individuals already diagnosed with open-angle glaucoma, meanwhile, roughly six times as many people were classified as high-risk based on their polygenic scores compared to those with known monogenic disease risk. The researchers found that some 15.7 percent of individuals with glaucoma fell into the top 5 percent risk group based on the PRS, while just 2.6 percent of glaucoma-affected individuals carried a heterogeneous version of the most common glaucoma-related variant in MYOC.

Members of the team are co-inventors on a patent related to the glaucoma polygenic score, and are working through a spinout company called StratifEYE that they co-founded to launch a related genetic test for use in clinical trials that are expected to kick off as early as next year.

"Genetic testing is not currently a routine part of glaucoma diagnosis and care, but this test has the potential to change that," senior author Jamie Craig, a consulting ophthalmologist and head of the Flinders University glaucoma research program, said in a statement. "We're now in a strong position to start testing this in clinical trials."

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