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A risk score incorporating genetic variants for open-angle glaucoma is accurate enough to help with diagnosis of the condition, an interim study reveals. Although hundreds of genetic changes are linked to the condition, the new study is the first to support using a polygenic risk score to identify patients who require further evaluation.

Almost 35% of people in the highest decile of risk had primary open-angle glaucoma (POAG) compared with only 7% in the lowest decile, according to the researchers, who presented the findings on May 5 at the 2024 annual meeting of the Association for Research in Vision and Ophthalmology (abstract 1010). 

"We expected there to be a clear difference, but we didn't expect the difference to be as remarkable as it was," Hetince Zhao, BS, a medical student at Renaissance School of Medicine at Stony Brook University, Stony Brook, New York, and leader of the study, told Medscape Medical News. "We're very happily surprised by that." 

This distinction supports screening with a polygenic risk score in clinical practice toward the aim of earlier detection and treatment, she said.

Glaucoma is a leading cause of irreversible blindness worldwide. In addition, about half of diagnoses are made when the condition is more advanced and people have already experienced some loss of vision. Determining whether a risk score based on genetics could flag people at higher risk sooner and give clinicians more time to intervene was an aim of the study, Zhao said. 

Along with Louis R. Pasquale, MD, and colleagues from The Mount Sinai Hospital in New York City and Mass Eye and Ear in Boston, Zhao examined the eyes of 261 people with a mean age of 66 years. Participants were between 35 and 90 years old, and almost 57% were women. 

A confirmed diagnosis of POAG was based on two independent assessors masked to the patients' risk status. Investigators used structural and functional data from measurement of the circumpapillary retinal nerve fiber layer using optical coherence tomography and Humphrey visual field tests. They did not diagnose POAG using intraocular pressure. About half of participants in the high-risk group diagnosed with POAG were previously undiagnosed.

Eying More Diverse Risk Score

To create their polygenic risk score, the investigators turned to a 2021 meta-analysis and the UK Biobank with 14,171 cases of open-angle glaucoma. They then calculated risk on the basis of more than 99,000 individuals from the Mount Sinai BioMe and Mass General Brigham Biobank repositories. 

"Because we're in New York City, we probably have one of the most diverse population of patients to examine," Zhao said. Even so, the group hopes to recruit up to 800 participants and create a population sample more representative of the US population. 

"If we're going to use a polygenic risk or to screen for eye disease, we want to make sure that it works well for the general population. Currently, a lot of biobanks have genetic data for people of European descent," Zhao said. "That might be a part of why our risk score right now works better in people of European descent than people of color."

Developing a polygenic risk score makes sense to Zhao. The estimated inheritance or familial risk for POAG was 9.4% in a 2021 study in which researchers identified 127 significant associated single nucleotide polymorphisms (SNPs). Another study in 2023 put familial risk closer to 14% on the basis of 263 significant SNPs discovered through genome-wide analysis. 

The investigators looked at the link between the risk score and POAG after adjusting for age, sex, body mass index, diabetes, hypertension and genetically inferred ancestry in a multivariate logistic regression analysis. 

More Than Eight Times the Risk

Given the different levels of clinical evidence for POAG in the highest and lowest decile, the overall odds ratio was 8.5 (95% CI, 3.62-19.0) between these groups. The odds ratio was 14.8 (95% CI, 4.66-47.1) for those of European ancestry and 3.23 (95% CI, 0.69-15.1) for people of African ancestry. 

The sample sizes were too small to calculate odds ratios for the admixed Americans and Asian ancestral groups.

"I look forward to our results in the future, when we can say our polygenic risk score also works for non-European subgroups," Zhao said. 

An Illustrative Study

"This study exemplifies the future direction of the field, which is the using genetic data to stratify patients for risk of disease," said Zhenxun Wang, PhD, an assistant professor at the Centre for Vision Research and the Signature Research Program in Cardiovascular & Metabolic Disorders at the Duke-NUS Medical School in Singapore. "What's useful about this study is that it not only can validate the polygenic risk score algorithms, but it potentially can give more information regarding disease progression of enrolled patients." 

Hetince Zhao and Zhenxun Wang had no financial disclosures. Pasquale is a consultant/contractor for Twenty Twenty. The researchers were supported by grants from the National Eye Institute, a National Institutes of Health K23 grant, Research to Prevent Blindness, and The Glaucoma Foundation. 

Damian McNamara is a staff journalist based in Miami. He covers a wide range of medical specialties, including infectious diseases, gastroenterology and critical care. Follow Damian on Twitter:  @MedReporter.