Polygenic risk scores for intraocular pressure and vertical cup-disc ratio, two critical glaucoma risk factors, provide a framework for early detection and personalized glaucoma management in recent research. 

This genetic association study sought to construct and validate polygenic risk scores (PRSs) for intraocular pressure (IOP) and vertical cup-disc ratio (VCDR) to enhance risk stratification for primary open-angle glaucoma (POAG). Data from three cohorts—6,959 individuals aged 45 to 85 years from the Canadian Longitudinal Study on Aging (CLSA), 4,960 individuals aged 46 to 64 years from the Busselton Healthy Aging Study (BHAS), and a multi-ethnic population of approximately 500,000 participants aged 40 to 69 years from the UK Biobank—were analyzed from June to November 2023.

In their article published in JAMA Ophthalmology, the researchers noted that family studies estimate the heritability of IOP to range between 40% and 70%, while VCDR has heritability estimates of 48% to 57%. They explained that the strong genetic link between IOP, VCDR, and glaucoma has led to the development of PRSs based on IOP and VCDR loci, which are effective tools for assessing POAG risk. Additionally, a recent genome-wide association study combining data on POAG, IOP, and VCDR identified over 300 loci associated with POAG. The researchers also noted that POAG is most common in African and European individuals.

In this study, VCDR PRS explained 22.0% and 19.7% of phenotypic variance in CLSA and BHAS, respectively, and high VCDR PRS suggested glaucoma risk even with normal IOP. IOP PRS explained 12.9% and 9.6% of phenotypic variance in CLSA and BHAS, respectively, and the researchers noted that high IOP PRS can identify individuals who may benefit from intensive IOP-lowering treatments. The researchers noted that the PRSs showed their usefulness in categorizing individuals according to their VCDR or IOP levels. For instance, comparing the highest decile to the reference decile (fifth decile) revealed increases of approximately 0.15 units in VCDR and 2.5 mm Hg in IOP. These effects were notable, as a moderate-penetrance 368X variant in MYOC raised IOP by roughly 2 mm Hg.

PRS performance varied by ancestry, with lower prediction accuracy in non-European populations. “The VCDR PRS variance explained 5.2%, 12.1%, and 14.3% and the IOP PRS variance explained 2.3%, 3.2% and 7.5% across African, East Asian, and South Asian populations, respectively,” they wrote.

Overall, PRSs enabled preclinical risk stratification and improved early detection in populations with no noticeable glaucoma symptoms. Indeed, “while the translation of IOP and VCDR PRSs still needs more research, in theory, the stratification of risk through a VCDR or IOP PRS can be performed even before the clinical manifestation of the disease,” the investigators observed. Their findings suggested that tailored interventions based on individual PRS profiles could reduce disease progression and vision loss.

A full list of author disclosures can be found in the published research