New IOVS study recommends a polygenic approach towards advancing risk stratification in normal-tension glaucoma
Normal-tension glaucoma (NTG) presents a significant diagnostic and therapeutic challenge due to its progression despite intraocular pressures (IOPs) staying within normal range.
As traditional screening methods often overlook this variant, particularly in its early stages, there is increasing interest in identifying high-risk individuals through genetic means.
In this context, a group of researchers from the QIMR Berghofer Medical Research Institute in Brisbane, Australia, have conducted a pivotal study assessing the utility of polygenic risk scores (PRSs) for NTG prediction using European-ancestry data sets.
The team leveraged genome-wide association study (GWAS) summary statistics to develop NTG-specific PRSs. Two approaches were employed: a conventional clumping and thresholding (C+T) method, and a more advanced Bayesian approach (SBayesRC) that integrates functional genomic annotations. These PRSs were computed using 317 NTG cases and 634 controls from the National Institutes of Health (NIH) “All of Us” dataset, and then validated using 89 NTG cases and 267 controls from a combined Genetics of Glaucoma (GOG) and QSkin Sun and Health Study dataset.
Both PRS construction methods demonstrated a statistically significant association between higher polygenic scores and increased NTG risk. Notably, the SBayesRC method yielded odds ratios (ORs) of 1.53 in the “All of Us” dataset and 1.83 in the GOG + QSkin cohort. Adjusted models accounting for age, sex, and genetic principal components showed consistent results, reinforcing the robustness of the findings.
Notably, individuals in the top 10% of PRSs had NTG prevalence rates nearly double those in the bottom 10%, supporting the PRS’s clinical relevance. However, area under the curve (AUC) values were modest, suggesting at this stage that PRS is better suited for risk stratification than standalone diagnostics.
The study findings present a promising step toward personalized glaucoma risk assessment, particularly for patients with normal IOPs and ambiguous clinical findings. While NTG remains underdiagnosed due to reliance on IOP-based screening, PRS implementation could aid in identifying genetically predisposed individuals earlier, possibly before optic nerve damage ensues.
