An Intraocular Pressure Polygenic Risk Score Stratifies Multiple Primary Open-Angle Glaucoma Parameters Including...

Area of Science:

• Ophthalmology
• Genetics
• Public Health

Background:

• Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness.
• Intraocular pressure (IOP) is a major risk factor for POAG, influenced by numerous genetic variants.
• Understanding the combined genetic contribution to POAG phenotype is crucial for risk stratification and management.

Purpose of the Study:

• To investigate the cumulative effect of common genetic variants associated with IOP on the POAG phenotype.
• To stratify POAG patients based on a polygenic risk score (PRS) derived from IOP-associated variants.
• To analyze the correlation between genetic risk tiers and clinical glaucoma characteristics.

Main Methods:

• A cross-sectional study design was employed.
• A PRS was developed using IOP genome-wide association study summary statistics.
• POAG patients (n=2154) were stratified into low, intermediate, and high genetic risk groups based on the IOP PRS.

Main Results:

• A significant dose-response relationship was observed between the IOP PRS and maximum recorded IOP.
• High genetic risk was associated with higher maximum IOP (1.7 mmHg increase), younger age at diagnosis (3.7 years earlier), and increased need for incisional surgery.
• Replication in an independent cohort confirmed associations with maximum IOP, family history, and treatment intensity.

Conclusions:

• The IOP PRS is a valuable tool for stratifying POAG patients based on genetic predisposition.
• Genetic factors influencing IOP have significant and reproducible clinical implications for POAG severity and management.
• These findings support the role of IOP-mediated pathways in POAG pathogenesis and highlight potential for personalized risk assessment.