**Background:** Glaucoma and age-related macular degeneration (AMD) are leading causes of irreversible blindness worldwide, with glaucoma predicted to affect 111.8 million people by 2040 and AMD 288 million by 2040. Both conditions are highly heritable (glaucoma heritability ~80%, AMD 45–70%) and often asymptomatic in early stages, leading to underdiagnosis (approximately half of glaucoma cases undiagnosed). Current screening guidelines are limited and not cost-effective. Polygenic risk scores (PRS) aggregate the effects of common genetic variants and could enable population risk stratification. This study aims to prospectively assess the clinical validity of PRS for glaucoma and AMD in a general population sample.
**Methods:** The GRADE study is a prospective cohort approved by the Southern Adelaide Clinical Human Research Ethics Committee. Targeted recruitment is 1000 individuals aged ≥50 years, with no exclusion for prior diagnosis or ethnicity. Participants provide blood (2×9ml EDTA tubes) or saliva samples for DNA extraction and genotyping on Illumina GSA v3 arrays. Imputation uses 1000 Genomes reference panel. Glaucoma PRS is derived using a multitrait analysis of GWAS (MTAG) approach; AMD PRS uses a similar MTAG method. PRS percentiles are determined relative to 1000 Genomes populations. A subset of 300 participants (100 from bottom decile, 100 from top decile, 100 from middle 80% for each disease) undergo detailed eye examinations including best-corrected visual acuity, IOP by Goldmann applanation tonometry, corneal pachymetry, 24-2 Humphrey perimetry, spectral-domain OCT of optic disc and macula, fundus autofluorescence, anterior segment OCT, and stereo-disc/fundus photography. Examiners and clinicians are blinded to PRS results. Glaucoma classification follows PROGRESSA study definitions (normal, suspect, OAG, non-OAG). AMD classification follows standard stages (none, early, intermediate, late). Primary outcome is prevalence of glaucoma and AMD across PRS deciles. Secondary outcomes include sensitivity/specificity, predictive values, comparison with family history, comorbidity, treatment intensity, and disease severity. Power calculations: for glaucoma, assuming ~10% prevalence in top decile vs ~3% in bottom decile (including suspects ~30% vs 9%), sample size yields >95% power (α=0.05). For AMD, based on published data (22.7% top decile vs 0.7% bottom decile in those >75 years), >80% power is expected. Statistical analyses use logistic/linear regression with age, genetic sex, and ancestry as covariates.
**Key Results:** This is a protocol paper; no results are reported. The study is ongoing. Expected findings include higher prevalence of glaucoma and AMD in the high PRS group compared to middle and low groups, supporting clinical validity.
**Clinical Implications:** If positive, the study would provide evidence for implementing PRS as a screening tool to identify high-risk individuals for closer monitoring and earlier intervention. This could reduce vision loss from these common conditions. The study also addresses barriers to implementation, including cost-effectiveness, communication of results, and applicability across ethnicities. Current PRS are based on European populations; the study includes non-European individuals but acknowledges reduced accuracy. Future work will need to develop pan-ancestry scores and health economic frameworks.