Abstract
To evaluate the independent and synergistic effects of phenotypic age acceleration (PhenoAgeAccel) and genetic risk on age-related eye diseases (AREDs). We analyzed 395,322 participants from the UK Biobank to assess the association between PhenoAgeAccel and polygenic risk scores for age-related macular degeneration (AMD) and age-related cataract (ARC). Cox proportional hazards models evaluated independent effects and potential synergistic interactions, adjusting for demographic, socioeconomic, and lifestyle factors. PhenoAgeAccel was independently associated with increased risk of AMD (HR = 1.15, 95% CI 1.10-1.21) and ARC (HR = 1.14, 95% CI 1.12-1.17). High genetic risk conferred stronger effects for AMD (HR = 1.88, 95% CI 1.78-1.98) and ARC (HR = 1.31, 95% CI 1.27-1.35). Participants with both elevated PhenoAgeAccel and high genetic risk had markedly higher risk (AMD: HR = 2.19; ARC: HR = 1.47) compared with biologically younger, low-risk individuals. A significant multiplicative interaction was observed for AMD, indicating a synergistic effect between accelerated phenotypic aging and genetic susceptibility. PhenoAgeAccel and genetic risk each contribute to the development of AREDs, and their combination exerts a synergistic effect. Integrating aging biomarkers with genetic profiling could enhance risk stratification and inform targeted prevention strategies for ocular health.