Associations Between Structural Phenotype and Polygenic Risk Scores in Intermediate Age-Related Macular Degeneration – A MACUSTAR Report

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Purpose: The purpose of this study was to analyze genotype-phenotype associations in intermediate age-related macular degeneration (iAMD) based on global and pathway-specific polygenic risk scores (psPRS) in participants of the prospective European multicenter cohort study MACUSTAR. Methods: Assessed structural biomarkers included reticular pseudodrusen (RPD), pigmentary abnormalities, hyper-reflective foci (HRF), and incomplete or complete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA and cRORA). Blood samples were genotyped and imputed via a local pipeline. Global and pathway-specific PRS (complement PRS [C-PRS], with and without ARMS2/HTRA1 variants [C+AH-PRS and AH-PRS]; extracellular matrix PRS [E-PRS]; and lipid PRS [L-PRS]) were calculated. The associations between global and pathway-specific PRS and structural iAMD biomarkers were assessed with multivariable models, controlling for age and sex. Results: In total, 404 participants (263 women, 65.1%; mean age = 71.5 ± 7.0 years, mean ± standard deviation [SD]) were included in the analysis. Multivariable regression models revealed that RPD was associated with a higher AH-PRS (estimate = 7.11 × 10-2, P = 9.0 × 10-3), C+AH-PRS (estimate = 9.96 × 10-2, P = 5.0 × 10-3), and E-PRS (estimate = 3.28 × 10-2, P = 3.1 × 10-2). The presence of cRORA was associated with a higher AH-PRS (estimate = 1.34 × 10-1, P = 2 × 10-3) and a higher C+AH-PRS (estimate = 1.59 × 10-1, P = 6 × 10-3). Conclusions: Structural risk biomarkers are associated with psPRS in iAMD. These findings further underscore the heterogeneity of pathogenic pathways in AMD and indicate differential risk characteristics across the broad spectrum of iAMD. Translational Relevance: Our findings reveal subgroups in iAMD based on genotype-phenotype associations which can help identifying patients at high risk for iAMD and establish new endpoints for clinical trials in iAMD.

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