Associations Between Structural Phenotype and Polygenic Risk Scores in Intermediate Age-Related Macular Degeneration...

Area of Science:

• Ophthalmology
• Genetics
• Biomarkers

Background:

• Intermediate age-related macular degeneration (iAMD) is a complex condition with varying clinical presentations.
• Understanding the genetic underpinnings of iAMD is crucial for identifying disease subtypes and progression risks.

Purpose of the Study:

• To investigate genotype-phenotype associations in iAMD using global and pathway-specific polygenic risk scores (psPRS).
• To analyze these associations in participants of the prospective European multicenter cohort study MACUSTAR.

Main Methods:

• Assessed structural biomarkers: reticular pseudodrusen (RPD), pigmentary abnormalities, hyper-reflective foci (HRF), and retinal pigment epithelium/outer retinal atrophy (iRORA/cRORA).
• Calculated global and pathway-specific PRS (complement PRS [C-PRS], C-PRS without ARMS2/HTRA1 [C+AH-PRS and AH-PRS], extracellular matrix PRS [E-PRS], and lipid PRS [L-PRS]).
• Utilized multivariable regression models to assess PRS associations with structural iAMD biomarkers, controlling for age and sex.

Main Results:

• RPD was significantly associated with higher AH-PRS, C+AH-PRS, and E-PRS.
• cRORA was significantly associated with higher AH-PRS and C+AH-PRS.
• These associations suggest differential risk characteristics across the iAMD spectrum.

Conclusions:

• Structural risk biomarkers in iAMD are associated with psPRS.
• Findings underscore the heterogeneity of pathogenic pathways in AMD.
• Identified patient subgroups based on genotype-phenotype associations can aid in risk stratification and clinical trial endpoint development.