Associations between structural phenotype and pathway-specific polygenic risk scores in intermediate age-related macular degeneration – a MACUSTAR report

Abstract

Purpose : To analyze genotype-phenotype associations in intermediate age-related macular degeneration (iAMD) based on pathway-specific polygenic risk scores (PRS) in participants of the prospective European multicenter cohort study MACUSTAR.

Methods : MACUSTAR study participants with iAMD underwent examinations with a standardized battery of imaging modalities across 20 study sites. Blood samples were obtained from a subset of participants who gave consent. All images were graded by a central reading center (GRADE) for structural biomarkers, including reticular pseudodrusen (RPD), pigmentary abnormalities (PA), and incomplete or complete retinal pigment epithelium and outer retinal atrophy (iRORA, cRORA) of the study eye. Blood samples were genotyped with the Illumina Infinium GSA Array and imputed via a local pipeline comparable to the Michigan Imputation Server. Pathway-specific PRS (complement-specific, C-PRS; extracellular matrix-specific, E-PRS; lipid-specific, L-PRS) were calculated based on AMD risk variants identified in previous research, with higher PRS indicating higher polygenetic risk. The associations between pathway-specific PRS and structural iAMD biomarkers were assessed with multivariable models, controlling for age and sex.

Results : Baseline data from the cross-sectional part of the MACUSTAR study of 442 participants (291 female, 65.8%; mean age 72±7 years) were included in the analysis. 26.5%, 49.5%, 10.2%, and 8.4% of participants had RPD, PA, iRORA, and cRORA, respectively. The presence of RPD was associated with a higher C-PRS (p≤0.002), higher E-PRS (p=0.046), and a lower L-PRS (p=0.023). The presence of iRORA was associated with a higher E-PRS (p=0.026) and cRORA was associated with a higher C-PRS (p≤0.004), while PA was not associated with pathway-specific PRS.

Conclusions : Structural risk biomarkers of progression are significantly associated with pathway-specific PRS in iAMD. These findings further underscore the heterogeneity of pathogenic AMD pathways and indicate differential risk characteristics across the broad spectrum of iAMD. Longitudinal analyses on the impact of these findings on the risk of progression to late AMD are ongoing.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.