Association between the genetic risk score and extramacular drusen in an age-related macular degeneration cohort - The Coimbra Eye Study

Abstract

Purpose : To evaluate the association between the genetic risk score (GRS) for AMD and the presence of extramacular drusen (EMD) and to explore if EMD share a common genetic basis with AMD.

Methods : For EMD classification, the 3-field 45-degree color fundus photography images were re-evaluated for drusen presence outside the macular grid, and characteristics including size, type, location, and predominance in distribution compared to the macula, were analyzed. GRS for AMD was calculated with 52 single nucleotide polymorphisms identified by the International AMD Genomics Consortium. GRS was compared between groups: 1) AMD without EMD, 2) AMD with EMD, 3) EMD without AMD, and 4) healthy controls. Associations of GRS with EMD and AMD were assessed using generalized estimated equations logistic regression models, adjusting for age and sex.

Results : 1.846 eyes (939 subjects) were included in EMD grading: 902 eyes had no macular drusen or EMD, 570 eyes had EMD without AMD, 252 eyes had EMD and AMD, and 122 eyes had AMD without EMD. Small hard drusen and intermediate soft drusen were the most common EMD, but the percentage of extramacular large soft drusen was higher in those with co-existing AMD compared to those without(60.7% vs 24.0%). For the genetic association analysis, the phenotype-genotype sample comprised 1.612 eyes(829 subjects) – 346 eyes with AMD and 1266 eyes without AMD. The GRS for control eyes was inferior compared to AMD eyes with and without EMD (p=1.4e-07;p=0.0001), and the GRS for eyes with only EMD was also inferior compared with AMD eyes with and without EMD (p= 2.5e-05,p=0.0019). The overlap in GRS distribution between the 4 groups was substantial. There was a strong association between EMD and AMD, with eyes with EMD showing an approximately 3-fold increased risk for AMD compared to eyes without EMD (OR=3.118,95% CI 2.239-4.342,p<0.001). The GRS was associated with AMD (OR=1.444,95% CI 1.248-1.670,p<0.001) but no association with EMD was found, adjusting for coexistence of AMD (OR=1.092,95% CI 0.964-1.235,p=0.16).

Conclusions : There is a relationship between the presence of macular drusen in AMD and EMD, and the presence of one increases the risk of the other, suggesting common pathogenesis. GRS was tailored for genetic AMD risk and a future analysis to assess single variants should be considered.

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