Modeling Macular Degeneration Using Quantitative Phenotypes

Abstract

Age-related macular degeneration (AMD) is one of the most common causes of visual impairment in the United States (US). Although a multitude of studies have shown that both genetic and environmental factors contribute to the pathogenesis of AMD, little is known on how genetics affects the disease’s rate of progression. We performed a quantitative genetic analysis of drusen progression during the intermediate stage of the disease to understand the role of known AMD genetic variation to this phenotype. Drusen progression was tested against 19 previously identified genetic variants using a cumulative genetic risk score, single variant analyses, and a pathway analysis. We do not observe significant correlation between the 19 variant cumulative genetic risk score and drusen progression (rho = 0.039; p = 0.543). Single marker tests of the remaining 15 variants shows a nominally significant association with rs943080 in VEGFA (p = 0.028). The most highly associated pathway in our pathway analysis is the cell adhesion molecule pathway (p < 0.0001). To understand the contribution of rare-genetic variation to AMD, we performed exome sequencing in five members of a small nuclear Amish family who lack the common risk alleles at the major AMD risk loci. We identified a variant (P503A) in CFH that is not present in dbSNP or 1000Genomes and is associated with AMD in an Ohio and Indiana cohort (p = 9.27x10-13).