The role of age-related macular degeneration associated variants in drusen progression

Abstract

 

Purpose

 

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 impacts the disease’s rate of progression. In this analysis we performed a quantitative analysis of drusen progression during the intermediate stage of the disease to understand the influence of AMD genetic variation on this phenotype.

 

Methods

 

Color fundus photographs deposited by the Age-related Eye Diseases Study (AREDS) to the database of Genotypes and Phenotypes (dbGAP) were retrieved on subjects that showed absence of geographic atrophy (GA) and choroidal neovascularization (CNV) and a baseline diagnosis of intermediate to large drusen. Automated drusen detection and quantification was carried out on all subject eyes and visits that met these criteria using a previously developed algorithm. Drusen progression was tested against 19 previously identified genetic variants using both a cumulative genetic risk score and single variant analyses. Pathway analysis using results from a genome-wide quantitative association analysis of progression rates was carried out using Pathway Analysis by Randomization Incorporating Structure (PARIS).

 

Results

 

In the 246 subjects AREDS subjects that met our selection criteria we observe significant correlation in bilateral drusen progression (rho = 0.30, p-value = 0.004). We do not observe significant correlation between the 19-variant cumulative genetic risk score and drusen progression (rho = 0.039; p = 0.543). We do not observe a significant association with rs10490924 in ARMS2 (p = 0.161), rs10737680 in CFH (p = 0.156), rs116503776 in C2/CFB (p = 0.713), or rs2230199 in C3 (p = 0.728). Single marker tests of the remaining 15 variants show 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).

 

Conclusions

 

In this analysis we attempt to isolate the role of known AMD genetic variation to one aspect of this phenotypically heterogeneous disease. The 19 common variants examined cumulatively and individually do not associate with progression in our dataset, although pathway analysis suggests unidentified loci may be important for drusen progression.