February 16, 2018 – Genome-wide Analysis of Disease Progression in Age-related Macular Degeneration
Family- and population-based genetic studies have successfully identified multiple disease-susceptibility loci for Age-related Macular Degeneration (AMD), one of the first batch and most successful examples of genome-wide association study (GWAS). However, most genetic studies to date have focused on case-control studies of late AMD (choroidal neovascularization [CNV] or geographic atrophy [GA]). The genetic influences on disease progression are largely unexplored. We assembled unique resources to perform a genome-wide bivariate time-to-event analysis to test for association of time-to-late-AMD with ∼9 million variants on 2,721 Caucasians from a large multi-center randomized clinical trial, the Age-Related Eye Disease Study. To our knowledge, this is the first GWAS study of disease progression (bivariate survival outcome) in AMD genetic studies, thus providing novel insights to AMD genetics. We used a robust Cox proportional hazards model to appropriately account for between-eye correlation when analyzing the progression time in the two eyes of each participant. We identified four previously-reported susceptibility loci showing genome-wide significant association with AMD progression: ARMS2-HTRA1 (P=8.1 × 10-43), CFH (P=3.5 × 10-37), C2-CFB-SKIV2L (P=8.1 × 10-10), and C3 (P=1.2 × 10-9). Furthermore, we detected association of rs58978565 near TNR (P=2.3 × 10-8), rs28368872 near ATF7IP2 (P=2.9 × 10-8) and rs142450006 near MMP9 (P=0.0006) with progression to CNV but not GA. Secondary analysis limited to 34 reported risk variants revealed that LIPC and CTRB2-CTRB1 were also associated with AMD progression (P<0.0015). Our genome-wide analysis thus expands the genetics in both development and progression of AMD and should assist in early identification of high risk individuals.