The genetics of age-related macular degeneration: exploring pathway and epistatic effects

Abstract

Age-related macular degeneration (AMD) is a neurodegenerative disease that leads to a loss of central vision and is the leading cause of blindness in the elderly in developed countries. AMD can significantly reduce quality of life and there is no way to cure or prevent the disease. The prevalence of AMD is expected to increase worldwide as lifespans increase. Of the two subtypes of AMD — geographic atrophy and neovascular AMD — only the neovascular form has treatment options, yet treatment does not reverse vision loss and is required for the life of a patient. AMD is known to be highly heritable (45-70%) but previous genetic studies only explain a portion of the heritability. In this work we perform genetic pathway analyses of AMD to localize additional heritability and develop novel methods to test for cumulative epistatic (interaction) effects potentially influencing risk for AMD. We show that genetic variation in complement activation-related genes, excluding previously associated risk variants, contributes to a statistically significant proportion of risk for AMD (9.7%). Additionally, we develop methods to calculate orthogonal genetic relationship matrices to estimate additive, dominant, and epistatic genetic effects. We applied this method to test for interactions between the ARMS2 gene and three AMD-related pathways and were able to conclusively rule out epistatic effects influencing risk for AMD from the specific interactions that were tested.