Age-related macular degeneration (AMD) is a complex disease in which multiple genetic and environmental components influence the clinical phenotype. The condition is now the major cause of legal blindness in older people in the USA. Understanding the complete genetic epidemiology will enable the development of new therapies and preventive strategies. Several common genetic variants associated with AMD have been identified. We hypothesize that the remaining etiology is explained by a number of individually less common, but functionally significant genetic variants. This project is the beginning of a new and exciting collaboration between the Macular Degeneration Center at the Casey Eye Institute/Oregon Health and Science University and the Department of Genetics to accomplish at the Southwest Foundation for Biomedical Research. Novel AMD-susceptibility genes will be identified by using a powerful joint genome-wide linkage and association strategy in our pre-existing collection of 150 pedigrees enriched for their susceptibility to AMD. We will increase the likelihood of identifying susceptibility-related genetic variation by careful quantification of the phenotype using stored retinal images to identify biological characteristics more closely related to the action of genes. Genes showing the best evidence for each AMD-related phenotype following high-density SNP-array genotyping will be replicated in unrelated AMD cases and controls. Whole Exome Next Generation sequencing will also be undertaken to identify rare or potentially private mutations present in the families. Bayesian QTN and bioinformatics analysis will be used to predict functional variants. PUBLIC HEALTH RELEVANCE: Macular degeneration is a common complex disease that results from the interplay of genes and environmental factors. The objective of this application is to resolve existing and identify novel AMD genetic susceptibility variants using a powerful joint linkage and association strategy in our pre-existing collection of extended pedigrees with the condition. Genotyping will employ SNP-array and Next Generation Whole Exome sequencing techniques.