Project Summary: Although there are numerous genetic variants associated with age-related degeneration (AMD), a meaningful fraction of missing heritability has yet to be exlained. Many studies have focused on identifying the common variants contributing to this disease in the general population. One aim of this project is to discover rare, highly penetrant genetic variants contributing to familial forms of AMD. The AMD Registry and Biorepository is a large cohort with unique characteristics that include standardized clinical phenotype data and longitudinal prospective data. Some families from this cohort have multiple members with advanced AMD that cannot be explained by known AMD-associated genetic variants and will be sequenced using next-generation sequencing to discover novel variants. Variants found to perfectly segregate with the disease in these families will be assessed for association with AMD in an independent case-control cohort. To discover additional genetic variants contributing to the missing heritability, a second aim is to assess known and novel genetic variants for their role in progression of AMD over time, particularly the effect each variant has on the initiation of the disease and the transition to early, intermediate, and advanced stages. To further the understanding of AMD as a complex trait, quantitative and semi-quantitative intermediate sub-phenotypes will be assessed for association with these genetic variants. Results from this study will fill gaps in our knowledge about the genetics of AMD. We will use these discoveries to develop improved predictive models for AMD progression, and our results may lead to more accurate diagnoses and better therapeutic targets. The ultimate goal is to prevent or slow the progression of AMD and reduce the burden of visual loss due to this disease.