Macular diseases (MDs) represent a major cause of vision impairment. We can distinguish inherited MDs (iMDs), which are relatively rare and typically result in several decades of vision impairment, and the more prevalent age-related macular degeneration (AMD) that generally affects the elderly. Although great progress has been made in identifying genes and risk factors for these MDs, we still lack knowledge regarding genetic and non-genetic factors that influence the expression of MD, and the etiology has remained unknown for ~2/3 of the clinically less defined MDs after whole exome sequencing. We also discovered that some frequent mild ABCA4 variants, when present together with a severe ABCA4 variant, show a reduced penetrance of Stargardt disease (STGD1) and a gender imbalance, suggesting the existence of non-ABCA4 modifiers. We hypothesize that the missing heritability in MDs can be explained by exploring the genetic continuum between iMD and AMD. Genetic interactions between genes and risk factors may have been underappreciated. The overall objectives of this project therefore are to: 1) Sequence 1,000 iMD cases, 1,000 AMD cases and 1,000 controls for variants in all iMD/AMD-associated genes and risk factors, 2) Re-classify iMD/AMD probands based on genetic data, and 3) Calculate genetic risk scores for all MD probands based on iMD/AMD-associated genetic variants. These studies will significantly increase the diagnostic yield in MD cases which should identify individuals that may be eligible for novel therapies. A better insight into the genetic risk factors where appropriate may aid people to make lifestyle and dietary changes, thereby improving long-term vision prospects. The identification of genetic interactions and modifiers of MDs will increase our knowledge of molecular pathways underlying MDs. The study will bring together an extensive network of clinical collaborators, scientists and patient groups to address this important group of conditions.
