7. PROJECT SUMMARY/ABSTRACT This application proposes an innovative and powerful multidimensional approach to discover novel genes and pathways that may serve as therapeutic targets for ocular hypertension (OH). It focuses on a secondary form of OH caused by treatment with glucocorticoids (GCs). GCs are used to treat a wide variety of diseases, including many eye diseases. A drawback however, is that use of GCs in the eye results in a potentially sight threatening increase in intraocular pressure (IOP) in up to half of patients. This is genetically determined, thus, steroid-induced OH (SIOH) can be investigated using genetic approaches that requires no a prior biological knowledge. The pathophysiology of SIOH bears similarities to a much more common form of OH that leads to Primary Open Angle Glaucoma (POAG), but SIOH also has unique features as well. Importantly, SIOH has the advantages of a much shorter observation period and much larger effect sizes than POAG. Therefore, the study of SIOH could make it possible to discover pathways that would not have been revealed any other way. In addition, sensitivity to SIOH is important to study in its own right, as it limits the usefulness of a very effective class of anti-inflammatory drugs and genetic variants discovered might be used predictively to make steroid use safer for patients. In work conducted over a number of years, the multi-PIs have demonstrated the power and effectiveness of their approach for discovery of novel genes and pathways, several of which represent promising new therapeutic targets. Now ready for a full-fledged discovery effort, they have partnered with leaders of a large clinical practice to utilize a unique cohort of demographically homogenous Fuch's endothelial corneal dystrophy (FECD) patients that received corneal transplants, all treated in a highly uniform way with GCs following surgery, with careful pre-surgical characterization and post-surgical IOP follow-up. Thus this cohort is already fully phenotyped. Moreover, many patients have been enrolled in an NIH-funded genetic study of FECD, meaning many DNA samples have already been collected. In the planned study, the maximum change in IOP following GC treatment (ΔIOP) will serve as the quantitative trait, as in previous studies from this team. DNA sequencing will be added to microarray-based genotyping to enhance opportunity for discovery of rare genetic variants. At the same time the research team will continue follow-up, adding new leads as they arise. The proposed Specific Aims are as follows: 1) complete collection of DNA; 2) perform hybrid genomic analysis, combining microarray genotyping with whole genome sequencing; 3) identify genomic variants statistical associated with the quantitative trait; 4) investigate functional significance of the top quantitative trait loci and associated genes. Application of the multidimensional approach outlined here is predicted to have high impact, leading to the advancement of pre...