Genetics of central serous chorioretinopathy and choroidal thickening - PROJECT SUMMARY Overview: This resubmission describes a 4-year training program in statistical genetics through the study of genetics of central serous chorioretinopathy (CSC) and choroidal vasculature. Background: CSC is a disease of the choroid and retina seen commonly by retina specialists, and it causes progressive vision loss. Patients tend to have a thick and dilated choroid. Evidence suggests that both CSC and choroidal thickness are heritable, but only a handful of loci have been reported. Discovery of new genetic associations for CSC can reveal underappreciated pathophysiologic mechanisms. CSC shares some genetic overlap with age-related macular degeneration (AMD), and a better understanding of CSC and choroidal vasculature genetics is needed. This K23 proposal seeks to identify common genetic variation associated to CSC and choroidal thickness and to investigate how this variation overlaps with known genetic associations to AMD. Training: The proposal is designed to provide foundational training in statistical genetics and automated optical coherence tomography (OCT) image analysis for the PI, Dr. Elizabeth Rossin, who will learn these skills from mentors, collaborators, seminars and training sessions. This training will cover techniques of data assembly and quality control of biobank data, the approach to genome-wide association study and meta- analysis, and skills of patient recruitment and prospective genotyping for the clinician-scientist. It will foster experience in the use of existing OCT and genetic data to develop skills in the application of machine learning to choroidal measurements on OCT and additional statistical genetics skills for quantitative trait analyses. Finally, the PI will learn genetic correlation analysis, an area of genetics that is becoming increasingly important to understand shared biological mechanisms in disease, here applied to CSC and AMD. Research: Aim 1 proposes to perform a CSC genome-wide association study (GWAS) meta-analysis across biobanks and available data and to replicate findings in a deeply phenotyped cohort of prospectively recruited patients. Aim 2 proposes to measure a hallmark of CSC – choroidal thickness – on OCT and to perform quantitative trait GWAS meta-analyses. Finally, Aim 3 investigates the overlap of CSC and AMD genetics using modern statistical approaches including LD-score regression and colocalization. This proposed research seeks to identify novel loci for CSC and choroidal thickness and to link this to AMD, which can point to critical pathways in macular disease. Summary: Through this K23 mentored training, the PI intends to develop skills that are applicable broadly to a career in patient-oriented retinal genetics research.
