The Role of Genetic and Non-Genetic Factors and Causal Mechanisms Underlying Cataract Susceptibility For Risk Prediction

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Abstract Age-related cataract, defined as ocular lens opacity, is a leading cause of blindness worldwide. Cataract is also associated with injurious falls and increased mortality and is a significant public health problem in the U.S., accounting for approximately 60% of Medicare costs related to vision. Given the aging U.S. population, cataract surgery demand is expected to double over the next 25 years. Thus, it is important to understand the etiology of cataract to identify at-risk patients and develop effective prevention strategies. Recently, we conducted a large- scale multiethnic genome-wide association study (GWAS) meta-analysis of cataract that has identified 55 genetic loci, including 38 novel loci, that underlie the risk of cataract. Majority of the genes in these loci were independently supported as promising candidates for cataract by the database iSyTE (integrated Systems Tool for Eye gene discovery), based on their significant expression in the lens. While these data uncovered potential new causal genes in the identified loci, their function in the lens is not defined and their role underlying cataract risk remains largely unknown. Further, whether cataract-loci regulate genes and how regulation differs across tissues has not yet been explored. Our study also identified strong genetic correlations between cataract and several disorders/traits, including, glaucoma, myopia, cigarettes smoking, and BMI, supporting previous observational studies. However, it is not clear that these associations are causal. Finally, no predictive tool exists for evaluating individuals at-risk for cataract. The overall objective of this proposal is to understand the role of genetic and non-genetic factors and causal mechanisms underlying the etiology of cataract and develop a prediction tool to facilitate risk-stratified screening for cataract. By leveraging a rich multiethnic cohort, with both genome-wide genotype data and extensive clinical data collected through electronic health records, and using whole-exome sequencing (WES) data of UK Biobank participants, we will accomplish the following specific aims: 1.a) Identify novel genetic predictors of cataract risk using high quality WES data and transcriptome-wide association study (TWAS) approach; 1.b) Evaluate whether glaucoma, myopic refractive error, diabetes, high blood pressure, high BMI, cigarette smoking, or alcohol consumption and other clinical and behavioral factors are causal risk factors of cataract using a Mendelian randomization approach; 2) Develop risk prediction models of cataract risk by integrating polygenic risk scores along with other risk factors; and 3) Determine the function – in the lens using animal models – of novel candidate genes prioritized in cataract-associated loci. This proposed research is significant because it will fill an important gap in cataract genetics and will provide important mechanistic insights into the pathogenesis of cataract. The project is innovative in the development of prediction models of cataract risk based on genetic and non-genetic risk factors as well as the development of novel animal models of cataract. The long-term goal of this research is to advance cataract etiology knowledge for effective interventions and non-surgical therapeutics for its prevention, delay or treatment.