Exfoliation syndrome (XFS) is a common systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates and that is associated with glaucoma (XFG), pre-mature cataract formation, and complications during cataract surgery as well as several systemic conditions. Our goal is to elucidate the pathogenesis of exfoliation syndrome (XFS) and the associated glaucoma (XFG), which will facilitate effective screening and prevention strategies and the development of novel therapies. Aggregated LOXL1 is one component of the pathogenic fibrillar aggregates, and LOXL1 is a major genetic risk factor for XFS/XFG, with LOXL1 risk variants occurring in up to 98% of patients. However, XFS/XFG is genetically complex, and these same common risk variants are also present in many unaffected individuals, indicating that additional genetic and/or environmental factors are necessary for disease development. During the previous funding period we have made significant progress defining environmental exposures influencing XFS/XFG risk including time spent outdoors, residential latitude, UV light exposure, heavy coffee consumption and low folate intake. In collaboration with our international consortium, we have identified new genetic factors influencing risk including protective LOXL1 variants. We have also completed a metabolomics study using pre-diagnostic samples from the longitudinal Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS) that identified 2 plasma metabolites classes (lysophosphatidylcholines and phosphatidylethanolamine plasmalogens), measured as much as a decade before disease onset, associated with increased XFS/XFG risk, and the individual metabolite cortisone and the metabolite classes of steroids and triglycerides inversely associated with risk. For the next funding period, we will build on these results using data from the NHS, NHS2 and HPFS, Mass Eye and Ear clinical case control set, and UK Biobank, to further define the complex set of risk factors contributing to this important blinding disease. We propose the following specific aims: 1) Investigate associations between steroids, lipid metabolites, environmental factors and XFS/XFG risk; 2) Investigate the contributions of rare/low frequency LOXL1 variants to XFS/XFG risk and 3) Evaluate integrated metabolomic and genomic effects on XFS/XFG risk. This unique study with comprehensive prospective environmental, genetic and metabolomic data and a multi-disciplinary team (expertise in genetics, metabolomics, epidemiology) will cost-efficiently address a significant cause of ocular morbidity. The findings will be directly relevant for clinical and public health practice.