Summary Statement Primary open-angle glaucoma (POAG) represents a pressing public health problem in African Americans. This disease is the leading cause of irreversible blindness in these individuals. POAG affects African Americans more severely at earlier ages, contributing to younger generations with vision loss and adverse health and economic outcomes. Current pressure-lowering treatments for the disease have mixed success, with approximately 30% of patients still experiencing vision loss. POAG is a familial disease and there is a need for large genetic studies that elucidate disease mechanisms. This need is especially pronounced in African Americans, who, despite their increased burden of disease, remain seriously understudied. In its initial funding phase, the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study addressed this disparity by conducting the largest-ever POAG genetics study on African Americans recruited from a single city. For this renewal, we will study genetic data from a genome- wide association study of 7765 subjects and whole-exome sequencing of 8082 subjects, as well as rich phenotypic data on >90% of POAG cases. The proposed renewal will allow us to further investigate and identify variants of biologic importance to African American POAG. The aims of this study are: 1) to conduct post-GWAS analyses on genome-wide significant variants from the POAAGG study to elucidate their role in this disease, 2) to identify additional regions of interest for African American POAG through whole-exome and structural genomics analyses, and 3) to evaluate the functional impact of regions of interest in cellular model systems. Our findings will begin to define relevant biologic pathways for African American POAG, which can potentially provide targets for population screening and precision therapeutics.