Primary open-angle glaucoma (POAG) is an intraocular pressure (IOP) related progressive optic neuropathy that ultimately leads to blindness. Permanent visual field loss from POAG is a condition of public health significance worldwide. The etiology of POAG is poorly understood and primary prevention is not possible. Current treatments can slow but do not cure this progressive neuropathy. The overall goal of our research is to elucidate the pathogenesis of primary open-angle glaucoma (POAG) making it possible to implement effective screening and prevention strategies and to develop novel therapies. POAG has significant heritability and recent genome-wide association studies, including our NEIGHBOR/GLAUGEN meta-analysis, have identified POAG-related genes. However, to comprehensively define the POAG complex genetic architecture large datasets with well-defined phenotypes are required. To achieve the sample size necessary for POAG gene discovery we formed the NEIGHBORHOOD consortium (NEIGHBOR Heritable Overall Operational Database) that includes harmonized genotype and phenotype data for 3,873 cases and 33,642 controls. During the prior funding period we have 1) developed infrastructure for the NEIGHBORHOOD consortium; 2) conducted analyses using the NEIGHBORHOOD data including: GWAS for POAG and the normal-tension subgroup (NTG), gene-phenotype studies, endophenotype genetic association studies, pathway analyses and functional assessment of rare coding variants in associated genes. The immediate goals of this competing renewal are: 1) Add new datasets that contribute cases and controls with clinical features of particular relevance and interest; 2) perform genetic analyses to identify new genes/genomic regions contributing to POAG and related subgroups and also to assess gene- gene interactions and molecular pathway contributions; 3) Explore gene-phenotype relationships for novel genes discovered through recent GWAS; and 4) continue to support the consortium resources and logistics. Additionally, this proposal will provide resources supporting studies investigating gene-environment interactions and molecular studies defining disease mechanisms relevant to POAG and NTG. Ultimately this information will form the basis of novel, and ideally neuro-protective, therapies.