PROJECT SUMMARY Glaucoma is a leading cause of blindness world-wide. In particular, primary angle-closure glaucoma (PACG) and primary open angle glaucoma (POAG) cause significant ocular morbidity in India and the United States. The genetic architecture of common forms of glaucoma (such as PACG and POAG) includes multiple genes and complex interactions that make gene discovery efforts challenging. The consideration of individual disease-related quantitative traits, or endophenotypes, is one approach that can successfully identify genetic risk factors influencing complex disorders. Genome-wide association studies (GWAS) have identified common variants associated with several glaucoma-related quantitative traits, however genetic linkage and genome- wide sequencing to identify rare or low frequency variants, which are also likely to contribute to these traits, has not yet been investigated. Our collaborative group of investigators have completed a pilot study funded by NIH/DBT under the US-INDO research agreement to assess the feasibility of using consanguineous pedigrees to identify loci for ocular quantitative traits related to common complex disorders such as glaucoma. Using these families we completed a genome-wide linkage analysis and identified 8 novel loci for 6 ocular traits. The overall goal of this proposal is to use whole genome sequencing to identify genes within the novel linkage regions that are driving the quantitative trait variation and assess the contributions of these genes to glaucoma. We propose the following specific aims: 1) Expand and curate the quantitative trait database using consanguineous pedigrees; 2) Comprehensively identify genetic variants in consanguineous pedigrees using whole genome sequencing (WGS); 3) Discover DNA variants contributing to ocular quantitative trait loci; and 4) Using the quantitative trait data complete a phenome-wide association study (PheWAS) for known glaucoma genes to identify specific gene-quantitative trait relationships that may define glaucoma subphenotypes more responsive to specific therapeutic approaches. This proposed research is significant because it will be the first study to identify rare variants contributing to ocular quantitative traits related to glaucoma. The project is innovative in using large consanguineous pedigrees for quantitative trait mapping and whole genome sequencing to identify variants responsible for the quantitative trait variation in these pedigrees. We also propose the first-ever PheWAS to assess the relationships between quantitative traits and known glaucoma genes, providing the deep phenotyping required for a `precision-medicine approach' for glaucoma by selecting gene-based treatment strategies directed toward a specific quantitative trait.