Visual impairment (VI), defined as blindness or low vision, is a major public health concern. Approximately 10% of the world's population (~733 million) is visually impaired and approximately 660 million of these individuals reside in developing countries. More than half of the worlds' visually impaired are of advancing age (> 50 years). The global economic burden of VI is estimated at a staggering US $2.95 trillion and at the individual level VI negatively impacts independence, diminishes quality of life and, increases rates of depression and mortality. Two of the leading causes of VI, uncorrected refractive error and cataract, are significantly influenced by genetic mechanisms and are highly prevalent in developing countries. This project aims to identify rare functional variants influencing ocular biometry and VI metrics in a large extended pedigree, the Jirel people of Dolakha District, eastern Nepal (a developing country). Over the past 28 years extensive genetic research has been conducted in the Jirel ethnic group which provides a solid framework for additional genetic studies. This geographically and culturally isolated population with minimal inbreeding provides a powerful resource to identify rare functional variants influencing ocular biology. To achieve our objective of discovering rare functional variants influencing normal and disease-state ocular biology we will (1) recruit 2,000 members of the Jirel pedigree to undergo an eye examination to identify the distribution and prevalence of ocular biometry and factors contributing to VI, (2) determine the genetic contributions (i.e. heritability and pleiotropy) influencing these ocular trat measures, (3) localize genomic regions (QTLs) most likely to harbor ocular candidate genes, (4) utilize an exome sequencing strategy to objectively prioritize rare functional variants influencing these ocular QTLs, and (5) conduct a replication study of our prioritized ocular variants in a large independent, population-based cohort (n = 2,200) from Bhaktapur District, Nepal. For this project, an existing collection of genome-wide SNP data combined with a novel catalogue of protein coding variants and our extensive family-based study design is a powerful means to identify rare variants influencing ocular biology. Replication of identified variants will lend strng support to pursue deep gene sequencing strategies and/or characterize their functional molecular properties to further elucidate their role in normal and disease-state ocular biology. The current (direct and indirect) impact of VI is only set to increase with the ever increasing, an aging global population. This project will yield novel information on the genetic determinants of eye-related traits and genetic risk for eye diseases of major public health importance. These new insights may also identify novel, or modify existing druggable targets for treatment and prevention of ocular disease. This is required if we are to significantly reduce the negative impact of VI on human well-being.