Genetic Epidemiology of Ocular Health and Disease

描述（由申请人提供）：视力障碍（VI），定义为失明或低视力，是一个主要的公共卫生问题。世界上约有10%的人口（约7.33亿人）视力受损，其中约6.6亿人居住在发展中国家。世界上一半以上的视力受损者年龄较大（大约50岁）。VI的全球经济负担估计达到惊人的2.95万亿美元，在个人层面，VI对独立性产生负面影响，降低生活质量，增加抑郁症和死亡率。VI的两个主要原因，未矫正的屈光不正和白内障，受遗传机制的影响很大，在发展中国家非常普遍。该项目旨在确定影响尼泊尔东部（一个发展中国家）多拉卡地区一个大型扩展谱系的吉雷尔人眼部生物计量和VI指标的罕见功能变异。在过去28年中，对吉雷尔族进行了广泛的遗传研究，为进一步的遗传研究提供了坚实的框架。这种地理上和文化上孤立的种群具有最小的近亲繁殖，为识别影响眼生物学的罕见功能变异提供了强大的资源。实现我们的

DESCRIPTION (provided by applicant): 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.