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）是视力受损者，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（> 50岁）。据估计，VI造成的全球经济负担高达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，并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，受到遗传机制的显著影响，在发展中国家非常普遍。该项目旨在确定影响尼泊尔东部Dolakha区Jirel人（发展中国家）的大型扩展谱系中的眼部生物统计学和VI指标的罕见功能变体。在过去28年中，对吉热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。这种在地理和文化上隔离的人群具有最小的近亲繁殖，为鉴定影响眼部生物学的罕见功能变体提供了强大的资源。实现我们 为了发现影响正常和疾病状态眼部生物学的罕见功能变异，我们将（1）招募2，000名Jirel家系成员进行眼部检查，以确定眼部生物学的分布和患病率以及导致VI的因素，（2）确定遗传贡献（3）定位最有可能携带眼部候选基因的基因组区域（QTL），（4）利用外显子组测序策略来客观地优先考虑罕见的功能变体， 这些眼部QTL，和（5）在来自尼泊尔巴克塔普尔区的大型独立的、基于人群的队列（n = 2，200）中对我们优先考虑的眼部变体进行复制研究。对于这个项目，现有的全基因组SNP数据集合，结合蛋白质编码变体的新目录和我们广泛的基于家族的研究设计，是识别影响眼部生物学的罕见变体的有力手段。鉴定的变体的复制将为追求深度基因测序策略和/或表征其功能分子特性提供强有力的支持，以进一步阐明其在正常和疾病状态的眼部生物学中的作用。VI目前的（直接和间接）影响只会随着全球人口老龄化的不断增加而增加。该项目将产生关于与眼睛相关的性状的遗传决定因素和具有重大公共卫生意义的眼病的遗传风险的新信息。这些新的见解还可以确定新的或修改现有的可药用靶标，用于治疗和预防眼部疾病。如果我们要大幅减少虚拟化对人类福祉的负面影响，就必须这样做。

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.