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10%的人口(约7.33亿)患有视力障碍，其中约6.6亿人居住在发展中国家。世界上超过一半的视障人士是高龄(50岁)。全球VI的经济负担估计高达惊人的2.95万亿美元，在个人层面上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。导致VI的两个主要原因是未矫正的屈光不正和白内障，它们受到遗传机制的显著影响，在发展中国家非常普遍。该项目旨在确定尼泊尔东部多拉卡地区(一个发展中国家)的一个庞大的系谱--吉雷尔人--中影响眼部生物测量和VI指标的罕见功能变异。在过去的28年里，在吉雷尔族进行了广泛的遗传学研究，这为进一步的遗传学研究提供了坚实的框架。这一地理和文化上隔离的种群与近亲交配最少，为鉴定影响眼生物学的罕见功能变异提供了强大的资源。为了实现我们的目标 目的为了发现影响正常和疾病状态眼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，以确定眼睛生物测量的分布和流行情况以及导致VI的因素，(2)确定影响这些眼睛Trat测量的遗传贡献(即遗传性和多效性)，(3)定位最可能包含眼睛候选基因的基因组区域(QTL)，(4)利用外显子组测序策略客观地优先选择影响眼睛候选基因的罕见功能变异 这些眼部QTL，以及(5)在尼泊尔巴克塔布尔区的一个大型独立、基于人群的队列(n=2,200)中，对我们优先考虑的眼部变异进行了重复研究。对于这个项目，现有的全基因组SNP数据集合，结合新的蛋白质编码变体目录和我们广泛的基于家庭的研究设计，是识别影响眼生物学的罕见变异的有力手段。已识别的突变体的复制将为深入的基因测序策略和/或表征它们的功能分子特性提供支持，以进一步阐明它们在正常和疾病状态眼生物学中的作用。目前VI的影响(直接和间接)只会随着不断增加的全球人口老龄化而增加。该项目将在眼睛相关特征的遗传决定因素和对公共卫生具有重大意义的眼部疾病的遗传风险方面产生新的信息。这些新的见解还可能确定新的或修改现有的治疗和预防眼病的可用药靶点。如果我们要显著减少VI对人类福祉的负面影响，就需要这样做。

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.