Integrative Data Analysis for Refractive Error

描述(申请人提供)：屈光不正是世界上最常见的眼病，其对公众健康和经济的影响是相当大的。治疗美国人群屈光不正的费用是青光眼的两倍，是AMD或糖尿病视网膜病变的10倍，是美国公共卫生系统的主要负担。目前治疗屈光不正的方法并不针对继发性并发症。这些并发症包括脉络膜新生血管、视网膜脱离和青光眼。青光眼是近视的一种并发症，低度近视眼和中高度近视眼的青光眼患病率分别为4.2%和4.4%，而非近视眼的青光眼患病率为1.5%。远视患者患高眼压的几率比正视患者高40%。屈光不正的眼视网膜脱离增加~近视眼视网膜脱离的风险增加4-10倍。最后，脉络膜新生血管的风险从轻度近视的2倍增加到重度近视的9倍。目前的治疗方法不能预防继发于屈光不正的眼部并发症，因为它们的目标不是阻止屈光不正的进展。以前尝试用来控制屈光不正的进展 光学和药物方法取得的成功有限。有广泛的证据表明，远视和近视的重要遗传成分。如果人们能够识别与这些疾病相关的基因，就可以识别意外的疾病机制，开发这些机制的动物模型，并使用这些模型来开发和测试新的治疗方法，确定这些基因与可改变的环境风险因素的相互作用，并在疾病过程中很早就对人们进行治疗，以防止继发性并发症。目前生物医学研究面临的主要挑战之一是发现特定的疾病机制，这些机制是表现出复杂遗传模式的遗传性疾病的基础。这包括复杂的眼部疾病，如屈光不正。一个吸引人的假说是，与其他复杂疾病一样，序列变异在屈光不正中发挥着重要作用。基因技术和生物信息学的进步使进行实验成为可能，这些实验在大量个体中检查数十万个基因变异，并确定它们影响疾病的位置和意义。在这项提案中，我们将扩展我们之前的CREAM工作，以确定影响屈光不正的潜在基因变异。这项工作将利用已经从多个队列中获得的GWAs和外显子组芯片数据来识别导致屈光不正的潜在遗传变异。我们还将扩展我们的分析，以确定我们队列中的基因-环境相互作用，以及确定青光眼和RE基因之间是否有任何潜在的重叠。

DESCRIPTION (provided by applicant): Refractive error is the most common eye disorder in the world, and its public health and economic impact are considerable. Treatment of the U.S population for refractive error costs twice as much as glaucoma and 10x the amount for AMD or diabetic retinopathy and is a major burden to the U.S. public health system. Current treatments for refractive error are not directed at the secondary complications. Such complications include choroidal neovascularization, retinal detachment and glaucoma. Glaucoma is a complication of myopia~ prevalence of glaucoma is 4.2% in eyes with low myopia and 4.4% of eyes with moderate to high myopia compared to 1.5% of eyes without myopia. Individuals with hyperopia are 40% more likely to develop ocular hypertension than those who are emmetropic. Retinal detachment is increased in eyes with refractive error~ risk of retinal detachment is increased 4-10 fold in myopic eyes. Finally, the risk for choroidal neo-vascularization is increased from 2-fold for mild myopia to 9-fold for severe myopia. Current treatments do not prevent the ocular complications secondary to refractive error because they are not targeted at stopping progression of refractive error. Previous attempts to control progression of refractive error with optical and drug approaches have met with limited success. There is extensive evidence for significant heritable components for hyperopia and myopia. If one can identify the genes involved in these disorders, one can identify unsuspected disease mechanisms, develop animal models of these mechanisms and use these models to develop and test new treatments, identify interactions of these genes with modifiable environmental risk factors, and treat people very early in the course of the disease to prevent secondary complications. One of the major challenges now facing biomedical research is the discovery of specific disease mechanisms that underlie heritable disorders that display a complex mode of inheritance. This includes complex eye diseases such as refractive error. An appealing hypothesis is that sequence variations play an important role in refractive error similar to other complex diseases. Advances in genetic technology and bioinformatics have made it possible to perform experiments that examine hundreds of thousands of genetic variants in large numbers of individuals and to determine their location and significance for influencing disease. In this proposal, we will extend our previous CREAM work to identify the underlying genetic variation influencing refractive error. This work will take advantage of already acquired GWAS and exome chip data from multiple cohorts to identify the underlying genetic variants modifying refractive error. We will also extend our analysis to identify gene-environment interactions in our cohorts as well as determine any potential overlap between the glaucoma and RE genes.