Genetics of Quantitative Traits Associated with Glaucoma

描述（由申请人提供）：青光眼是失明和视力障碍的主要原因，对数百万美国人的生活质量和生产力产生重大影响。青光眼是由数量特征定义的，包括视神经拔火罐、视野丧失和中央角膜厚度。眼压是青光眼患者监测的另一个重要的定量特征。导致青光眼的一系列事件尚不清楚，这阻碍了早期发现和治疗青光眼的努力。研究青光眼发病机制的方法之一是确定致病基因。青光眼是一种异质性疾病，可能是由多种基因相互作用引起的。这种复杂性给鉴定导致青光眼的基因带来了挑战。因此，迫切需要研究复杂性较低的青光眼表型，以促进致病基因的发现。我们的长期目标是确定和定义从基因组DNA变异到青光眼视力丧失的途径。随着青光眼发病阶段的发现，新的预防视力丧失的干预措施将成为可能。青光眼表型的几个定量特征（杯盘比、角膜厚度和眼压）都与青光眼独立相关，且具有高度遗传性。我们假设，决定青光眼这些特征大小的相同基因在青光眼的整体发病机制中也很重要。此外，青光眼的单个特征比整个疾病的复杂性要小。这种降低的复杂性将有助于发现青光眼表型组成部分的遗传因素。控制青光眼数量性状的基因将通过对人类群体和近交小鼠的研究来确定。高眼压治疗研究（OHTS）是一项大型治疗试验，旨在显示治疗高眼压患者的疗效。我们将通过对本试验患者进行全基因组关联研究，确定控制杯盘比、眼压和角膜厚度大小的遗传因素（Specific Aim 1）。数量性状通常是由许多遗传因素的作用决定的。研究具有固定遗传背景的近交系小鼠具有降低这些性状复杂性的优势。通过杂交自交系，在统一的遗传背景下更容易识别决定数量性状的特定风险等位基因。因此，我们将通过近交系小鼠的杂交研究青光眼的一个重要定量特征（角膜中央厚度）的遗传基础（Specific Aim 2）。我们期望我们提出的研究将确定青光眼定量特征的新的风险等位基因。这些风险等位基因的发现将通过促进青光眼的早期诊断和开发新的视力保护治疗方法，对未来青光眼的临床管理产生重要影响。

DESCRIPTION (provided by applicant): Glaucoma is a leading cause of blindness and visual disability that has a major impact on the quality of life and productivity of millions of Americans. Glaucoma is defined by quantitative traits including, optic nerve cupping, visual field loss, and central corneal thickness. Intraocular pressure is another crucial quantitative trait that is monitored in glaucoma patients. The cascade of events that lead to glaucoma is not well known, which has hindered efforts for early detection and treatment of this condition. One way to investigate the pathogenesis of glaucoma is to identify disease-causing genes. Glaucoma is a heterogeneous disease and is likely caused by the interactions of many genes. This complexity has challenged efforts to identify genes that cause glaucoma. As a result, there is a critical need for research that focuses on glaucoma phenotypes with reduced complexity to facilitate the discovery of disease-causing genes. Our long-term goal is to identify and define pathways that lead from DNA variations in the genome to the vision loss of glaucoma. As stages of glaucoma pathogenesis are discovered, new interventions to prevent vision loss will become possible. Several quantitative features of the glaucoma phenotype (cup-to-disc ratio, corneal thickness, and intraocular pressure) are each independently associated with glaucoma and highly heritable. We hypothesize that the same genes that determine the magnitudes of these features of glaucoma will also be important in the pathogenesis of glaucoma overall. Furthermore, a single feature of glaucoma has less complexity than the whole disease. This reduced complexity will facilitate discovery of genetic factors for components of the glaucoma phenotype. Genes that control quantitative traits of glaucoma will be identified with studies of human cohorts and inbred mice. The Ocular Hypertension Treatment Study (OHTS) is a large treatment trial designed to show the efficacy of treating patients with high intraocular pressure. We will identify genetic factors that control the magnitude of cup-to-disc ratio, intraocular pressure, and corneal thickness by conducting a genome-wide association study of the patients in this trial (Specific Aim 1). Quantitative traits are often determined by the actions of many genetic factors. Studies of inbred mice with fixed genetic backgrounds have the advantage of reducing the complexity of these traits. By crossing inbred strains, specific risk alleles that determine a quantitative trait may be more easily recognized against the uniform genetic background. Therefore, we will study the genetic basis of an important quantitative feature of glaucoma (central corneal thickness) with crosses of inbred mice (Specific Aim 2). We expect that our proposed studies will identify new risk alleles for quantitative features of glaucoma. The discovery of such risk alleles will have an important impact on the future clinical management of glaucoma by facilitating early diagnosis and enabling the development of new sight- saving treatments.