Genetics of Quantitative Traits Associated with Glaucoma

描述（由申请人提供）：青光眼是失明和视力残疾的主要原因，对数百万美国人的生活质量和生产力产生重大影响。青光眼由包括视神经杯状、视野丧失和中央角膜厚度的数量特征定义。眼内压是青光眼患者中监测的另一个重要的定量特征。导致青光眼的级联事件并不为人所知，这阻碍了早期检测和治疗这种疾病的努力。研究青光眼发病机制的一种方法是鉴定致病基因。青光眼是一种异质性疾病，可能是由许多基因的相互作用引起的。这种复杂性挑战了鉴定导致青光眼的基因的努力。因此，迫切需要以降低复杂性为重点的青光眼表型研究，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中的DNA变异导致青光眼视力丧失的途径。随着青光眼发病机制阶段的发现，预防视力丧失的新干预措施将成为可能。青光眼表型的几个定量特征（杯盘比、角膜厚度和眼内压）各自独立地与青光眼相关并且是高度遗传的。我们假设，决定青光眼这些特征的大小的相同基因在青光眼的发病机制中也是重要的。此外，青光眼的单一特征比整个疾病的复杂性要低。这种降低的复杂性将有助于发现青光眼表型组分的遗传因素。控制青光眼数量性状的基因将通过对人类群体和近交系小鼠的研究来确定。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中的患者进行全基因组关联研究，确定控制杯盘比、眼内压和角膜厚度大小的遗传因素（具体目标1）。数量性状往往是由许多遗传因素的作用决定的。对具有固定遗传背景的近交系小鼠的研究具有减少这些特征的复杂性的优点。通过杂交近交系，决定数量性状的特定风险等位基因可能更容易在统一的遗传背景下识别。因此，我们将研究青光眼的一个重要的定量特征（中央角膜厚度）与近交系小鼠杂交的遗传基础（特定目标2）。我们希望我们提出的研究将确定新的风险等位基因青光眼的定量特征。这些风险等位基因的发现将通过促进早期诊断和使新的挽救视力的治疗方法的开发对青光眼的未来临床管理产生重要影响。公共卫生相关性：虽然青光眼是影响数百万美国人的遗传性失明原因，但对导致这种情况的遗传风险因素知之甚少。我们提出的实验，将确定基因的控制组件功能的整体青光眼表型。这些发现将提供对导致疾病的生物学途径的深入了解，也将有助于改善诊断，预后和治疗这种使人衰弱的疾病。

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. PUBLIC HEALTH RELEVANCE: Although glaucoma is a heritable cause of blindness that affects millions of Americans, little is known about the genetic risk factors that contribute to this condition. We propose experiments that will identify genes that control component features of the overall glaucoma phenotype. These discoveries will provide insight into the biological pathways that lead to disease and will also facilitate improved diagnosis, prognosis, and treatments for those with this debilitating condition.