Genetics of Quantitative Traits Associated with Glaucoma

描述(申请人提供)：青光眼是导致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有重大影响。青光眼是由数量性状定义的，包括视神经拔罐、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量化指标。导致青光眼的一连串事件并不为人所知，这阻碍了对这种情况的早期发现和治疗。研究青光眼发病机制的一种方法是确定致病基因。青光眼是一种异质性疾病，很可能是由许多基因相互作用引起的。这种复杂性对识别导致青光眼的基因的努力构成了挑战。因此，迫切需要研究降低复杂性的青光眼表型，以促进致病基因的发现。我们的长期目标是识别和定义从基因组DNA变异到青光眼视力丧失的途径。随着青光眼发病机制分期的发现，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、角膜厚度和眼压)都与青光眼独立相关，并具有很高的遗传性。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整个发病机制中也将是重要的。此外，青光眼的一个特征比整个疾病的复杂性要小。这种复杂性的降低将有助于发现青光眼表型成分的遗传因素。控制青光眼数量性状的基因将通过对人类队列和近交系小鼠的研究来确定。眼压治疗研究(OHTS)是一项大型治疗试验，旨在展示治疗高眼压患者的疗效。我们将通过对这项试验中的患者进行全基因组相关性研究(特定目标1)，确定控制杯盘比、眼压和角膜厚度大小的遗传因素。数量性状通常是由许多遗传因素决定的。对具有固定遗传背景的近交系小鼠的研究具有降低这些特征的复杂性的优势。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被识别出来。因此，我们将利用近交系小鼠的杂交(特定目标2)来研究青光眼的一个重要数量特征(中央角膜厚度)的遗传基础。我们期望我们提出的研究将为青光眼的数量特征确定新的风险等位基因。这些危险等位基因的发现将有助于青光眼的早期诊断和新的视力保护治疗方法的开发，对未来的青光眼临床治疗具有重要影响。与公共卫生相关：尽管青光眼是影响数百万美国人的遗传性失明原因，但人们对导致这种疾病的遗传风险因素知之甚少。我们提出的实验将确定控制整个青光眼表型的成分特征的基因。这些发现将提供对导致疾病的生物途径的洞察，还将有助于改善对这种虚弱疾病的诊断、预后和治疗。

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.