Gene Linkage Study of Multiple Sclerosis Sibling Pairs

项目摘要 多发性硬化症(MS)是一种常见的严重的中枢神经系统疾病 以慢性炎症、髓鞘丢失、胶质增生、不同程度的轴突和 少突胶质细胞病理学和进行性神经功能障碍。多发性硬化发病机制 包括一种复杂的遗传成分。尽管进行了长期密集的努力，但 关于多发性硬化症遗传学的知识仍然不完整。我们的总体目标是描述 易患多发性硬化症和调节多发性硬化症表现的基因谱系。他们的身份 现在是可能的，因为在定义基因的格局方面取得了快速进展 组织和编目人类基因组中的变异。这项建议的基础是 新的高质量全基因组关联结果的可用性和全面的 大型纵向MS队列中的表型数据。我们提出了三个主要研究目标： 特定目标1描述了全基因组范围内1,000个病例/1,000个对照的高分辨率 关联屏幕，以及多分析方法，以明确映射 来自序列和拷贝数多态的关联信号，导致可测试 关于哪些是导致易感性的特定等位基因变异的假说。此外, 确诊的疾病SNPs将在多病例家族性数据集中进行测试，以确定 区分受影响家庭成员和未受影响家庭成员的最小基因组合。 将对数据进行分析，以模拟已确认的等位基因变异在 敏感度。特定目标2利用了丰富的表型数据 用于评估病程、临床变量和相关性的不同数据集 基因分型。横断面和纵向临床数据，如年龄和发病部位 发病、进入研究和进展时的残疾、治疗和病变的变化 分布和负担将纳入遗传数据的分析。这一目标 直接解决了多发性硬化症的临床异质性问题以及 不同的表型和基因型。 这里描述的一大批特征良好的队列的可用性，再加上 借助高性能的实验室技术，提供了一个绝佳的机会来识别 以及MS相关基因的特征。这些信息可能会揭示治疗的新靶点。

Project Summary Multiple sclerosis (MS) is a common and severe disorder of the central nervous system characterized by chronic inflammation, myelin loss, gliosis, varying degrees of axonal and oligodendrocyte pathology, and progressive neurological dysfunction. MS pathogenesis includes a complex genetic component. In spite of intensive long-standing efforts, the knowledge of MS genetics remains incomplete. Our overall objective is to characterize the repertoire of genes that predispose to MS and modulate its presentation. Their identification is now possible as a result of rapid progress in defining the landscape of genetic organization and cataloging variation across the human genome. This proposal builds on the availability of new, high-quality genome-wide association results and comprehensive phenotypic data in a large longitudinal MS cohort. We propose three main research goals: Specific Aim 1 describes a 1,000 cases/1,000 controls high-resolution genome-wide association screen, together with a multi-analytical approach to map unambiguous association signals from sequence and copy number polymorphisms, leading to testable hypotheses as to which are the specific allelic variants conferring susceptibility. In addition, confirmed disease SNPs will be tested in a multi-case familial dataset to determine the minimal combination of genes that differentiate affected and unaffected family members. Data will be analyzed to model the relative contribution of the confirmed allelic variants in susceptibility. Specific Aim 2 takes advantage of the wealth of phenotypic data available for the different datasets to assess disease course, clinical variables, and correlations to genotype. Cross-sectional and longitudinal clinical data, such as age and site of disease onset, disability at entry of study and progression, treatment, and changes in lesion distribution and burden will be incorporated into the analysis of genetic data. This aim directly addresses the question of clinical heterogeneity in MS and the correlation between different phenotypes and genotypes. The availability of a large and well-characterized cohort as described here, coupled with the aid of high-powered laboratory technologies, provides an outstanding opportunity to identify and characterize MS-related genes. This information may reveal novel targets for therapy.