Gene Linkage Study of Multiple Sclerosis Sibling Pairs

描述（由申请人提供）：多发性硬化症（MS）是一种常见且严重的中枢神经系统疾病，其特征是慢性炎症、髓磷脂丢失、神经胶质瘤、不同程度的轴突和少突胶质细胞病理以及进行性神经功能障碍。多发性硬化症的发病机制包括一个复杂的遗传因素。尽管经过长期的努力，对MS遗传学的了解仍然不完整。我们的总体目标是表征易患多发性硬化症的基因库，并调节其表现。由于在定义遗传组织格局和编目人类基因组变异方面取得的快速进展，鉴定它们现在是可能的。该建议建立在新的、高质量的全基因组关联结果和大型纵向MS队列的综合表型数据的可用性基础上。我们提出了三个主要的研究目标：具体目标1描述了一个1000例/ 1000例对照的高分辨率全基因组关联筛选，以及一种多分析方法，从序列和拷贝数多态性中绘制明确的关联信号，从而得出可测试的假设，即哪些是特定的等位基因变异赋予易感性。此外，确认的疾病snp将在多病例家族数据集中进行测试，以确定区分受影响和未受影响家庭成员的最小基因组合。将对数据进行分析，以建立确定的等位基因变异在易感性中的相对贡献模型。特异性目标2利用不同数据集的丰富表型数据来评估病程、临床变量以及与基因型的相关性。横断面和纵向临床数据，如年龄和发病部位、研究开始和进展时的残疾、治疗、病变分布和负担的变化将被纳入遗传数据的分析。这一目的直接解决了MS的临床异质性问题以及不同表型和基因型之间的相关性。如本文所述，一个庞大且特征明确的队列的可用性，加上高性能实验室技术的帮助，为识别和表征ms相关基因提供了一个绝佳的机会。这一信息可能揭示新的治疗靶点。公共卫生相关性：多发性硬化症（MS）是人类典型的脱髓鞘疾病，是成年早期至中期神经功能障碍的常见原因。目前尚无治愈性治疗，大约90%的患者最终残疾。这种长期疾病的社会经济后果令人震惊，因为75-85%的患者最终失业，并面临社会孤立的高风险。多发性硬化症是仅次于阿尔茨海默病的第二昂贵的神经系统疾病。我们的目标是绘制编码MS易感性相关产物的基因。我们预计可能有几个基因参与ms，这些基因可能单独或共同起作用，并与环境因素一起影响易感性。遗传基因的特定组合也可能决定症状何时出现，或疾病如何发展。它们的识别将有助于确定MS的基本病因，改善风险评估，并影响治疗方法。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Multiple sclerosis (MS), the prototypic demyelinating disease in humans, is a common cause of neurological dysfunction arising from early to middle adulthood. No curative therapy is currently available and approximately 90% of afflicted individuals are ultimately disabled. The socioeconomic consequences of this long-lasting disease are staggering as 75-85% of patients are eventually unemployed and at high risk for social isolation. MS is the second most costly neurological disorder after Alzheimer's disease. We aim to map genes that code for products involved in MS susceptibility. We anticipate that there may be several genes involved in MS. These genes may work independently or together, and affect susceptibility in concert with environmental factors. Particular combinations of inherited genes may also determine when symptoms develop, or how the disease progresses. Their identification will help to define the basic etiology of MS, improve risk assessment, and influence therapeutics.