Gene Linkage Study of Multiple Sclerosis Sibling Pairs

描述（由申请人提供）：多发性硬化（MS）是一种常见且严重的中枢神经系统疾病，其特征为慢性炎症、髓鞘丢失、神经胶质增生、不同程度的轴突和少突胶质细胞病理学以及进行性神经功能障碍。MS发病机制包括复杂的遗传成分。尽管长期以来一直在努力，但对MS遗传学的了解仍然不完整。我们的总体目标是表征易患MS并调节其表达的基因库。由于在定义遗传组织和编目人类基因组变异方面的快速进展，它们的识别现在是可能的。该建议建立在一个大型纵向MS队列中新的、高质量的全基因组关联结果和综合表型数据的可用性的基础上。我们提出了三个主要的研究目标：具体目标1描述了一个1,000例/1,000对照高分辨率全基因组关联筛选，以及一个多分析方法来映射明确的关联信号从序列和拷贝数多态性，导致可测试的假设，即特定的等位基因变异赋予易感性。此外，将在多病例家族数据集中测试确认的疾病SNP，以确定区分受影响和未受影响家族成员的基因的最小组合。将对数据进行分析，以模拟确认的等位基因变体在易感性中的相对贡献。具体目标2利用了不同数据集可用的大量表型数据来评估疾病过程、临床变量以及与基因型的相关性。遗传数据分析中将纳入横断面和纵向临床数据，如年龄和疾病发作部位、进入研究和进展时的残疾、治疗以及病变分布和负荷的变化。这一目标直接解决了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。这里描述的一个大的和良好表征的队列的可用性，加上高性能的实验室技术的帮助，提供了一个很好的机会，以确定和表征MS相关基因。这些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。目前没有治愈性疗法，大约90%的患者最终残疾。这种长期存在的疾病的社会经济后果是惊人的，因为75-85%的患者最终失业，并处于社会孤立的高风险之中。MS是仅次于阿尔茨海默病的第二大神经系统疾病。我们的目标是映射基因编码的产品参与MS易感性。我们预计，可能有几个基因参与MS。这些基因可能独立或共同工作，并影响与环境因素的易感性。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进展。他们的鉴定将有助于确定MS的基本病因，改善风险评估，并影响治疗。

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.