A Haplotype Map for Multiple Sclerosis

描述（由申请人提供）：由于在描绘人类物种遗传变异景观方面的快速进展，现在可以鉴定多发性硬化症（MS）中涉及的主要基因。我们的总体目标是表征易患MS并调节其表达的基因的完整库。MS是一种复杂的多基因疾病，其中可能存在生物异质性（即不同个体中的不同潜在原因）和基因座异质性（不同个体中的不同基因），因此仔细描绘具有遗传成分的亚表型对于充分剖析MS易感基因型至关重要。我们组织了国际多发性硬化症遗传学联盟（TJMSGC），目的是汇集来自多个学术机构的团队，这些团队具有必要的专业知识并致力于实现这一目标。一个真正独特的临床数据集的可用性，结合最先进的基因鉴定方法，将用于鉴定新的MS基因座，并表征负责目前已知的6p21，17q21和19ql3连锁信号的疾病特异性变异。在第一个目标中，我们将通过关注2个大型独立MS队列的表型特征来解决MS异质性问题，包括新前瞻性收集的数据集。将仔细记录临床和实验室数据，如年龄和疾病发作部位、残疾累积、病变分布和进展，并将其纳入基因组数据分析。在具体目标2中，我们将在1000个受影响的MS同胞对中使用超过5，500个SNP进行高密度全基因组连锁筛选，以定位携带MS基因的区域。在具体目标3中，我们将进行全面的关联分析，以确定6p21处4 Mb MHC基因座内的因果变异。最后，在具体目标4中，我们将利用基于单倍型的关联研究来确定19ql3和17q21基因座内的因果变异。对于特定目标3和4，将采用1000个MS trios的筛选集和1500个trios的复制集。这些研究成功的关键是提供大量信息丰富的数据集，将严格和一致的方法标准化以收集相关临床数据作为遗传分析的分层变量，以及应用有效的基因分型和统计分析方法。熟练的团队之间强大的合作关系，获得强大的DNA收集，一流的研究环境和大量的初步数据，都表明这个项目有很高的成功机会。由此产生的知识，使用不受任何关于MS根本原因的现有假设偏见的方法获得，可以彻底改变我们对这种疾病的理解以及我们以有意义的方式进行治疗干预的能力。

DESCRIPTION (provided by applicant): Identification of the major genes involved in multiple sclerosis (MS) is now possible as a result of the rapid progress in delineating the landscape of genetic variation across the human species. Our overall objective is to characterize the complete repertoire of genes that predispose to MS and modulate its presentation. MS is a complex polygenic disorder in which biologic heterogeneity (i.e. different underlying causes in different individuals) and locus heterogeneity (different genes in different individuals) is likely to exist, thus a careful delineation of subphenotypes that have a hereditable component will be essential to fully dissect the MS-prone genotype. We organized the International Multiple Sclerosis Genetics Consortium (TJMSGC) with the purpose of bringing together teams from multiple academic institutions with the requisite expertise and commitment towards this goal. The availability of a truly unique clinical dataset, combined with state-of-the-art approaches to gene identification, will be used to identify new MS loci and to characterize disease-specific variations responsible for currently known linkage signals at 6p21, 17q21, and 19ql3. In the first aim, we will address the issue of heterogeneity in MS by focusing on the phenotypic characterization of 2 large independent MS cohorts, including a newly prospectively collected dataset. Clinical and laboratory data such as age and site of disease onset, accumulation of disability, lesion distribution, and progression will be carefully recorded and incorporated into the analysis of genomic data. In specific aim 2, we will carry out a high-density whole genome linkage screen with over 5,500 SNPs in 1000 affected MS sibling pairs to localize regions harboring MS genes. In specific aim 3, we will perform a comprehensive association analysis to identify the causal variation(s) within the 4 Mb MHC locus at 6p21. This locus represents the strongest and most consistent genetic factor identified in MS. Finally, in specific aim 4, we will utilize haplotype-based association studies to identify the causal variations within the 19ql3 and 17q21 loci. For specific aims 3 and 4, a screening set of 1000 MS trios, and a replication set of 1500 trios, will be employed. Key to the success of these studies is the availability of a large and informative dataset, the standardization of rigorous and consistent methods to collect relevant clinical data as stratifying variables for genetic analyses, and the application of efficient methods for genotyping and statistical analysis. Strong collaborative ties between skillful teams, access to a formidable DNA collection, a superb research environment and substantial preliminary data, all indicate that this project has a high chance for success. The resulting knowledge, obtained using methods that are not biased by any preexisting hypothesis about the underlying cause of MS, could revolutionize our understanding of this disease and our capacity to intervene therapeutically in a meaningful fashion.