A Haplotype Map for Multiple Sclerosis

多发性硬化症的单倍型图谱

基本信息

批准号：
7628355
负责人：
STEPHEN L HAUSER
金额：
$ 190.1万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-05 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7628355
关键词：
17q21 6p21 6p21.3 Abnormal coordination Address Affect Age Aliquot Alleles Arts Autoimmune Process Blindness Candidate Disease Gene Chromosome Mapping Chromosomes Classification Climate Clinical Clinical Data Codon Nucleotides Cognition Collection Communities Complex Confidence Intervals DNA DNA Library Data Data Set Databases Development Disease Disease Progression Disease susceptibility Environment Epigenetic Process European Event Family Follow-Up Studies Foundations Generations Genes Genetic Genetic Polymorphism Genetic Variation Genome Genome Scan Genomic Segment Genomics Genotype Goals Haplotypes Hereditary Disease Heterogeneity Homeostasis Human Immune Immune response Individual Inflammatory Informatics Institutes Institution International Laboratories Lesion Link Logistic Models MHC Class II Genes Maps Methods Microsatellite Repeats Modeling Molecular Multiple Sclerosis Neurologic Nomads Nutritional Onset of illness Outcome Parents Pathogenesis Patients Phenotype Polygenic Traits Population Predisposition Principal Investigator Probability Process Research Research Infrastructure Research Personnel Resolution Resources Role Sampling Scanning Screening procedure Self Tolerance Sensory Severities Siblings Signal Transduction Single Nucleotide Polymorphism Site Sphincter Standardization Susceptibility Gene Symptoms System Technology Testing Time Variant Vertigo base cell transformation clinical phenotype cohort density diagnosis evaluation disability family genetics genetic analysis genome-wide linkage interest knowledge of results member non-genomic programs repository response success transmission process

项目摘要

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.

描述（由申请人提供）：由于描绘人类物种遗传变异景观的快速进展，现在可以鉴定与多发性硬化症（MS）有关的主要基因。我们的总体目标是确定易患多发性硬化症的完整基因库并调节其表现。 MS 是一种复杂的多基因疾病，其中可能存在生物异质性（即不同个体的不同根本原因）和位点异质性（不同个体的不同基因），因此仔细描述具有遗传成分的亚表型对于充分了解 MS 至关重要。剖析易患 MS 的基因型。我们组织了国际多发性硬化症遗传学联盟 (TJMSGC)，目的是将来自多个学术机构的团队聚集在一起，他们具有实现这一目标所需的专业知识和承诺。真正独特的临床数据集的可用性，结合最先进的基因识别方法，将用于识别新的 MS 基因座，并表征负责当前已知的 6p21、17q21 和 17q21 连锁信号的疾病特异性变异。 19ql3。第一个目标是，我们将通过关注 2 个大型独立 MS 队列的表型特征（包括新的前瞻性收集的数据集）来解决 MS 的异质性问题。年龄和发病部位、残疾累积、病变分布和进展等临床和实验室数据将被仔细记录并纳入基因组数据分析中。在具体目标 2 中，我们将对 1000 个受影响的 MS 兄弟对中的 5,500 多个 SNP 进行高密度全基因组连锁筛选，以定位含有 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 位点内的因果变异。该基因座代表了 MS 中发现的最强且最一致的遗传因素。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识别 19ql3 和 17q21 位点内的因果变异。对于具体目标 3 和 4，将采用 1000 个 MS 三人组的筛选组和 1500 个三人组的复制组。这些研究成功的关键是提供大量信息丰富的数据集，收集相关临床数据作为遗传分析分层变量的严格且一致的方法标准化，以及基因分型和统计分析的有效方法的应用。技术精湛的团队之间紧密的协作关系、强大的 DNA 收藏、一流的研究环境和大量的初步数据，所有这些都表明该项目成功的机会很大。由此产生的知识，使用不受任何关于多发性硬化症根本原因的现有假设的偏见的方法获得，可能会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。