Gene linkage study of multiple sclerosis sibling pairs

多发性硬化症兄弟姐妹对的基因连锁研究

• 批准号: 7276591
• 负责人: STEPHEN L HAUSER
• 金额: $ 33.22万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-12-01 至 2009-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7276591
• 关键词: 6p21; 6p21.3; Address; Affect; African American; Age; Alleles; Apolipoprotein E; Autoantibodies; Autoimmune Diseases; Benign; Biological; Biology; CCR5 gene; Candidate Disease Gene; Central Nervous System Diseases; Chromosomes; Class; Classification; Clinical; Clinical Data; Code; Collection; Complementary DNA; Complex; DNA; Data; Data Set; Development; Disease; Disease susceptibility; Dose; Environment; Etiology; Evolution; Family; Foundations; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Recombination; Genetic Variation; Genomic Segment; Genomics; Genotype; Goals; HLA-DR2 Antigen; HLA-DRB1; Haplotypes; Heterogeneity; Human; Human Genome; Individual; Inflammatory; Informatics; Institutes; Laboratories; Lesion; Link; Linkage Disequilibrium; Logistic Models; Major Histocompatibility Complex; Maps; Methods; Microsatellite Repeats; Modeling; Molecular; Multiple Sclerosis; Neuraxis; Normal Statistical Distribution; Numbers; Onset of illness; Optic Nerve; Outcome; Pathogenesis; Pathology; Patients; Phenotype; Predisposing Factor; Predisposition; Primary Progressive Multiple Sclerosis; Process; Quantitative Trait Loci; Research; Resolution; Role; Severities; Siblings; Signs and Symptoms; Single Nucleotide Polymorphism; Site; Spinal; Spinal Cord; Standardization; Structure; Susceptibility Gene; Symptoms; TGFB1 gene; Tail; Testing; Variant; base; clinical phenotype; density; design; disability; genetic analysis; interest; size; success; transmission process

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a common inflammatory disorder of the central nervous system characterized by a complex etiology that includes a strong genetic component. Identification of the major genes that confer susceptibility to MS is now possible as a result of the rapid progress in delineating the extent of genetic variation across the human species. Emerging evidence indicates that the human genome retains blocks (haplotypes) of varying size (averaging 20-30kappaB) in which genes are held together in linkage disequilibrium (LD). These blocks define genomic segments of sequence unbroken by recombination in modern evolution, allowing for the efficient testing of all genetic variation within a region regardless of whether all variants have been discovered. A haplotype-map approach can now be used to finely map the regions of genetic interest. In specific aim 1 we describe the haplotype-based association analysis for the final identification of the causal variation(s) within the 4 MB major histocompatibility complex (MHC) locus at 6p21. This locus represents the strongest and most consistent genetic factor identified in MS. A robust haplotype-map of this region is already available. The haplotype-tagged (ht) SNPs will be genotyped in 1000 MS trios. Family-based association testing for alleles, haplotypes and genotypes in each block will be performed using transmission disequilibrium testing methods. MS susceptibility genes located within blocks of interest will then be identified by direct sequencing. In the second aim, we will address the issue of genetic modifiers in MS focusing first on the underlying causes of optico-spinal MS. Clinical and laboratory data such as age and site of disease onset, disability at entry of study (EDSS), lesion distribution, progression, and presence of autoantibodies will be also incorporated into the analysis of genomic data to directly address the question of heterogeneity in MS by analysis of the correlation between different phenotypes and genotypes. Based on the hypothesis that MS encompasses more than one fundamental phenotype, a genetic approach using family-based association studies was designed to identify genetic factors affecting disease pathogenesis. 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 of genotyping and statistical analysis. Collaborative ties with skillful teams, access to a formidable DNA collection, a superb research environment and suggestive preliminary results, all indicate that this project has a high chance for success.

描述（由申请人提供）：多发性硬化症（MS）是一种常见的中枢神经系统炎症性疾病，其病因复杂，其中包括很强的遗传因素。由于描述人类遗传变异程度的快速进展，现在可以鉴定导致多发性硬化症易感性的主要基因。 新出现的证据表明，人类基因组保留了不同大小（平均 20-30kappaB）的块（单倍型），其中基因以连锁不平衡 (LD) 方式结合在一起。这些模块定义了现代进化中未被重组破坏的基因组序列片段，允许有效测试一个区域内的所有遗传变异，无论是否已发现所有变异。现在可以使用单倍型图谱方法来精细地绘制感兴趣的遗传区域的图谱。 在具体目标 1 中，我们描述了基于单倍型的关联分析，用于最终识别 6p21 处 4 MB 主要组织相容性复合体 (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。该区域的可靠单倍型图谱已经可用。单倍型标记 (ht) SNP 将在 1000 个 MS 三重奏中进行基因分型。将使用传递不平衡测试方法对每个区块中的等位基因、单倍型和基因型进行基于家族的关联测试。 然后，将通过直接测序来鉴定位于感兴趣的块内的 MS 易感性基因。在第二个目标中，我们将解决多发性硬化症的基因修饰问题，首先关注视神经脊髓多发性硬化症的根本原因。 年龄和发病部位、研究开始时的残疾 (EDSS)、病变分布、进展和自身抗体的存在等临床和实验室数据也将纳入基因组数据分析中，以直接解决多发性硬化症的异质性问题通过分析不同表型和基因型之间的相关性。 基于多发性硬化症包含不止一种基本表型的假设，设计了一种使用基于家族的关联研究的遗传方法来识别影响疾病发病机制的遗传因素。这些研究成功的关键是拥有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，以及有效的基因分型和统计分析方法的应用。与熟练团队的合作关系、强大的 DNA 收藏、一流的研究环境和具有启发性的初步结果，所有这些都表明该项目成功的机会很大。