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（MS）是一种常见的中枢神经系统炎症性疾病，其特征在于包括强遗传成分的复杂病因。由于人类物种间遗传变异程度的快速进展，现在有可能鉴定出对MS易感的主要基因。 新出现的证据表明，人类基因组保留了不同大小（平均20- 30 kB）的基因块（单倍型），其中基因以连锁不平衡（LD）的方式保持在一起。这些区块定义了现代进化中未被重组破坏的基因组序列片段，允许有效测试区域内的所有遗传变异，无论是否发现了所有变异。现在可以使用单倍型图谱方法来精细地绘制遗传感兴趣的区域。 在具体目标1中，我们描述了基于单倍型的关联分析，用于最终鉴定6p 21处4 MB主要组织相容性复合体（MHC）基因座内的因果变异。该位点代表了MS中确定的最强和最一致的遗传因子。该区域的一个强大的单倍型图已经可用。将在1000个MS trios中对单倍型标记的（ht）SNP进行基因分型。将使用传递不平衡检验方法对每个区组中的等位基因、单倍型和基因型进行基于家系的关联检验。 然后通过直接测序鉴定位于感兴趣区块内的MS易感基因。在第二个目标中，我们将解决MS中遗传修饰剂的问题，首先关注视神经脊髓MS的根本原因。临床和实验室数据，如年龄和疾病发作部位，进入研究时的残疾（EDSS），病变分布，进展，和自身抗体的存在也将被纳入基因组数据的分析中，以通过分析不同表型和基因型之间的相关性。 基于MS包括一个以上的基本表型的假设，设计了使用基于家族的关联研究的遗传方法来确定影响疾病发病机制的遗传因素。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。与熟练团队的合作关系，获得强大的DNA收集，一流的研究环境和暗示性的初步结果，都表明这个项目有很高的成功机会。