A Whole Genome Admixture Scan for Multiple Sclerosis

描述（由申请人提供）：多发性硬化症（MS）是一种CNS炎性疾病。据认为，当活化的髓磷脂反应性T细胞迁移到CNS中并对髓磷脂、少突胶质细胞和轴突造成损伤时，发生组织损伤。最终，MS是一种复杂的遗传性疾病，因为对双胞胎、同父异母兄弟姐妹和被收养者的研究表明，MS具有很强的家族遗传性。然而，迄今为止，试图确定影响该疾病的基因的大规模研究取得的成功有限，需要更强大的搜索策略。寻找基因的经典方法--连锁作图--适用于在家族中发生的罕见的单基因疾病。但连锁扫描未能找到包括多发性硬化症在内的更常见、遗传复杂疾病的基因。最有可能发现基因的方法是直接评估人群中的变异及其与疾病的关联。以目前的技术，做这件事的最著名的方法-单倍型作图-是不切实际的，因为它需要研究基因组中太多的位点。因为MS在欧洲人中比在非洲人中更常见，一种新的方法，混合物作图，可能是使用关联研究找到疾病基因的捷径。具体来说，我们假设非裔美国人MS的中间遗传风险几乎完全来自他们的小比例（10-40%）欧洲血统。通过沿着非裔美国人的基因组扫描MS，寻找异常高的欧洲血统区域，我们可以识别出可能包含与MS风险相关的基因的“欧洲”基因片段。在这项研究中，我们建议进行人类疾病基因的第一次全基因组混合扫描，使用比基于单体型的研究少100倍的标记。混合物扫描具有快速识别疾病区域的潜力，特别是对于在两个人群中具有不同患病率的疾病子集。混合作图方法在过去一年才变得可行，因为在非洲裔和欧洲裔美国人中发现了大量已知频率的SNP。SNP资源和新的分析工具现在已经与非洲裔美国MS患者的大样本集合融合。该项目的中心目标是对1,000名非裔美国MS患者和340名匹配良好的对照组进行MS基因混合扫描。为了跟踪与疾病相关的所有基因组区域，我们将标记物的密度增加三倍，以增加结果的统计置信度并改进位置。然后，我们将在最感兴趣的区域进行基于单体型的靶向关联研究，以克隆与MS相关的新基因。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an inflammatory disease of the CNS. It is thought that tissue injury occurs when activated, myelin-reactive T cells migrate into the CNS and cause damage to myelin, oligodendrocytes and axons. Ultimately, MS is a complex genetic disease as studies in twins, half-siblings, and adoptees indicate a strong family inheritability. However, large-scale studies attempting to identify genes affecting the disease have so far had limited success, calling for a more powerful search strategy. The classic method of finding genes--linkage mapping--works well for rare, single gene disorders that run simply in families. But linkage scans have failed to find the genes for more common, genetically complex diseases including MS. The approach most likely to work for gene discovery is the direct assessment of variation in populations and its association to disease. With present technology, the best-known way of doing this---haplotype mapping--is not practical because it requires studying too many sites in the genome. Because MS is significantly more common in Europeans than in Africans, a new approach, admixture mapping, may be a shortcut for using association studies to find disease genes. Specifically, we hypothesize that the intermediate genetic risk of MS in African Americans is derived almost entirely from their small percentage (10-40%) of European ancestry. By scanning along the genomes of African Americans with MS looking for regions of unusually high European ancestry, we can identify the 'European' gene segments that are likely to contain the genes that are related to MS risk. In this study, we propose to carry out the first whole-genome admixture scan for human disease genes, using 100-times fewer markers than a haplotype-based study. An admixture scan has the potential to rapidly identify disease regions especially for the subset of diseases that have different prevalences in two populations. The admixture mapping approach has only become feasible in the past year because of the large numbers of SNPs discovered with known frequencies in both African- and European-Americans. The SNP resources and novel analytical tools have now converged with large sample collections of African-American MS patients. The central aim of this project will be to carry out an admixture scan for MS genes in a sample of 1,000 African Americans with MS and 340well-matched controls. To follow-up all the genomic regions associated with disease, we will triple density of markers to increase statistical confidence in the results and refine the positions. We will then move to a targeted haplotype-based association study in the most interesting regions to clone new genes associated with MS.