A Whole Genome Admixture Scan for Multiple Sclerosis

描述(申请人提供)：多发性硬化症(MS)是一种中枢神经系统炎症性疾病。据认为，当髓鞘反应性T细胞被激活时，就会发生组织损伤，并迁移到中枢神经系统，对髓鞘、少突胶质细胞和轴突造成损害。归根结底，多发性硬化症是一种复杂的遗传病，因为对双胞胎、同父异母的兄弟姐妹和被领养人的研究表明，有很强的家族遗传性。然而，到目前为止，试图识别影响这种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--连锁图谱--对罕见的单基因疾病很有效，这些疾病只是在家族中发生。但连锁扫描未能找到包括多发性硬化症在内的更常见、基因复杂的疾病的基因。最有可能用于基因发现的方法是直接评估人群中的变异及其与疾病的关联。在目前的技术下，最著名的方法--单倍型作图--是不现实的，因为它需要研究基因组中太多的位置。因为多发性硬化症在欧洲人中比在非洲人中更常见，所以一种新的方法，混合图谱，可能是利用关联研究发现疾病基因的捷径。具体地说，我们假设非裔美国人患多发性硬化症的中等遗传风险几乎完全来自他们的一小部分欧洲血统(10-40%)。通过扫描患有多发性硬化症的非裔美国人的基因组，寻找具有异常高欧洲血统的区域，我们可以识别可能包含与多发性硬化症风险相关的基因的“欧洲”基因片段。在这项研究中，我们建议进行第一次全基因组混合扫描人类疾病基因，使用的标记比基于单倍型的研究少100倍。混合扫描有可能快速识别疾病区域，特别是在两个人群中具有不同流行率的疾病子集。混合作图方法直到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具有已知频率的SNP。SNP资源和新的分析工具现在已经与非裔美国多发性硬化症患者的大量样本集合汇合在一起。该项目的中心目标将是在1000名患有多发性硬化症的非裔美国人和340名匹配良好的对照组样本中进行MS基因的混合扫描。为了跟踪所有与疾病相关的基因组区域，我们将标记密度增加两倍，以增加对结果的统计信心，并改进位置。然后，我们将在最感兴趣的区域进行有针对性的基于单倍型的关联研究，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.