A Whole Genome Admixture Scan for Multiple Sclerosis

描述（由申请人提供）：多发性硬化症（MS）是一种中枢神经系统炎症性疾病。据认为，当活化的髓磷脂反应性T细胞迁移到中枢神经系统并造成髓磷脂、少突胶质细胞和轴突损伤时，组织损伤发生。最终，多发性硬化症是一种复杂的遗传疾病，对双胞胎、同父异母兄弟姐妹和被收养者的研究表明，多发性硬化症具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，这需要一种更强大的搜索策略。寻找基因的经典方法——连锁图谱——对那些只在家族中遗传的罕见的单基因疾病很有效。但是连锁扫描未能找到包括多发性硬化症在内的更常见的遗传复杂疾病的基因。最有可能用于基因发现的方法是直接评估种群变异及其与疾病的关系。以目前的技术，最著名的方法——单倍型定位——并不实用，因为它需要研究基因组中太多的位点。由于多发性硬化症在欧洲人中比在非洲人中更为常见，一种新的方法——混合作图，可能是利用关联研究寻找疾病基因的捷径。具体来说，我们假设非裔美国人患多发性硬化症的中间遗传风险几乎完全来自于他们很小的欧洲血统比例（10-40%）。通过扫描患有多发性硬化症的非裔美国人的基因组，寻找异常高的欧洲血统区域，我们可以确定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，我们建议对人类疾病基因进行首次全基因组混合扫描，使用比单倍型研究少100倍的标记。混合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流行率的疾病子集。由于在非洲裔和欧裔美国人中发现了大量已知频率的snp，这种混合图谱方法直到去年才变得可行。SNP资源和新的分析工具现已与非洲裔美国MS患者的大量样本集合融合。该项目的中心目标是对1000名患有多发性硬化症的非裔美国人样本和340名匹配良好的对照组进行多发性硬化症基因的混合扫描。为了跟踪所有与疾病相关的基因组区域，我们将标记密度提高三倍，以增加结果的统计可信度并改进位置。然后，我们将在最有趣的区域进行靶向单倍型关联研究，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.