A Conserved Sequence Approach for MS Association Studies

描述（由申请人提供）：基因组连锁筛选在过去十年中一直是复杂疾病遗传研究的主力。尽管这些筛选在鉴定复杂疾病的感兴趣区域方面取得了成功，但用候选基因方法对连锁区域的后续研究在很大程度上未能鉴定致病基因座。目前的建议的目标是采用一种新的方法来调查一个复杂的遗传疾病的连锁峰的规模上的遗传关联。使用多发性硬化症（MS）作为一个模型，这种方法的重点是选择SNP标记位于多物种的保守序列，使用新的比较序列分析工具确定。对于许多复杂的遗传疾病，研究人员已经进行了大量的基因组筛选，试图确定可能含有MS基因座的区域。对MS所有连锁区域中的所有候选基因进行彻底随访已被证明在时间和成本方面都是令人望而却步的，并且最终未能鉴定出主要组织相容性复合体之外的易感基因。MS的这些候选基因研究可能受到与疾病病理生理学直接相关的基因或调控元件的不完全鉴定和表征的阻碍。本研究提案旨在制定一个系统的方法，以加快后续的位置候选区域确定通过连锁研究，并将这种方法应用于一个基因组区域，表现出显着的连锁MS。我们假设，通过专注于位于进化保守区域的SNP，我们可以增加检测变异的可能性与疾病相关。拟议项目的具体目标是：1.）基于人、小鼠、大鼠和鸡基因组序列之间的保守性，优先考虑用于染色体1 q43上的MS关联研究的SNP标记; 2.）测量位于染色体1 q43上感兴趣的保守区域中的密集SNP群体与约200个多重和约600个单纯MS家族的数据集之间的关联。本研究中提出的跟踪连锁研究的新方法将增加成功识别1 q43区域中遗传因子的可能性，并可能展示加速MS和其他复杂疾病中基因搜索的范例。

DESCRIPTION (provided by applicant): Genomic linkage screens have served as the workhorse of genetic studies for complex diseases over the past decade. Despite the success of these screens in identifying regions of interest for complex diseases, follow-up of linkage regions with candidate gene approaches have largely failed to identify causative loci. The goal of the current proposal is to employ a novel approach to investigate genetic association on the scale of a linkage peak for a complex genetic disease. Using multiple sclerosis (MS) as a model, this approach focuses on selection of SNP markers located in multi-species conserved sequences identified using new comparative sequence analysis tools. As for many complex genetic diseases, researchers have conducted numerous genomic screens in an attempt to identify regions potentially harboring MS loci. Thorough follow-up of all candidate genes in all regions of linkage for MS has proven to be prohibitive in terms of both time and cost, and has ultimately failed to identify susceptibility genes outside of the major histocompatibility complex. It is likely that these candidate gene studies for MS have been hampered by the incomplete identification and characterization of genes or regulatory elements that are directly related to disease pathophysiology. This research proposal aims to formulate a systematic approach to expedite the follow-up of positional candidate regions identified through linkage studies and apply this approach to a genomic region that demonstrates significant linkage to MS. We hypothesize that by focusing on SNPs located in evolutionarily conserved regions, we can increase the likelihood of detecting variants that are associated with disease. The specific aims of the proposed project are to: 1.) Prioritize SNP markers for an MS association study on chromosome 1q43 based on conservation between human, mouse, rat, and chick genome sequences; 2.) Measure association between a dense population of SNPs located in conserved regions of interest on chromosome 1q43 and a dataset of ~200 multiplex and ~600 simplex MS families. The novel approach for follow-up of linkage studies proposed in this study will increase the likelihood of successfully identifying a genetic factor in the 1q43 region and will potentially demonstrate a paradigm that expedites the search for genes in MS and other complex diseases.