A Conserved Sequence Approach for MS Association Studies

描述(由申请人提供)：在过去的十年中，基因组连锁筛选一直是复杂疾病的遗传学研究的主力。尽管这些筛查在识别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识别致病基因。当前提案的目标是采用一种新的方法来研究复杂遗传病的连锁高峰规模上的遗传关联。该方法以多发性硬化症(MS)为模型，利用新的比较序列分析工具筛选位于多物种保守序列中的SNP标记。对于许多复杂的遗传性疾病，研究人员进行了大量的基因组筛选，试图确定可能存在MS基因座的区域。在MS的所有连锁区域中对所有候选基因进行彻底的跟踪已被证明在时间和成本上都是令人望而却步的，并且最终未能识别主要组织相容性复合体之外的易感基因。多发性硬化症的这些候选基因研究很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识别和表征的阻碍。这项研究建议旨在制定一种系统的方法，以加快对通过连锁研究确定的位置候选区域的跟踪，并将该方法应用于显示与MS显著连锁的基因组区域。我们假设，通过关注位于进化保守区域的SNPs，我们可以增加发现与疾病相关的变异的可能性。拟议项目的具体目标是：1.根据人类、小鼠、大鼠和小鸡基因组序列之间的保守性，为染色体1q43上的MS关联研究确定SNP标记的优先顺序；测量位于染色体1q43保守区的密集SNPs群体与约200个多重和~600个单链多发性多发性硬化家系之间的关联性。这项研究中提出的后续连锁研究的新方法将增加成功识别1q43区域遗传因素的可能性，并可能展示一种加速寻找多发性硬化症和其他复杂疾病基因的范例。

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.