A Conserved Sequence Approach for MS Association Studies

MS 关联研究的保守序列方法

• 批准号: 7036281
• 负责人: DOUGLAS P MORTLOCK
• 金额: $ 7.63万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7036281
• 关键词: Internet; autoimmune disorder; chromosome aberrations; clinical research; developmental genetics; disease /disorder model; functional /structural genomics; genetic disorder diagnosis; genetic library; genetic mapping; genetic markers; genetic susceptibility; genotype; high throughput technology; human data; human genetic material tag; linkage disequilibriums; linkage mapping; method development; microarray technology; molecular biology information system; multiple sclerosis; single nucleotide polymorphism; statistics /biometry

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.

描述（由申请人提供）：在过去的十年中，基因组联系筛查一直是复杂疾病的遗传研究的主力。尽管这些筛查在确定复杂疾病的兴趣区域方面取得了成功，但对候选基因方法的连锁区域的随访基本上未能鉴定出病因。当前建议的目的是采用一种新型方法来研究复杂遗传疾病的连锁峰的规模。使用多发性硬化症（MS）作为模型，这种方法着重于使用新的比较序列分析工具鉴定的多种物种保守序列中的SNP标记。至于许多复杂的遗传疾病，研究人员进行了许多基因组筛查，以识别潜在携带MS基因座的区域。事实证明，对MS的所有链接区域中所有候选基因的彻底随访在时间和成本方面都令人难以置信，并且最终未能鉴定出主要的组织相容性复合物之外的敏感性基因。这些用于MS的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节元素的不完全鉴定和表征。该研究建议旨在制定一种系统的方法，以加快通过连锁研究确定的位置候选区域的随访，并将这种方法应用于与MS的显着联系的基因组区域。我们假设通过关注位于进化保守区域中的SNP，我们可以增加检测与疾病相关的变体的可能性。拟议项目的具体目的是：1。）基于人，小鼠，大鼠和雏鸡基因组序列之间的保护，将SNP标记确定为MS关联1 Q43的MS关联研究； 2.）衡量位于染色体1 Q43染色体的保守区域的密集的SNP与〜200多重多重型染色体和〜600个单纯级MS系列之间的关联。在本研究中提出的联系研究的新方法将增加成功识别1q43区域遗传因素的可能性，并有可能证明一种范式，该范式加快了在MS和其他复杂疾病中搜索基因的搜索。