Association Mapping in PD Linkage Regions

PD连锁区域中的关联映射

• 批准号: 6812937
• 负责人: William K SCOTT
• 金额: $ 26.35万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6812937
• 关键词: Parkinson' s disease; biotechnology; family genetics; functional /structural genomics; gene expression; gene frequency; gene mutation; genetic polymorphism; genetic screening; genetic susceptibility; genotype; high performance liquid chromatography; human genetic material tag; linkage disequilibriums; linkage mapping; parkin gene /protein; single nucleotide polymorphism

Linkage analysis is a powerful tool to identify the genes that lead to disease. Using this approach, we previously identified five regions, on chromosomes 5, 6, 8, 9 and 17 (Scott et al. 2001) that potentially contained PD risk genes. Recent results from independent genomic screens have now replicated our linkages to chromosomes 5 and 9. We have demonstrated the chromosome 6 region was due to Parkin gene mutations and follow-up on chromosome 17 indeed detected association between PD and the H1 haplotype associated with the tau gene. We now have significant association with a gene on chromosome 8 as well, supporting this linkage. However, linkage peaks in complex diseases present several new problems when attempting to use this method to identify the causal gene. First, the linkage peaks are very large, often 20-30 megabases (Mb) or more. This creates a great need for prioritizing candidate genes in a cost-effective and labor-saving approach, which led in part to our genomic convergence approach. Second, where the endpoint of a disorder like cystic fibrosis is a gene mutation, in complex diseases the endpoint of linkage analysis is identification era gene with "significant" disease association. But how significant? How does one know that a significantly associated gene is actually the gene producing the linkage result? Could a more important gene in the region, yet unexplored, be the actual gene that one is seeking? Also, is only one association contributing to these peaks? This project proposes to take a genomic approach to answer this question. We will apply a DNA pooling strategy (Hoogendoom et al. 1999) using single base-pair extension with denaturing high performance liquid chromatography to apply a new technique, "iterative association mapping" (IAM) to the entire linkage peak in an efficient manner. We will then focus on the strongest, most dominant peak of association, move from pooling to genotyping (Taqman) to identify haplotype-tagging SNPs on a small test set, then genotype the htSNPs on the full data set. Finally, we will test genes lying in the associated htSNP region for association with PD.

连锁分析是识别导致疾病的基因的有力工具。使用这种方法，我们先前确定了5、6、8、9和17号染色体上的五个区域(Scott等人。2001)，可能含有帕金森病风险基因。最近来自独立基因组筛选的结果复制了我们与5号和9号染色体的联系。我们已经证明了6号染色体区域是由于Parkin基因突变，对17号染色体的跟踪确实发现了PD与与tau基因相关的H1单倍型之间的关联。我们现在也与8号染色体上的一个基因有重大关联，支持这种联系。然而，复杂疾病中的连锁峰在以下情况下出现了一些新的问题 试图用这种方法来确定致病基因。首先，链接峰非常大，通常是20-30兆基数(Mb)或更多。这就产生了以经济有效和省力的方法优先处理候选基因的巨大需求，这在一定程度上导致了我们的基因组融合方法。其次，在囊性纤维化等疾病的终点是基因突变的情况下，在复杂疾病中，连锁分析的终点是识别与“显著”疾病关联的Era基因。但有多重要呢？一个人如何知道一个显著相关的基因实际上是产生连锁结果的基因？该地区还没有被发现的更重要的基因，会不会是人们正在寻找的真正的基因呢？此外，是否只有一个关联导致了这些峰值？这个项目建议用基因组学的方法来回答这个问题。我们将应用DNA池策略(Hoogdoom等人)。1999)使用单碱基对延伸 用变性高效液相色谱仪将一种新技术--“迭代关联图谱”(IAM)有效地应用于整个连接峰。然后，我们将专注于最强、最主要的关联峰，从汇集转移到基因分型(Taqman)，以在小测试集上识别单倍型标记SNP，然后在整个数据集上对htSNPs进行基因分型。最后，我们将测试位于相关htSNP区域的基因与帕金森病的关联。