Identification and Characterization of Novel AD Genes

新型 AD 基因的鉴定和表征

• 批准号: 6630162
• 负责人: RUDOLPH Emile TANZI
• 金额: $ 81.51万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6630162
• 关键词: Alzheimer's disease; biotechnology; case history; cell line; chromosomes; clinical research; enzyme linked immunosorbent assay; family genetics; gene expression; genetic markers; genotype; human genetic material tag; human subject; linkage disequilibriums; linkage mapping; phenotype; single strand conformation polymorphism; tissue /cell culture

DESCRIPTION (provided by applicant): This is a resubmission of our competing renewal application to continue a highly productive study previously funded for three years as an IRPG. The study has been led by Dr Rudolph Tanzi at Mass General Hospital in collaboration with co-investigators at the U Alabama and Johns Hopkins U These investigators worked together since 1989 to ascertain, evaluate, and follow the NIMH Genetics Initiative Alzheimer's disease (AD) sample, which currently includes 1527 individuals in 457 families, the largest uniformly ascertained and evaluated sample assembled for the study of AD genetics The IRPG was aimed at analyzing and performing preliminary follow up of a high-resolution genome screen of the NIMH sample. Having substantially completed the original aims, the IRPG has been dissolved and we are applying for funds to identify novel AD genes within linkage peaks identified in the genome screen, using a positional candidate approach, augmented by linkage disequilibrium mapping In addition to the expected highly significant linkage peak on chromosome 19q (at the APOE locus), our screen yielded several regions with evidence of "suggestive" linkage to AD. In accord with the reviewers' suggestion, the follow up studies in our revised application focus on the two highest-priority confirmed AD linkage regions on chromosomes 9 and 10, where we and other groups have observed consistent evidence for linkage. We plan to refine these linkage regions using highly polymorphic markers in linkage and family-based association analyses. We will then test clusters of tightly spaced single nucleotide polymorphisms (SNPs) for association with AD, initially in compelling and then in plausible candidate genes. Putative AD genes will also be tested in an independent sample assembled for association analyses, the Consortium on Alzheimer's Genetics (CAG) sample. If the initial candidate gene approach does not lead to the disease loci, we will continue by analyzing SNP clusters in genes not previously considered AD candidates, and - if necessary - in intergenic regions. Any SNPs found to be strongly associated with AD will be phenotypically and functionally characterized using a variety of statistical and experimental methods. Only as time and funds permit, we will employ the same general approach to follow up other loci that meet criteria for 'suggestive' linkage. While we have devised a strategy that integrates the best available methods to identify genes involved in a complex disease like AD, we realize that the field is evolving rapidly. Thus, as the study progresses we will routinely adjust our methods to take advantage of advances in methodology.

描述（由申请人提供）：这是我们重新提交的竞争续展申请，以继续之前作为 IRPG 资助的三年的高效研究。这项研究由麻省总医院的 Rudolph Tanzi 博士领导，与阿拉巴马大学和约翰霍普金斯大学的共同研究人员合作。这些研究人员自 1989 年以来一直合作，确定、评估和跟踪 NIMH 遗传学计划阿尔茨海默病 (AD) 样本，该样本目前包括 457 个家庭的 1527 名个体，这是为 AD 研究而收集的最大的统一确定和评估样本 遗传学 IRPG 旨在对 NIMH 样本的高分辨率基因组筛选进行分析和初步跟踪。基本完成了最初的目标后，IRPG 已解散，我们正在申请资金，以在基因组筛选中确定的连锁峰内识别新的 AD 基因，使用位置候选方法，并通过连锁不平衡图谱进行增强。除了 19q 染色体（在 APOE 基因座）上预期的高度显着的连锁峰外，我们的筛选还产生了几个具有与 AD“暗示”连锁证据的区域。根据审稿人的建议，我们修订后的申请中的后续研究集中在9号和10号染色体上两个最高优先级的已确认的AD连锁区域，我们和其他小组在这两个区域观察到了一致的连锁证据。我们计划在连锁和基于家族的关联分析中使用高度多态性标记来细化这些连锁区域。然后，我们将测试紧密间隔的单核苷酸多态性 (SNP) 簇与 AD 的关联，最初是在令人信服的候选基因中，然后是在合理的候选基因中。推定的 AD 基因也将在为关联分析而组装的独立样本（阿尔茨海默病遗传学联盟 (CAG) 样本）中进行测试。如果最初的候选基因方法没有导致疾病位点，我们将继续分析先前未考虑的 AD 候选基因中的 S​​NP 簇，以及（如有必要）基因间区域中的 SNP 簇。任何被发现与 AD 密切相关的 SNP 将使用各种统计和实验方法进行表型和功能表征。只有在时间和资金允许的情况下，我们才会采用相同的一般方法来追踪符合“暗示”连锁标准的其他基因座。虽然我们已经制定了一种策略，整合了现有的最佳方法来识别与 AD 等复杂疾病相关的基因，但我们意识到该领域正在迅速发展。因此，随着研究的进展，我们将定期调整我们的方法，以利用方法论的进步。