Identification and Characterization of Novel AD Genes

描述(由申请人提供)：这是我们的竞争性续签申请的重新提交，以继续一项以前作为IRPG资助三年的高成效研究。这项研究由麻省总医院的鲁道夫·坦齐博士与阿拉巴马大学和约翰·霍普金斯大学的合作研究人员共同领导。这些研究人员自1989年以来一直合作确定、评估和跟踪NIMH遗传学倡议阿尔茨海默病(AD)样本，该样本目前包括457个家庭的1527人，是为研究AD遗传学而收集的最大的统一确定和评估的样本IRPG旨在分析和执行NIMH样本的高分辨率基因组筛查的初步跟进。在基本上完成了最初的目标后，IRPG已经解散，我们正在申请资金，以在基因组筛查中确定的连锁峰中识别新的AD基因，使用位置候选方法，并通过连锁不平衡作图以及预期的19q染色体上的极显著连锁峰(在APOE基因座)，我们的筛查产生了几个区域，证据表明与AD有“暗示”的连锁。根据审查者的建议，在我们修订的申请中的后续研究集中在9号和10号染色体上的两个最优先确认的AD连锁区域，我们和其他小组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的标记来提炼这些连锁区域。然后，我们将测试密集分布的单核苷酸多态(SNPs)簇与AD的关联，最初是在引人注目的候选基因中，然后是在看似合理的候选基因中。推测的AD基因也将在一个独立的样本中进行测试，以进行关联分析，该样本是阿尔茨海默氏症遗传学联合会(CAG)样本。如果最初的候选基因方法没有导致疾病位点，我们将继续分析以前没有被认为是AD候选基因的SNP簇，如果必要的话-在基因间区。任何被发现与阿尔茨海默病密切相关的SNP都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跟踪符合“暗示”连锁标准的其他基因座。虽然我们设计了一种策略，整合了最好的可用方法来识别与阿尔茨海默病等复杂疾病有关的基因，但我们意识到该领域正在迅速演变。因此，随着研究的进展，我们将定期调整我们的方法，以利用方法学的进步。

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.