Identification and Characterization of Novel AD Genes

描述（由申请人提供）：这是我们竞争续期申请的重新提交，以继续之前作为IRPG资助的三年高效研究。这项研究由麻省总医院的Rudolph Tanzi博士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进行，这些研究人员自1989年以来一直在一起确定，评估和跟踪NIMH遗传倡议阿尔茨海默病（AD）样本，目前包括457个家庭的1527名个体。IRPG的目的是对NIMH样本的高分辨率基因组筛选进行分析和初步随访。在基本完成了最初的目标后，IRPG已经被解除，我们正在申请资金，使用定位候选方法，通过连锁不平衡定位，在基因组筛选中鉴定出的连锁峰中鉴定出新的AD基因，除了在染色体19q （APOE位点）上预期的高度显著的连锁峰外，我们的筛选还产生了几个与AD“暗示”连锁的区域。根据审稿人的建议，我们修改后的申请的后续研究集中在9号染色体和10号染色体上两个最优先确认的AD连锁区域，我们和其他小组已经观察到一致的连锁证据。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完善这些连锁区域。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，首先是在令人信服的候选基因中，然后是在可信的候选基因中。假定的阿尔茨海默病基因也将在一个独立的样本中进行测试，该样本是为关联分析而组装的，即阿尔茨海默病遗传学联合会（CAG）样本。如果最初的候选基因方法不能导致疾病位点，我们将继续分析以前未被认为是AD候选基因的SNP簇，并且-如果必要的话-在基因间区域。任何被发现与AD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，我们才会采用同样的一般方法来跟进其他符合“暗示性”联系标准的基因座。虽然我们已经设计了一种策略，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.