Identification and Characterization of Novel AD Genes

描述（由申请人提供）：这是我们竞争性更新申请的重新提交，以继续之前作为IRPG资助三年的高效研究。该研究由马萨诸塞州总医院的Rudolph Tanzi博士与亚拉巴马大学和约翰霍普金斯大学的共同研究者合作领导。这些研究人员自1989年以来一直在一起工作，以确定，评估和跟踪NIMH遗传学倡议阿尔茨海默病（AD）样本，目前包括457个家庭的1527名个体，为AD遗传学研究而收集的最大的统一确定和评估的样品IRPG旨在分析和执行NIMH样品的高分辨率基因组筛选的初步跟踪。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，使用位置候选方法，通过连锁不平衡作图来鉴定基因组筛选中鉴定的连锁峰内的新AD基因。（在APOE基因座处），我们的筛选产生了具有与AD“暗示性”连锁的证据的几个区域。雅阁评审员的建议，我们修订后的申请中的后续研究集中在9号和10号染色体上两个优先级最高的已确认AD连锁区域，我们和其他小组在那里观察到了连锁的一致证据。我们计划完善这些连锁区域使用高度多态性标记的连锁和家庭为基础的关联分析。然后，我们将测试密集的单核苷酸多态性（SNP）与AD的关联，最初在令人信服的，然后在合理的候选基因。假定的AD基因也将在一个独立的样本中进行测试，该样本是阿尔茨海默氏症遗传学协会（CAG）样本。如果最初的候选基因方法没有导致疾病位点，我们将继续通过分析先前未被认为是AD候选基因的SNP簇，以及-如果必要的话-在基因间区域。发现与AD强烈相关的任何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通用方法来跟踪符合“暗示性”连锁标准的其他基因座。虽然我们已经设计了一种策略，整合了最好的方法来识别参与AD等复杂疾病的基因，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.