Identification of Genetic Risk Factors for AD and FTD

描述（由申请人提供）：痴呆症的遗传基础的鉴定仍然是研究的一个重要目标，其目的是提高我们对这些疾病的理解并开发新的治疗方法。在额颞叶痴呆（FTD）遗传病例中发现的tau突变表明，tau失调可导致神经退行性疾病。但是，尚未在AD中描述tau突变，并且tau突变占家族性FTD病例的约15%。许多研究小组不断发展的工作表明，参与修饰tau的基因，特别是那些调节tau磷酸化的基因，是导致这些AD和FTD遗传风险的诱人候选者。在病理学或遗传学基础上尚未确定tau异常的情况下，参与蛋白质加工的关键机制的失调 并且折叠装置可以提供额外的遗传风险因素。本提案的目标是使用一种新的重新测序方法来识别和确认额颞叶痴呆（FTD）和阿尔茨海默病（AD）中的这些新的遗传风险因素，该方法允许对由NIA资助的ADC的多中心协作组招募的患者进行大规模平行，具有成本效益的基因重新测序，完全符合所述RFA目标。这种方法将允许对假设进行巡回评估，即这些通路与神经退行性疾病有关，并且对这些通路有很强的潜在生物学和病理生理学原理，而不是简单地一次测试一个基因。其中一些研究将在研究不足的少数民族中完成，提供尚未详细研究的人群中序列变异的重要数据，这些数据通常尚未在公共或商业数据库中获得。来自这些患者的生物材料和临床数据，沿着获得的遗传数据将被保存在NACC和NCRAD，从而提供了宝贵的遗传资源。这些数据将与更多病例和对照组中的其他潜在SNP整合，以便最大限度地利用单倍型信息。将进行相关性研究，以确定FTD和每个AD受试者种族队列中的疾病相关变异，从而确定可提供重要数据的任何人群特异性风险变异，这些数据将作为这些人群未来研究的基础。

DESCRIPTION (provided by applicant): The identification of the genetic bases of dementias remains an important goal of research whose aims are to improve our understanding and develop new therapeutics for these diseases. The discovery of tau mutations in inherited cases of frontotemporal dementia (FTD) demonstrated that tau dysregulation can cause neurodegenerative disease. But, tau mutations have not been described in AD, and tau mutations account for about 15% of familial FTD cases. An evolving body of work from many groups suggests that genes involved in modifying tau, especially those that modulate tau phosphorylation are enticing candidates for contributing to the genetic risk for these AD and FTD. In cases where tau abnormalities have not been identified on a pathological or genetic basis, dysregulation in key machinery involved in protein processing and folding apparatus may provide additional genetic risk elements. The goal of this proposal is to identify and confirm these novel genetic risk factors in Frontotemporal Dementia (FTD) and Alzheimer's Disease (AD) using a novel re-sequencing approach that allows massively parallel, cost-effective gene re-sequencing in patients recruited by a multi-center collaborative group of NIA funded ADCs, fully consistent with the stated RFA goals. This approach will allow a tour de force assessment of the hypothesis that these pathways that have been implicated in neurodegenerative disease, and for whom there is a strong underlying biological and pathophysiological rationale are involved, rather than simply testing one gene at a time. Some of these studies will be completed in understudied ethnic minorities, providing important data on sequence variants in populations that have not been studied in this detail and for whom such data is typically not yet available in public or commercial databases. The biomaterials and clinical data from these patients, along with the genetic data obtained will be deposited with the NACC and NCRAD, thus providing an invaluable genetic resource. This data will be integrated with other potential SNPs in a larger set of cases and controls, so as to make maximum use of haplotype information. Association studies will be performed to identify disease-associated variants in FTD and in each ethnic cohort of AD subjects, so as to identify any population specific risk variants that can provide important data that will serve as the foundation for future studies in these groups.