Investigation of chromosomally integrated Human Herpesvirus 6 as a risk factor for Alzheimer's disease

项目摘要 微生物和抗菌素防御在阿尔茨海默病(AD)发病机制中的重要作用 从1952年的Sjögren开始，至少60年来一直被假定和调查。病毒的扩散 关注阿尔茨海默病(AD)的大型多组学数据集提供了前所未有的、公正的观点 作为AD基础的分子网络。通过在NEXT中直接检测病毒RNA和DNA序列 世代测序数据，我们已经观察到许多病毒物种在老化的大脑中的存在，并与 多种病毒与AD生物学，包括AD遗传风险网络的调控，AD基因的表达 变化，以及与临床痴呆评分和神经病理负担的关系。总而言之，这些发现 表明多种病毒在AD中的丰度增加，跨越多个脑组织，显著 玫瑰花叶病毒HHV-6A、HHV-6B和HHV-7的作用(Readhead等人，in Press，Neuron)。 阿尔茨海默病“病原体假说”的一个关键挑战是理解这些发现是否代表着一种 因果贡献，或反映机会主义乘客的一般神经退变过程。HHV-6A，HHV- 6B和HHV-7在病毒中是引人注目的，因为它们能够整合到宿主的亚端粒区域 细胞染色体，最近的研究表明，遗传的、染色体整合的HHV-6(CIHHV-6)是 存在于大约1%的美国和英国人口中。这为自然实验提供了机会， 在那里，我们可以潜在地将遗传的病毒因素与AD风险联系起来，并更好地解决 像这样的病毒能够因果地促进AD的发生和/或进展，至少在 在某些情况下。我们的假设是，iciHHV-6将成为发展为AD的危险因素。这是一个 评估有价值的假设：(1)它代表了识别新的AD患者亚群的机会， 这可能会为后续的翻译研究提供信息，以及(2)以遗传形式研究这些病毒，将 使我们能够更好地理解病毒在AD中的因果作用的合理性。 全基因组序列(WGS)和全外显子组序列(WES)的初步研究 在上述队列中的个人身上产生的，已经显示出一些证据表明 在阿尔茨海默病患者中，ICHHV-6，然而，队列大小只能适度地检测出 罕见的遗传变异，如iciHHV-6。这项拟议研究的目标是将现有的遗传数据 阿尔茨海默病测序项目和加速阿尔茨海默病的医疗伙伴关系 确定该队列中的iciHHV-6实例，并进行遗传关联研究，以评估 IciHHV-6是AD或AD相关特征的危险因素。

Project Summary Important roles for microbes and antimicrobial defenses in the pathogenesis of Alzheimer's disease (AD) have been postulated and investigated for at least six decades, beginning with Sjögren in 1952. The proliferation of large, multiomic Alzheimer's disease (AD) focused data sets offer unprecedented and unbiased views of the molecular networks that underlie AD. Through the direct examination of viral RNA and DNA sequences in next generation sequencing data, we have observed the presence of many viral species in the aging brain, and linked multiple viral species with AD biology, including regulation of AD genetic risk networks, AD gene expression changes, and association with clinical dementia rating and neuropathology burden. Together, these findings indicate that multiple viruses are at increased abundance in AD, across multiple brain tissues, with prominent roles for Roseoloviruses HHV-6A, HHV-6B and HHV-7 (Readhead et al, In Press, Neuron). A key challenge for the “pathogen hypothesis” of AD, is to understand whether such findings represent a causal contribution, or reflect opportunistic passengers of a general neurodegenerative process. HHV-6A, HHV- 6B, and HHV-7 are remarkable among viruses for their capacity to integrate into subtelomeric regions of host cell chromosomes, and recent studies have shown that inherited, chromosomally integrated HHV-6 (ciHHV-6) is present in approximately 1% of the US and UK population. This offers the opportunity for a natural experiment, where we can potentially link an inherited viral factor, with AD risk, and better address the plausibility of whether viruses such as these, are capable of causally contributing to the onset and/or progression of AD, at least under some circumstances. Our hypothesis is that iciHHV-6 will emerge as a risk factor for developing AD. This is a valuable hypothesis to evaluate, as: (1) it represents an opportunity to identify a novel AD patient subpopulation, which could inform subsequent translational studies, and (2) studying these viruses in an inherited form, will enable us to better understand the plausibility of a causal role for viruses in AD. Our preliminary studies of whole genome sequences (WGS) and whole exome sequences (WES) generated on the individuals in the cohort described above, have shown some evidence of increased rates of iciHHV-6 among individuals with AD, however the cohort size is only modestly powered to detect differences in rare inherited variations like iciHHV-6. The goal of this proposed study, is to combine available genetic data from the Alzheimer's Disease Sequencing Project and Accelerating Medical Partnerships in Alzheimer's disease to identify instances of iciHHV-6 within this cohort, and perform a genetic association study that evaluates whether iciHHV-6 is a risk factor for AD, or AD related traits.