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

染色体整合人类疱疹病毒 6 作为阿尔茨海默病危险因素的研究

• 批准号: 9904309
• 负责人: Benjamin Readhead
• 金额: $ 20.66万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904309
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Antibodies; Antibody Repertoire; Autopsy; Biological Markers; Biology; Cells; Chromosomes; Classification; Clinical; Communities; DNA; DNA Markers; DNA Sequence; Data; Data Set; Dementia; Development; Fluorescent in Situ Hybridization; Future; Gene Expression; Genetic; Genetic Diseases; Genetic Risk; Goals; HHV-6A; HHV-6B; Herpesviridae; Human Herpesvirus 6; Human Herpesvirus 7; Immunocompromised Host; Individual; Inherited; Investigation; Link; Medical; Microbe; Molecular; Natural experiment; Nerve Degeneration; Neurons; Outcome; Pathogenesis; Patients; Population; Process; RNA Sequences; Regulation; Reporting; Research; Research Personnel; Resolution; Risk Factors; Risk stratification; Role; Roseolovirus; Senile Plaques; Sjogren' s Syndrome; Suggestion; Time; Validation; Variant; Viral; Viral Physiology; Viral Proteins; Virus; aging brain; antimicrobial; brain tissue; cohort; comparative; density; digital; disorder subtype; endophenotype; exome; genetic association; improved; insight; interest; molecular diagnostics; multiple omics; neuropathology; next generation sequencing; novel; pathogen; pathogenic bacteria; pathogenic virus; patient subsets; pre-clinical; risk variant; trait; transcriptome sequencing; transcriptomics; translational study; viral RNA; whole genome

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.

项目概要 微生物和抗菌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，人们对这一现象的假设和研究至少已经有 60 年了。 以大型、多组学阿尔茨海默病 (AD) 为中心的数据集提供了前所未有的、公正的观点 AD 背后的分子网络。通过下一步直接检查病毒RNA和DNA序列 通过生成测序数据，我们观察到衰老大脑中存在许多病毒种类，并将 与 AD 生物学相关的多种病毒，包括 AD 遗传风险网络的调节、AD 基因表达 变化以及与临床痴呆评级和神经病理学负担的关联。综合起来，这些发现 表明AD中多种病毒在多个脑组织中的丰度增加，并且具有显着的特征 玫瑰病毒 HHV-6A、HHV-6B 和 HHV-7 的作用（Readhead 等人，In Press，Neuron）。 AD“病原体假说”的一个关键挑战是了解这些发现是否代表了 AD 的“病原体假说”。 因果贡献，或反映一般神经退行性过程的机会主义乘客。 HHV-6A、HHV- 6B 和 HHV-7 在病毒中因其整合到宿主亚端粒区域的能力而引人注目 细胞染色体，最近的研究表明，遗传性、染色体整合的 HHV-6 (ciHHV-6) 是 大约有 1% 的美国和英国人口存在。这提供了进行自然实验的机会， 我们可以将遗传性病毒因素与 AD 风险联系起来，并更好地解决以下问题的合理性： 诸如此类的病毒能够导致 AD 的发作和/或进展，至少在以下情况下 某些情况下。我们的假设是 iciHHV-6 将成为 AD 的危险因素。这是一个 值得评估的假设，如：(1) 它代表了识别新的 AD 患者亚群的机会， 这可以为后续的转化研究提供信息，并且（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。 我们对全基因组序列（WGS）和全外显子组序列（WES）的初步研究 对上述队列中的个体产生的结果显示，有一些证据表明， iciHHV-6 存在于 AD 个体中，但是队列大小仅能适度检测 AD 患者中的差异 罕见的遗传变异，如 iciHHV-6。这项拟议研究的目标是结合来自 阿尔茨海默病测序项目和加速阿尔茨海默病医疗合作伙伴关系 识别该队列中的 iciHHV-6 实例，并进行遗传关联研究，评估是否 iciHHV-6 是 AD 或 AD 相关特征的危险因素。