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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease patient Alzheimer&apos 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&apos 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

项目摘要

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.

项目摘要微生物和抗菌防御的重要作用在阿尔茨海默氏病（AD）的发病机理中从1952年开始从Sjögren开始，我们进行了假定和调查至少六十年。大型，多瘤的阿尔茨海默氏病（AD）的集中数据集提供了前所未有的无偏见的观点基于AD的分子网络。通过直接检查下一个病毒RNA和DNA序列生成测序数据，我们观察到衰老的大脑中存在许多病毒物种，并连接具有AD生物学的多种病毒物种，包括调节AD遗传风险网络，AD基因表达变化以及与临床痴呆评级和神经病理学的关联。在一起，这些发现表明多种病毒在多个脑组织中的AD中的丰度增加，显着 HHV-6A，HHV-6B和HHV-7的角色（Readhead等人，印刷中，神经元）。 AD的“病原体假设”的主要挑战是了解此类发现是否代表因果贡献，或反映一般神经退行性过程的机会主义密码。 HHV-6A，HHV- 6B和HHV-7在病毒中非常出色，因为它们能够整合到宿主的亚teloseric区域细胞染色体，最近的研究表明，遗传性的，染色体整合的HHV-6（CIHHV-6）为大约有1％的美国和英国人口。这为自然实验提供了机会我们可以将遗传病毒因素与AD风险联系起来，并更好地解决是否可以解决是否存在的合理性诸如此类的病毒能够随便促进AD的发作和/或进展某些情况。我们的假设是ICIHHV-6将成为开发AD的危险因素。这是一个值得评估的有价值的假设，因为：（1）它代表了识别新型AD患者亚群的机会可以为随后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了解病毒在AD中的因果作用的合理性。我们对整个基因组序列（WGS）和整个外显子组序列（WES）的初步研究上述人群中的个体产生，显示了一些证据表明 ICIHHV-6在患有AD的个体中，但同队的大小仅适度地检测罕见的继承变体，例如ICIHHV-6。这项拟议的研究的目的是将可用的遗传数据结合在一起阿尔茨海默氏病测序项目和加速阿尔茨海默氏病的医疗伙伴关系确定ICIHHV-6在该队列中的实例，并进行遗传关联研究，以评估是否评估是否 ICIHHV-6是AD或与AD相关性状的危险因素。