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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微生物防御在阿尔茨海默病（AD）发病机制中的重要作用，从1952年Sjögren开始，至少有60年的假设和研究。扩散大型，多组阿尔茨海默病（AD）集中的数据集提供了前所未有的和公正的观点， AD的分子网络。通过对病毒RNA和DNA序列的直接检测，根据第二代测序数据，我们观察到许多病毒种类在衰老的大脑中存在，并与之相关。多种病毒种属与AD生物学，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相关性。总之，这些发现表明多种病毒在AD中的丰度增加，在多种脑组织中，对于玫瑰花状病毒HHV-6A、HHV-6 B和HHV-7的作用（Readhead等，In Press，Neuron）。 AD的“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的一个重要特征。因果关系的贡献，或反映一般神经退行性过程的机会乘客。HHV-6A、HHV- HHV-6 B和HHV-7在病毒中具有显著的整合到宿主的亚端粒区域的能力细胞染色体，最近的研究表明，遗传的，染色体整合的HHV-6（ciHHV-6）是目前在美国和英国人口的约1%。这为自然实验提供了机会，我们可以潜在地将遗传性病毒因素与AD风险联系起来，并更好地解决诸如这些的病毒能够至少在一定程度上导致AD的发作和/或进展。一些情况。我们的假设是，iciHHV-6将成为发展AD的危险因素。这是一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，这可以为后续的翻译研究提供信息，（2）以遗传形式研究这些病毒，使我们能够更好地了解病毒在AD中因果作用的可能性。我们对全基因组序列（WGS）和全外显子组序列（WES）进行了初步研究在上述队列中的个体上产生的，已经显示出一些证据表明，然而，队列规模仅具有适度的把握度来检测AD个体中的iciHHV-6的差异，像iciHHV-6这样罕见的遗传变异这项研究的目的是将联合收割机的可用遗传数据，阿尔茨海默病测序项目和加速阿尔茨海默病医疗合作，确定该队列中的iciHHV-6实例，并进行遗传关联研究，评估是否 iciHHV-6是AD或AD相关性状的危险因素。