Developmental methylomics of childhood trauma and its health consequences

儿童创伤的发育甲基组学及其健康后果

基本信息

批准号：
8884675
负责人：
EDWIN VAN DEN OORD
金额：
$ 62.21万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8884675
关键词：
Address Adult Adverse event Affect Age Algorithms Animals Bioinformatics Biological Biological Assay Biological Markers Blood Brain Cells Cessation of life Child Childhood Clinical Cost Measures DNA DNA Methylation DSM-IV Data Development Diagnostic Environmental Risk Factor Event Family Family Violence Finding by Cause Goals Health Human Human Genome Intervention Length Life Link Long-Term Effects Longitudinal Studies Measures Mediating Mediator of activation protein Medical Mental Health Methylation Modeling Natural experiment Outcome Pathway interactions Personality Poverty Prevention Procedures Process Protein Binding Domain Reading Reporting Research Risk Role Sampling Sexual abuse Site Social Functioning Socioeconomic Status Staging Stress Study Subject Technology Testing Time Trauma Variant abuse neglect bisulfite case control cost data reduction design emotional distress experience genome wide association study human data illegal behavior improved insight interest maltreated children methyl group methylation biomarker methylome next generation sequencing outcome forecast pediatric trauma physical abuse physical conditioning prospective psychologic pyrosequencing response stressor

项目摘要

DESCRIPTION (provided by applicant): By age 16, close to 2 children in 3 have suffered at least one adverse experience such as parental death, life-threatening illness, or family violence. Adversities have been robustly linked to an array of psychiatric and other medical conditions where the consequences can persist far into adulthood. The medical costs, mental health utilization, societal cost, and the psychological toll on its victims are tremendous. It is not wel understood how early adverse experiences are biologically embedded and what processes might be set into effect that would sustain long term health risks. To address these key questions we need prospective, longitudinal studies that begin in childhood and continue into adulthood and where data on adverse experiences can be linked to biosamples collected before and after adverse experiences as well as in adulthood. We propose just such a study, using already available samples from the Great Smoky Mountains Study (GSMS) and DNA methylation as the biological mechanism of interest. Methylation involves the addition of a methyl group to DNA and, in human non-embryonic cells, occurs mainly at CpGs. Animal and human research have shown that adverse events can result in persistent methylation changes with long-term phenotypic consequences. Capitalizing on these observations we propose a comprehensive study in a real life setting. First, we will use next-generation sequencing (NGS) to assay all >28 million CpGs in the human genome to study adversity-induced methylation changes and their persistence over time. To avoid false positive findings caused by pre-existing "case-control" differences (e.g. personality related or environmental factors such as poverty) we use a design that considers within-subject changes before and after DSM-IV extreme stressor events. Random assignment to trauma being impossible, this "natural experiment" is arguably the next best option this topic in children. Consistent with a model assuming a mediator role of methylation, we will select only the methylation sites that changed as a result of adversity for association testing with health risks. For the substantive and methodological reasons, we propose to treat maltreated children as a separate group in these analyses. Finally, we will replicate the 175 top findings in independent samples using a different and targeted technology to minimize the risk of false positives due to sampling and/or possibly technical errors. Successful completion of this project implies that we gained insight into how childhood adversities alters the methylome and what changes persist over time. We will also have identified processes associated with health risks in childhood/adulthood and found replicable methylation biomarkers associated with these risks. Methylation markers are stable and can be measured cost-effectively in blood, which is relatively easy to collect. Our findings therefore als have considerable translational potential as, for example, diagnostic "biomarkers of health risk" that could guide intervention strategies.

描述（由申请人提供）：到16岁，近3名儿童至少遭受了一种不利的经历，例如父母死亡，威胁生命的疾病或家庭暴力。逆境与一系列精神病和其他医疗状况有着牢固的联系，在这种情况下，后果可能会持续到成年。医疗费用，心理健康利用，社会成本以及受害者的心理损失是巨大的。尚不理解生物学嵌入的早期不良经历是多么早期的不良经历，以及可以将长期健康风险的哪些过程设定为生效。为了解决这些关键问题，我们需要从童年开始并持续到成年的前瞻性研究，以及在不良经历的数据中与不良经历和成年后收集的生物样本有关的数据。我们仅提出了一项研究，使用大烟山研究（GSM）和DNA甲基化的已经可用的样品作为感兴趣的生物学机制。甲基化涉及将甲基添加到DNA中，并且在人非胚胎细胞中主要发生在CPGS。动物和人类的研究表明，不良事件会导致持续的甲基化变化，而长期表型后果。利用这些观察结果，我们在现实生活中提出了一项全面的研究。首先，我们将使用下一代测序（NGS）在人类基因组中分析所有> 2800万个CPG，以研究逆境引起的甲基化变化及其持久性。为了避免由现有的“病例对照”差异（例如人格相关或环境因素（例如贫困））引起的假阳性发现，我们使用了一种考虑在DSM-IV极端压力事件之前和之后考虑受试者内部变化的设计。随机分配创伤是不可能的，这种“自然实验”可以说是儿童中这个主题的下一个最佳选择。与假设甲基化作用的模型一致，我们将仅选择因逆境而改变的甲基化位点，以与健康风险结合测试。出于实质性和方法上的原因，我们建议将虐待儿童视为这些分析中的一个单独的群体。最后，我们将使用不同的和有针对性的技术在独立样本中复制175个最佳发现，以最大程度地降低由于采样和/或可能的技术错误而导致假阳性的风险。该项目的成功完成意味着我们深入了解了童年的逆境如何改变甲基化的甲基团以及变化的变化随着时间的流逝。我们还将确定与儿童/成年期健康风险相关的过程，并发现与这些风险相关的可复制甲基化生物标志物。甲基化标记是稳定的，可以在血液中成本效益，这相对容易收集。因此，我们的发现具有相当大的转化潜力，例如，可以指导干预策略的诊断“健康风险生物标志物”。