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：
8759696
负责人：
EDWIN VAN DEN OORD
金额：
$ 71.69万
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 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8759696
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 methylome next generation sequencing outcome forecast pediatric trauma physical abuse physical conditioning prospective psychologic public health relevance 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 岁时，三分之二的儿童中就有近 2 人经历过至少一种不良经历，例如父母死亡、危及生命的疾病或家庭暴力。逆境与一系列精神疾病和其他疾病密切相关，其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。目前尚不清楚早期的不良经历是如何在生物学上嵌入的，以及可能采取哪些过程来维持长期的健康风险。为了解决这些关键问题，我们需要从儿童期开始并持续到成年期的前瞻性纵向研究，其中不良经历的数据可以与不良经历前后以及成年期收集的生物样本联系起来。我们提出这样一项研究，使用来自大烟山研究 (GSMS) 的现有样本和 DNA 甲基化作为感兴趣的生物机制。甲基化涉及在 DNA 上添加甲基，在人类非胚胎细胞中，主要发生在 CpG 处。动物和人类研究表明，不良事件可能导致持续的甲基化变化，并产生长期的表型后果。利用这些观察结果，我们提出在现实生活环境中进行一项全面的研究。首先，我们将使用下一代测序 (NGS) 来检测人类基因组中所有超过 2800 万个 CpG，以研究逆境诱导的甲基化变化及其随时间的持续性。为了避免因预先存在的“病例对照”差异（例如性格相关或贫困等环境因素）而导致假阳性结果，我们使用的设计考虑了 DSM-IV 极端压力事件前后受试者内部的变化。随机分配创伤是不可能的，这种“自然实验”可以说是儿童中该主题的下一个最佳选择。与假设甲基化中介作用的模型一致，我们将仅选择因逆境而改变的甲基化位点来进行与健康风险的关联测试。出于实质性和方法论的原因，我们建议在这些分析中将受虐待的儿童视为一个单独的群体。最后，我们将使用不同的针对性技术在独立样本中复制 175 个最重要的发现，以最大程度地减少由于采样和/或可能的技术错误而导致误报的风险。该项目的成功完成意味着我们深入了解了童年逆境如何改变甲基化组以及随着时间的推移持续存在哪些变化。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的甲基化生物标志物。甲基化标记物稳定，可以在相对容易收集的血液中经济高效地进行测量。因此，我们的研究结果也具有相当大的转化潜力，例如，作为可以指导干预策略的诊断“健康风险生物标志物”。