Developmental methylomics of childhood trauma and its health consequences

描述(申请人提供)：到16岁时，近2/3的儿童至少经历过一次不良经历，如父母死亡、危及生命的疾病或家庭暴力。逆境与一系列精神和其他医疗状况密切相关，其后果可能会一直持续到成年。其医疗成本、心理健康利用率、社会成本以及受害者的心理代价都是巨大的。我们还不知道早期的不良体验是如何在生物学上嵌入的，以及可能实施哪些过程来维持长期的健康风险。为了解决这些关键问题，我们需要从童年开始并一直持续到成年的前瞻性、纵向研究，其中关于不良经历的数据可以与在不良经历之前、之后以及成年期间收集的生物样本联系起来。我们建议进行这样一项研究，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学机制。甲基化包括将甲基加到DNA上，在人类非胚胎细胞中，主要发生在CPGS。动物和人类的研究表明，不良事件可能导致持久的甲基化变化，并产生长期的表型后果。基于这些观察，我们建议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)来分析人类基因组中的所有&GT；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。为了避免因先前存在的“病例对照”差异(例如，个性相关或环境因素，如贫困)而导致的假阳性结果，我们使用了一种设计，该设计考虑了DSM-IV极端应激源事件前后受试者内部的变化。随机分配给创伤是不可能的，这一“自然实验”可以说是儿童这个话题的次佳选择。与假设甲基化起中介作用的模型一致，我们将只选择因逆境而改变的甲基化位点，用于与健康风险的关联测试。出于实质和方法上的原因，我们建议在这些分析中将虐待儿童作为一个单独的群体对待。最后，我们将使用不同和有针对性的技术在独立样本中复制175个最大的发现，以最大限度地减少由于采样和/或可能的技术错误而导致的假阳性风险。这个项目的成功完成意味着我们洞察到童年的逆境是如何改变甲基组的，以及随着时间的推移，哪些变化会持续下去。我们还将确定与儿童/成人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记物。甲基化标记物是稳定的，可以在血液中经济有效地测量，这相对容易收集。因此，我们的发现具有相当大的翻译潜力，例如，可以作为可以指导干预策略的诊断性“健康风险生物标志物”。

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.