Developmental methylomics of childhood trauma and its health consequences

描述（由申请人提供）：到16岁时，近三分之二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。逆境与一系列精神疾病和其他医疗状况密切相关，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代价都是巨大的。目前尚不清楚早期的不良经历是如何在生物学上根深蒂固的，以及哪些过程可能会产生影响，从而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持续到成年的前瞻性纵向研究，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学机制。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CpGs上。动物和人类研究表明，不良事件可导致持续的甲基化变化，并带来长期的表型后果。利用这些观察结果，我们建议在现实生活中进行全面的研究。首先，我们将使用下一代测序（NGS）分析人类基因组中所有的bb1028万个CpGs，以研究逆境诱导的甲基化变化及其随时间的持久性。为了避免由于预先存在的“病例对照”差异（如性格相关或环境因素，如贫困）引起的假阳性结果，我们使用了一种设计，考虑了DSM-IV极端压力源事件前后受试者内部的变化。随机分配创伤是不可能的，这个“自然实验”可以说是这个主题在儿童中的次佳选择。与假设甲基化具有中介作用的模型一致，我们将只选择由于逆境而改变的甲基化位点进行与健康风险的关联测试。出于实质性和方法学上的原因，我们建议在这些分析中将受虐待儿童作为一个单独的群体来对待。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个最重要的发现，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深入了解了童年逆境是如何改变甲基组的，以及什么变化会随着时间的推移而持续。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。甲基化标记物是稳定的，可以在血液中成本有效地测量，相对容易收集。因此，我们的研究结果也具有相当大的转化潜力，例如，作为诊断“健康风险的生物标志物”，可以指导干预策略。

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.