Linking DNA methylation with child maltreatment and mental health across adolescence

摘要 虐待儿童是最具破坏性的童年逆境之一，并增加了 多个功能领域的有害后果。然而，并不是所有经历过孩子的人 虐待会出现问题，而那些有类似虐待经历的人可能会表现出非常不同的情况 结果。虐待的不同生物嵌入可能解释了结果的这种异质性。 表观遗传学，或影响基因表达的过程，对于我们理解儿童是如何 虐待会影响到以后的发展。DNA甲基化(DNaM)是研究最充分的表观遗传学 早期生活经历与基因表达和精神状态的改变有关 健康症状。只有少数几项研究使用全基因组方法来检查这些关联 重要的是，在与心理健康相关的基因中，受到虐待的青少年显示出不同的dNaM模式， 但实际上并没有评估结果。没有纵向研究测试全基因组范围内的差异 DNaM在虐待后出现，并预测心理健康症状的出现或变化。一个 相对较新的生物脆弱性指标dNaM年龄已经成为生物老化的一个指标。 这与生活压力有关，并初步支持预测心理健康功能不良的风险。 尽管使用其他指标(例如，端粒长度)将虐待与高级生物老化联系在一起， 还没有纵向研究来检验虐待对dNaM年龄的影响，也没有测试dNaM 年龄在虐待和后来的精神健康症状之间起中介作用。为了解决这些差距，我们将 使用现有的受虐待儿童和对照儿童的纵向样本(n=454)，跟踪调查10年，其中4名 一波又一波的存档样本和无数的心理社会数据。该数据最适合于评估 虐待对全基因组dNaM的影响，与随后的精神健康相关的dNaM模式，以及 青春期(9-23岁)有问题的dNaM模式的潜在解决方案。这是一个 利用一项精心设计的虐待行为纵向研究的现有数据获得前所未有的机会 青年与匹配的对照组，这使我们能够将虐待的影响与其他方面分开 早年的生活压力和逆境，包括邻居和社会经济因素。这项研究将有助于 重要的新证据对我们理解虐待如何影响全基因组表观遗传学至关重要 导致心理健康问题的脆弱性模式。这将进一步发展临床风险。 对受虐待青年的评估和预防方法将对人口产生重大好处 健康。

Abstract Child maltreatment is among the most devastating of childhood adversities and increases vulnerability for deleterious outcomes across a number of domains of functioning. However, not all who experience child maltreatment develop problems and those with similar maltreatment experiences may show very different outcomes. Differential biological embedding of maltreatment likely explains this heterogeneity in outcomes. Epigenetics, or the processes that influence gene expression, are crucial to our understanding of how child maltreatment influences later development. DNA methylation (DNAm) is the most well-studied epigenetic mechanism and has been proposed to link early life experiences to alterations in gene expression and mental health symptoms. Only a few studies have used a genome-wide approach to examine these associations and importantly have shown different DNAm patterns for maltreated youth within genes linked with mental health, but did not actually assess outcomes. No longitudinal investigations have tested genome-wide differences in DNAm that emerge after maltreatment and predict the emergence of, or change in, mental health symptoms. A relatively new measure of biological vulnerability, DNAm age, has emerged as an indicator of biological aging that is associated with life stress and has initial support for predicting risk for poor mental health functioning. Although maltreatment is linked with advanced biological aging using other indices (e.g., telomere length), there have been no longitudinal studies testing the effect of maltreatment on DNAm age, nor testing DNAm age as a mediator between maltreatment and later mental health symptoms. To address these gaps, we will use an existing longitudinal sample of maltreated and comparison children (n=454) followed for 10 years with 4 waves of archived samples and a myriad of psychosocial data. This data is optimal to assess the timing of maltreatment effects on genome-wide DNAm, DNAm patterns associated with subsequent mental health, and the potential resolution of problematic DNAm patterns across adolescence (ages 9-23). This is an unprecedented opportunity to capitalize on existing data from a well-designed longitudinal study of maltreated youth with a matched comparison group, which allows us to separate maltreatment effects from other aspects of early life stress and adversity, including neighborhood and socioeconomic factors. This study will contribute important new evidence crucial to our understanding of how maltreatment affects genome-wide epigenetic patterns of vulnerability that result in mental health problems. This will further the development of clinical risk assessment and prevention approaches for maltreated youth which will be of substantial benefit to population health.