How early stress gets under the skin: The role of DNA methylation in the development of youth conduct problems and comorbid symptoms

在英国，行为问题是儿童转介治疗的最常见原因，每年花费约220亿英镑。有行为问题的儿童从事一系列攻击性和反社会行为（例如打架、偷窃、欺凌），影响他们遵守规则和适应社会的能力，影响他们在学校的良好表现，影响他们与同龄人建立健康关系的能力。那些不接受治疗的人在成年后面临许多负面后果的风险也会增加，包括更低的就业前景和收入，更多地与警察接触，以及更低的生活质量。因此，预防和治疗行为问题是一项重要的公共卫生优先事项。迄今为止，由于有行为问题的儿童经常会出现一些额外的精神症状，如焦虑、抑郁和多动，成功的治疗变得复杂起来。有趣的是，研究表明，许多增加行为问题风险的因素——例如贫困、家庭冲突、严厉的纪律和父母的精神疾病——也增加了这些其他精神症状的风险，指出了一个可能的共同原因。然而，目前对早期逆境增加行为问题和同时发生的精神症状风险的具体过程知之甚少。最近的发现表明，我们在环境中经历的事情可以通过引起基因表达的“表观遗传”变化来影响我们的发育。通过打开或关闭特定的基因。动物研究发现，早期的逆境，比如糟糕的母性照顾，会改变对动物如何应对未来压力事件很重要的基因活动，导致类似焦虑和攻击的行为增加。重要的是，这项工作还表明，基因的变化可能不是永久性的，而是在整个生命周期中动态的，并且可能是可逆的。到目前为止，对人类的少量现有研究支持环境可以通过表观遗传变化影响心理健康的观点。然而，这些研究通常涉及成年参与者，询问他们的童年经历，并只包括一个时间点的遗传信息。因此，很难理解基因活性是如何随着时间的推移而随着环境的影响而变化的，以及这些变化是否有助于儿童时期精神问题的发展。该项目将首次研究从妊娠期到青春期的环境风险、表观遗传学和精神问题之间的关系。分析将基于从两大儿童组收集的数据，这是雅芳父母和儿童纵向研究（英国）和R世代研究（荷兰）的一部分。这些出生队列非常独特，因为他们在发育过程中多次具有表观遗传数据。此外，它们还包含有关产前和产后环境风险以及从幼儿期开始的精神症状的数据。总的来说，这些信息将使我们能够实现三个主要目标：(i)追踪环境风险如何影响从出生到童年后期的基因活动；（ii）确定表观遗传变化是否在行为问题的发展中起作用；（三）检查这些相同的变化是否也有助于并发精神症状的发展。通过这项研究，我们希望更好地了解早期生活压力是如何“深入皮肤”影响儿童发展的。我们还希望，通过观察这些过程如何随着时间的推移而发生，我们将能够确定预防的关键发育窗口。最后，通过检查行为问题和共同出现的症状是否涉及共同或不同的生物学因素，我们希望有助于制定更有效的治疗策略。

Conduct problems are the most common reason for child treatment referral in the UK, costing an estimated £22 billion a year. Children with conduct problems engage in a range of aggressive and antisocial behaviours (e.g. fighting, stealing, bullying), that affect their ability to follow rules and adapt to society, do well in school, and form healthy relationships with peers. Those who do not receive treatment are also at increased risk for many negative outcomes in adult life, including lower job prospects and earnings, more contact with the police and a lower quality of life. As a result, preventing and treating conduct problems is a major public health priority. To date, successful treatment has been complicated by the fact that children with conduct problems often experience a number of additional psychiatric symptoms, such as anxiety, depression and hyperactivity. Interestingly, studies have shown that many of the factors that increase risk for conduct problems - for example poverty, family conflict, harsh discipline and parental mental illness - also increase risk for these other psychiatric symptoms, pointing to a possible common cause. However, little is currently known about the specific processes by which early adversity increases risk for both conduct problems and co-occurring psychiatric symptoms. Recent discoveries suggest that what we experience in our environment can influence our development by causing 'epigenetic' changes to gene expression- in other words; by switching specific genes on or off. Animal research has found that early adversity, such as poor maternal care, can change the activity of genes important for how animals will respond to future stressful events, leading to increased anxiety-like and aggressive behaviour. Importantly, this work has also demonstrated that changes to genes may not be permanent, but dynamic over the lifespan and potentially reversible. So far, the small number of existing studies in humans supports the idea that the environment can influence mental health through epigenetic changes. However, these studies have typically involved adult participants, asked about their childhood experiences retrospectively and included genetic information only at one time point. Therefore, it has been difficult to understand how gene activity changes in response to environmental influences over time, and whether these changes contribute to the development of psychiatric problems in childhood. The proposed project will be the first to examine associations between environmental risk, epigenetics and psychiatric problems, starting from gestation through to adolescence. Analyses will be based on data collected from two large groups of children as part of the Avon Longitudinal Study of Parents and Children (UK) and Generation R study (Netherlands). These birth cohorts are very unique because they have epigenetic data at multiple times during development. Moreover, they contain data on pre- and post-natal environmental risk, and psychiatric symptoms from early childhood onward. Together, this information will allow us to address three main aims: (i) to trace how environmental risks influence the activity of genes from birth to late childhood; (ii) to establish whether epigenetic changes play a role in the development of conduct problems; and (iii) to examine whether these same changes also contribute to the development of co-occurring psychiatric symptoms. Through this research, we hope to better understand how early life stress 'gets under the skin' to influence child development. We also hope that by looking at how these processes occur over time, we will be able to pinpoint key developmental windows for prevention. Finally, by examining whether conduct problems and co-occurring symptoms involve common or distinct biological factors, we hope to contribute to the development of more effective treatment strategies.