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

早期压力如何渗透到皮肤之下：DNA甲基化在青少年行为问题和共病症状发展中的作用

• 批准号: ES/N001273/1
• 负责人: Charlotte Cecil
• 金额: $ 31.92万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=ES%2FN001273%2F1
• 关键词: How; early; stress; gets; under

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.

行为问题是英国儿童治疗转诊的最常见原因，估计每年花费220亿英镑。有行为问题的儿童有一系列攻击性和反社会行为（如打架、偷窃、欺凌），影响他们遵守规则和适应社会的能力，在学校表现良好，与同龄人建立健康的关系。那些得不到治疗的人在成年生活中也更有可能遭受许多负面后果，包括就业前景和收入较低、与警察接触较多以及生活质量较低。因此，预防和治疗行为问题是一个主要的公共卫生优先事项。到目前为止，成功的治疗已经复杂的事实，即儿童与行为问题往往会遇到一些额外的精神症状，如焦虑，抑郁和多动症。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，目前所知甚少的具体过程中，早期逆境增加风险的行为问题和共同发生的精神症状。最近的发现表明，我们在环境中的经历可以通过引起基因表达的“表观遗传”变化来影响我们的发展-换句话说，通过打开或关闭特定基因。动物研究发现，早期的逆境，如产妇护理不良，可以改变基因的活性，这些基因对动物如何应对未来的压力事件很重要，导致焦虑和攻击行为增加。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变化的，并且可能是可逆的。到目前为止，现有的少量人类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，回顾性地询问他们的童年经历，并仅在一个时间点包括遗传信息。因此，很难理解随着时间的推移，基因活性如何随着环境的影响而变化，以及这些变化是否有助于儿童期精神问题的发展。拟议的项目将是第一个研究环境风险，表观遗传学和精神问题之间的联系，从怀孕到青春期。分析将基于从两大儿童群体收集的数据，这两大群体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，因为它们在发育过程中多次具有表观遗传数据。此外，它们还包含关于产前和产后环境风险以及幼儿期以后精神症状的数据。总之，这些信息将使我们能够解决三个主要目标：（i）追踪环境风险如何影响从出生到儿童晚期的基因活动;（ii）确定表观遗传变化是否在行为问题的发展中发挥作用;（iii）检查这些相同的变化是否也有助于共同发生的精神症状的发展。通过这项研究，我们希望更好地了解早期生活压力如何“深入皮肤”影响儿童发育。我们还希望，通过研究这些进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展窗口。最后，通过研究行为问题和共同发生的症状是否涉及共同或不同的生物因素，我们希望有助于更有效的治疗策略的发展。

项目成果

Schizophrenia polygenic risk is associated with child mental health problems through early childhood adversity: evidence for a gene-environment correlation.

• DOI: 10.1007/s00787-021-01727-4
• 发表时间: 2022-03
• 期刊: European child & adolescent psychiatry
• 影响因子: 6.4
• 作者: Bolhuis K;Steenkamp LR;Blanken LME;Neumann A;Jansen PR;Hillegers MHJ;Cecil CAM;Tiemeier H;Kushner SA
• 通讯作者: Kushner SA

The Wiley Handbook of Disruptive and Impulse-Control Disorder

威利破坏性和冲动控制障碍手册

• 发表时间: 2017
• 作者: Barker ED

DNA methylation and substance-use risk: a prospective, genome-wide study spanning gestation to adolescence.

• DOI: 10.1038/tp.2016.247
• 发表时间: 2016-12-06
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Cecil CA;Walton E;Smith RG;Viding E;McCrory EJ;Relton CL;Suderman M;Pingault JB;McArdle W;Gaunt TR;Mill J;Barker ED
• 通讯作者: Barker ED

Inflammation-related epigenetic risk and child and adolescent mental health: A prospective study from pregnancy to middle adolescence.

• DOI: 10.1017/s0954579418000330
• 发表时间: 2018-08
• 期刊: Development and psychopathology
• 影响因子: 3.3
• 作者: Barker ED;Cecil CAM;Walton E;Houtepen LC;O'Connor TG;Danese A;Jaffee SR;Jensen SKG;Pariante C;McArdle W;Gaunt TR;Relton CL;Roberts S
• 通讯作者: Roberts S

A Methylome-Wide Association Study of Trajectories of Oppositional Defiant Behaviors and Biological Overlap With Attention Deficit Hyperactivity Disorder.

• DOI: 10.1111/cdev.12957
• 发表时间: 2018-09
• 期刊: Child development
• 影响因子: 4.6
• 作者: Barker ED;Walton E;Cecil CAM;Rowe R;Jaffee SR;Maughan B;O'Connor TG;Stringaris A;Meehan AJ;McArdle W;Relton CL;Gaunt TR
• 通讯作者: Gaunt TR