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

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.

Who will benefit from this research?
Given that the proposed project primarily constitutes novel 'basic' research, it is anticipated that the key direct beneficiaries will be researchers working in the fields of developmental psychopathology, biological psychiatry and epigenetics. However, the findings also have the potential to indirectly benefit a range of other users, including professionals working with CP youth (e.g. clinicians, psychologists, social workers), policy makers interested in translating basic scientific findings and the wider public.

How will they benefit from this research?
Researchers: Findings will benefit these users in the short to medium term, by (i) bearing on the advancement of basic science in the area of biological psychiatry and epigenetics, (ii) shedding light into dynamic changes in DNAm across childhood, (iii) increasing understanding of how environmental and epigenetic factors interrelate over time to affect developmental outcomes, such as CP, (iv) identifying common vs distinct biological markers underpinning comorbid symptoms, and (v) illustrating the application of innovative, cross-disciplinary methodologies to the study of longitudinal epigenetic data. As previously stated, pathways to impact within this group will primarily involve publication of papers and conference presentations.

Professionals working with CP youth: Although immediate practical applications are unlikely, professionals working with CP youth may benefit from this research in the medium to long term. In the first instance, research findings may inform a theoretical framework for practitioners to understand how adverse experiences 'get under the skin' to influence child outcomes. Findings may also identify important windows of opportunity for prevention, by tracing the timing of environmental and epigenetic effects on the development of CP and comorbid symptoms. On the longer term, epigenetic findings such as these may help lay the foundation for personalised treatment of CP youth. The potential clinical implications of the research will be communicated to professionals, particularly psychologists, psychiatrists and social workers working with CP youth, in the context of clinical conferences. I also plan to draw on my collaborative network to identify potential clinical outlets. For example, my PhD supervisors (Profs Viding and McCrory) have a continued track record of this type of involvement.

Policy makers: As a postdoctoral researcher, I have been an active participant in forums that consider the applications of basic science findings, for example by participating in special interest parliamentary group seminars and workshops. Meetings such as these represent an ideal opportunity to disseminate findings to parliamentary members who are interested in translating scientific findings to inform policy. With regards to longer term outlets, findings from the proposed project may contribute towards an evidence base for mental health and social policies relevant to youth with CP and comorbid difficulties.

Wider community: Genetic and epigenetic research on behaviour sometimes arouses concerns in the media and the general public. During the course of the project, I plan to utilise media channels to disseminate findings, clarify the use and implications of this type of research and raise awareness of the mechanisms by which environmental factors can influence child development. Furthermore, I plan to draw on my close collaboration with Kids Company as an additional outlet for knowledge exchange, for example by participating in their frequent public engagement initiatives. Kids Company is a charity that provides practical, emotional and educational support to vulnerable inner-city youth, and has shown a strong commitment to fostering open communication between researchers, professionals, the wider public and youth themselves concerning issues relevant to child development and behaviour.