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

Lead Research Organisation: King's College London
Department Name: Psychology

Abstract

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 tha 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.

Planned Impact

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.

Publications

10 25 50
 
Description The aim of this three-year, ESRC-funded project is to characterise the role of epigenetic factors in the development of conduct problems and co-occurring psychiatric symptoms.

The project has three main objectives:
(i) to trace how exposure to early life stress influences epigenetic patterns of gene activity from birth to late childhood;
(ii) to establish whether these epigenetic changes play a role in the development of conduct problems in childhood and adolescence; and
(iii) to examine whether these same changes also contribute to the development of co-occurring psychiatric symptoms.

The project is now completed, and significant findings have emerged that address all three of these objectives.
Specifically, using longitudinal data from ALSPAC - and more recently, Generation R - birth cohorts, we have found that:
(i) Exposure to risk factors during pregnancy, such as maternal smoking (Cecil et al., 2016), poor diet (Rijlaarsdam, Cecil et al., 2016) and stressful life events (Rijlaarsdam, Pappa et al., 2016), is associated with alterations in offspring DNA methylation patterns at birth, particularly in genes important for brain development and function.
(ii) In turn, epigenetic patterns at birth are associated with later risk for conduct problems. For example, using hypothesis-free, genome-wide analyses we have found that DNA methylation levels in a number of genes important for pain sensitivity and neurotransmitter function differentiated children who go on to develop an early-onset vs low trajectory of conduct problems between the ages of 4 to 13 years (Cecil et al., 2017).
(iii) Similarly, we have found that epigenetic patterns at birth (but not later in childhood) also associate with risk for a range of co-occurring psychiatric symptoms during childhood and adolescence, including ADHD (Walton, Pingault, Cecil et al., 2017), oppositional defiant behaviour (Barker, et al., 2017), adolescent substance use (Cecil et al., 2016), and broader internalizing and externalizing problems (Barker, Cecil et al., 2018).
(iv) Using novel integrative developmental models, our data provides preliminary evidence for epigenetic mediation of environmental effects on child mental health. For example, we have found that a prenatal diet high in saturated fat and sugars is associated with child ADHD symptoms partly via alterations in DNA methylation of IGF2 at birth - a gene previously shown to be sensitive to the nutritional environment and known to play a key role in fetal growth during pregnancy (Rijlaarsdam, Cecil et al., 2016; Cecil, Walton & Barker, 2016). Furthermore, we have found that maternal prenatal smoking associated with offsprings' own risk of substance use during adolescence (i.e. tobacco, cannabis and alcohol use), partly via epigenetic alterations at birth in a network of genes involved in neural and developmental processes (Cecil et al., 2016).
(v) Our findings pinpoint potential biological pathways linking early adversity, epigenetics and mental health problems, including chronic low-grade inflammation (Barker, Cecil et al., 2018) and changes in brain structure (e.g. amygdala:hippocampus volume ratio: Walton, Cecil et al., 2017).

Interestingly, we have also found that epigenetic patterns at birth not only associate with risk for psychiatric problems later in life, but also resilience. Specifically, we have recently published data showing that DNA methylation levels the Oxytocin Receptor Gene at birth (a gene implicated in social behaviours, such as empathy and bonding) predict resilient behaviour in children exposed to prenatal adversity (Milaniak, Cecil et al., 2017).

Overall, these findings provide preliminary support for a role of DNA methylation as a potential biological mechanism through which genes and environment combine to influence long-term development, mental health and behaviour (Barker, Walton & Cecil, 2017). The findings also suggest timing effects, whereby neonatal patterns of DNA methylation are found to predict later child psychiatric symptoms more strongly and consistently than DNA methylation patterns during childhood.

References:
Barker ED, Cecil CAM, Walton E, Houtepen L, O'Connor TG, Danese A, Jaffee S, Jensen SKG, Pariante CM, McArdle W, Gaunt TR, & Relton C (2018). Inflammation-related epigenetic risk and child and adolescent mental health: A prospective study from pregnancy to mid-adolescence. Special Issue on developmental origins of psychopathology: Development and Psychopathology.

Barker ED, Walton E & Cecil CAM (2018). Annual Research Review: DNA methylation as a mediator in the association between risk exposure and child and adolescent psychopathology. Journal of Child Psychology and Psychiatry. doi: 10.1111/jcpp.12782.

Barker ED, Walton E, Cecil CAM, Jaffee SR, Rowe R, O'Connor TG, Maughan B, Stringaris A, Meehan A, McArdle W, Relton CL, & Gaunt TR (2017). A methylome-wide association study of trajectories of oppositional defiant behaviors and biological overlap with attention deficit hyperactivity disorder. Child Development. doi: 10.1111/cdev.12957.

Cecil CAM, Walton E & Barker ED (2016). Prenatal diet and childhood ADHD: The potential role of IGF2 methylation. Invited editorial. Epigenomics. Epub ahead of print: 18 Nov. doi: 10.2217/epi-2016-0131.

Cecil CAM, Walton E, Jaffee SR, O'Connor TG, Maughan B, Smith RG, Relton CL, McArdle W, Gaunt TR, Ouellet-Morin I & Barker ED (2017). Neonatal DNA methylation and early-onset conduct problems: A genome-wide, prospective study. Development & Psychopathology. doi: 10.1017/S095457941700092X.

Cecil CAM, Walton E, Smith RG, Viding E, McCrory EJ, Relton CL, Suderman M, Pingault JB, McArdle W, Gaunt TR, Mill J & Barker ED (2016). DNA methylation and substance use risk: A prospective, genome-wide study spanning gestation to adolescence.

Milaniak I, Cecil CAM, Barker ED, Relton CL, Gaunt TR, McArdle W & Jaffee SR (2017). Variation in methylation of the Oxytocin Receptor gene predicts children's resilience to prenatal stress. Special Issue on bio-behavioural effects of early adversity on multiple levels of development. Development and Psychopathology.

Rijlaarsdam, J., Cecil CAM, Walton E, Mesirow MSC, Relton CL, Gaunt TR, McArdle W & Barker ED (2016). Prenatal unhealthy diet, IGF2 methylation and ADHD for early-onset conduct problem youth. Journal of Child Psychology and Psychiatry. doi: 10.1111/jcpp.12589.

Rijlaarsdam J, Pappa I, Walton E, Bakermans-Kranenburg M, Cecil CAM Van Ijzendoorn, MH (2016). An epigenome-wide association meta-analysis of prenatal maternal stress in neonates: a model approach for replication. Epigenetics. doi: http://dx.doi.org/10.1080/15592294.2016.1145329.

Walton E, Cecil CAM, Suderman M, Liu J, Turner JA, Calhoun VD, Ehrlich S, Relton CL, & Barker, ED (2017). Longitudinal epigenetic predictors of amygdala:hippocampus volume ratio. Journal of Child Psychology and Psychiatry. doi: 10.1111/jcpp.12740.

Walton E, Pingault JB, Cecil CAM, Gaunt TR, Relton CL, Mill J & Barker ED (2016). Epigenetic profiling of ADHD symptoms trajectories: A prospective, methylome-wide study. Molecular Psychiatry. doi: http://dx.doi.org/10.1038/mp.2016.85.
Exploitation Route The work stemming from this project has made a number of key contributions to the growing field of psychiatric epigenetics, including:
- Building a bridge between the disciplines of epigenetics and developmental psychopathology, which before the project were largely kept separate;
- Applying prospective designs and longitudinal modelling (SEM) to psychiatric epigenetics;
- Active role in introducing the study of child psychiatric phenotypes within the Pregnancy and Childhood Epigenetics (PACE) consortium, the largest paediatric epigenetic consortium in the world (40+ cohorts)
- Providing key evidence for
** Prospective associations between epigenetic patterns in early life and psychiatric as well as behavioural outcomes in childhood and adolescence
** Delineating early epigenetic risk markers (pre-symptom manifestation) for child disruptive behaviour problems and externalizing symptoms, having performed the first prospective epigenome-wide studies on conduct problems, ADHD, oppositional defiant symptoms and adolescent substance use.
** Timing effects: showing for the first time that prospective epigenetic patterns at birth associate more strongly with childhood outcomes, compared to cross-sectional epigenetic patterns in childhood (supporting a 'sensitive period' hypothesis) - my team and I first described this phenomenon across many behavioural phenotypes in ALSPAC, and we have recently confirmed this in the first consortium study of child psychiatric problems (ADHD; including over 2500 children across 10 cohorts; epigenetics measured at birth and childhood)
** Epigenetic mediation: building some of the first integrative models spanning environmental risks, epigenetics and psychiatric outcomes to test the role of epigenetic patterns as a mediator (e.g. Cecil et al., 2016; Transl Psy).
** Characterizing the role of the brain: conducting the first prospective study to examine the association between early epigenetic patterns and brain structure in adolescence, and relevance to psychiatric symptoms (Walton et al., 2016, published in JCPP). As a result of this work, I was awarded a Marie Curie fellowship in January 2019 to initiate a Neuroimaging Epigenetics research programme at Generation R to better understand the role of epigenetics and the brain in the development of disruptive behaviour problems.

While these findings have led to promising insights into the role of DNA methylation as a potential biological link between environmental influences and child mental health outcomes, it is important to note that findings are preliminary, correlational and in need of replication.

In the coming years, as longitudinal epigenetic data becomes available, it will be important to conduct more multi-cohort studies to identify robust and replicable associations. In addition to replication, it will be important establish whether the observed associations between environmental risk, DNA methylation and psychiatric symptoms are truly causal, or simply correlational. For example, the use of advanced methodologies such as Mendelian Randomisation will considerably help in this respect.

Bearing this in mind, there are a number of ways in which findings may be put to use by others. First, in an educational context, these findings may be used to increase awareness about the relevance of epigenetic mechanisms in health and development, as well as clarifying the use and potential implications of epigenetic research. This is a necessary first step in achieving impact, as current knowledge in this area has yet to permeate non-academic spheres in a substantive way. Second, if found to be replicable and robust, these research findings may be used to inform clinical practice. For example, the identification of vulnerable developmental periods (e.g. prenatal risks; epigenetic changes at birth) may enable us to pinpoint key windows of opportunity for intervention as well as informing the allocation of available resources. Finally, in the longer term, there is potential for these findings to improve the evidence-base for social policies and approaches targeted to reducing the mental health burden. Findings may also help to identify potential targets for the development of novel treatments.
Sectors Communities and Social Services/Policy,Education,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description The findings have generated considerable public interest, being reported in blogs, popular science books and a wide range of media outlets to illustrate the potential role of epigenetics as a link between the environment and health outcomes in children. Examples of such impacts are listed below: - Invited blog contributor for high-profile blogs, including the The Conversation and the UK Economic and Social Research Council (ESRC) ? https://theconversation.com/smoking-during-pregnancy-may-lead-to-later-substance-use-in-the-child-69929 ? https://blog.esrc.ac.uk/2018/03/22/epigenetics-how-genes-and-the-environment-shape-childrens-mental-health/#more-4967 - Research findings reported across multiple media channels (>60; Altmetric), including public press, internet and television. I was Interviewed to provide expertise for several popular science books, including "Uncivilized genes: Human evolution and the urban paradox" by Dr Gustav Milne (2017), and "Blueprint: How our childhood makes us who we are" by Dr Lucy Maddox (2018). News outlets include CNN, Daily Mail, Medical Research, Nature Research News, Newsweek, NHS, Science Daily, The Evening Standard, The Guardian, The Times, and The Week: ? http://europe.newsweek.com/smoking-cigarettes-pregnancy-babies-substance-abuse-mother-529189?rm=eu ? https://www.theguardian.com/society/2016/aug/18/unhealthy-pregnancy-diet-high-fat-sugar-adhd-children-dna ? https://edition.cnn.com/2016/08/19/health/pregnancy-adhd-unhealthy-diet/index.html ? http://www.nature.com/content/A38971/index.html?WT.mc_id=TWT_1704_DNADAY
First Year Of Impact 2016
Sector Education,Healthcare
Impact Types Cultural,Societal,Policy & public services

 
Description Improved training to allied mental health professionals performed via the Anna Freud Centre
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact As stated in my grant application, I have been working with the Anna Freud Centre Senior Leadership Team to maximise impact from the funded research in the following ways: ? Developing the translational value of the work with the input of a multidisciplinary group of senior AFC clinicians, ensuring 'take-home' findings from the study are honed so that they are accessible and relevant to frontline mental health practitioners; ? Communicating the research findings through joint organisation of a large scale conference on childhood adversity (funded by AFC - "Child maltreatment: New frontiers in research and practice", London, 2016), working with Dr Sheila Redfern, Head of AFC Maltreatment Services; and ? Working with the Senior Leadership Team towards incorporating epigenetic research into their future training strategy and workshop programme, helping practitioners understand how adverse experiences 'get under the skin' to influence child outcomes. This has resulted in the development of a dedicated lecture - which I deliver - starting from 2016 on epigenetics within the MSc in Developmental Neuroscience and Psychopathology and MSc in Developmental Psychology and Clinical Practice Programmes. Furthermore, due to the popularity and positive evaluation of this lecture (which scored a perfect 5/5 based on student feedback - the highest score of any lecture), it has been allocated twice the length of time from 2017, in order to allow for more in-depth coverage of this field.
 
Description Influenced training of medical doctors specializing in psychiatry
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Introduced a half-day training session on 'Epigenetics, development and psychopathology' in the curriculum of medical students specializing in child psychiatry at Erasmus Medical Centre. Prior to that epigenetics did not feature at all in the curriculum. This addition enables medical students to be informed regarding the rapidly growing field of psychiatric epigenetics, thus expanding their level of education and research awareness on this topic.
 
Description Leading Fellows (Marie Sklodowska-Curie and EU Horizon 2020 COFUND)
Amount € 183,796 (EUR)
Organisation Marie Sklodowska-Curie Actions 
Sector Academic/University
Country Global
Start 01/2019 
End 12/2021
 
Title Database of longitudinal trajectories of DNA methylation across the genome from birth to adolescence 
Description We are currently creating a freely-accessible, fully-searchable online database that will enable individuals to view genome-wide trajectories of DNA methylation spanning birth to adolescence. This data was generated as part of a project we led characterizing changes in DNA methylation across development in circa half a million sites across the genome, based on findings in two population birth cohorts (ALSPAC and Generation R). Given that access to repeated measures of DNA methylation continues to be extremely rare - with researchers typically having access to epigenetic measurements at a single time point - this resource has the scope to be widely used and of high-value to the research community. 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? No  
Impact The resource is currently being finalized and is scheduled to be online in the Summer of 2019. 
 
Description ALSPAC 
Organisation University of Bristol
Department Queen's School of Engineering
Country United Kingdom 
Sector Academic/University 
PI Contribution The objective of this ESRC-funded project is to examine epigenetic pathways from early risk exposure to childhood conduct problems and comorbid psychiatric symptoms, using data from two large birth cohorts - ALSPAC and Generation R. Over the course of this project, we have published multiple studies based on ALSPAC data and more are currently under way. In addition, I have been active in disseminating ALSPAC-based findings via numerous conferences, workshops, press releases, blogs and in the context of graduate teaching. Furthermore, I have developed active collaborations with several members of the ALSPAC team, which are resulting in close partnership on new projects.
Collaborator Contribution The ALSPAC team has made substantial contributions to the success of the project. For example, the ALSPAC team has helped me navigate and make best use of this large scale epidemiological data-set, as well as offering unique opportunities for interdisciplinary skill development, by enabling me to learn about new analytic methods currently being developed by the team, who are internationally renowned for their work in epidemiology.
Impact Since the start of the grant, I have published over 20 articles related to the project, half of which have been empirical studies based on collaborations with ALSPAC. This collaboration has been highly inter-disciplinary, spanning the fields of epidemiology, child psychiatry, developmental psychopathology and epigenetics, within the context of population-based research. Outputs resulting from this collaboration include the publication of the first set of studies to characterise prospective, epigenome-wide patterns associated with developmental trajectories of child conduct problems, as well as common comorbidities, including ADHD, oppositional defiant behaviour and adolescent substance use (Barker, Walton, Cecil et al, 2017; Cecil et al., 2016; Cecil et al., 2018; Walton, Pingault, Cecil et al., 2016). Multiple other projects are currently underway or planned. As a result of this work, I recently had the honour to contribute as a senior (last) author to the 2018 Annual Research Review issue of the Journal of Child Psychology and Psychiatry - a leading journal in the field. The goal of this review was to evaluate the current state of knowledge regarding epigenetics and child mental health, identify major gaps in the literature and provide concrete recommendations for future research (Barker, Walton & Cecil, 2018).The review offered a unique opportunity to position epigenetics at the forefront of research priorities in child psychiatry and propose key ways to move the field forward.
Start Year 2016
 
Description Epigenetic and early life stress analyses in high-risk samples 
Organisation Anna Freud Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution Over the course of the grant, I have sought to draw on the different strengths of large-scale, longitudinal birth-cohorts (e.g. ALSPAC, Generation R) as well as data from smaller cohorts at high risk for early adversity and psychiatric problems. In addition to using data that I collected myself as part of my PhD (124 high-risk youth from deprived areas of London), I have also initiated collaborations with several international teams who have access to other high-risk samples. These include collaborations with (a) a Canadian research group led by Prof Richard Tremblay (Université de Montréal), with longitudinal data on individuals who have been following a trajectory of chronic physical aggression since childhood; (b) a UK-based group (in collaboration with Dr Tobias Nolte; Anna Freud Centre), with data from a large sample of adults diagnosed with major psychiatric disorders; and (c) a Dutch research group led by Prof Manon Hillegers (Erasmus Medical Centre), with detailed biological and phenotypic data from an offspring cohort of parents diagnosed with bipolar disorder.
Collaborator Contribution The partners have provided access to their unique data from high-risk cohorts, as well as interdisciplinary expertise during study design, analysis and interpretation.
Impact As a result of the above collaborations, we have completed a study examining epigenetic correlates of physical aggression using a multi-sample, cross-tissue design, which was published in the American Journal of Medical Genetics Part B: Neuropsychiatric Genetics (Cecil et al., 2018). The study, for which I am first and corresponding author, is the first to characterise the epigenome-wide signature of physical aggression in buccal cells. We found that lower DNA methylation levels in one region spanning the DRD4 gene - a key candidate gene for aggression - survived genome-wide correction, was associated with higher physical aggression even after taking into account for co-occurring psychiatric problems, and showed strong cross-tissue concordance with both blood and brain tissue, based on independent data. We successfully replicated these findings in an independent, longitudinal sample of young adults with a chronic-high vs low history of physical aggression in childhood and adolescence. Two other projects have been initiated, one with the UK team examining links between childhood maltreatment and psychiatric outcomes; and the other with the Dutch team investigating epigenetic predictors of risk vs resilience in offspring of parents diagnosed with Bipolar Disorder. Overall, these projects are highly interdisciplinary, spanning the fields of epigenetics, molecular biology, developmental psychopathology, longitudinal modelling and psychiatric epidemiology.
Start Year 2017
 
Description Epigenetic and early life stress analyses in high-risk samples 
Organisation Erasmus University Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution Over the course of the grant, I have sought to draw on the different strengths of large-scale, longitudinal birth-cohorts (e.g. ALSPAC, Generation R) as well as data from smaller cohorts at high risk for early adversity and psychiatric problems. In addition to using data that I collected myself as part of my PhD (124 high-risk youth from deprived areas of London), I have also initiated collaborations with several international teams who have access to other high-risk samples. These include collaborations with (a) a Canadian research group led by Prof Richard Tremblay (Université de Montréal), with longitudinal data on individuals who have been following a trajectory of chronic physical aggression since childhood; (b) a UK-based group (in collaboration with Dr Tobias Nolte; Anna Freud Centre), with data from a large sample of adults diagnosed with major psychiatric disorders; and (c) a Dutch research group led by Prof Manon Hillegers (Erasmus Medical Centre), with detailed biological and phenotypic data from an offspring cohort of parents diagnosed with bipolar disorder.
Collaborator Contribution The partners have provided access to their unique data from high-risk cohorts, as well as interdisciplinary expertise during study design, analysis and interpretation.
Impact As a result of the above collaborations, we have completed a study examining epigenetic correlates of physical aggression using a multi-sample, cross-tissue design, which was published in the American Journal of Medical Genetics Part B: Neuropsychiatric Genetics (Cecil et al., 2018). The study, for which I am first and corresponding author, is the first to characterise the epigenome-wide signature of physical aggression in buccal cells. We found that lower DNA methylation levels in one region spanning the DRD4 gene - a key candidate gene for aggression - survived genome-wide correction, was associated with higher physical aggression even after taking into account for co-occurring psychiatric problems, and showed strong cross-tissue concordance with both blood and brain tissue, based on independent data. We successfully replicated these findings in an independent, longitudinal sample of young adults with a chronic-high vs low history of physical aggression in childhood and adolescence. Two other projects have been initiated, one with the UK team examining links between childhood maltreatment and psychiatric outcomes; and the other with the Dutch team investigating epigenetic predictors of risk vs resilience in offspring of parents diagnosed with Bipolar Disorder. Overall, these projects are highly interdisciplinary, spanning the fields of epigenetics, molecular biology, developmental psychopathology, longitudinal modelling and psychiatric epidemiology.
Start Year 2017
 
Description Epigenetic and early life stress analyses in high-risk samples 
Organisation University of Montreal
Country Canada 
Sector Academic/University 
PI Contribution Over the course of the grant, I have sought to draw on the different strengths of large-scale, longitudinal birth-cohorts (e.g. ALSPAC, Generation R) as well as data from smaller cohorts at high risk for early adversity and psychiatric problems. In addition to using data that I collected myself as part of my PhD (124 high-risk youth from deprived areas of London), I have also initiated collaborations with several international teams who have access to other high-risk samples. These include collaborations with (a) a Canadian research group led by Prof Richard Tremblay (Université de Montréal), with longitudinal data on individuals who have been following a trajectory of chronic physical aggression since childhood; (b) a UK-based group (in collaboration with Dr Tobias Nolte; Anna Freud Centre), with data from a large sample of adults diagnosed with major psychiatric disorders; and (c) a Dutch research group led by Prof Manon Hillegers (Erasmus Medical Centre), with detailed biological and phenotypic data from an offspring cohort of parents diagnosed with bipolar disorder.
Collaborator Contribution The partners have provided access to their unique data from high-risk cohorts, as well as interdisciplinary expertise during study design, analysis and interpretation.
Impact As a result of the above collaborations, we have completed a study examining epigenetic correlates of physical aggression using a multi-sample, cross-tissue design, which was published in the American Journal of Medical Genetics Part B: Neuropsychiatric Genetics (Cecil et al., 2018). The study, for which I am first and corresponding author, is the first to characterise the epigenome-wide signature of physical aggression in buccal cells. We found that lower DNA methylation levels in one region spanning the DRD4 gene - a key candidate gene for aggression - survived genome-wide correction, was associated with higher physical aggression even after taking into account for co-occurring psychiatric problems, and showed strong cross-tissue concordance with both blood and brain tissue, based on independent data. We successfully replicated these findings in an independent, longitudinal sample of young adults with a chronic-high vs low history of physical aggression in childhood and adolescence. Two other projects have been initiated, one with the UK team examining links between childhood maltreatment and psychiatric outcomes; and the other with the Dutch team investigating epigenetic predictors of risk vs resilience in offspring of parents diagnosed with Bipolar Disorder. Overall, these projects are highly interdisciplinary, spanning the fields of epigenetics, molecular biology, developmental psychopathology, longitudinal modelling and psychiatric epidemiology.
Start Year 2017
 
Description Generation R, Netherlands 
Organisation Erasmus University Medical Center
Department Department of Epidemiology
Country Netherlands 
Sector Academic/University 
PI Contribution As part of this grant, I have established an active collaboration with the Generation R Study team (GenR; Erasmus Medical Center, Netherlands), in order to carry out projects examining epigenetic pathways to child emotional and behavioral problems. Multiple projects are currently underway as part of this trans-national collaboration, bringing together data from GenR and ALSPAC. I have taken a lead in setting up these projects, securing the participation of the ALSPAC team in Bristol and the GenR team in the Netherlands, and providing expertise on epigenetic analyses, longitudinal modelling and developmental psychopathology. I have ensured good progress via regular contact and multiple research visits to both Erasmus MC and Bristol university.
Collaborator Contribution The GenR team is a highly productive, collaborative and interdisciplinary research group, spanning the fields of child and adolescent psychiatry, psychology, epidemiology, medicine, genetics and neuroscience. The GenR team is dedicating time and personnel to assist in the development of cutting edge methodologies for examining multi-cohort, longitudinal patterns of DNA methylation, and associations with psychopathology. GenR has also been active in hosting me over multiple research visits and allowing me to partake in the research centre's activities for knowledge exchange and professional development.
Impact As a result of the collaborative work undertaken for this project, I was offered in 2018 a position as Assistant Professor at Erasmus Medical Center to lead all psychiatric epigenetic research within the Generation R Study. This position has enabled me to establish my own research line at Generation R, expand my collaborative network and place me in an optimal position to advance biosocial research on the epigenetics basis of child mental health. Specifically, we are currently working on multiple, large-scale projects that have the potential to result in high-impact outputs. These projects are especially demanding in terms of time and effort, but represent a unique opportunity to address key knowledge gaps in the field. For example, one of these projects is examining, for the first time, how epigenetic patterns change across development, from birth to adolescence, using the only two cohorts in the world that have collected repeated measures of DNA over such a large time-scale. This project will provide an unprecedented insight into the stability vs change of epigenetic patterns across sensitive periods of development; identify which epigenetic marks change the most over time; and how this relates to genetic and environmental influences. Another project will combine for the first time genome-wide epigenetic data and brain imaging during childhood. GenR is the largest pediatric neuroimaging study in the world - making it a unique resource for conducting these analyses. Findings from this project will be highly informative in showing the extent to which epigenetic patterns in peripheral blood index processes inside the brain - currently a major gap in field. Both projects feature a strong international component, make use of multi-cohort, large-scale longitudinal data and are interdisciplinary (biosocial research, epigenetics, epidemiology, developmental psychopathology). Findings will be made publicly available as a fully searchable online resource, which will likely be extensively used and of high-value to the research community.
Start Year 2016
 
Description PACE Consortium 
Organisation National Institute of Environmental Health Sciences
Department Pregnancy And Childhood Epigenetics Consortium
Country United States 
Sector Public 
PI Contribution In 2017 I became a member of the Pregnancy and Childhood Epigenetics (PACE) Consortium, with the role of representing and managing all psychiatric epigenetic research in the Generation R Study. PACE is the largest existing epigenetic consortium focused on pre- and postnatal child development and health. It currently features over 40 independent cohorts from more than 13 countries around the world. Since joining PACE, I have contributed to the consortium activities by setting up new collaborative projects and strengthening the emphasis on psychiatric, neurodevelopmetnal and behavioral outcomes (traditionally, the consortium has been mainly focused on 'physical' prenatal exposures and health outcomes).
Collaborator Contribution Being a PACE partner is of tremendous benefit to this project. This collaboration enables me to connect with the largest cohorts in the world that have collected environmental, epigenetic and developmental data. The consortium is highly interdisciplinary, which makes it possible for me to access and share knowledge, skills, tools and expertise with a wide range of investigators, including biologists, statisticians, geneticists, epidemiologists, clinicians, etc. It also makes problem-solving much more efficient, as well as ensuring that I am kept up to date with the latest theoretical and methodological developments in the field.
Impact As this is a recently established collaboration, projects are still ongoing. So far, I am either taking a lead, supervising or collaborating on a total of 7 transnational, multi-site consortium projects, examining associations between epigenetic patterns at birth and a range of prenatal exposures (maternal anxiety, depression, and stress) as well as childhood outcomes (ADHD, sleep, general psychopathology and brain development). We have now completed the first ever consortium-led epigenetic meta-analysis of a child psychiatric disorder, in which we characterized associations between genome-wide DNA methylation and ADHD symptoms across10 cohorts, bringing together data from over 2500 children. We have found that DNA methylation patterns prospectively associate with later ADHD symptoms implicating a number of genes involved in neurotransmission and neurodevelopment. Importantly, we found evidence of timing effects, whereby DNA methylation patterns at birth associate more strongly to ADHD symptoms than DNA methylation patterns in childhood, supporting my previous observations in ALSPAC (Cecil et al., 2016, Translational Psychiatry; Walton, Pingault, Cecil et al., 2017, Molecular Psychiatry; Barker, Walton & Cecil, 2018, JCPP).
Start Year 2017
 
Description TBCT Team, Brazil 
Organisation Federal University of Bahia
Country Brazil 
Sector Academic/University 
PI Contribution Role of consultant, senior collaborator, and research lead for specific projects. Specifically, I am involved in assisting the Brazilian team with study conception, analysis and interpretation of results based on data collected as part of their large study on youth at high-risk of violence exposure, as well as preparation and revision of manuscripts.
Collaborator Contribution The team (led by Prof de Oliveira) is contributing to this collaboration by providing access to data they collected in a large sample of Brazilian of high-risk youth, assisting with statistical analyses and providing clinical expertise.
Impact This collaboration has resulted in the recent publication of a cross-cohort, trans-national replication study characterizing the effects of different forms of childhood maltreatment on youth mental health, for which I am senior (last) author (de Oliveira et al., 2018; Disentangling the mental health impact of childhood abuse and neglect: A replication and extension study in a Brazilian sample of high-risk youth). Based on data from two independent high-risk samples of adolescents in the UK and Brazil, a highly consistent pattern of findings emerged. Specifically, we found that: (i) maltreatment types often co-occur; (ii) the number of maltreatment types experienced linearly associates with severity of mental health problems (i.e. cumulative effect); and (iii) emotional abuse was found to be the most consistent independent predictor of poor mental health across different psychiatric domains, raters, and gender - over and above the effect of other forms of maltreatment. Findings underscore the need for increased awareness among clinicians that multi-type maltreatment may more common than the experience of single forms of maltreatment, with implications for risk assessment, the identification of more comprehensive maltreatment profiles, and the development of strategies to reduce risk for re-victimization across maltreated individuals. Furthermore, findings point to emotional abuse as a particularly detrimental form of maltreatment that necessitates greater attention in research, policy and clinical practice.
Start Year 2017
 
Description Anna Freud Centre conference (London) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presented findings at the Anna Freud Centre 'Child Maltreatment: New Frontiers in Research and Practice' - a one day conference providing a unique overview of recent advances in research and practice in the field of childhood maltreatment. Other speakers included experts in psychological treatment, social care, neuroscience and policy. The aim of the conference was to provide clinicians, social workers, policy makers and other professionals with an overview of research advances in our understanding of the impact of maltreatment, and the implications for prevention, care and treatment of children who have been affected. As well as giving one of the talks, I participated as a panel speaker in the round-table discussion about the impact of childhood maltreatment from a multi-level research perspective.
Year(s) Of Engagement Activity 2016
URL http://www.annafreud.org/training-research/training-and-conferences-overview/conferences-and-seminar...
 
Description Belgian Association of Paediatrics Annual Congress 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I have been invited as keynote speaker to close off the 'Epigenetics and Environment' plenary session of the 47th Annual Congress of the Belgian Association of Paediatrics. The talk is taking place on the 21st of March 2019 and is expected to be attended by 600-800 practitioners.
Year(s) Of Engagement Activity 2019
URL http://www.bvksbp2019.be/EventTool/event/572/Scientific+program
 
Description Blog contribution to The Conversation 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Invited to disseminate findings based on this ESRC-funded project on The Conversation, a well-respected, curated and independent journalistic platform, delivering expert commentary on a wide range of social, healthcare and political issues to the wider public.
Year(s) Of Engagement Activity 2016
URL https://theconversation.com/smoking-during-pregnancy-may-lead-to-later-substance-use-in-the-child-69...
 
Description ESRC Biosocial Blog 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I was invited to contribute an entry to the ESRC Biosocial blog, to discuss the relevance of epigenetics in biosocial research on mental health and describe my work as part of the current grant. The entry has now been submitted and is in the pipeline for publication online.
Year(s) Of Engagement Activity 2018
 
Description Invited Speaker - Health Sciences Research Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I was invited to give a talk as part of a symposium session on 'omics and mental health' within the Health Sciences Research Day organized by Erasmus Medical Centre (Rotterdam, the Netherlands), attended by a range of different medical specialists and practitioners, researchers and open to the wider public. The session featured a thirty-minute round-table after the talk, to debate the role of omics in mental healthcare.
Year(s) Of Engagement Activity 2019
 
Description LHRS Conference (Amsterdam) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Disseminated findings by giving a talk at the LHRS Meeting 2016, which focuses on the potential of prospective longitudinal research for understanding human development.
Year(s) Of Engagement Activity 2016
 
Description Media engagement 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Three publications stemming from this ESRC-funded project received widespread media attention, resulting in press releases, media interviews and coverage in multiple international media channels, including CNN, Daily Mail, Newsweek, NHS, Science Daily, The Evening Standard, The Guardian, The Times, and The Week.
Year(s) Of Engagement Activity 2016,2017,2018
URL https://www.theguardian.com/society/2016/aug/18/unhealthy-pregnancy-diet-high-fat-sugar-adhd-childre...
 
Description Oxford Loebel Lectures & Research Programme 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Participated as a workshop speaker in The Oxford Loebel Lectures and Research Programme (OLLRP). OLLPR is an interdisciplinary scientific and philosophical project dedicated to discussing the causal and conceptual links between the biological, psychological, and social factors that contribute to mental illness. Its aim is to lay the ground work for a unified theory that can form the basis for clinical work, and involved discussion between different disciplines, particularly psychiatry and philosophy.
Year(s) Of Engagement Activity 2016
URL http://www.loebelprogramme.ox.ac.uk/2016
 
Description Postgraduate student training 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Delivering post-graduate student training in epigenetics and developmental psychopathology to multiple MSc programmes:
o MSc Developmental Neuropsychopathology (AFC, UCL)
o MSc Developmental Psychopathology (Leiden University, NL)
o MSc Genes, Environment and Development (IOPPN, KCL)
o MSc Mindfulness & MSc Health Psychology (IOPPN, KCL)
Year(s) Of Engagement Activity 2016,2017,2018
 
Description Press release for new study on the neural profile of child callous traits 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact In 2018, I led the largest study characterizing the neural profile of child callous traits, based on data from over 2000 ten-year old children from the Generation R Study. As senior and corresponding author of the study, published in Biological Psychiatry, I was approached by the journal to prepare a press-release and respond to media inquiries. The press release received substantial attention on social media platforms (e.g. Twitter) and online news outlets (e.g. Science Daily).
Year(s) Of Engagement Activity 2018
URL https://els-jbs-prod-cdn.literatumonline.com/pb/assets/raw/Health%20Advance/journals/bps/BPS_181213_...
 
Description Two invited symposia presentations at the Biennial SRCD Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker for two separate symposia to present findings stemming from the current grant at the Society for Research in Child Development Biennial Meeting (Austin, USA). In these presentations I discussed findings from two studies, one characterising the epigenetic signatures of child abuse and neglect (based on data from high-risk samples), and the other showing the longitudinal associations between maternal prenatal smoking, epigenetic changes at birth, and substance use risk in adolescence (based on prospective data from the ALSPAC cohort). The talks were attended by a varied audience primarily comprising of researchers and practitioners working in the field of child mental health.
Year(s) Of Engagement Activity 2017
 
Description UCL Institute of Education, Centre for Longitudinal Studies 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact I was invited to give a talk about my research at the Centre for Longitudinal Studies, as part of the UCL Institute of Education Seminar Series. The talk was attended by around 40 researchers and practitioners, amongst others. The talk sparked an active discussion about the potential translational applications of epigenetic research, as well as leading to the beginning of a collaboration with the National Child Development Study research team.
Year(s) Of Engagement Activity 2017