Community Research and Development Information Service - CORDIS

Periodic Report Summary 2 - ACTION (Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strateg)

Project Context and Objectives:
Childhood aggression and its resulting social impairments inflict a huge personal and financial burden on children, their relatives, peers, teachers and society as a whole. Early onset childhood aggression may continue into adolescence and adulthood in a substantial proportion of children and may not occur in isolation: children with aggression problems suffer from other emotional, behavioral and cognitive problems. To obtain an understanding of why children differ from each in other in levels of aggression, the ACTION consortium was established. ACTION stands for “Aggression in Children: Unravelling gene-environment interplay to inform Treatment and InterventiON strategies”. Within ACTION, partners with access to large population and patient cohorts and with expertise in biomarker and (epigenetic) studies from Finland, Sweden, UK, the Netherlands, Italy and Australia collaborate to solve questions indicated by clinicians, social workers, parents and teachers of children with aggression. The ACTION project defined a set of interrelated objectives to realize our aims:

Within our work package Clinical Epidemiology we focus on the following objectives:
• Gain insight in the current treatment and diagnostic practice in Europe and identify the critical needs for stakeholders.
• Quantify and identify the long-term societal outcomes of childhood aggressive behavior.
• Develop long-term positive and negative trajectories from early childhood to adulthood for subtypes of aggression.
• Select children from clinical setting and collect buccal swabs and urine samples.
• Evaluate biomarkers, epigenetic marks in clinical setting and population registries.

Within our work package Genetic Epidemiology:
• Unravel the genetic longitudinal architecture of aggression and estimate heritability as a function of age and gender.
• Resolve patterns of comorbidity of aggression and emotional and behavioral problems as a function of genes and environment.
• Detect genomic regions for aggression in children in genome-wide association (GWA) studies.
• Identify differentially methylated regions related to aggression in a genome-wide approach.
• Select monozygotic twin pairs for epigenetic and biomarkers studies.

Within our work package Gene-Environment Interplay:
• Identify environmental risks that have effects on the development of aggression independent of genetics.
• Identify environmental effects on the development of aggression that depend on genetic propensities (GxE interaction).
• Identify genetically driven experiences associated with aggression in which children select, modify or create environments correlated with their genetic propensities (GE correlation; rGE).
• Apply methods for SNP heritability and polygenetic predictors of aggression to confirm results of twin analyses of GxE and rGE and to identify some of the genes responsible for GxE and rGE.
• Extend analyses of epigenetics to investigate GxE and rGE.

Within our work package Metabolomics & Biomarkers:
• Iidentify biomarker profiles to diagnose aggression.
• Iidentify biomarkers to differentiate between sub-groups of aggression.
• Iidentify treatment options for (different sub-groups) of aggression.

Within our work package treatment and prevention strategies:
• Develop an evidence-based model on effectiveness of existing preventative and treatment strategies.
• Integration of insights in a comprehensive theoretical framework.
• Development of risk assessment charts and guidelines to improve clinical decision making.
• Assessment of this framework and risk assessment charts with respect to ethical, legal and social implications (ELSI).

Within our work package Dissemination and stakeholder interaction:
• Definition of a recognizable and global project identity.
• Update participations and participating agencies.
• Inform stakeholders and general public about the project.
• Inform scientists about the project.
• Create an updated list of stakeholders and end-user groups.

Project Results:
Aggressive behavior is complex, and no single factor can explain why children differ in aggression levels. In ACTION protective and risk factors for the development of aggression from (epi)genetic, biomarker, and environmental domains are studied together, so that a cumulative risk model may be proposed.

To improve our understanding of the etiology of aggression and to inform prevention and treatment, the ACTION consortium, which brings together large twin and child cohorts, has in its first 3 years:

• Provided an inventory of treatment, prevention and intervention across Europe
• Revealed societal outcomes of childhood aggression
• Unravelled causes of individual differences in aggression and its comorbidities
• Worked towards identifying genetic variants and differentially methylated regions
• Identified environmental influences on childhood aggression
• Developed methods to study gene-environment interplay
• Developed metabolomic profiles in urine to validate existing and new biomarkers
• Created channels for dissemination

In a study of experts and clinicians from 24 countries of practices in Europe, experts supported developing European guidelines and emphasized a need to develop Evidence Based Methods. Clinicians emphasized limited usefulness of guidelines for clinical practice. Therapeutic alliance, focus on positives, improving parent-child interactions, and collaboration with schools and teachers were stressed to improve prevention and treatment of severe behavioural problems. Comorbidity was identified as a major theme.

A systematic literature review of effectiveness of prevention and intervention described effect sizes across treatments and moderator effects. For prevention and intervention, effects were small or medium. For moderators, effects were mixed. Moderators with a positive effect on treatment effectiveness for childhood aggression were pre-test levels of aggression, individual implementation, and parental involvement. Future research should distinguish between targets of treatment, focus on individual differences between children in treatment effectiveness and parental influences.

A record linkage study in Sweden of long-term societal outcomes of childhood aggression revealed how long-term positive and negative trajectories from early childhood to adulthood develop for aggression subtypes; how early detection of aggressive problems and access to treatment results in significantly lower crime records and higher average income. Suicide risk might also decrease.

The individual differences in aggression are due to large heritability, with estimates of >50% with smaller shared environmental effects in girls than in boys. Longitudinal genetic correlations are the main reason for the high stability of aggressive behavior. The co-occurrence of aggression and other childhood behavioral and emotional problems shows a high degree of co-occurrence of aggression with attention problems, rule breaking, oppositional behavior. However, substantial associations are also seen with depression, anxiety, and autism. The ACTION website has an interactive tool showing the comorbidities of aggression:

To identify genes and differentially methylated regions, two large meta-analyses are in progress for which new methods were developed, with > 500.000 data points and > 10.000 in the genetic and methylation projects, respectively.

Our study of environment and interplay of genes and environment shows that perinatal factors explained up to 5% of the variance in adolescent aggression. Maternal smoking during pregnancy predicted aggression at all ages independent of other perinatal and demographic factors. A multidimensional risk score based on home and school risks predicted 10% of adolescent aggression.

Validation of existing and new biomarkers in urine is in progress in a technical (n = 20) and a large biochemical pilot study (n=222). Analyses (n=1600-2000) starts at the end of the summer.

Potential Impact:
In the next period, ACTION will finalize collection of urine and DNA samples in selected groups of children characterized by high or low aggression or treatment for childhood psychiatric problems and begin analyses for the biomarker and epigenetic studies. For the epigenetic study, the Illumina EPIC array, which interrogates of 850K methylation sites, is to be used. ACTION will also report on its Epigenome-Wide Association Study of aggression across the lifespan in nearly 10.000 subjects. Simultaneously, the Genome Wide Association (GWA) meta-analysis of childhood aggression will be completed and published. The GWA is based on data from over 20 childhood cohorts, on ratings aggression and attention problems from 4 raters (father, mother, teacher and self) and based on over 500,000 longitudinal observations for these phenotypes. Papers on method development and power analyses accompany this work. These results will provide important information for the broader psychiatric genetics community by making the full meta-analysis results available through the ACTION website, so that polygenetic scores (PGS) can be obtained for prediction into other traits and other ages in independent cohorts. The studies of the importance of childhood aggression in Sweden will guide prediction analyses of other societal important outcomes. Equally important are results pertaining to the modification of genetic polymorphisms by environment, either through considering the totality of such influences by modeling of genetic relatedness matrices, or though considering the interaction of PGS and environment.

Expected results in the next period include also the elucidation of the multidimensional nature of Childhood Disruptive Behavior Problems (DBP), through a focus on single item characteristics of multiple instruments designed to assess aggression, oppositional and disobedient behavior, rule-breaking, physical aggression, and irritability. Items associated with stability over time and with comorbidity are identified through genetic structural modeling. The multiple facets of DBP are comorbid with other childhood behavioral and emotional problems and here ACTION will offer new insights into the etiology of clustering through genetic covariance modeling and molecular genetic approaches. Broadening the comorbidity perspective will offer similar insights on the relation of aggression / DBP and cognitive and learning problems.

Research on the biological and genetic components of aggression needs to be balanced by attention to the context and environment in which children develop. ACTION contributes to a better understanding of aggression by examining children’s aggressive behavior in the context in which it develops. For example, a child who is aggressive in the school context may require different treatment than one who is aggressive in the context of chronic stress associated with parental psychopathology. ACTION allows us to pay attention to the broader social context in which aggression occurs. The type of intervention that is adaptive for children and adolescents exposed to long-lasting economic hardship and socio-economic disadvantage may differ from youth who live in more economically advantaged environments. From the results of the genetic analyses genes will be selected that influence stability over age or have an amplifying effect over age, leading to persistence. Using transcriptomic databases, a further selection of most likely genetic variants, e.g. genetic variants that influence expression in the brain, will be done. PGS based on these variants can be applied, together with the results from the methylation, biomarker, environmental context analyses to build a model predicting which children have the highest risk for persistent aggression. This model can be used in future for stratification of high and low risk groups to investigate whether and which more intense treatments improve outcomes for high risk children.

List of Websites:

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