Project

Aggression inflicts a huge personal, psychological and financial burden on affected individuals, their relatives, and society at large. Despite large scientific, preventive, and treatment investments, no decrease in aggressive behavior is seen. This calls for a shift to new approaches. By capitalising on comprehensive longitudinal cohorts, recent advances in genetic, biological, epidemiological, and clinical fields, and combining such interdisciplinary expertise the ACTION consortium will dissect the etiology and pathogenesis of aggression. Based on new insights, ACTION will inform the development of novel diagnostic tools and causative targets and guide the development of treatment and prevention strategies. ACTION is built on interrelated work packages with a focus on a) clinical epidemiology and current classification and treatment problems; b) genetic epidemiology, including Genome Wide Association studies and epigenetics; c) gene-environment correlation and interaction; d) biomarkers and metabolomics. ACTION will deliver an overarching framework that combines a thorough understanding of pathways leading to aggression with a map of current gaps, best practices on clinical, ethical, legal, and social issues. Based on this framework, ACTION will develop novel biomarkers suitable for large-scale applications in children and combine biomarker data with new insights into the effects of gender, age, and comorbidity. ACTION will provide guidance in optimising current intervention programs and deliver new biological targets to pave the way for novel therapeutic interventions. ACTION will provide a decision tree to guide personalised intervention programmes and will have direct and sustained impact on reducing paediatric aggression. Its overarching aim is to reduce aggression by developing approachesthat take individual differences in genetic and environmental susceptibility into account, thereby leading to better understanding of personalised intervention programs.

Action's Objectives

  • Main Objective Improve the understanding of the causes of individual differences in aggression among children in order to better inform the development of prevention and treatment strategies.
  • All the objectives • Investigate current classification and diagnostic problems in paediatric aggression, including the differential expression of aggression as a function of gender, developmental stage, and patterns of comorbidity;
    • Reveal predictive outcome of childhood aggression by examining longitudinal trajectories in large scale nation-wide longitudinal data;
    • Quantify the influences of genes and environment as a function of gender, age, birth cohort, and environmental modifiers;
    • Identify genomic regions of interest for aggression by means of a genome-wide association (GWA) studies;
    • Apply and develop new methods to study gene-environment correlation and interaction by including measured genes and measured environment;
    • Select informative groups of children for inclusion in epigenetic and metabolomic biomarkers studies of paediatric aggression;
    • Initiate a large scale genome-wide epigenetics study; including longitudinal epigenetic profiling in subsamples;
    • Develop new biomarkers based on metabolic markers in urine;
    • Combine twin samples and metabolomic biomarker data to establish direction of causation;
    • Gain insight into metabolomic profiles for discovery of environment influences such as nutritional status and environmental toxins;
    • Develop risk assessment charts and guidelines based on decision tree methodology to improve clinical decision making;
    • Inform novel tailored psychological and pharmacological prevention strategies;
    • Inform implementation of these strategies in clinical practice and families

 

Work packages

  • WP1 Management
  • WP2 Clinical epidemiology• to provide an inventory of diagnostics practices, prevention, and therapeutic interventions, and investigate current needs and questions among child psychiatrists, clinicians, and health professionals treating aggression.
    • to examine societal outcome of childhood aggression later in life by studying longitudinal trajectories in large-scale prospective population-based data.
  • WP3 Genetic epidemiology • to unravel the causes of individual differences in aggression and the associated comorbidities in children and adolescents by disentangling genetic and environmental effects and examining genetic heterogeneity as a function of gender, age, birth cohort, and age at onset.
    • to identify genetic variants and differentially methylated regions related to differences in aggression by means of genome-wide association (GWA) and genome-wide epigenetic analyses.
  • WP4 Gene-Environment interplay• to develop and apply new methods to study gene-environment correlation and interaction by including measured genes and measured environments in analyses.
    • to identify novel pure environmental influences on aggression in childhood based on indepth interviews with extremely discordant identical twins
  • WP5 Metabolomics and biomarkers • to investigate the metabolomic profile (in urine samples) of aggressive behaviour to validate and establish existing and new biomarkers to aid the classification of individuals into different sub-diagnostic categories.
    • to explore the causal relationships between the suggested biomarkers
  • WP6 Novel Treatment and prevention strategies • to combine the empirical findings into a comprehensive framework that will enhance our understanding of aggression and its risk indicators.
    • to develop risk assessment charts together with guidelines to improve decision making on the development and implementation of treatment and prevention programmes, addressing
    the critical needs and problems identified in WP2
  • WP7 Dissemination and stakeholder interaction • to translate findings for stakeholders to provide patients and their families with insights into the causes of aggression.
    • to guide the development of tailored, optimized, and novel prevention and treatment strategies based on better patient profiling

 

Short summary in each partner's language

Deliverables

The Public deliverables (PU) can be downloaded as soon as available.

  • D1.1 Project Management
  • D2.1 List of critical needs in aggression prevention and treatment from clinicians and social workers and other stakeholders
  • D2.2 Report on long-term consequences, sub-typing and heterogeneity of aggression
  • D2.3 Submit study protocol, ethics approval, required training certificate, and informed consent forms for biological sample collection in clinical cases
  • D2.4 Evaluation of biomarkers, epigenetic marks and feasibility of their use in clinical and general population samples
  • D3.1 Submit Informed Consent Forms for consisting data
  • D3.2 Establish partner database op phenotype data  from participating twin cohorts
  • D3.3 Submit study protocol, ethics approval, required training certificate, and informed consent forms for biological sample collection in twin pairs for partner 2
  • D3.4 Submit study protocol, ethics approval, required training certificate, and IC forms for biological sample collection in twin pairs for partner 2
  • D3.5 Submit study protocol, ethics approval, required training certificate, and IC forms for biological sample collection in twin pairs for partner 5
  • D3.6 Submit study protocol, ethics approval, required training certificate, and IC forms for biological sample collection in twin pairs for partner 6
  • D3.7 Report on the longitudinal genetic architecture for aggression throughout childhood into adulthood and insights in underlying causes of comorbidity with other behavioral and emotional problems
  • D3.8 Catalogue of genomic regions implied in aggression, based on GWA and on differentially methylated regions, based on genome-wide assessment of epigenetic marks
  • D4.1 Environmental risk factors for aggression
  • D4.2 Report of molecular genetic, including chromosome specific, estimates of heritability
  • D4.3 Interplay of the genome and of specific (epi)genomic regions with environmental factors explaining gene-environment interaction and correlation for aggression
  • D5.1 List of explorative biomarkers of pilot study (metabolites & peptides / proteins) and diagnostic biomarkers after replication study
  • D5.2 List of diagnostic biomarkers and their biological pathways for subgroups of aggression
  • D6.1 Report on the effectiveness of existing preventative and treatment strategies for paediatric aggression and associated disorders
  • D6.2 Comprehensive framework on the aetiology of paediatric aggression and susceptibility to intervention, and risk assessment charts together with guidelines to improve clinical decision making
  • D7.1 LOGO and activation web portal (members area)
  • D7.2 Organization of International Workshops, including workshops for junior staff & training via web
  • D7.3 Posting of results to WHO or ICMJE-approved registry
  • D7.4 ACTION international meeting; launching of guidelines and ACTION results