Plain English Summary
Background and study aims
Childhood aggression and its resulting social impairment inflict a huge personal and financial burden on affected children, their relatives, peers and society as a whole. The prevalence of clinical aggression in children ranges from 2-16%, and early-onset childhood aggression continues into adolescence and adulthood in a substantial proportion of children. There are large differences between children in aggression levels and this study asks “what are the causes of individual differences between in children for aggressive behaviour and associated behavioural problems?”. We look at genetic, epigenetic and metabolomics markers, in different cohorts that collected these data in birth cohorts and population-based registries. We combine information from cohorts in a series of meta-analyses.
Who can participate?
Children below age 18 years for whom information on aggression and attention problems is available and who have been genotyped on a genome-wide SNP (Single nucleotide polymorphism) arrays; participants of any age with information on aggressive and attention problems and genome-wide epigenetic data; children for whom information on aggressive and attention problems is available and for whom urine samples for metabolomics were collected.
What does the study involve?
Estimating the associations between the phenotypes (aggression and attention problems) and the biomarker data. Primary analyses are carried out by each cohort and results are combined in meta-analyses.
What are the possible benefits and risks of participating? This project generates information on associations of behaviour with biomarkers. There are no individual-level risks or benefits to participants.
Where is the study run from?
The cohort studies run in their own countries (USA, UK, Europe, Australia and New Zealand). The meta-analyses is carried out in the Netherlands.
When is the study starting and how long is it expected to run for?
The cohort studies run in their own countries and typically are longitudinal projects. The meta-analyses will be finished and submitted for publication in 2019.
Who is funding the study?
Who is the main contact?
ACTION: Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies
Improve the understanding of the genetic and non-genetic etiology of aggression in children to inform the development of novel prevention and treatment strategies by unraveling in large twin and genotyped cohorts the causes of variation in aggression, disentangling (epi)genetic and environmental effects and their interplay with a focus on critical developmental periods, gender, and comorbid disorders; by investigating metabolomic profiles of aggressive behavior to establish direction of causation for existing and new biomarkers and gain insight regarding the predictive power of pediatric aggression for adult outcome variables.
Meta-analysis of existing cohort studies does not require ethical approval (confirmed by Central Ethics Committee on Research Involving Human Subjects of the VU University Medical Centre; BS7 Kamer H-565l; +31 (0)20 44 45585; email@example.com), ref: 2014.252
Primary study design
Secondary study design
Patient information sheet
Childhood behavioral problems, with a focus on aggression and attention problems
The researchers are doing a series of large meta-analyses, which either take cross-sectional or longitudinal data and test associations of trait outcomes (aggression and attention problems) with SNP data, epigenetics and metabolomics markers. in this work there is no follow-up (though the data mainly derive from ongoing population-based cohorts).
Data were drawn from the following cohorts:
Amsterdam Born Children and their Development Study
Avon Longitudinal Study of Parents and Children
Brain dEvelopment and Air polluTion ultrafine particles in scHool childrEn
Child and Adolescent Twin Study in Sweden
Christchurch Health and Development Study
Collaborative Studies on the Genetics of Alcoholism
Copenhagen Prospective Studies on Asthma in Childhood 2010
Dunedin Multidisciplinary Health and Development Study
Environmental Risk Longitudinal Twin Study
Finnish Twin Cohort
Generation R Study
German Infant study on the influence of Nutrition Intervention PLUS environmental and genetic influences on allergy development / The influence of Life-style factors on the development of the Immune System and Allergies in East and West Germany
Great Smoky Mountains Study
Institute for Behavioral Genetics
Infancia y Medio Ambiente
Impact of Neurodevelopmental disorders and School performance: genes and environment
Minnesota Center for Twin and Family Research
Norwegian Mother and Child Cohort Study
Michigan State University Twin Register
Mater University of Queensland Study of Pregnancy
Northern Finland Birth Cohort 1986
Netherlands Twin Register
Queensland Institute of Medical Research
Western Australian Pregnancy Cohort (Raine) Study
Swedisch Twin study of CHild and Adolescent Development
Twin Early Development Study
TRacking Adolescents' Individual Lives Survey
Virginia Twin Study of Adolescent Behavioral Development
Young Finns Study
Primary outcome measure
Measures of association (from regression analyses) for biomarker-outcome analyses.
For each set of biomarkers (metabolomics, SNP and epigenetic data) an appropriate level of statistical significance is specified. Outcome data on problem behaviors were collected by birth and child cohorts by standardized surveys.
The most commonly employed instruments to assess childhood aggressive and attention problems came from the Achenbach System of Empirically based Assessment (ASEBA; Achenbach et al. 2017) and the Strengths and Difficulties Questionnaire (SDQ; Goodman 2001). These two instruments accounted for > 70% of the phenotype data.
-Achenbach TM, Ivanova MY, Rescorla LA (2017) Empirically based assessment and taxonomy of psychopathology for ages 1½–90+ years: Developmental, multi-informant, and multicultural findings. Compr Psychiatry 79:4–18. doi: 10.1016/J.COMPPSYCH.2017.03.006
- Goodman R (2001) Psychometric Properties of the Strengths and Difficulties Questionnaire. J Am Acad Child Adolesc Psychiatry 40:1337–1345. doi: 10.1097/00004583-200111000-00015
Secondary outcome measures
Based on primary analyses, gene-based and network tests were carried out.
Overall trial start date
Overall trial end date
Reason abandoned (if study stopped)
Participant inclusion criteria
Biomarker- outcome associations are tested in child (2-18 years) cohorts and for epigenetics also in adults. Inclusions into the original population-based cohort studies were voluntary.
Target number of participants
For metabolomics the target number of participants was 1600. For genetics and epigenetics meta-analyses the target was the largest possible number of participants.
Participant exclusion criteria
For genetic studies, to avoid population stratification, ancestries that are different from EU are excluded
Recruitment start date
Recruitment end date
Countries of recruitment
Australia, Denmark, Finland, Germany, Netherlands, New Zealand, Norway, Sweden, Switzerland, United Kingdom, United States of America
Trial participating centre
Van der Boechorststraat 7
Seventh Framework Programme
EC Seventh Framework Programm, European Commission Seventh Framework Programme, EU Seventh Framework Programme, European Union Seventh Framework Programme, EU 7th Framework Programme, European Union 7th Framework Programme, FP7
Funding Body Type
Funding Body Subtype
Results and Publications
Publication and dissemination plan
Planned publication in a high-impact peer-reviewed journal
IPD sharing statement
Over 30 cohorts are included in this effort, which each have their own repositories. The association results from all cohorts are uploaded to a central repository in the Netherlands. The full set of meta-analysis association results will be made available upon publication of the papers.
Intention to publish date
Participant level data
Stored in repository
Basic results (scientific)