Genetic association study of childhood aggression across raters, instruments, and age
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Abstract
Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGG overall ) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGG overall . The gene-based analysis returned three significant genes: ST3GAL3 ( P = 1.6E–06), PCDH7 ( P = 2.0E–06), and IPO13 ( P = 2.5E–06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations ( r g ) among rater-specific assessment of AGG ranged from r g = 0.46 between self- and teacher-assessment to r g = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong r g s with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range $$\left| {r_g} \right|$$ r g : 0.19–1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation ( r g = ~−0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range $$\left| {r_g} \right|$$ r g : 0.46–0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
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Self-citation
- Authors
- Ip, H. F., van der Laan, C. M., Krapohl, E. M. L., Brikell, I., Sánchez-Mora, C., Nolte, I. M., St Pourcain, B., Bolhuis, K., Palviainen, T., Zafarmand, H., Colodro-Conde, L., Gordon, S., Zayats, T., Aliev, F., Jiang, C., Wang, C. A., Saunders, G., Karhunen, V., Hammerschlag, A. R., Adkins, D. E., Border, R., Peterson, R. E., Prinz, J. A., Thiering, E., Seppälä, I., Vilor-Tejedor, N., Ahluwalia, T. S., Day, F. R., Hottenga, J.-J., Allegrini, A. G., Rimfeld, K., Chen, Q., Lu, Y., Martin, J., Soler Artigas, M., Rovira, P., Bosch, R., Español, G., Ramos Quiroga, J. A., Neumann, A., Ensink, J., Grasby, K., Morosoli, J. J., Tong, X., Marrington, S., Middeldorp, C., Scott, J. G., Vinkhuyzen, A., Shabalin, A. A., Corley, R., Evans, L. M., Sugden, K., Alemany, S., Sass, L., Vinding, R., Ruth, K., Tyrrell, J., Davies, G. E., Ehli, E. A., Hagenbeek, F. A., De Zeeuw, E., Van Beijsterveldt, T. C. E. M., Larsson, H., Snieder, H., Verhulst, F. C., Amin, N., Whipp, A. M., Korhonen, T., Vuoksimaa, E., Rose, R. J., Uitterlinden, A. G., Heath, A. C., Madden, P., Haavik, J., Harris, J. R., Helgeland, Ø., Johansson, S., Knudsen, G. P. S., Njolstad, P. R., Lu, Q., Rodriguez, A., Henders, A. K., Mamun, A., Najman, J. M., Brown, S., Hopfer, C., Krauter, K., Reynolds, C., Smolen, A., Stallings, M., Wadsworth, S., Wall, T. L., Silberg, J. L., Miller, A., Keltikangas-Järvinen, L., Hakulinen, C., Pulkki-Råback, L., Havdahl, A., Magnus, P., Raitakari, O. T., Perry, J. R. B., Llop, S., Lopez-Espinosa, M.-J., Bønnelykke, K., Bisgaard, H., Sunyer, J., Lehtimäki, T., Arseneault, L., Standl, M., Heinrich, J., Boden, J., Pearson, J., Horwood, L. J., Kennedy, M., Poulton, R., Eaves, L. J., Maes, H. H., Hewitt, J., Copeland, W. E., Costello, E. J., Williams, G. M., Wray, N., Järvelin, M.-R., McGue, M., Iacono, W., Caspi, A., Moffitt, T. E., Whitehouse, A., Pennell, C. E., Klump, K. L., Burt, S. A., Dick, D. M., Reichborn-Kjennerud, T., Martin, N. G., Medland, S. E., Vrijkotte, T., Kaprio, J., Tiemeier, H., Davey Smith, G., Hartman, C. A., Oldehinkel, A. J., Casas, M., Ribasés, M., Lichtenstein, P., Lundström, S., Plomin, R., Bartels, M., Nivard, M. G., & Boomsma, D. I.
- Affiliations
- Vrije Universiteit Amsterdam (NL)
- King's College London (GB)
- Karolinska Institutet (SE)
- University Medical Center Groningen (NL)
- Erasmus MC (NL)
- University of Helsinki (FI)
- QIMR Berghofer Medical Research Institute (AU)
- Broad Institute (US)
- University of Florida (US)
- University of Newcastle Australia (AU)
- University of Minnesota (US)
- MRC Centre for Environment and Health (GB)
- The University of Queensland (AU)
- University of Utah (US)
- University of Colorado Boulder (US)
- Virginia Commonwealth University (US)
- Duke University (US)
- Helmholtz Munich (DE)
- Tampere University (FI)
- University of Copenhagen (DK)
- University of Cambridge (GB)
- Universitat Autònoma de Barcelona (ES)
- Jewish General Hospital (CA)
- Amsterdam UMC Location University of Amsterdam (NL)
- Universitat Pompeu Fabra (ES)
- University of Exeter (GB)
- Avera Institute for Human Genetics (US)
- Örebro University (SE)
- Mental Health Services (DK)
- Indiana University Bloomington (US)
- Washington University in St. Louis (US)
- Haukeland University Hospital (NO)
- Norwegian Institute of Public Health (NO)
- University of Bergen (NO)
- University of California San Diego (US)
- University of Colorado Anschutz (US)
- University of California, Riverside (US)
- University of Otago (NZ)
- University of Turku (FI)
- Universitat Jaume I (ES)
- The University of Melbourne (AU)
- University of Vermont (US)
- The Kids Research Institute Australia (AU)
- Michigan State University (US)
- Harvard University (US)
- University of Gothenburg (SE)
- Amsterdam Public Health (NL)
- Corresponding author
- Bartels, Meike
- Nivard, Michel G.
- Boomsma, Dorret I.
- ORCID
- Ip, Hill F.
- Krapohl, Eva M. L.
- Brikell, Isabell
- Sánchez-Mora, Cristina
- Nolte, Ilja M.
- St Pourcain, Beate
- Bolhuis, Koen
- Palviainen, Teemu
- Colodro-Conde, Lucía
- Gordon, Scott
- Zayats, Tetyana
- Aliev, Fazil
- Jiang, Chang
- Wang, Carol A.
- Saunders, Gretchen
- Karhunen, Ville
- Hammerschlag, Anke R.
- Adkins, Daniel E.
- Border, Richard
- Peterson, Roseann E.
- Thiering, Elisabeth
- Seppälä, Ilkka
- Ahluwalia, Tarunveer S.
- Day, Felix R.
- Hottenga, Jouke-Jan
- Allegrini, Andrea G.
- Rimfeld, Kaili
- Chen, Qi
- Lu, Yi
- Martin, Joanna
- Soler Artigas, María
- Rovira, Paula
- Bosch, Rosa
- Ramos Quiroga, Josep Antoni
- Neumann, Alexander
- Ensink, Judith
- Grasby, Katrina
- Morosoli, José J.
- Tong, Xiaoran
- Marrington, Shelby
- Middeldorp, Christel
- Scott, James G.
- Vinkhuyzen, Anna
- Shabalin, Andrey A.
- Corley, Robin
- Evans, Luke M.
- Sugden, Karen
- Alemany, Silvia
- Sass, Lærke
- Vinding, Rebecca
- Ruth, Kate
- Ehli, Erik A.
- Hagenbeek, Fiona A.
- Larsson, Henrik
- Snieder, Harold
- Verhulst, Frank C.
- Amin, Najaf
- Whipp, Alyce M.
- Korhonen, Tellervo
- Vuoksimaa, Eero
- Rose, Richard J.
- Uitterlinden, André G.
- Heath, Andrew C.
- Madden, Pamela
- Haavik, Jan
- Harris, Jennifer R.
- Helgeland, Øyvind
- Johansson, Stefan
- Knudsen, Gun Peggy S.
- Njolstad, Pal Rasmus
- Lu, Qing
- Rodriguez, Alina
- Henders, Anjali K.
- Mamun, Abdullah
- Brown, Sandy
- Hopfer, Christian
- Krauter, Kenneth
- Reynolds, Chandra
- Smolen, Andrew
- Stallings, Michael
- Wadsworth, Sally
- Wall, Tamara L.
- Silberg, Judy L.
- Miller, Allison
- Keltikangas-Järvinen, Liisa
- Hakulinen, Christian
- Havdahl, Alexandra
- Magnus, Per
- Raitakari, Olli T.
- Perry, John R. B.
- Llop, Sabrina
- Bønnelykke, Klaus
- Bisgaard, Hans
- Sunyer, Jordi
- Lehtimäki, Terho
- Arseneault, Louise
- Standl, Marie
- Heinrich, Joachim
- Boden, Joseph
- Pearson, John
- Horwood, L. John
- Kennedy, Martin
- Poulton, Richie
- Maes, Hermine H.
- Hewitt, John
- Copeland, William E.
- Costello, Elizabeth J.
- Williams, Gail M.
- Wray, Naomi
- Järvelin, Marjo-Riitta
- McGue, Matt
- Iacono, William
- Caspi, Avshalom
- Moffitt, Terrie E.
- Whitehouse, Andrew
- Pennell, Craig E.
- Klump, Kelly L.
- Burt, S. Alexandra
- Dick, Danielle M.
- Martin, Nicholas G.
- Medland, Sarah E.
- Vrijkotte, Tanja
- Kaprio, Jaakko
- Tiemeier, Henning
- Davey Smith, George
- Hartman, Catharina A.
- Oldehinkel, Albertine J.
- Ribasés, Marta
- Lichtenstein, Paul
- Lundström, Sebastian
- Plomin, Robert
- Bartels, Meike
- Nivard, Michel G.
- Boomsma, Dorret I.
- Venue
- Translational Psychiatry
- Published
- 2021-07-30
- Volume
- 11
- Issue
- 1
- Pages
- 413-413
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC8324785
- OpenAlex
- W3186061193
- Cited by
- 71
- References
- 51
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 15 · 2023: 15 · 2022: 12 · 2021: 6 · 2020: 2
- FWCI
- 6.79
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Translational Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by)
- Bristol Research (University of Bristol) (publishedVersion, cc-by)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- SUNY Digital Repository Support (State University of New York System) (submittedVersion, cc-by-nc-nd)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Työväentutkimus Vuosikirja (submittedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Site cant be reached (submittedVersion, cc-by)
- UWA Profiles and Research Repository (UWA) (submittedVersion, cc-by)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
- Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion, public-domain)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
- Radboud Repository (Radboud University) (submittedVersion)
- VU Research Portal (submittedVersion, other-oa)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Tampere University Institutional Repository (Tampere University) (submittedVersion, cc-by)
- NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (106047/Z/14/Z, 213514/Z/18/Z)
- European Commission (2007–2013, FP7 2007-2013, 602768, FP7/2007)
- Lundbeckfonden (R163-2013-16235)
- Novo Nordisk Fonden (NNF18OC0052457, NNF18OC0054741)
- National Institutes of Health (UL1TR001863)
- Medical Research Council (MC_UU_12015/2, MC_UU_00011/1)
- Economic and Social Research Council (ES/P010113/1)
- National Institute on Drug Abuse (T32DA050560)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- child aggression, genetic association, heritability, self-report, teacher reports, mothers' reports, ST3GAL3, PCDH7, polygenic risk score, genetic correlation, psychiatric traits, cognitive characteristics, age at first birth
- MeSH terms
- Adolescent, Aggression, Mental Disorders, Child, Child, Preschool, Female, Humans, Infant, Retrospective Studies, Genome-Wide Association Study, Genetic Association Studies
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