Translational Psychiatry (Jul 2021)
Genetic association study of childhood aggression across raters, instruments, and age
- Hill F. Ip,
- Camiel M. van der Laan,
- Eva M. L. Krapohl,
- Isabell Brikell,
- Cristina Sánchez-Mora,
- Ilja M. Nolte,
- Beate St Pourcain,
- Koen Bolhuis,
- Teemu Palviainen,
- Hadi Zafarmand,
- Lucía Colodro-Conde,
- Scott Gordon,
- Tetyana Zayats,
- Fazil Aliev,
- Chang Jiang,
- Carol A. Wang,
- Gretchen Saunders,
- Ville Karhunen,
- Anke R. Hammerschlag,
- Daniel E. Adkins,
- Richard Border,
- Roseann E. Peterson,
- Joseph A. Prinz,
- Elisabeth Thiering,
- Ilkka Seppälä,
- Natàlia Vilor-Tejedor,
- Tarunveer S. Ahluwalia,
- Felix R. Day,
- Jouke-Jan Hottenga,
- Andrea G. Allegrini,
- Kaili Rimfeld,
- Qi Chen,
- Yi Lu,
- Joanna Martin,
- María Soler Artigas,
- Paula Rovira,
- Rosa Bosch,
- Gemma Español,
- Josep Antoni Ramos Quiroga,
- Alexander Neumann,
- Judith Ensink,
- Katrina Grasby,
- José J. Morosoli,
- Xiaoran Tong,
- Shelby Marrington,
- Christel Middeldorp,
- James G. Scott,
- Anna Vinkhuyzen,
- Andrey A. Shabalin,
- Robin Corley,
- Luke M. Evans,
- Karen Sugden,
- Silvia Alemany,
- Lærke Sass,
- Rebecca Vinding,
- Kate Ruth,
- Jess Tyrrell,
- Gareth E. Davies,
- Erik A. Ehli,
- Fiona A. Hagenbeek,
- Eveline De Zeeuw,
- Toos C.E.M. Van Beijsterveldt,
- Henrik Larsson,
- Harold Snieder,
- Frank C. Verhulst,
- Najaf Amin,
- Alyce M. Whipp,
- Tellervo Korhonen,
- Eero Vuoksimaa,
- Richard J. Rose,
- André G. Uitterlinden,
- Andrew C. Heath,
- Pamela Madden,
- Jan Haavik,
- Jennifer R. Harris,
- Øyvind Helgeland,
- Stefan Johansson,
- Gun Peggy S. Knudsen,
- Pal Rasmus Njolstad,
- Qing Lu,
- Alina Rodriguez,
- Anjali K. Henders,
- Abdullah Mamun,
- Jackob M. Najman,
- Sandy Brown,
- Christian Hopfer,
- Kenneth Krauter,
- Chandra Reynolds,
- Andrew Smolen,
- Michael Stallings,
- Sally Wadsworth,
- Tamara L. Wall,
- Judy L. Silberg,
- Allison Miller,
- Liisa Keltikangas-Järvinen,
- Christian Hakulinen,
- Laura Pulkki-Råback,
- Alexandra Havdahl,
- Per Magnus,
- Olli T. Raitakari,
- John R. B. Perry,
- Sabrina Llop,
- Maria-Jose Lopez-Espinosa,
- Klaus Bønnelykke,
- Hans Bisgaard,
- Jordi Sunyer,
- Terho Lehtimäki,
- Louise Arseneault,
- Marie Standl,
- Joachim Heinrich,
- Joseph Boden,
- John Pearson,
- L. John Horwood,
- Martin Kennedy,
- Richie Poulton,
- Lindon J. Eaves,
- Hermine H. Maes,
- John Hewitt,
- William E. Copeland,
- Elizabeth J. Costello,
- Gail M. Williams,
- Naomi Wray,
- Marjo-Riitta Järvelin,
- Matt McGue,
- William Iacono,
- Avshalom Caspi,
- Terrie E. Moffitt,
- Andrew Whitehouse,
- Craig E. Pennell,
- Kelly L. Klump,
- S. Alexandra Burt,
- Danielle M. Dick,
- Ted Reichborn-Kjennerud,
- Nicholas G. Martin,
- Sarah E. Medland,
- Tanja Vrijkotte,
- Jaakko Kaprio,
- Henning Tiemeier,
- George Davey Smith,
- Catharina A. Hartman,
- Albertine J. Oldehinkel,
- Miquel Casas,
- Marta Ribasés,
- Paul Lichtenstein,
- Sebastian Lundström,
- Robert Plomin,
- Meike Bartels,
- Michel G. Nivard,
- Dorret I. Boomsma
Affiliations
- Hill F. Ip
- Department of Biological Psychology, Vrije Universiteit Amsterdam
- Camiel M. van der Laan
- Department of Biological Psychology, Vrije Universiteit Amsterdam
- Eva M. L. Krapohl
- Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Isabell Brikell
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Cristina Sánchez-Mora
- Department of Psychiatry, Hospital Universitari Vall d’Hebron
- Ilja M. Nolte
- Department of Epidemiology, University of Groningen, University Medical Center Groningen
- Beate St Pourcain
- MRC Integrative Epidemiology Unit, University of Bristol
- Koen Bolhuis
- Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center
- Teemu Palviainen
- Institute for Molecular Medicine FIMM, HiLife, University of Helsinki
- Hadi Zafarmand
- Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam UMC, Academic Medical Center, University of Amsterdam
- Lucía Colodro-Conde
- QIMR Berghofer Medical Research Institute
- Scott Gordon
- QIMR Berghofer Medical Research Institute
- Tetyana Zayats
- Department of Biomedicine, University of Bergen
- Fazil Aliev
- Department of Psychology, Virginia Commonwealth University
- Chang Jiang
- Department of Epidemiology and Biostatistics, Michigan State University
- Carol A. Wang
- Faculty of Medicine and Health, School of Medicine and Public Health, The University of Newcastle
- Gretchen Saunders
- Department of Psychology, University of Minnesota
- Ville Karhunen
- Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London
- Anke R. Hammerschlag
- Department of Biological Psychology, Vrije Universiteit Amsterdam
- Daniel E. Adkins
- Department of Sociology, College of Social and Behavioral Science, University of Utah
- Richard Border
- Institute for Behavioral Genetics, University of Colorado Boulder
- Roseann E. Peterson
- Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University
- Joseph A. Prinz
- Center for Genomic and Computational Biology, Duke University
- Elisabeth Thiering
- Institute of Epidemiology, Helmholtz Zentrum München – German Research Center for Environmental Health
- Ilkka Seppälä
- Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center – Tampere, Faculty of Medicine and Health Technology, Tampere University
- Natàlia Vilor-Tejedor
- ISGlobal, Barcelona Institute for Global Health
- Tarunveer S. Ahluwalia
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen
- Felix R. Day
- MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine
- Jouke-Jan Hottenga
- Department of Biological Psychology, Vrije Universiteit Amsterdam
- Andrea G. Allegrini
- Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Kaili Rimfeld
- Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Qi Chen
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Yi Lu
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Joanna Martin
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- María Soler Artigas
- Department of Psychiatry, Hospital Universitari Vall d’Hebron
- Paula Rovira
- Department of Psychiatry, Hospital Universitari Vall d’Hebron
- Rosa Bosch
- Department of Psychiatry, Hospital Universitari Vall d’Hebron
- Gemma Español
- Department of Psychiatry, Hospital Universitari Vall d’Hebron
- Josep Antoni Ramos Quiroga
- Department of Psychiatry, Hospital Universitari Vall d’Hebron
- Alexander Neumann
- Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center
- Judith Ensink
- Department of Child and Adolescent Psychiatry, Academic Medical Center
- Katrina Grasby
- QIMR Berghofer Medical Research Institute
- José J. Morosoli
- QIMR Berghofer Medical Research Institute
- Xiaoran Tong
- Department of Epidemiology and Biostatistics, Michigan State University
- Shelby Marrington
- School of Public Health, Faculty of Medicine, The University of Queensland
- Christel Middeldorp
- Department of Biological Psychology, Vrije Universiteit Amsterdam
- James G. Scott
- School of Public Health, Faculty of Medicine, The University of Queensland
- Anna Vinkhuyzen
- Institute for Molecular Bioscience, University of Queensland
- Andrey A. Shabalin
- Department of Psychiatry, School of Medicine, University of Utah
- Robin Corley
- Institute for Behavioral Genetics, University of Colorado Boulder
- Luke M. Evans
- Institute for Behavioral Genetics, University of Colorado Boulder
- Karen Sugden
- Center for Genomic and Computational Biology, Duke University
- Silvia Alemany
- ISGlobal, Barcelona Institute for Global Health
- Lærke Sass
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen
- Rebecca Vinding
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen
- Kate Ruth
- Genetics of Complex Traits, Royal Devon & Exeter Hospital, University of Exeter Medical School
- Jess Tyrrell
- Genetics of Complex Traits, Royal Devon & Exeter Hospital, University of Exeter Medical School
- Gareth E. Davies
- Avera Institute for Human Genetics
- Erik A. Ehli
- Avera Institute for Human Genetics
- Fiona A. Hagenbeek
- Department of Biological Psychology, Vrije Universiteit Amsterdam
- Eveline De Zeeuw
- Department of Biological Psychology, Vrije Universiteit Amsterdam
- Toos C.E.M. Van Beijsterveldt
- Department of Biological Psychology, Vrije Universiteit Amsterdam
- Henrik Larsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Harold Snieder
- Department of Epidemiology, University of Groningen, University Medical Center Groningen
- Frank C. Verhulst
- Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center
- Najaf Amin
- Department of Epidemiology, Erasmus University Medical Center
- Alyce M. Whipp
- Institute for Molecular Medicine FIMM, HiLife, University of Helsinki
- Tellervo Korhonen
- Institute for Molecular Medicine FIMM, HiLife, University of Helsinki
- Eero Vuoksimaa
- Institute for Molecular Medicine FIMM, HiLife, University of Helsinki
- Richard J. Rose
- Department of Psychological and Brain Sciences, Indiana University
- André G. Uitterlinden
- Department of Epidemiology, Erasmus University Medical Center
- Andrew C. Heath
- Washington University
- Pamela Madden
- Washington University
- Jan Haavik
- Department of Biomedicine, University of Bergen
- Jennifer R. Harris
- Division of Health Data and Digitalisation, The Norwegian Institute of Public Health
- Øyvind Helgeland
- Department of Genetics and Bioinformatics, Division of Health Data and Digitalization, The Norwegian Institute of Public Health
- Stefan Johansson
- Department of Biomedicine, University of Bergen
- Gun Peggy S. Knudsen
- Division of Health Data and Digitalisation, The Norwegian Institute of Public Health
- Pal Rasmus Njolstad
- Department of Clinical Science, University of Bergen
- Qing Lu
- Department of Epidemiology and Biostatistics, Michigan State University
- Alina Rodriguez
- Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London
- Anjali K. Henders
- Institute for Molecular Bioscience, University of Queensland
- Abdullah Mamun
- Institute for Social Science Research, University of Queensland
- Jackob M. Najman
- School of Public Health, Faculty of Medicine, The University of Queensland
- Sandy Brown
- Department of Psychiatry, University of California
- Christian Hopfer
- University of Colorado School of Medicine
- Kenneth Krauter
- Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder
- Chandra Reynolds
- Department of Psychology, University of California Riverside
- Andrew Smolen
- Institute for Behavioral Genetics, University of Colorado Boulder
- Michael Stallings
- Institute for Behavioral Genetics, University of Colorado Boulder
- Sally Wadsworth
- Institute for Behavioral Genetics, University of Colorado Boulder
- Tamara L. Wall
- Department of Psychiatry, University of California
- Judy L. Silberg
- Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University
- Allison Miller
- Department of Pathology and Biomedical Science, and Carney Centre for Pharmacogenomics, University of Otago Christchurch
- Liisa Keltikangas-Järvinen
- Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki
- Christian Hakulinen
- Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki
- Laura Pulkki-Råback
- Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki
- Alexandra Havdahl
- Nic Waals Institute, Lovisenberg Diaconal Hospital
- Per Magnus
- Centre for Fertility and Health, Norwegian Institute of Public Health
- Olli T. Raitakari
- Centre for Population Health Research, University of Turku and Turku University Hospital
- John R. B. Perry
- MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine
- Sabrina Llop
- Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València
- Maria-Jose Lopez-Espinosa
- Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València
- Klaus Bønnelykke
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen
- Hans Bisgaard
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen
- Jordi Sunyer
- ISGlobal, Barcelona Institute for Global Health
- Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center – Tampere, Faculty of Medicine and Health Technology, Tampere University
- Louise Arseneault
- Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine
- Marie Standl
- Institute of Epidemiology, Helmholtz Zentrum München – German Research Center for Environmental Health
- Joachim Heinrich
- Institute of Epidemiology, Helmholtz Zentrum München – German Research Center for Environmental Health
- Joseph Boden
- Christchurch Health and Development Study, Department of Psychological Medicine, University of Otago Christchurch
- John Pearson
- Biostatistics and Computational Biology Unit, Department of Pathology and Biomedical Science, University of Otago Christchurch
- L. John Horwood
- Christchurch Health and Development Study, Department of Psychological Medicine, University of Otago Christchurch
- Martin Kennedy
- Department of Pathology and Biomedical Science, and Carney Centre for Pharmacogenomics, University of Otago Christchurch
- Richie Poulton
- Dunedin Multidisciplinary Health and Development Research Unit, University of Otago
- Lindon J. Eaves
- Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University
- Hermine H. Maes
- Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University
- John Hewitt
- Institute for Behavioral Genetics, University of Colorado Boulder
- William E. Copeland
- Department of Psychiatry, College of Medicine, University of Vermont
- Elizabeth J. Costello
- Department of Psychiatry, School of Medicine, Duke University
- Gail M. Williams
- School of Public Health, Faculty of Medicine, The University of Queensland
- Naomi Wray
- Institute for Molecular Bioscience, University of Queensland
- Marjo-Riitta Järvelin
- Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London
- Matt McGue
- Department of Psychology, University of Minnesota
- William Iacono
- Department of Psychology, University of Minnesota
- Avshalom Caspi
- Center for Genomic and Computational Biology, Duke University
- Terrie E. Moffitt
- Center for Genomic and Computational Biology, Duke University
- Andrew Whitehouse
- Telethon Kids Institute, The University of Western Australia
- Craig E. Pennell
- Faculty of Medicine and Health, School of Medicine and Public Health, The University of Newcastle
- Kelly L. Klump
- Department of Psychology, Michigan State University
- S. Alexandra Burt
- Department of Psychology, Michigan State University
- Danielle M. Dick
- Department of Psychology, Virginia Commonwealth University
- Ted Reichborn-Kjennerud
- Department of Mental Disorders, Norwegian Institute of Public Health
- Nicholas G. Martin
- QIMR Berghofer Medical Research Institute
- Sarah E. Medland
- QIMR Berghofer Medical Research Institute
- Tanja Vrijkotte
- Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam UMC, Academic Medical Center, University of Amsterdam
- Jaakko Kaprio
- Institute for Molecular Medicine FIMM, HiLife, University of Helsinki
- Henning Tiemeier
- Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center
- George Davey Smith
- MRC Integrative Epidemiology Unit, University of Bristol
- Catharina A. Hartman
- Department of Psychiatry, University of Groningen, University Medical Center Groningen
- Albertine J. Oldehinkel
- Department of Psychiatry, University of Groningen, University Medical Center Groningen
- Miquel Casas
- Department of Psychiatry, Hospital Universitari Vall d’Hebron
- Marta Ribasés
- Department of Psychiatry, Hospital Universitari Vall d’Hebron
- Paul Lichtenstein
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Sebastian Lundström
- Gillberg Neuropsychiatry Centre, University of Gothenburg
- Robert Plomin
- Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Meike Bartels
- Department of Biological Psychology, Vrije Universiteit Amsterdam
- Michel G. Nivard
- Department of Biological Psychology, Vrije Universiteit Amsterdam
- Dorret I. Boomsma
- Department of Biological Psychology, Vrije Universiteit Amsterdam
- DOI
- https://doi.org/10.1038/s41398-021-01480-x
- Journal volume & issue
-
Vol. 11,
no. 1
pp. 1 – 9
Abstract
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 (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. 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.
