Meta-Analysis

. 2021 Jul 30;11(1):413.

doi: 10.1038/s41398-021-01480-x.

Genetic association study of childhood aggression across raters, instruments, and age

Hill F Ip¹, Camiel M van der Laan^{1

2}, Eva M L Krapohl³, Isabell Brikell⁴, Cristina Sánchez-Mora^{5

6

7}, Ilja M Nolte⁸, Beate St Pourcain^{9

10

11}, Koen Bolhuis¹², Teemu Palviainen¹³, Hadi Zafarmand^{14

15}, Lucía Colodro-Conde¹⁶, Scott Gordon¹⁶, Tetyana Zayats^{17

18

19}, Fazil Aliev^{20

21}, Chang Jiang^{22

23}, Carol A Wang²⁴, Gretchen Saunders²⁵, Ville Karhunen²⁶, Anke R Hammerschlag^{1

27

28}, Daniel E Adkins^{29

30}, Richard Border^{31

32

33}, Roseann E Peterson³⁴, Joseph A Prinz³⁵, Elisabeth Thiering^{36

37}, Ilkka Seppälä³⁸, Natàlia Vilor-Tejedor^{39

40

41

42

43}, Tarunveer S Ahluwalia^{44

45}, Felix R Day⁴⁶, Jouke-Jan Hottenga¹, Andrea G Allegrini³, Kaili Rimfeld³, Qi Chen⁴, Yi Lu⁴, Joanna Martin^{4

47}, María Soler Artigas^{5

6

7}, Paula Rovira^{5

6

7}, Rosa Bosch^{5

6

48}, Gemma Español⁵, Josep Antoni Ramos Quiroga^{5

6

7

48}, Alexander Neumann^{12

49}, Judith Ensink^{50

51}, Katrina Grasby¹⁶, José J Morosoli¹⁶, Xiaoran Tong^{22

23}, Shelby Marrington⁵², Christel Middeldorp^{1

27

53}, James G Scott^{52

54

55}, Anna Vinkhuyzen⁵⁶, Andrey A Shabalin³⁰, Robin Corley^{31

57}, Luke M Evans^{31

57}, Karen Sugden^{35

58}, Silvia Alemany^{39

40

41}, Lærke Sass⁴⁴, Rebecca Vinding⁴⁴, Kate Ruth⁵⁹, Jess Tyrrell⁵⁹, Gareth E Davies⁶⁰, Erik A Ehli⁶⁰, Fiona A Hagenbeek¹, Eveline De Zeeuw¹, Toos C E M Van Beijsterveldt¹, Henrik Larsson^{4

61}, Harold Snieder⁸, Frank C Verhulst^{12

62}, Najaf Amin⁶³, Alyce M Whipp¹³, Tellervo Korhonen¹³, Eero Vuoksimaa¹³, Richard J Rose⁶⁴, André G Uitterlinden^{63

65

66}, Andrew C Heath⁶⁷, Pamela Madden⁶⁷, Jan Haavik^{17

68}, Jennifer R Harris⁶⁹, Øyvind Helgeland⁷⁰, Stefan Johansson^{17

71}, Gun Peggy S Knudsen⁶⁹, Pal Rasmus Njolstad⁷², Qing Lu^{22

23}, Alina Rodriguez^{26

73}, Anjali K Henders⁵⁶, Abdullah Mamun⁷⁴, Jackob M Najman⁵², Sandy Brown⁷⁵, Christian Hopfer⁷⁶, Kenneth Krauter⁷⁷, Chandra Reynolds⁷⁸, Andrew Smolen³¹, Michael Stallings^{31

32}, Sally Wadsworth³¹, Tamara L Wall⁷⁵, Judy L Silberg^{34

79}, Allison Miller⁸⁰, Liisa Keltikangas-Järvinen⁸¹, Christian Hakulinen⁸¹, Laura Pulkki-Råback⁸¹, Alexandra Havdahl^{82

83}, Per Magnus⁸⁴, Olli T Raitakari^{85

86

87}, John R B Perry⁴⁶, Sabrina Llop^{88

89}, Maria-Jose Lopez-Espinosa^{88

89

90}, Klaus Bønnelykke⁴⁴, Hans Bisgaard⁴⁴, Jordi Sunyer^{39

40

41

91}, Terho Lehtimäki³⁸, Louise Arseneault⁹², Marie Standl³⁶, Joachim Heinrich^{36

93

94}, Joseph Boden⁹⁵, John Pearson⁹⁶, L John Horwood⁹⁵, Martin Kennedy⁸⁰, Richie Poulton⁹⁷, Lindon J Eaves^{34

79}, Hermine H Maes^{34

79

98}, John Hewitt^{31

32}, William E Copeland⁹⁹, Elizabeth J Costello¹⁰⁰, Gail M Williams⁵², Naomi Wray^{56

101}, Marjo-Riitta Järvelin^{26

102}, Matt McGue²⁵, William Iacono²⁵, Avshalom Caspi^{35

58

92

103}, Terrie E Moffitt^{35

58

92

103}, Andrew Whitehouse¹⁰⁴, Craig E Pennell²⁴, Kelly L Klump¹⁰⁵, S Alexandra Burt¹⁰⁵, Danielle M Dick^{20

106

107}, Ted Reichborn-Kjennerud^{83

108}, Nicholas G Martin¹⁶, Sarah E Medland¹⁶, Tanja Vrijkotte¹⁴, Jaakko Kaprio^{13

109}, Henning Tiemeier^{12

110}, George Davey Smith^{9

111}, Catharina A Hartman¹¹², Albertine J Oldehinkel¹¹², Miquel Casas^{5

6

7

48}, Marta Ribasés^{5

6

7}, Paul Lichtenstein⁴, Sebastian Lundström^{113

114}, Robert Plomin³, Meike Bartels^{115

116}, Michel G Nivard¹¹⁷, Dorret I Boomsma^{118

119}

Affiliations

¹ Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
² Netherlands Institute for the Study of Crime and Law Enforcement, Amsterdam, The Netherlands.
³ Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁵ Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
⁶ Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain.
⁷ Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
⁸ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
¹⁰ Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
¹¹ Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
¹² Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Rotterdam, The Netherlands.
¹³ Institute for Molecular Medicine FIMM, HiLife, University of Helsinki, Helsinki, Finland.
¹⁴ Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
¹⁵ Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam Public Health Research Institute, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
¹⁶ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
¹⁷ Department of Biomedicine, University of Bergen, Bergen, Norway.
¹⁸ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁰ Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA.
²¹ Faculty of Business, Karabuk University, Karabuk, Turkey.
²² Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA.
²³ Department of Biostatistics, University of Florida, Gainesville, FL, USA.
²⁴ Faculty of Medicine and Health, School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia.
²⁵ Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
²⁶ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
²⁷ Child Health Research Centre, the University of Queensland, Brisbane, QLD, Australia.
²⁸ Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.
²⁹ Department of Sociology, College of Social and Behavioral Science, University of Utah, Salt Lake City, UT, USA.
³⁰ Department of Psychiatry, School of Medicine, University of Utah, Salt Lake City, UT, USA.
³¹ Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.
³² Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
³³ Department of Applied Mathematics, University of Colorado Boulder, Boulder, CO, USA.
³⁴ Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
³⁵ Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.
³⁶ Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
³⁷ Division of Metabolic Diseases and Nutritional Medicine, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany.
³⁸ Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
³⁹ ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain.
⁴⁰ Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁴¹ CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.
⁴² Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
⁴³ Barcelona Beta Brain Research Center, Pasqual Maragall Foundation (FPM), Barcelona, Spain.
⁴⁴ COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
⁴⁵ Steno Diabetes Center Copenhagen, Gentofte, Denmark.
⁴⁶ MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, UK.
⁴⁷ MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
⁴⁸ Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
⁴⁹ Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.
⁵⁰ Department of Child and Adolescent Psychiatry, Academic Medical Center, Amsterdam, The Netherlands.
⁵¹ De Bascule, Academic Centre for Child and Adolescent Psychiatry, Amsterdam, The Netherlands.
⁵² School of Public Health, Faculty of Medicine, The University of Queensland, Herston, QLD, Australia.
⁵³ Children's Health Queensland Hospital and Health Service, Child and Youth Mental Health Service, Brisbane, QLD, Australia.
⁵⁴ Metro North Mental Health, University of Queensland, St Lucia, QLD, Australia.
⁵⁵ Queensland Centre for Mental Health Research, St Lucia, QLD, Australia.
⁵⁶ Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD, Australia.
⁵⁷ Department of Ecology and Evolutionary Biology, University of Colorado Boulder, Boulder, CO, USA.
⁵⁸ Department of Psychology and Neuroscience and Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.
⁵⁹ Genetics of Complex Traits, Royal Devon & Exeter Hospital, University of Exeter Medical School, Exeter, UK.
⁶⁰ Avera Institute for Human Genetics, Sioux Falls, SD, USA.
⁶¹ School of Medical Sciences, Orebro University, Orebro, Sweden.
⁶² Child and Adolescent Mental Health Centre, Mental Health Services Capital Region, Research Unit, Copenhagen University Hospital, Copenhagen, Denmark.
⁶³ Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁶⁴ Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
⁶⁵ Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁶⁶ Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands.
⁶⁷ Washington University, St Louis, MO, USA.
⁶⁸ Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
⁶⁹ Division of Health Data and Digitalisation, The Norwegian Institute of Public Health, Oslo, Norway.
⁷⁰ Department of Genetics and Bioinformatics, Division of Health Data and Digitalization, The Norwegian Institute of Public Health, Bergen, Norway.
⁷¹ K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Clinical Science, University of Bergen, Bergen, Norway.
⁷² Department of Clinical Science, University of Bergen, Bergen, Norway.
⁷³ School of Psychology, University of Lincoln, Lincolnshire, UK.
⁷⁴ Institute for Social Science Research, University of Queensland, Long Pocket, QLD, Australia.
⁷⁵ Department of Psychiatry, University of California, San Diego, CA, USA.
⁷⁶ University of Colorado School of Medicine, Aurora, CO, USA.
⁷⁷ Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA.
⁷⁸ Department of Psychology, University of California Riverside, Riverside, CA, USA.
⁷⁹ Department of Human & Molecular Genetics, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
⁸⁰ Department of Pathology and Biomedical Science, and Carney Centre for Pharmacogenomics, University of Otago Christchurch, Christchurch Central City, New Zealand.
⁸¹ Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁸² Nic Waals Institute, Lovisenberg Diaconal Hospital, Oslo, Norway.
⁸³ Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway.
⁸⁴ Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
⁸⁵ Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland.
⁸⁶ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
⁸⁷ Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
⁸⁸ Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain.
⁸⁹ Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain.
⁹⁰ Faculty of Nursing and Chiropody, Universitat de València, Valencia, Spain.
⁹¹ IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
⁹² Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA.
⁹³ Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University of Munich Medical Center, Ludwig-Maximilians-Universität München, Munich, Germany.
⁹⁴ Allergy and Lung Health Unit, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia.
⁹⁵ Christchurch Health and Development Study, Department of Psychological Medicine, University of Otago Christchurch, Christchurch Central City, New Zealand.
⁹⁶ Biostatistics and Computational Biology Unit, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch Central City, New Zealand.
⁹⁷ Dunedin Multidisciplinary Health and Development Research Unit, University of Otago, Dunedin, New Zealand.
⁹⁸ Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
⁹⁹ Department of Psychiatry, College of Medicine, University of Vermont, Burlington, VT, USA.
¹⁰⁰ Department of Psychiatry, School of Medicine, Duke University, Durham, UK.
¹⁰¹ Queensland Brain Institute, Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD, Australia.
¹⁰² Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
¹⁰³ Social, Genetic, and Developmental Psychiatry Research Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
¹⁰⁴ Telethon Kids Institute, The University of Western Australia, Perth, WA, Australia.
¹⁰⁵ Department of Psychology, Michigan State University, East Lansing, MI, USA.
¹⁰⁶ Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
¹⁰⁷ College Behavioral and Emotional Health Institute, Virginia Commonwealth University, Richmond, VA, USA.
¹⁰⁸ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹⁰⁹ Department of Public Health, Medical Faculty, University of Helsinki, Helsinki, Finland.
¹¹⁰ Department of Social and Behavioral Science, Harvard TH Chan School of Public Health, Boston, MA, USA.
¹¹¹ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
¹¹² Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹¹³ Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden.
¹¹⁴ Centre for Ethics, Law and Mental Health, University of Gothenburg, Gothenburg, Sweden.
¹¹⁵ Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. m.bartels@vu.nl.
¹¹⁶ Amsterdam Public Health Research Institute, Amsterdam, The Netherlands. m.bartels@vu.nl.
¹¹⁷ Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. m.g.nivard@vu.nl.
¹¹⁸ Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. di.boomsma@vu.nl.
¹¹⁹ Amsterdam Public Health Research Institute, Amsterdam, The Netherlands. di.boomsma@vu.nl.

PMID: 34330890
PMCID: PMC8324785
DOI: 10.1038/s41398-021-01480-x

Meta-Analysis

Genetic association study of childhood aggression across raters, instruments, and age

Hill F Ip et al. Transl Psychiatry. 2021.

. 2021 Jul 30;11(1):413.

doi: 10.1038/s41398-021-01480-x.

Authors

Affiliations

¹ Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
² Netherlands Institute for the Study of Crime and Law Enforcement, Amsterdam, The Netherlands.
³ Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁵ Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
⁶ Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain.
⁷ Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
⁸ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
¹⁰ Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
¹¹ Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
¹² Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Rotterdam, The Netherlands.
¹³ Institute for Molecular Medicine FIMM, HiLife, University of Helsinki, Helsinki, Finland.
¹⁴ Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
¹⁵ Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam Public Health Research Institute, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
¹⁶ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
¹⁷ Department of Biomedicine, University of Bergen, Bergen, Norway.
¹⁸ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁰ Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA.
²¹ Faculty of Business, Karabuk University, Karabuk, Turkey.
²² Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA.
²³ Department of Biostatistics, University of Florida, Gainesville, FL, USA.
²⁴ Faculty of Medicine and Health, School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia.
²⁵ Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
²⁶ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
²⁷ Child Health Research Centre, the University of Queensland, Brisbane, QLD, Australia.
²⁸ Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.
²⁹ Department of Sociology, College of Social and Behavioral Science, University of Utah, Salt Lake City, UT, USA.
³⁰ Department of Psychiatry, School of Medicine, University of Utah, Salt Lake City, UT, USA.
³¹ Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.
³² Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
³³ Department of Applied Mathematics, University of Colorado Boulder, Boulder, CO, USA.
³⁴ Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
³⁵ Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.
³⁶ Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
³⁷ Division of Metabolic Diseases and Nutritional Medicine, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany.
³⁸ Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
³⁹ ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain.
⁴⁰ Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁴¹ CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.
⁴² Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
⁴³ Barcelona Beta Brain Research Center, Pasqual Maragall Foundation (FPM), Barcelona, Spain.
⁴⁴ COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
⁴⁵ Steno Diabetes Center Copenhagen, Gentofte, Denmark.
⁴⁶ MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, UK.
⁴⁷ MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
⁴⁸ Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
⁴⁹ Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.
⁵⁰ Department of Child and Adolescent Psychiatry, Academic Medical Center, Amsterdam, The Netherlands.
⁵¹ De Bascule, Academic Centre for Child and Adolescent Psychiatry, Amsterdam, The Netherlands.
⁵² School of Public Health, Faculty of Medicine, The University of Queensland, Herston, QLD, Australia.
⁵³ Children's Health Queensland Hospital and Health Service, Child and Youth Mental Health Service, Brisbane, QLD, Australia.
⁵⁴ Metro North Mental Health, University of Queensland, St Lucia, QLD, Australia.
⁵⁵ Queensland Centre for Mental Health Research, St Lucia, QLD, Australia.
⁵⁶ Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD, Australia.
⁵⁷ Department of Ecology and Evolutionary Biology, University of Colorado Boulder, Boulder, CO, USA.
⁵⁸ Department of Psychology and Neuroscience and Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.
⁵⁹ Genetics of Complex Traits, Royal Devon & Exeter Hospital, University of Exeter Medical School, Exeter, UK.
⁶⁰ Avera Institute for Human Genetics, Sioux Falls, SD, USA.
⁶¹ School of Medical Sciences, Orebro University, Orebro, Sweden.
⁶² Child and Adolescent Mental Health Centre, Mental Health Services Capital Region, Research Unit, Copenhagen University Hospital, Copenhagen, Denmark.
⁶³ Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁶⁴ Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
⁶⁵ Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁶⁶ Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands.
⁶⁷ Washington University, St Louis, MO, USA.
⁶⁸ Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
⁶⁹ Division of Health Data and Digitalisation, The Norwegian Institute of Public Health, Oslo, Norway.
⁷⁰ Department of Genetics and Bioinformatics, Division of Health Data and Digitalization, The Norwegian Institute of Public Health, Bergen, Norway.
⁷¹ K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Clinical Science, University of Bergen, Bergen, Norway.
⁷² Department of Clinical Science, University of Bergen, Bergen, Norway.
⁷³ School of Psychology, University of Lincoln, Lincolnshire, UK.
⁷⁴ Institute for Social Science Research, University of Queensland, Long Pocket, QLD, Australia.
⁷⁵ Department of Psychiatry, University of California, San Diego, CA, USA.
⁷⁶ University of Colorado School of Medicine, Aurora, CO, USA.
⁷⁷ Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA.
⁷⁸ Department of Psychology, University of California Riverside, Riverside, CA, USA.
⁷⁹ Department of Human & Molecular Genetics, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
⁸⁰ Department of Pathology and Biomedical Science, and Carney Centre for Pharmacogenomics, University of Otago Christchurch, Christchurch Central City, New Zealand.
⁸¹ Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁸² Nic Waals Institute, Lovisenberg Diaconal Hospital, Oslo, Norway.
⁸³ Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway.
⁸⁴ Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
⁸⁵ Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland.
⁸⁶ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
⁸⁷ Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
⁸⁸ Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain.
⁸⁹ Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain.
⁹⁰ Faculty of Nursing and Chiropody, Universitat de València, Valencia, Spain.
⁹¹ IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
⁹² Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA.
⁹³ Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University of Munich Medical Center, Ludwig-Maximilians-Universität München, Munich, Germany.
⁹⁴ Allergy and Lung Health Unit, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia.
⁹⁵ Christchurch Health and Development Study, Department of Psychological Medicine, University of Otago Christchurch, Christchurch Central City, New Zealand.
⁹⁶ Biostatistics and Computational Biology Unit, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch Central City, New Zealand.
⁹⁷ Dunedin Multidisciplinary Health and Development Research Unit, University of Otago, Dunedin, New Zealand.
⁹⁸ Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
⁹⁹ Department of Psychiatry, College of Medicine, University of Vermont, Burlington, VT, USA.
¹⁰⁰ Department of Psychiatry, School of Medicine, Duke University, Durham, UK.
¹⁰¹ Queensland Brain Institute, Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD, Australia.
¹⁰² Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
¹⁰³ Social, Genetic, and Developmental Psychiatry Research Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
¹⁰⁴ Telethon Kids Institute, The University of Western Australia, Perth, WA, Australia.
¹⁰⁵ Department of Psychology, Michigan State University, East Lansing, MI, USA.
¹⁰⁶ Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
¹⁰⁷ College Behavioral and Emotional Health Institute, Virginia Commonwealth University, Richmond, VA, USA.
¹⁰⁸ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹⁰⁹ Department of Public Health, Medical Faculty, University of Helsinki, Helsinki, Finland.
¹¹⁰ Department of Social and Behavioral Science, Harvard TH Chan School of Public Health, Boston, MA, USA.
¹¹¹ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
¹¹² Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹¹³ Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden.
¹¹⁴ Centre for Ethics, Law and Mental Health, University of Gothenburg, Gothenburg, Sweden.
¹¹⁵ Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. m.bartels@vu.nl.
¹¹⁶ Amsterdam Public Health Research Institute, Amsterdam, The Netherlands. m.bartels@vu.nl.
¹¹⁷ Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. m.g.nivard@vu.nl.
¹¹⁸ Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. di.boomsma@vu.nl.
¹¹⁹ Amsterdam Public Health Research Institute, Amsterdam, The Netherlands. di.boomsma@vu.nl.

PMID: 34330890
PMCID: PMC8324785
DOI: 10.1038/s41398-021-01480-x

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_gs 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 [Formula: see text]: 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 [Formula: see text]: 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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Conflict of interest statement

MC has received travel grants and research support from Eli Lilly and Co., Janssen-Cilag, Shire, and Lundbeck and served as consultant for Eli Lilly and Co., Janssen-Cilag, Shire, and Lundbeck. JARQ was on the speakers’ bureau and/or acted as consultant Eli Lilly, Janssen-Cilag, Novartis, Shire, Lundbeck, Almirall, Braingaze, Sincrolab, Medicine, Exeltis, and Rubió in the last 5 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire, Medice, and Eli-Lilly. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 5 years: Eli-Lilly, Lundbeck, Janssen-Cilag, Actelion, Shire, Ferrer, Oryzon, Roche, Psious, and Rubió.

Figures

**Fig. 1. Manhattan plot of overall meta-analysis for childhood aggression (AG_Goverall).**
Red triangles represent SNPs that were included in the significant genes from the gene-based analysis. SNPs for *ST3GAL3* and *IPO13* are included in the same locus on chromosome 1.

**Fig. 2. Proportion of explained variance (vertical axis) in childhood aggression at age 7 by polygenic scores from the overall GWAMA for multiple P value thresholds (horizontal axis).**
Numbers above the bars represent unadjusted P values for two-sided test of significance.

**Fig. 3. Proportion of explained variance (vertical axis) in retrospective adolescent CD (two-sided tests).**
Blue bars indicate positive correlation with the conduct disorder score.

**Fig. 4. Genetic correlation with external phenotypes.**
Phenotypes are ordered by domain. Bars indicate 95% confidence intervals.

See this image and copyright information in PMC

References

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Genetic association study of childhood aggression across raters, instruments, and age

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Genetic association study of childhood aggression across raters, instruments, and age

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Medical