title: A genome-wide approach to children's aggressive behavior: The EAGLE consortium.
abstract: Individual differences in aggressive behavior emerge in early childhood and predict persisting behavioral problems and disorders. Studies of antisocial and severe aggression in adulthood indicate substantial underlying biology. However, little attention has been given to genome-wide approaches of aggressive behavior in children. We analyzed data from nine population-based studies and assessed aggressive behavior using well-validated parent-reported questionnaires. This is the largest sample exploring children's aggressive behavior to date (N = 18,988), with measures in two developmental stages (N = 15,668 early childhood and N = 16,311 middle childhood/early adolescence). First, we estimated the additive genetic variance of children's aggressive behavior based on genome-wide SNP information, using genome-wide complex trait analysis (GCTA). Second, genetic associations within each study were assessed using a quasi-Poisson regression approach, capturing the highly right-skewed distribution of aggressive behavior. Third, we performed meta-analyses of genome-wide associations for both the total age-mixed sample and the two developmental stages. Finally, we performed a gene-based test using the summary statistics of the total sample. GCTA quantified variance tagged by common SNPs (10-54%). The meta-analysis of the total sample identified one region in chromosome 2 (2p12) at near genome-wide significance (top SNP rs11126630, P = 5.30 × 10(-8) ). The separate meta-analyses of the two developmental stages revealed suggestive evidence of association at the same locus. The gene-based analysis indicated association of variation within AVPR1A with aggressive behavior. We conclude that common variants at 2p12 show suggestive evidence for association with childhood aggression. Replication of these initial findings is needed, and further studies should clarify its biological meaning. © 2015 Wiley Periodicals, Inc.
authors.affiliation: School of Pedagogical and Educational Sciences, Erasmus University Rotterdam, Rotterdam, The Netherlands.|Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Irene
authors.initials: I
authors.lastname: Pappa
authors.affiliation: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.|School of Oral and Dental Sciences, University of Bristol, Bristol, United Kingdom.|School of Experimental Psychology, University of Bristol, Bristol, United Kingdom.
authors.forename: Beate
authors.initials: B
authors.lastname: St Pourcain
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Mental Health Department, Baltimore, Maryland.
authors.forename: Kelly
authors.initials: K
authors.lastname: Benke
authors.affiliation: Population, Policy and Practice, UCL Institute of Child Health, University College London, London, United Kingdom.|Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Alana
authors.initials: A
authors.lastname: Cavadino
authors.affiliation: Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
authors.forename: Christian
authors.initials: C
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authors.affiliation: Netherlands Twin Register, Department of Biological Psychology, VU University, Amsterdam, The Netherlands.|Neuroscience Campus Amsterdam (NCA), Amsterdam, The Netherlands.
authors.forename: Michel G
authors.initials: MG
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authors.affiliation: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Ilja M
authors.initials: IM
authors.lastname: Nolte
authors.affiliation: Institute of Epidemiology I, Helmholtz Zentrum Munich, German Research Centre for Environmental Health, Neuherberg, Germany.|Division of Metabolic Diseases and Nutritional Medicine, Dr von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Carla M T
authors.initials: CM
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authors.affiliation: Centre for Child and Family Studies, Leiden University, Leiden, The Netherlands.
authors.forename: Marian J
authors.initials: MJ
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authors.affiliation: Avera Institute for Human Genetics, Sioux Falls, South Dakota.
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authors.initials: GE
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authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Brisbane, Australia.
authors.forename: David M
authors.initials: DM
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authors.affiliation: Population, Policy and Practice, UCL Institute of Child Health, University College London, London, United Kingdom.|McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Geoffroy
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum Munich, German Research Centre for Environmental Health, Neuherberg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Grallert
authors.affiliation: Netherlands Twin Register, Department of Biological Psychology, VU University, Amsterdam, The Netherlands.|EMGO+ Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands.
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authors.initials: MM
authors.lastname: Groen-Blokhuis
authors.affiliation: Vermont Center for Children, Youth, and Families, Department of Psychiatry, University of Vermont, College of Medicine, Vermont.|Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center-Sophia Children's Hospital, The Netherlands.
authors.forename: James J
authors.initials: JJ
authors.lastname: Hudziak
authors.affiliation: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.|University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Brisbane, Australia.|School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: John P
authors.initials: JP
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authors.affiliation: Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
authors.forename: Liisa
authors.initials: L
authors.lastname: Keltikangas-Järvinen
authors.affiliation: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.|University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Brisbane, Australia.|School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: McMahon
authors.affiliation: School of Pedagogical and Educational Sciences, Erasmus University Rotterdam, Rotterdam, The Netherlands.
authors.forename: Viara R
authors.initials: VR
authors.lastname: Mileva-Seitz
authors.affiliation: Department of Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Ehsan
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authors.lastname: Motazedi
authors.affiliation: Population, Policy and Practice, UCL Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Christine
authors.initials: C
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authors.affiliation: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
authors.forename: Olli T
authors.initials: OT
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authors.affiliation: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.|School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
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authors.initials: SM
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authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center-Sophia Children's Hospital, The Netherlands.|Department of Epidemiology, Erasmus University Medical Center-Sophia Children's Hospital, The Netherlands.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.affiliation: Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom.
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authors.initials: A
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authors.affiliation: Department of Epidemiology, University of Texas/MD Anderson Cancer Center, Houston, Texas.
authors.forename: Paul A
authors.initials: PA
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authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere School of Medicine, Tampere, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Seppälä
authors.affiliation: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Harold
authors.initials: H
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authors.affiliation: Institute of Epidemiology I, Helmholtz Zentrum Munich, German Research Centre for Environmental Health, Neuherberg, Germany.
authors.forename: Marie
authors.initials: M
authors.lastname: Standl
authors.affiliation: Institute of Epidemiology I, Helmholtz Zentrum Munich, German Research Centre for Environmental Health, Neuherberg, Germany.|Division of Metabolic Diseases and Nutritional Medicine, Dr von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Elisabeth
authors.initials: E
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authors.affiliation: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.|School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
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authors.initials: NJ
authors.lastname: Timpson
authors.affiliation: Department of Sociology, University of Groningen, Groningen, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Veenstra
authors.affiliation: Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Fleur P
authors.initials: FP
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authors.affiliation: Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: Andrew J O
authors.initials: AJ
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authors.affiliation: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.|School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.affiliation: Institute of Epidemiology I, Helmholtz Zentrum Munich, German Research Centre for Environmental Health, Neuherberg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Heinrich
authors.affiliation: School of Pedagogical and Educational Sciences, Erasmus University Rotterdam, Rotterdam, The Netherlands.|School of Population Health and Sansom Institute, University of South Australia, Adelaide, Australia.|South Australian Health and Medical Research Institute, Adelaide, Australia.
authors.forename: Elina
authors.initials: E
authors.lastname: Hypponen
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere School of Medicine, Tampere, Finland.
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.affiliation: Netherlands Twin Register, Department of Biological Psychology, VU University, Amsterdam, The Netherlands.|Neuroscience Campus Amsterdam (NCA), Amsterdam, The Netherlands.|Department of child and adolescent psychiatry, GGZ in Geest/VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Christel M
authors.initials: CM
authors.lastname: Middeldorp
authors.affiliation: Interdisciplinary Center Psychopathology and Emotion Regulation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Albertine J
authors.initials: AJ
authors.lastname: Oldehinkel
authors.affiliation: School of Women's and Infants' Health, University of Western Australia, Perth, Australia.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Pennell
authors.affiliation: Netherlands Twin Register, Department of Biological Psychology, VU University, Amsterdam, The Netherlands.
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.affiliation: Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Epidemiology, Erasmus University Medical Center-Sophia Children's Hospital, The Netherlands.|Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Henning
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authors.lastname: Tiemeier
mesh_terms: D000293:Adolescent; D000374:Aggression / Q000502:physiology* / Q000523:psychology; D001519:Behavior; D002648:Child; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D005824:Genetics, Behavioral / Q000379:methods; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017483:Receptors, Vasopressin / Q000235:genetics / Q000502:physiology; D011795:Surveys and Questionnaires
chemical_list: C000599871:AVPR1A protein, human; D017483:Receptors, Vasopressin
keywords: aggression; childhood; genome-wide complex trait analysis (GCTA); meta-analysis; population-based