DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
Abstract DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N=15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha=1.2×10 −7 ; Bonferroni correction). In cord blood samples of 2,425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression ( r =0.74, p=0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripherl blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range=3-82%) of the aggression–methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.
Authors 88
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Jenny van Dongen corresponding
Vrije Universiteit Amsterdam · Amsterdam Public Health
Affiliation as printed
Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Vrije Universiteit Amsterdam · Amsterdam Public Health
Affiliation as printed
Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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University of Bristol · MRC Integrative Epidemiology Unit
Affiliation as printed
MRC Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
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Leiden University Medical Center
Affiliation as printed
Curium-LUMC, Department of Child and Adolescent Psychiatry, Leiden University Medical Center in Oegstgeest, The Netherlands
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Affiliation as printed
Center for Genomic and Computational Biology, Duke University, Durham, NC, USA
Department of Psychology and Neuroscience, Duke University, Durham, NC, USA
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Affiliation as printed
University Hospital Frankfurt; Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy; Frankfurt am Main, Germany
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy
Frankfurt am Main, Germany
University Hospital Frankfurt
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University of Helsinki · Institute for Molecular Medicine Finland
Affiliation as printed
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
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Leiden University · Erasmus MC
Affiliation as printed
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
Institute of Education and Child Studies, Leiden University, Leiden, the Netherlands
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Affiliation as printed
Division of Psychiatry, University of Edinburgh
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Affiliation as printed
Division of Psychiatry, University of Edinburgh
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Affiliation as printed
Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh
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Affiliation as printed
Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh
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University of Helsinki · University of Turku
Affiliation as printed
Department of Psychology and logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Turku Institute for Advances Studies, University of Turku, Turku Finland
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University Medical Center Groningen · University of Groningen
Affiliation as printed
University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands
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Universitat de Barcelona · Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública · Universitat de Girona
Affiliation as printed
CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
Dpt. of Biomedical Science, Faculty of Medicine and Health Science, University of Barcelona, Barcelona, Spain
Research Group on Statistics, Econometrics ans Health (GRECS), UdG
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Universitat Pompeu Fabra · Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública · Barcelona Institute for Global Health
Affiliation as printed
CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
ISGlobal, Barcelona, Spain
Universitat Pompeu Fabra (UPF), Barcelona, Spain
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
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Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
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Vrije Universiteit Amsterdam · Amsterdam Public Health
Affiliation as printed
Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Vrije Universiteit Amsterdam · Amsterdam University Medical Centers · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Vrije Universiteit Amsterdam · Amsterdam Public Health
Affiliation as printed
Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Affiliation as printed
Biocenter Oulu, University of Oulu, P.O. Box 5000, 90014, Finland
Center for Life Course Health Research, P.O. Box 5000, 90014, University of Oulu, Oulu, Finland
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University of Oulu · Queen's University Belfast
Affiliation as printed
Center for Life Course Health Research, P.O. Box 5000, 90014, University of Oulu, Oulu, Finland
Queen’s University Belfast
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Heidelberg University · Medizinische Fakultät Mannheim · Central Institute of Mental Health
Affiliation as printed
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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Heidelberg University · Medizinische Fakultät Mannheim · Central Institute of Mental Health
Affiliation as printed
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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Heidelberg University · Medizinische Fakultät Mannheim · Central Institute of Mental Health
Affiliation as printed
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany
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Heidelberg University · Medizinische Fakultät Mannheim · Central Institute of Mental Health
Affiliation as printed
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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Affiliation as printed
The Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, 17165 Stockholm, Sweden
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Affiliation as printed
The Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, 17165 Stockholm, Sweden
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Tampere University · University of Tampere · Fimlab (Finland)
Affiliation as printed
Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33520, Finland
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Leiden University Medical Center · Ghent University
Affiliation as printed
Curium-LUMC, Department of Child and Adolescent Psychiatry, Leiden University Medical Center in Oegstgeest, The Netherlands
Department of Special Needs Education, Ghent University, Ghent, Belgium
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Affiliation as printed
Center for Genomic and Computational Biology, Duke University, Durham, NC, USA
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Affiliation as printed
Dunedin Multidisciplinary Health and Development Research Unit, Department of Psychology, University of Otago, Dunedin, New Zealand
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Affiliation as printed
University of Exeter Medical School, University of Exeter, Exeter, UK
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Affiliation as printed
University of Exeter Medical School, University of Exeter, Exeter, UK
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Affiliation as printed
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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University of Helsinki · Institute for Molecular Medicine Finland
Affiliation as printed
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
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University of Helsinki · Institute for Molecular Medicine Finland
Affiliation as printed
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
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Affiliation as printed
Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
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Affiliation as printed
Clinical Child & Family Studies, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Affiliation as printed
Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh
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Affiliation as printed
Turku Institute for Advances Studies, University of Turku, Turku Finland
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Affiliation as printed
Turku Institute for Advances Studies, University of Turku, Turku Finland
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University Medical Center Groningen · University of Groningen
Affiliation as printed
University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands
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Universitat Pompeu Fabra · Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública · Barcelona Institute for Global Health
Affiliation as printed
CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
ISGlobal, Barcelona, Spain
Universitat Pompeu Fabra (UPF), Barcelona, Spain
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Affiliation as printed
Department of Environmental Sciences, Vytautas Magnus University, K. Donelaicio str. 58, 44248 Kaunas, Lithuania
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Norwegian Institute of Public Health
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Norwegian Institute of Public Health
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Norwegian Institute of Public Health
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Norwegian Institute of Public Health
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Affiliation as printed
Department of Social Medicine, University of Crete, Greece
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Radboud University Medical Center · University Medical Center Utrecht · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
University Medical Center Utrecht, UMC Utrecht Brain Center, Department of Psychiatry, Utrecht, The Netherlands
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University of Oslo · Maastricht University · Oslo University Hospital
Affiliation as printed
NORMENT, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway
School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
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Vrije Universiteit Amsterdam · Amsterdam Public Health
Affiliation as printed
Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Affiliation as printed
Good Biomarker Sciences, Leiden, The Netherlands
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Avera Institute for Human Genetics
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Avera Institute for Human Genetics, 3720 W. 69th Street, Sioux Falls, SD, 57108, USA
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Affiliation as printed
Department of Psychology and logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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Affiliation as printed
Department of Psychology and logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
Department of Psychiatry, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
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Affiliation as printed
University Hospital Frankfurt; Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy; Frankfurt am Main, Germany
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy
Frankfurt am Main, Germany
University Hospital Frankfurt
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Kerstin Konrad Aachen Department of Child and Adolescent Psychiatry JARA-Brain Institute II Child Neuropsychology Section
RWTH Aachen University · Universitätsklinikum Aachen · Jülich Aachen Research Alliance
Affiliation as printed
JARA-Brain Institute II, Molecular Neuroscience and Neuroimaging (INM-11), RWTH Aachen & Research Centre Juelich, Germany
University Hospital, RWTH Aachen, Child Neuropsychology Section, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Aachen, Germany
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University Hospital Mútua de Terrassa
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Hospital Universitario Mutua de Terrassa, Child and Adolescent Mental Health Service, Barcelona, Spain
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Bilbao University Hospital, Psychiatric Service, Osakidetza, Bilbao, Spain
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Affiliation as printed
Bilbao University Hospital, Psychiatric Service, Osakidetza, Bilbao, Spain
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University of Turku · Turku University Hospital
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Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
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Tampere University · University of Tampere · Fimlab (Finland)
Affiliation as printed
Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33520, Finland
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Leiden University Medical Center · Parnassia Groep
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Curium-LUMC, Department of Child and Adolescent Psychiatry, Leiden University Medical Center in Oegstgeest, The Netherlands
Youz, Parnassia Group, The Hague, The Netherlands
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Affiliation as printed
Helsinki University Central Hospital, Geriatrics, Helsinki, Finland
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Affiliation as printed
Department of Psychology and logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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University Medical Center Groningen · University of Groningen
Affiliation as printed
University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands
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Heidelberg University · Medizinische Fakultät Mannheim · Central Institute of Mental Health
Affiliation as printed
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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Heidelberg University · Medizinische Fakultät Mannheim · Central Institute of Mental Health
Affiliation as printed
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany
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Affiliation as printed
The Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, 17165 Stockholm, Sweden
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Affiliation as printed
The Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, 17165 Stockholm, Sweden
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Universitat Pompeu Fabra · Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública · Municipal Institute for Medical Research · Hospital del Mar Research Institute · Barcelona Institute for Global Health
Affiliation as printed
CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
ISGlobal, Barcelona, Spain
Universitat Pompeu Fabra (UPF), Barcelona, Spain
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
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University of Helsinki · Institute for Molecular Medicine Finland
Affiliation as printed
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
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University of Helsinki · Institute for Molecular Medicine Finland
Affiliation as printed
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
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King's College London · Duke University
Affiliation as printed
Center for Genomic and Computational Biology, Duke University, Durham, NC, USA
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, N.C., U.S.A
Department of Psychology and Neuroscience, Duke University, Durham, NC, USA
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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Harvard University · Erasmus MC
Affiliation as printed
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
Department of Social and Behavioral Science, Harvard TH Chan School of Public Health, Boston USA
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University of Cambridge · Erasmus University Rotterdam
Affiliation as printed
Department of Psychology, Education and Child Studies, Erasmus University Rotterdam, Rotterdam, the Netherlands
School of Clinical Medicine, University of Cambridge, Cambridge, UK
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University of Bristol · MRC Integrative Epidemiology Unit
Affiliation as printed
MRC Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
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Universitat Pompeu Fabra · Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública · Barcelona Institute for Global Health
Affiliation as printed
CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
ISGlobal, Barcelona, Spain
Universitat Pompeu Fabra (UPF), Barcelona, Spain
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Imperial College London · University of Oulu · Hammersmith Hospital
Affiliation as printed
Biocenter Oulu, University of Oulu, P.O. Box 5000, 90014, Finland
Center for Life Course Health Research, P.O. Box 5000, 90014, University of Oulu, Oulu, Finland
Section of Genomics of Common Disease, Department of Medicine, Imperial College. Paddington, W2 IPG, London, United Kingdom London, Hammersmith Hospital Campus, Burlington Danes Building, Du Cane Road, London, W12 0NN, UK
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Imperial College London · University of Oulu · Hammersmith Hospital · MRC Centre for Environment and Health
Affiliation as printed
Biocenter Oulu, University of Oulu, P.O. Box 5000, 90014, Finland
Center for Life Course Health Research, P.O. Box 5000, 90014, University of Oulu, Oulu, Finland
MRC-PHE Centre for Environment and Health, Imperial College London, Praed Street Wing, St Mary’s Campus, Paddington, W2 IPG, London, United Kingdom London, Hammersmith Hospital Campus, Burlington Danes Building, Du Cane Road, London, W12 0NN, UK
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King's College London · Duke University
Affiliation as printed
Center for Genomic and Computational Biology, Duke University, Durham, NC, USA
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, N.C., U.S.A
Department of Psychology and Neuroscience, Duke University, Durham, NC, USA
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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Affiliation as printed
Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh
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Affiliation as printed
Division of Psychiatry, University of Edinburgh
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Vrije Universiteit Amsterdam · Amsterdam Public Health
Affiliation as printed
Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Vrije Universiteit Amsterdam · Amsterdam Public Health
Affiliation as printed
Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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