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Associations of DNA methylation with behavioral problems, grey matter volumes and negative life events across adolescence: Evidence from the longitudinal IMAGEN study

  • Author Footnotes
    ∗ Equally Contributed
    Yan Sun
    Footnotes
    ∗ Equally Contributed
    Affiliations
    National Institute on Drug Dependence, Peking University, Beijing, China

    Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, London, United Kingdom
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  • Author Footnotes
    ∗ Equally Contributed
    Tianye Jia
    Footnotes
    ∗ Equally Contributed
    Affiliations
    Institute of Science and Technology for Brain-Inspired Intelligence, Ministry of Education-Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence and Research and Research Institute of Intelligent Complex Systems, Fudan University, Shanghai, China

    Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, London, United Kingdom
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  • Edward D. Barker
    Affiliations
    Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, London, United Kingdom

    Developmental Psychopathology Lab, Department of Psychology, King's College London, London, United Kingdom
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  • Di Chen
    Affiliations
    Institute of Science and Technology for Brain-Inspired Intelligence, Ministry of Education-Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence and Research and Research Institute of Intelligent Complex Systems, Fudan University, Shanghai, China
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  • Zuo Zhang
    Affiliations
    Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, London, United Kingdom
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  • Jiayuan Xu
    Affiliations
    Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, London, United Kingdom

    Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin, China
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  • Suhua Chang
    Affiliations
    State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Institutes of Brain Science and National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
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  • Guangdong Zhou
    Affiliations
    Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, London, United Kingdom

    Faculty of Psychology, Tianjin Normal University, Tianjin, China
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  • Yun Liu
    Affiliations
    Department of Biochemistry and Molecular Biology, MOE Key Laboratory of Metabolism and Molecular Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
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  • Nicole Tay
    Affiliations
    Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, London, United Kingdom
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  • Qiang Luo
    Affiliations
    Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, London, United Kingdom

    Institute of Science and Technology for Brain-Inspired Intelligence, Ministry of Education-Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence and Research and Research Institute of Intelligent Complex Systems, Fudan University, Shanghai, China

    State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Institutes of Brain Science and National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
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  • Xiao Chang
    Affiliations
    Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, London, United Kingdom

    Institute of Science and Technology for Brain-Inspired Intelligence, Ministry of Education-Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence and Research and Research Institute of Intelligent Complex Systems, Fudan University, Shanghai, China
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  • Tobias Banaschewski
    Affiliations
    Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, 68159 Mannheim, Germany
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  • Arun L.W. Bokde
    Affiliations
    Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland
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  • Herta Flor
    Affiliations
    Institute of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, Mannheim, Germany

    Department of Psychology, School of Social Sciences, University of Mannheim, 68131 Mannheim, Germany
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  • Antoine Grigis
    Affiliations
    NeuroSpin, CEA, Université Paris-Saclay, F-91191 Gif-sur-Yvette, France
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  • Hugh Garavan
    Affiliations
    Departments of Psychiatry and Psychology, University of Vermont, 05405 Burlington, Vermont, USA
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  • Andreas Heinz
    Affiliations
    Department of Psychiatry and Psychotherapy CCM, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
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  • Jean-Luc Martinot
    Affiliations
    Institut National de la Santé et de la Recherche Médicale, INSERM U1299 “Trajectoires développementales en psychiatrie”; Université Paris-Saclay, Ecole Normale supérieure Paris-Saclay, CNRS, Centre Borelli; and AP-HP. Sorbonne Université, Department of Child and Adolescent Psychiatry, Pitié-Salpêtrière Hospital, Paris, France
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  • Marie-Laure Paillère Martinot
    Affiliations
    Institut National de la Santé et de la Recherche Médicale, INSERM U1299 “Trajectoires développementales en psychiatrie”; Université Paris-Saclay, Ecole Normale supérieure Paris-Saclay, CNRS, Centre Borelli; and Psychiatry Department 91G16, Orsay Hospital, France
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  • Eric Artiges
    Affiliations
    Institut des Maladies Neurodégénératives, UMR 5293, CNRS, CEA, Université de Bordeaux, 33076 Bordeaux, France
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  • Frauke Nees
    Affiliations
    Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, 68159 Mannheim, Germany

    Institute of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, Mannheim, Germany

    Institute of Medical Psychology and Medical Sociology, University Medical Center Schleswig Holstein, Kiel University, Kiel, Germany
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  • Dimitri Papadopoulos Orfanos
    Affiliations
    NeuroSpin, CEA, Université Paris-Saclay, F-91191 Gif-sur-Yvette, France
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  • Tomáš Paus
    Affiliations
    School of Psychology and Global Brain Health Institute, Trinity College Dublin, Ireland

    Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital and Departments of Psychology and Psychiatry, University of Toronto, Toronto, Ontario, M6A 2E1, Canada
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  • Luise Poustka
    Affiliations
    Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Centre Göttingen, von-Siebold-Str. 5, 37075, Göttingen, Germany
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  • Sarah Hohmann
    Affiliations
    Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, 68159 Mannheim, Germany
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  • Sabina Millenet
    Affiliations
    Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, 68159 Mannheim, Germany
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  • Juliane H. Fröhner
    Affiliations
    Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany
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  • Michael N. Smolka
    Affiliations
    Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany
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  • Henrik Walter
    Affiliations
    Department of Psychiatry and Psychotherapy CCM, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
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  • Robert Whelan
    Affiliations
    School of Psychology and Global Brain Health Institute, Trinity College Dublin, Ireland
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  • Lin Lu
    Affiliations
    National Institute on Drug Dependence, Peking University, Beijing, China

    Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Chinese Academy of Medical Sciences Research Unit (No.2018RU006), Peking University, Beijing, China
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  • Jie Shi
    Affiliations
    National Institute on Drug Dependence, Peking University, Beijing, China
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  • Author Footnotes
    † Equally Contributed
    Gunter Schumann
    Footnotes
    † Equally Contributed
    Affiliations
    Institute of Science and Technology for Brain-Inspired Intelligence, Ministry of Education-Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence and Research and Research Institute of Intelligent Complex Systems, Fudan University, Shanghai, China

    PONS Research Group, Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charitéplatz 1, Berlin, Germany; PONS Centre, Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China
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  • Author Footnotes
    † Equally Contributed
    Sylvane Desrivières
    Correspondence
    Corresponding author: Sylvane Desrivières
    Footnotes
    † Equally Contributed
    Affiliations
    Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, London, United Kingdom
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  • Author Footnotes
    ∗ Equally Contributed
    † Equally Contributed

      Abstract

      Background

      Negative life experiences (NLE) increase the risk for externalizing (EB) and internalizing (IB) behaviors in adolescence and adult psychopathology. DNA methylation (DNAm) associated with behavioral problems may reflect this risk and long-lasting effects of NLE.

      Methods

      To identify consistent associations between blood DNAm and EB or IB across adolescence, we conducted longitudinal epigenome-wide association studies (EWAS) using data from the IMAGEN cohort, collected at ages 14 and 19 (n=506). Significant findings were validated in a separate sub-sample (n=823). Methylation risk scores (MRS) were generated by 10-fold cross validation and further tested for their associations with grey matter volumes (GMV) and NLE.

      Results

      No significant findings were obtained for the IB-EWAS. The EB-EWAS identified a genome-wide significant locus in a gene linked to ADHD (IQSEC1, cg01460382; p=1.26e-08). Other most significant CpG sites were near ADHD-related genes and enriched for genes regulating TNF and IFN-γ signaling, highlighting relevance the EB-EWAS findings for ADHD. Analyses with the EB MRS (eMRS) suggested that it was partly reflected comorbidity with IB in late adolescence. Specific to EB, eMRS correlated with smaller GMV in medial orbitofrontal and anterior/middle cingulate cortices, brain regions known to associate with ADHD and conduct problems. Longitudinal mediation analyses indicated that EB-related DNAm were more likely the outcomes of problematic behaviors accentuated by negative life experiences, and less likely the epigenetic bases of such behaviors.

      Conclusions

      Our findings suggest novel epigenetic mechanisms through which negative life events and their short and longer-term effects on behavior may contribute to ADHD.

      Keywords

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