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From gene to brain to behavior: schizophrenia-associated variation in AMBRA1 alters impulsivity-related traits

Authors

  • Angela Heinrich,

    Corresponding author
    1. Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
    • Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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  • Frauke Nees,

    1. Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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  • Anbarasu Lourdusamy,

    1. Institute of Psychiatry, King's College London, London, UK
    2. MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, London, UK
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  • Jelka Tzschoppe,

    1. Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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  • Sandra Meier,

    1. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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  • Sabine Vollstädt-Klein,

    1. Department of Addictive Behaviour and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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  • Mira Fauth-Bühler,

    1. Department of Addictive Behaviour and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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  • Sabina Steiner,

    1. Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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  • Christiane Bach,

    1. Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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  • Luise Poustka,

    1. Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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  • Tobias Banaschewski,

    1. Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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  • Gareth J. Barker,

    1. Institute of Psychiatry, King's College London, London, UK
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  • Christian Büchel,

    1. NeuroImage Nord, Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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  • Patricia J. Conrod,

    1. Institute of Psychiatry, King's College London, London, UK
    2. Department of Psychiatry, Université de Montreal, CHU Ste Justine Hospital, Montreal, QC, Canada
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  • Hugh Garavan,

    1. Departments of Psychiatry and Psychology, University of Vermont, Burlington, VT, USA
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  • Jürgen Gallinat,

    1. Department of Psychiatry and Psychotherapy, Charité, University Medicine Berlin, Berlin, Germany
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  • Andreas Heinz,

    1. Department of Psychiatry and Psychotherapy, Charité, University Medicine Berlin, Berlin, Germany
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  • Bernd Ittermann,

    1. Physikalisch-Technische Bundesanstalt, Berlin, Germany
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  • Eva Loth,

    1. Institute of Psychiatry, King's College London, London, UK
    2. MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, London, UK
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  • Karl Mann,

    1. Department of Addictive Behaviour and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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  • Eric Artiges,

    1. INSERM CEA Unit 1000 ‘Imaging & Psychiatry’, Institut National de la Santé et de la Recherche Médicale, University Paris Sud, Orsay
    2. AP-HP Department of Adolescent Psychopathology and Medicine, Maison de Solenn, University Paris Descartes, Paris, France
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  • Tomáš Paus,

    1. Rotman Research Institute, University of Toronto, Toronto, ON, Canada
    2. School of Psychology, University of Nottingham, Nottingham, UK
    3. Montreal Neurological Institute, McGill University, Montreal, QC, Canada
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  • Claire Lawrence,

    1. School of Psychology, University of Nottingham, Nottingham, UK
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  • Zdenka Pausova,

    1. Physiology and Nutritional Sciences, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
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  • Michael N. Smolka,

    1. Department of Psychiatry and Psychotherapy, Technische Universität Dresden, Dresden, Germany
    2. Neuroimaging Center, Department of Psychology, Technische Universität Dresden, Dresden, Germany
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  • Andreas Ströhle,

    1. Department of Psychiatry and Psychotherapy, Charité, University Medicine Berlin, Berlin, Germany
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  • Maren Struve,

    1. Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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  • Stephanie H. Witt,

    1. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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  • Gunter Schumann,

    1. Institute of Psychiatry, King's College London, London, UK
    2. MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, London, UK
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  • Herta Flor,

    1. Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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  • Marcella Rietschel,

    1. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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  • The IMAGEN consortium


Correspondence; Dr A. Heinrich,1 Department of Genetic Epidemiology in Psychiatry,as above. E-mail: Angela.Heinrich@zi-mannheim.de

Abstract

Recently, genome-wide association between schizophrenia and an intronic variant in AMBRA1 (rs11819869) was reported. Additionally, in a reverse genetic approach in adult healthy subjects, risk allele carriers showed a higher medial prefrontal cortex blood oxygen level-dependent (BOLD) response during a flanker task examining motor inhibition as an aspect of impulsivity. To test whether this finding can be expanded to further aspects of impulsivity, we analysed the effects of the rs11819869 genotype on impulsivity-related traits on a behavioral, temperament and neural level in a large sample of healthy adolescents. We consider this reverse genetic approach specifically suited for use in a healthy adolescent sample, as these individuals comprise those who will eventually develop mental disorders in which impulsivity is implicated. Healthy adolescents from the IMAGEN study were included in the neuropsychological analysis (= 848) and a functional magnetic resonance imaging (fMRI) task (= 512). Various aspects of impulsivity were assessed using the Temperament and Character Inventory-Revised, the Substance Use Risk Profile Scale, the Cambridge Cognition Neuropsychological Test Automated Battery, and the Stop Signal Task (SST) in the fMRI paradigm. On a behavioral level, increased delay aversion was observed in risk allele carriers. Furthermore, risk allele carriers showed a higher BOLD response in an orbito-frontal target region during the SST, which declined to trend status after Family Wise Error correction. Our findings support the hypothesis that the schizophrenia-related risk variant of rs11819869 is involved in various aspects of impulsivity, and that this involvement occurs on a behavioral as well as an imaging genetics level.

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