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Genetic Overlap Between Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder: Evidence From Genome-wide Association Study Meta-analysis

  • Author Footnotes
    1 contributed equally to this work.
    Kimm J.E. van Hulzen
    Footnotes
    1 contributed equally to this work.
    Affiliations
    Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands

    Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands
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  • Author Footnotes
    1 contributed equally to this work.
    Claus J. Scholz
    Footnotes
    1 contributed equally to this work.
    Affiliations
    Core Unit Systems Medicine, University of Würzburg, Würzburg
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  • Barbara Franke
    Affiliations
    Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands

    Department of Psychiatry, Radboud University Medical Center, Nijmegen, the Netherlands
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  • Stephan Ripke
    Affiliations
    Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts
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  • Marieke Klein
    Affiliations
    Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands

    Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands
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  • Andrew McQuillin
    Affiliations
    Division of Psychiatry, University College London, London
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  • Edmund J. Sonuga-Barke
    Affiliations
    Department of Psychology, University of Southampton, Southampton, United Kingdom
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  • PGC ADHD Working Group
  • John R. Kelsoe
    Affiliations
    Department of Psychiatry, University of California, San Diego, San Diego, California
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  • Mikael Landén
    Affiliations
    The Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg

    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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  • Ole A. Andreassen
    Affiliations
    NORMENT – K.G. Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo
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  • PGC Bipolar Disorder Working Group
  • Klaus-Peter Lesch
    Affiliations
    Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg
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  • Heike Weber
    Affiliations
    Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg

    Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Frankfurt, Frankfurt, Germany
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  • Stephen V. Faraone
    Affiliations
    K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway

    Departments of Psychiatry and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York
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  • Author Footnotes
    2 shared final responsibility for this work.
    Alejandro Arias-Vasquez
    Correspondence
    Address correspondence to Alejandro Arias-VásquezRadboudumc, Department of Human Genetics, route 855, Postbus 9101, 6500 HB Nijmegen, the Netherlands; .
    Footnotes
    2 shared final responsibility for this work.
    Affiliations
    Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands

    Department of Psychiatry, Radboud University Medical Center, Nijmegen, the Netherlands

    Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands

    Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands
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  • Author Footnotes
    2 shared final responsibility for this work.
    Andreas Reif
    Footnotes
    2 shared final responsibility for this work.
    Affiliations
    Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Frankfurt, Frankfurt, Germany
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  • Author Footnotes
    1 contributed equally to this work.
    2 shared final responsibility for this work.

      Abstract

      Background

      Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) are frequently co-occurring and highly heritable mental health conditions. We hypothesized that BPD cases with an early age of onset (≤21 years old) would be particularly likely to show genetic covariation with ADHD.

      Methods

      Genome-wide association study data were available for 4609 individuals with ADHD, 9650 individuals with BPD (5167 thereof with early-onset BPD), and 21,363 typically developing controls. We conducted a cross-disorder genome-wide association study meta-analysis to identify whether the observed comorbidity between ADHD and BPD could be due to shared genetic risks.

      Results

      We found a significant single nucleotide polymorphism–based genetic correlation between ADHD and BPD in the full and age-restricted samples (rGfull = .64, p = 3.13 × 10–14; rGrestricted = .71, p = 4.09 × 10–16). The meta-analysis between the full BPD sample identified two genome-wide significant (prs7089973 = 2.47 × 10–8; prs11756438 = 4.36 × 10–8) regions located on chromosomes 6 (CEP85L) and 10 (TAF9BP2). Restricting the analyses to BPD cases with an early onset yielded one genome-wide significant association (prs58502974 = 2.11 × 10–8) on chromosome 5 in the ADCY2 gene. Additional nominally significant regions identified contained known expression quantitative trait loci with putative functional consequences for NT5DC1, NT5DC2, and CACNB3 expression, whereas functional predictions implicated ABLIM1 as an allele-specific expressed gene in neuronal tissue.

      Conclusions

      The single nucleotide polymorphism–based genetic correlation between ADHD and BPD is substantial, significant, and consistent with the existence of genetic overlap between ADHD and BPD, with potential differential genetic mechanisms involved in early and later BPD onset.

      Keywords

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