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

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  • Kimm J E van Hulzen, Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address: marjolein.willemsen@radboudumc.nl.
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  • Claus J Scholz, Core Unit Systems Medicine, University of Würzburg, Würzburg.
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  • Barbara Franke, 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, Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin, Berlin, Germany; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts.
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  • Marieke Klein, Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address: marjolein.willemsen@radboudumc.nl.
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  • Andrew McQuillin, Molecular Psychiatry Laboratory, Division of Psychiatry, University College London
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  • Edmund J Sonuga-Barke, Department of Psychology, University of Southampton, Southampton, United Kingdom.
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  • PGC ADHD Working Group
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  • John R Kelsoe, Department of Psychiatry, University of California San Diego
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  • Mikael Landén, University of Gothenburg
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  • Ole A Andreassen, NORMENT - K.G. Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, Oslo, Norway.
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  • PGC Bipolar Disorder Working Group
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  • Klaus-Peter Lesch, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg.
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  • Heike Weber, 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, 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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  • Alejandro Arias-Vasquez, 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. Electronic address: alejandro.ariasvasquez@radboudumc.nl.
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  • Andreas Reif, Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Goethe-University, Frankfurt am Main, Germany.

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.

Original languageEnglish
JournalBiological Psychiatry
Volume82
Issue9
Pages (from-to)634-641
Number of pages8
ISSN0006-3223
DOIs
Publication statusPublished - 1 Nov 2017

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