title: Genetic Overlap Between Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder: Evidence From Genome-wide Association Study Meta-analysis.
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.
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands.
authors.forename: Kimm J E
authors.initials: KJE
authors.lastname: van Hulzen
authors.affiliation: Core Unit Systems Medicine, University of Würzburg, Würzburg.
authors.forename: Claus J
authors.initials: CJ
authors.lastname: Scholz
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Psychiatry, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Klein
authors.affiliation: Division of Psychiatry, University College London, London.
authors.forename: Andrew
authors.initials: A
authors.lastname: McQuillin
authors.affiliation: Department of Psychology, University of Southampton, Southampton, United Kingdom.
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Sonuga-Barke
authors.affiliation: Department of Psychiatry, University of California, San Diego, San Diego, California.
authors.forename: John R
authors.initials: JR
authors.lastname: Kelsoe
authors.affiliation: The Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Landén
authors.affiliation: 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.
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Frankfurt, Frankfurt, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Weber
authors.affiliation: 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.
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.affiliation: 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.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Arias-Vasquez
authors.affiliation: Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Frankfurt, Frankfurt, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
mesh_terms: D001289:Attention Deficit Disorder with Hyperactivity / Q000453:epidemiology / Q000235:genetics*; D001714:Bipolar Disorder / Q000453:epidemiology / Q000235:genetics*; D015897:Comorbidity; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans
keywords: Attention-deficit/hyperactivity disorder; GWAS; bipolar disorder; cross-disorder meta-analysis; genetic correlation; genetic overlap