title: Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder.
abstract: Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.
authors.affiliation: Institute of Medical Biometry and Epidemiology, University of Marburg, Marburg, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Jarick
authors.affiliation: Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany.
authors.forename: A-L
authors.initials: AL
authors.lastname: Volckmar
authors.affiliation: Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University of Duisburg-Essen, Essen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Pütter
authors.affiliation: Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University of Duisburg-Essen, Essen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Pechlivanis
authors.affiliation: Institute of Medical Biometry and Epidemiology, University of Marburg, Marburg, Germany.
authors.forename: T T
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: 1] Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany [2] University Hospital of Child and Adolescent Psychiatry, University of Bern, Bern, Switzerland.
authors.forename: M R
authors.initials: MR
authors.lastname: Dauvermann
authors.affiliation: Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Beck
authors.affiliation: Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany.
authors.forename: Ö
authors.initials: Ö
authors.lastname: Albayrak
authors.affiliation: Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Scherag
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University Clinics, Aachen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Gilsbach
authors.affiliation: 1] Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organization of the Brain, Genomic Imaging, Research Center Juelich, Juelich, Germany [2] Institute of Human Genetics, University of Bonn, Bonn, Germany [3] Deptartment of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Cichon
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Deptartment of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Deptartment of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Degenhardt
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Deptartment of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany [3] German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: M M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Institute of Epidemiology, German Research Center for Environmental Health, Helmholtz Center Munich, Neuherberg, Germany.
authors.forename: H-E
authors.initials: HE
authors.lastname: Wichmann
authors.affiliation: Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University of Duisburg-Essen, Essen, Germany.
authors.forename: K-H
authors.initials: KH
authors.lastname: Jöckel
authors.affiliation: Institute of Epidemiology, German Research Center for Environmental Health, Helmholtz Center Munich, Neuherberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Heinrich
authors.affiliation: 1] Institute of Epidemiology, German Research Center for Environmental Health, Helmholtz Center Munich, Neuherberg, Germany [2] Division of Metabolic Diseases and Nutritional Medicine, Dr von Hauner Children's Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: C M T
authors.initials: CM
authors.lastname: Tiesler
authors.affiliation: Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: S V
authors.initials: SV
authors.lastname: Faraone
authors.affiliation: Department of Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Walitza
authors.affiliation: 1] Department for Child and Adolescent Psychiatry, University of Cologne, Cologne, Germany [2] Department for Child and Adolescent Psychiatry and Psychotherapy, LVR-clinic Bonn, Bonn, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Sinzig
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe-Universität Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Freitag
authors.affiliation: Department of Neurobehavioral Genetics, Institute of Psychobiology, University of Trier, Trier, Germany.
authors.forename: J
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authors.lastname: Meyer
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University Clinics, Aachen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Herpertz-Dahlmann
authors.affiliation: Department for Child and Adolescent Psychiatry, University of Cologne, Cologne, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Lehmkuhl
authors.affiliation: Department of Child and Adolescent Psychiatry, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: T J
authors.initials: TJ
authors.lastname: Renner
authors.affiliation: Department of Child and Adolescent Psychiatry, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Warnke
authors.affiliation: 1] Department of Child and Adolescent Psychiatry, University of Wuerzburg, Wuerzburg, Germany [2] Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Munich, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Romanos
authors.affiliation: 1] Department of Psychiatry, Psychosomatics and Psychotherapy, Division of Molecular Psychiatry, ADHD Clinical Research Network, Laboratory of Translational Neuroscience, University of Wuerzburg, Wuerzburg, Germany [2] Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: K-P
authors.initials: KP
authors.lastname: Lesch
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Reif
authors.affiliation: 1] Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany [2] University Hospital of Child and Adolescent Psychiatry, University of Bern, Bern, Switzerland.
authors.forename: B G
authors.initials: BG
authors.lastname: Schimmelmann
authors.affiliation: Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hebebrand
authors.affiliation: Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University of Duisburg-Essen, Essen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Scherag
authors.affiliation: Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany.
authors.forename: A
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authors.lastname: Hinney
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D002648:Child; D018672:Community Health Planning; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D044767:Ubiquitin-Protein Ligases; C111567:parkin protein