title: Exome chip analyses in adult attention deficit hyperactivity disorder.
abstract: Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable childhood-onset neuropsychiatric condition, often persisting into adulthood. The genetic architecture of ADHD, particularly in adults, is largely unknown. We performed an exome-wide scan of adult ADHD using the Illumina Human Exome Bead Chip, which interrogates over 250 000 common and rare variants. Participants were recruited by the International Multicenter persistent ADHD CollaboraTion (IMpACT). Statistical analyses were divided into 3 steps: (1) gene-level analysis of rare variants (minor allele frequency (MAF)<1%); (2) single marker association tests of common variants (MAF⩾1%), with replication of the top signals; and (3) pathway analyses. In total, 9365 individuals (1846 cases and 7519 controls) were examined. Replication of the most associated common variants was attempted in 9847 individuals (2077 cases and 7770 controls) using fixed-effects inverse variance meta-analysis. With a Bonferroni-corrected significance level of 1.82E-06, our analyses of rare coding variants revealed four study-wide significant loci: 6q22.1 locus (P=4.46E-08), where NT5DC1 and COL10A1 reside; the SEC23IP locus (P=6.47E-07); the PSD locus (P=7.58E-08) and ZCCHC4 locus (P=1.79E-06). No genome-wide significant association was observed among the common variants. The strongest signal was noted at rs9325032 in PPP2R2B (odds ratio=0.81, P=1.61E-05). Taken together, our data add to the growing evidence of general signal transduction molecules (NT5DC1, PSD, SEC23IP and ZCCHC4) having an important role in the etiology of ADHD. Although the biological implications of these findings need to be further explored, they highlight the possible role of cellular communication as a potential core component in the development of both adult and childhood forms of ADHD.
authors.affiliation: K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: T
authors.initials: T
authors.lastname: Zayats
authors.affiliation: K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: K K
authors.initials: KK
authors.lastname: Jacobsen
authors.affiliation: K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: R
authors.initials: R
authors.lastname: Kleppe
authors.affiliation: Section of Molecular Psychiatry, Clinical Research Unit on Disorders of Neurodevelopment and Cognition Center of Mental Health, University of Wuerburg, Würzburg, Germany.
authors.forename: C P
authors.initials: CP
authors.lastname: Jacob
authors.affiliation: Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kittel-Schneider
authors.affiliation: Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addictions, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.|Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.|Biomedical Network Research Centre on Mental Health (CIBERSAM), Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Ribasés
authors.affiliation: Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addictions, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.|Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.|Biomedical Network Research Centre on Mental Health (CIBERSAM), Madrid, Spain.|Departments of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Ramos-Quiroga
authors.affiliation: Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addictions, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.|Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.|Biomedical Network Research Centre on Mental Health (CIBERSAM), Madrid, Spain.|Departments of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Richarte
authors.affiliation: Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addictions, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.|Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.|Biomedical Network Research Centre on Mental Health (CIBERSAM), Madrid, Spain.|Departments of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Casas
authors.affiliation: Department of Genetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: N R
authors.initials: NR
authors.lastname: Mota
authors.affiliation: Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: E H
authors.initials: EH
authors.lastname: Grevet
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Klein
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Ophtalmology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Corominas
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Bralten
authors.affiliation: Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
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authors.initials: T
authors.lastname: Galesloot
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: A A
authors.initials: AA
authors.lastname: Vasquez
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, Bonn, Germany.|Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Herms
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, Bonn, Germany.
authors.forename: A J
authors.initials: AJ
authors.lastname: Forstner
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Larsson
authors.affiliation: NIHR BRC for Mental Health, Institute of Psychiatry, Psychology and Neuroscience and SLaM NHS Trust, King's College London, London, UK.|MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Breen
authors.affiliation: NIHR BRC for Mental Health, Institute of Psychiatry, Psychology and Neuroscience and SLaM NHS Trust, King's College London, London, UK.|MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Asherson
authors.affiliation: Section of Molecular Psychiatry, Clinical Research Unit on Disorders of Neurodevelopment and Cognition Center of Mental Health, University of Wuerburg, Würzburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Gross-Lesch
authors.affiliation: Section of Molecular Psychiatry, Clinical Research Unit on Disorders of Neurodevelopment and Cognition Center of Mental Health, University of Wuerburg, Würzburg, Germany.
authors.forename: K P
authors.initials: KP
authors.lastname: Lesch
authors.affiliation: Department of Genomics, Life and Brain Center, Bonn, Germany.|Department of Biomedicine, University of Basel, Basel, Switzerland.|Institute of Neuroscience and Medicine, Structural and Functional Organization of the Brain (INM-1), Research Center Juelich, Juelich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Cichon
authors.affiliation: K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.|Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: M B
authors.initials: MB
authors.lastname: Gabrielsen
authors.affiliation: K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: O L
authors.initials: OL
authors.lastname: Holmen
authors.affiliation: Department of Genetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: C H D
authors.initials: CH
authors.lastname: Bau
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Buitelaar
authors.affiliation: Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Kiemeney
authors.affiliation: K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway.|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: Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.|Centro de Investigación BiomédicaAnchor en Red de Enfermedades Raras, Barcelona, Spain.|Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain.|Institut de Recerca Pediàtrica HosAnchorpital Sant Joan de Déu, Barcelona, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Cormand
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Franke
authors.affiliation: Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Reif
authors.affiliation: K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway.|Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
authors.forename: J
authors.initials: J
authors.lastname: Haavik
authors.affiliation: K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Clinical Science, University of Bergen, Bergen, Norway.|Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Johansson
mesh_terms: D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D001921:Brain / Q000378:metabolism; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D016366:Open Reading Frames / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D000073359:Exome Sequencing