title: Case-control genome-wide association study of persistent attention-deficit hyperactivity disorder identifies FBXO33 as a novel susceptibility gene for the disorder.
abstract: Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high heritability. At least 30% of patients diagnosed in childhood continue to suffer from ADHD during adulthood and genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. To date, genome-wide association studies (GWAS) of ADHD have been completed in seven independent datasets, six of which were pediatric samples and one on persistent ADHD using a DNA-pooling strategy, but none of them reported genome-wide significant associations. In an attempt to unravel novel genes for the persistence of ADHD into adulthood, we conducted the first two-stage GWAS in adults with ADHD. The discovery sample included 607 ADHD cases and 584 controls. Top signals were subsequently tested for replication in three independent follow-up samples of 2104 ADHD patients and 1901 controls. None of the findings exceeded the genome-wide threshold for significance (PGC<5e-08), but we found evidence for the involvement of the FBXO33 (F-box only protein 33) gene in combined ADHD in the discovery sample (P=9.02e-07) and in the joint analysis of both stages (P=9.7e-03). Additional evidence for a FBXO33 role in ADHD was found through gene-wise and pathway enrichment analyses in our genomic study. Risk alleles were associated with lower FBXO33 expression in lymphoblastoid cell lines and with reduced frontal gray matter volume in a sample of 1300 adult subjects. Our findings point for the first time at the ubiquitination machinery as a new disease mechanism for adult ADHD and establish a rationale for searching for additional risk variants in ubiquitination-related genes.
authors.affiliation: 1] Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addictions, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain [2] Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain [3] Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sánchez-Mora
authors.affiliation: 1] Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain [2] Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain [3] Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Josep A
authors.initials: JA
authors.lastname: Ramos-Quiroga
authors.affiliation: 1] Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain [2] Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Bosch
authors.affiliation: Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Montse
authors.initials: M
authors.lastname: Corrales
authors.affiliation: 1] Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addictions, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain [2] Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Iris
authors.initials: I
authors.lastname: Garcia-Martínez
authors.affiliation: Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Mariana
authors.initials: M
authors.lastname: Nogueira
authors.affiliation: 1] Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addictions, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain [2] Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Pagerols
authors.affiliation: Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Palomar
authors.affiliation: Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Richarte
authors.affiliation: Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Vidal
authors.affiliation: 1] Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands [2] Department of Psychiatry, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands [3] Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Arias-Vasquez
authors.affiliation: 1] Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain [2] IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain [3] CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain [4] Centre for Genomic Regulation (CRG), Barcelona, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Bustamante
authors.affiliation: 1] Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain [2] IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain [3] CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Forns
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Gross-Lesch
authors.affiliation: 1] Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain [2] IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain [3] CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
authors.forename: Monica
authors.initials: M
authors.lastname: Guxens
authors.affiliation: Department of Child and Adolescent Psychiatry, University Duisburg-Essen, Essen, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Hinney
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
authors.forename: Martine
authors.initials: M
authors.lastname: Hoogman
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Jacob
authors.affiliation: Department of Biomedicine, University of Bergen, K.G. Jebsen Center for Research on Neuropsychiatric Disorders, Bergen, Norway.
authors.forename: Kaya K
authors.initials: KK
authors.lastname: Jacobsen
authors.affiliation: Department of Psychiatry, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
authors.forename: Cornelis C
authors.initials: CC
authors.lastname: Kan
authors.affiliation: Department for Health Evidence, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: Lambertus
authors.initials: L
authors.lastname: Kiemeney
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kittel-Schneider
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Klein
authors.affiliation: 1] Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands [2] Department of Psychiatry, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
authors.forename: Marten
authors.initials: M
authors.lastname: Onnink
authors.affiliation: Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Rivero
authors.affiliation: Department of Biomedicine, University of Bergen, K.G. Jebsen Center for Research on Neuropsychiatric Disorders, Bergen, Norway.
authors.forename: Tetyana
authors.initials: T
authors.lastname: Zayats
authors.affiliation: 1] Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands [2] Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Buitelaar
authors.affiliation: Departments of Psychiatry and Neuroscience & Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.affiliation: 1] Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands [2] Department of Psychiatry, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.affiliation: Department of Biomedicine, University of Bergen, K.G. Jebsen Center for Research on Neuropsychiatric Disorders, Bergen, Norway.
authors.forename: Jan
authors.initials: J
authors.lastname: Haavik
authors.affiliation: Department of Biomedicine, University of Bergen, K.G. Jebsen Center for Research on Neuropsychiatric Disorders, Bergen, Norway.
authors.forename: Stefan
authors.initials: S
authors.lastname: Johansson
authors.affiliation: Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
authors.affiliation: 1] Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain [2] IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain [3] CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Sunyer
authors.affiliation: Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona (PCB), Barcelona, Spain.
authors.forename: Mònica
authors.initials: M
authors.lastname: Bayés
authors.affiliation: 1] Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain [2] Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain [3] Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Casas
authors.affiliation: 1] Department of Genetics, University of Barcelona, Catalonia, Spain [2] Biomedical Network Research Centre on Rare Diseases (CIBERER), Madrid, Spain [3] Institute of Biomedicine of the University of Barcelona (IBUB), Catalonia, Spain.
authors.forename: Bru
authors.initials: B
authors.lastname: Cormand
authors.affiliation: 1] Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addictions, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain [2] Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain [3] Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ribasés
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D044783:F-Box Proteins / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055815:Young Adult
chemical_list: D044783:F-Box Proteins