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Neuropsychopharmacology. 2015 Mar;40(4):915-26. doi: 10.1038/npp.2014.267. Epub 2014 Oct 6.

Case-control genome-wide association study of persistent attention-deficit hyperactivity disorder identifies FBXO33 as a novel susceptibility gene for the disorder.

Author information

1
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.
2
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.
3
1] Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain [2] Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.
4
Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
5
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.
6
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.
7
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.
8
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.
9
Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany.
10
Department of Child and Adolescent Psychiatry, University Duisburg-Essen, Essen, Germany.
11
Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
12
Department of Biomedicine, University of Bergen, K.G. Jebsen Center for Research on Neuropsychiatric Disorders, Bergen, Norway.
13
Department of Psychiatry, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
14
Department for Health Evidence, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
15
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.
16
Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany.
17
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.
18
Departments of Psychiatry and Neuroscience & Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.
19
Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona (PCB), Barcelona, Spain.
20
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.

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.

PMID:
25284319
PMCID:
PMC4330505
DOI:
10.1038/npp.2014.267
[Indexed for MEDLINE]
Free PMC Article

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