title: On the role of NOS1 ex1f-VNTR in ADHD-allelic, subgroup, and meta-analysis.
abstract: Attention deficit/ hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder featuring complex genetics with common and rare variants contributing to disease risk. In a high proportion of cases, ADHD does not remit during adolescence but persists into adulthood. Several studies suggest that NOS1, encoding nitric oxide synthase I, producing the gaseous neurotransmitter NO, is a candidate gene for (adult) ADHD. We here extended our analysis by increasing the original sample, adding two further samples from Norway and Spain, and conducted subgroup and co-morbidity analysis. Our previous finding held true in the extended sample, and also meta-analysis demonstrated an association of NOS1 ex1f-VNTR short alleles with adult ADHD (aADHD). Association was restricted to females, as was the case in the discovery sample. Subgroup analysis on the single allele level suggested that the 21-repeat allele caused the association. Regarding subgroups, we found that NOS1 was associated with the hyperactive/impulsive ADHD subtype, but not to pure inattention. In terms of comorbidity, major depression, anxiety disorders, cluster C personality disorders and migraine were associated with short repeats, in particular the 21-repeat allele. Also, short allele carriers had significantly lower IQ. Finally, we again demonstrated an influence of the repeat on gene expression in human post-mortem brain samples. These data validate the role of NOS-I in hyperactive/impulsive phenotypes and call for further studies into the neurobiological underpinnings of this association. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Goethe-University Frankfurt, Frankfurt am Main, Germany.|Microarray Core Unit, IZKF Würzburg, University Hospital of Würzburg, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Weber
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Goethe-University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kittel-Schneider
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Heupel
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Goethe-University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Weißflog
authors.affiliation: School of Medicine, University of St. Andrews, St. Andrews, Scotland, UK.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Kent
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Goethe-University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Freudenberg
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Goethe-University Frankfurt, Frankfurt am Main, Germany.|Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany.
authors.forename: Aet
authors.initials: A
authors.lastname: Alttoa
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Goethe-University Frankfurt, Frankfurt am Main, Germany.|Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany.
authors.forename: Antonia
authors.initials: A
authors.lastname: Post
authors.affiliation: Institute for Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Würzburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Herterich
authors.affiliation: Department of Biomedicine, K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Norway.|Department of Psychiatry, Haukeland University Hospital, Bergen, Norway.
authors.forename: Jan
authors.initials: J
authors.lastname: Haavik
authors.affiliation: Department of Biomedicine, K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Norway.|Department of Psychiatry, Haukeland University Hospital, Bergen, Norway.
authors.forename: Anne
authors.initials: A
authors.lastname: Halmøy
authors.affiliation: Department of Psychiatry, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Medicine, Section for Psychiatry, University of Bergen, Bergen, Norway.
authors.forename: Ole B
authors.initials: OB
authors.lastname: Fasmer
authors.affiliation: Department of Biomedicine, K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Norway.
authors.forename: Elisabeth T
authors.initials: ET
authors.lastname: Landaas
authors.affiliation: Department of Biomedicine, K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Norway.
authors.forename: Stefan
authors.initials: S
authors.lastname: Johansson
authors.affiliation: Departament of Genetics, Universiy of Barcelona, Barcelona, Spain.|Institute of Biomedicine, University of Barcelona (IBUB), Barcelona, Spain.|Biomedical Network Research Center on Mental Health (CIBERSAM), Institute of Salud Carlos III, Spain.
authors.forename: Bru
authors.initials: B
authors.lastname: Cormand
authors.affiliation: Biomedical Network Research Center on Mental Health (CIBERSAM), Institute of Salud Carlos III, Spain.|Department of Psychiatry, University Hospital, Vall d'Hebron, Barcelona, Spain.|Psychiatric Genetics Unit, University Hospital, Vall d'Hebron, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ribasés
authors.affiliation: Biomedical Network Research Center on Mental Health (CIBERSAM), Institute of Salud Carlos III, Spain.|Department of Psychiatry, University Hospital, Vall d'Hebron, Barcelona, Spain.|Psychiatric Genetics Unit, University Hospital, Vall d'Hebron, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sánchez-Mora
authors.affiliation: Biomedical Network Research Center on Mental Health (CIBERSAM), Institute of Salud Carlos III, Spain.|Department of Psychiatry, University Hospital, Vall d'Hebron, Barcelona, Spain.
authors.forename: Josep Antoni
authors.initials: JA
authors.lastname: Ramos-Quiroga
authors.affiliation: Department of Human Genetics and 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 Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany.|Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Goethe-University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
keywords: adult ADHD; association; glutamate; nitric oxide; polymorphism