title: Functional Impact of An ADHD-Associated DIRAS2 Promoter Polymorphism.
abstract: The DIRAS2 gene is coding for a small Ras GTPase with so far unknown function. In a previous study, we described the association of DIRAS2 rs1412005, as well as a haplotype containing this polymorphism and located in the promoter region of this gene with attention-deficit/hyperactivity disorder (ADHD). In the present study, we searched for rare variants within or near the DIRAS2 gene that might be associated with ADHD using next-generation sequencing. As we were not able to detect any rare variants associated with the disease, we sought to establish a functional role of DIRAS2 rs1412005 on the molecular or systems level. First, we investigated whether it has an influence on gene expression by means of a luciferase-based promoter assay. We could demonstrate that the minor risk allele goes along with the increased expression of the reporter gene. Next, we aimed to identify differences in response inhibition between risk-allele and non-risk allele carriers in children suffering from ADHD and healthy control individuals by analyzing event-related potentials in the electroencephalogram during a Go/NoGo task. Risk-allele carriers showed a changed NoGo anteriorization. Therefore, our results suggest an impact of the investigated polymorphism on the prefrontal response control in children with ADHD. These results imply that the promoter polymorphism is indeed the associated as well as in itself a causal variant. Further research is thus warranted to clarify the mechanisms linking DIRAS2 to ADHD.
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Translational Psychiatry, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Grünewald
authors.affiliation: Department of Biomedicine, K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
authors.forename: Elisabeth Toverud
authors.initials: ET
authors.lastname: Landaas
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Geissler
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Translational Psychiatry, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Weber
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Quast
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Röh
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Molecular Psychiatry Laboratory of Translational Neuroscience, University of Würzburg, Würzburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schartner
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Molecular Psychiatry Laboratory of Translational Neuroscience, University of Würzburg, Würzburg, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Romanos
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Translational Psychiatry, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kittel-Schneider
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.|Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Binder
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Translational Psychiatry, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Andreas
authors.identifier: 0000-0002-0992-634X
authors.initials: A
authors.lastname: Reif
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007266:Inhibition, Psychological; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D055815:Young Adult; D020741:rho GTP-Binding Proteins / Q000235:genetics*
chemical_list: D020741:rho GTP-Binding Proteins