title: Effects of dopaminergic genes, prenatal adversities, and their interaction on attention-deficit/hyperactivity disorder and neural correlates of response inhibition.
abstract: Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by impaired response inhibition; both have been associated with aberrant dopamine signalling. Given that prenatal exposure to alcohol or smoking is known to affect dopamine-rich brain regions, we hypothesized that individuals carrying the ADHD risk alleles of the dopamine receptor D4 (DRD4) and dopamine transporter (DAT1) genes may be especially sensitive to their effects.
  
  
  
  Functional MRI data, information on prenatal adversities and genetic data were available for 239 adolescents and young adults participating in the multicentre ADHD cohort study NeuroIMAGE (average age 17.3 yr). We analyzed the effects ofDRD4andDAT1, prenatal exposure to alcohol and smoking and their interactions on ADHD severity, response inhibition and neural activity.
  
  
  
  We found no significant gene × environment interaction effects. We did find that the DRD4 7-repeat allele was associated with less superior frontal and parietal brain activity and with greater activity in the frontal pole and occipital cortex. Prenatal exposure to smoking was also associated with lower superior frontal activity, but with greater activity in the parietal lobe. Further, those exposed to alcohol had more activity in the lateral orbitofrontal cortex, and theDAT1risk variant was associated with lower cerebellar activity.
  
  
  
  Retrospective reports of maternal substance use and the cross-sectional study design restrict causal inference.
  
  
  
  While we found no evidence of gene × environment interactions, the risk factors under investigation influenced activity of brain regions associated with response inhibition, suggesting they may add to problems with inhibiting behaviour.
authors.affiliation: From the University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands (van der Meer, Hartman, Hoekstra); the Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands (van Rooij); the Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands (Franke); the Clinical Neuropsychology Section, VU University Amsterdam, Amsterdam, the Netherlands (Heslenfeld, Oosterlaan); the Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York, USA (Faraone); the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway (Faraone); the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands (Buitelaar); and the Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, Netherlands (Buitelaar).
authors.forename: Dennis
authors.initials: D
authors.lastname: van der Meer
authors.affiliation: From the University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands (van der Meer, Hartman, Hoekstra); the Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands (van Rooij); the Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands (Franke); the Clinical Neuropsychology Section, VU University Amsterdam, Amsterdam, the Netherlands (Heslenfeld, Oosterlaan); the Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York, USA (Faraone); the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway (Faraone); the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands (Buitelaar); and the Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, Netherlands (Buitelaar).
authors.forename: Catharina A
authors.initials: CA
authors.lastname: Hartman
authors.affiliation: From the University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands (van der Meer, Hartman, Hoekstra); the Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands (van Rooij); the Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands (Franke); the Clinical Neuropsychology Section, VU University Amsterdam, Amsterdam, the Netherlands (Heslenfeld, Oosterlaan); the Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York, USA (Faraone); the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway (Faraone); the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands (Buitelaar); and the Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, Netherlands (Buitelaar).
authors.forename: Daan
authors.initials: D
authors.lastname: van Rooij
authors.affiliation: From the University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands (van der Meer, Hartman, Hoekstra); the Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands (van Rooij); the Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands (Franke); the Clinical Neuropsychology Section, VU University Amsterdam, Amsterdam, the Netherlands (Heslenfeld, Oosterlaan); the Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York, USA (Faraone); the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway (Faraone); the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands (Buitelaar); and the Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, Netherlands (Buitelaar).
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.affiliation: From the University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands (van der Meer, Hartman, Hoekstra); the Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands (van Rooij); the Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands (Franke); the Clinical Neuropsychology Section, VU University Amsterdam, Amsterdam, the Netherlands (Heslenfeld, Oosterlaan); the Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York, USA (Faraone); the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway (Faraone); the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands (Buitelaar); and the Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, Netherlands (Buitelaar).
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Heslenfeld
authors.affiliation: From the University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands (van der Meer, Hartman, Hoekstra); the Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands (van Rooij); the Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands (Franke); the Clinical Neuropsychology Section, VU University Amsterdam, Amsterdam, the Netherlands (Heslenfeld, Oosterlaan); the Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York, USA (Faraone); the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway (Faraone); the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands (Buitelaar); and the Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, Netherlands (Buitelaar).
authors.forename: Jaap
authors.initials: J
authors.lastname: Oosterlaan
authors.affiliation: From the University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands (van der Meer, Hartman, Hoekstra); the Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands (van Rooij); the Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands (Franke); the Clinical Neuropsychology Section, VU University Amsterdam, Amsterdam, the Netherlands (Heslenfeld, Oosterlaan); the Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York, USA (Faraone); the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway (Faraone); the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands (Buitelaar); and the Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, Netherlands (Buitelaar).
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.affiliation: From the University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands (van der Meer, Hartman, Hoekstra); the Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands (van Rooij); the Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands (Franke); the Clinical Neuropsychology Section, VU University Amsterdam, Amsterdam, the Netherlands (Heslenfeld, Oosterlaan); the Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York, USA (Faraone); the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway (Faraone); the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands (Buitelaar); and the Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, Netherlands (Buitelaar).
authors.forename: Jan K
authors.initials: JK
authors.lastname: Buitelaar
authors.affiliation: From the University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands (van der Meer, Hartman, Hoekstra); the Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands (van Rooij); the Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands (Franke); the Clinical Neuropsychology Section, VU University Amsterdam, Amsterdam, the Netherlands (Heslenfeld, Oosterlaan); the Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York, USA (Faraone); the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway (Faraone); the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands (Buitelaar); and the Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, Netherlands (Buitelaar).
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Hoekstra
mesh_terms: D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology* / Q000523:psychology; D001921:Brain / Q000000981:diagnostic imaging / Q000503:physiopathology*; D003430:Cross-Sectional Studies; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology / Q000523:psychology; D005500:Follow-Up Studies; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D007266:Inhibition, Psychological; D008279:Magnetic Resonance Imaging; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology / Q000523:psychology; D050638:Receptors, Dopamine D4 / Q000235:genetics*; D012189:Retrospective Studies; D012720:Severity of Illness Index; D012907:Smoking / Q000009:adverse effects
chemical_list: C493599:DRD4 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human; D050638:Receptors, Dopamine D4