title: Brain Correlates of the Interaction Between 5-HTTLPR and Psychosocial Stress Mediating Attention Deficit Hyperactivity Disorder Severity.
abstract: OBJECTIVE
  The serotonin transporter 5-HTTLPR genotype has been found to moderate the effect of stress on severity of attention deficit hyperactivity disorder (ADHD), with stronger effects of stress in carriers of the short allele than in individuals homozygous for the long allele. The underlying neurobiological mechanism of this gene-environment interaction in ADHD is unknown. The authors aimed to determine whether 5-HTTLPR moderates the effect of stress on brain gray matter volume and, if so, which brain regions mediate the effect of this gene-environment interaction on ADHD severity.
  
  
  METHODS
  Structural MRI, 5-HTTLPR genotype, and stress exposure questionnaire data were available for 701 adolescents and young adults participating in the multicenter ADHD cohort NeuroIMAGE study (from 385 families; 291 with ADHD, 78 with subthreshold ADHD, 332 healthy comparison subjects; 55.8% male; average age: 17.0 years). ADHD symptom count was determined through multi-informant questionnaires. For the analysis, a whole-brain voxel-based morphometry approach was combined with mediation analysis.
  
  
  RESULTS
  Stress exposure was associated with significantly less gray matter volume in the precentral gyrus, middle and superior frontal gyri, frontal pole, and cingulate gyrus in S-allele carriers compared with participants homozygous for the l-allele. The association of this gene-environment interaction with ADHD symptom count was mediated by gray matter volume in the frontal pole and anterior cingulate gyrus.
  
  
  CONCLUSIONS
  5-HTTLPR genotype moderates the effect of stress on brain regions involved in social cognitive processing and cognitive control. Specifically, regions important for cognitive control link this gene-environment interaction to ADHD severity.
authors.affiliation: From the Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; the Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands; the Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; the Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, the Netherlands; the Departments of Psychiatry and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, N.Y.; the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; and the Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, the Netherlands.
authors.forename: Dennis
authors.initials: D
authors.lastname: van der Meer
authors.affiliation: From the Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; the Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands; the Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; the Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, the Netherlands; the Departments of Psychiatry and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, N.Y.; the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; and the Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, the Netherlands.
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Hoekstra
authors.affiliation: From the Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; the Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands; the Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; the Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, the Netherlands; the Departments of Psychiatry and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, N.Y.; the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; and the Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, the Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Zwiers
authors.affiliation: From the Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; the Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands; the Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; the Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, the Netherlands; the Departments of Psychiatry and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, N.Y.; the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; and the Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, the Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: Mennes
authors.affiliation: From the Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; the Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands; the Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; the Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, the Netherlands; the Departments of Psychiatry and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, N.Y.; the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; and the Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, the Netherlands.
authors.forename: Lizanne J
authors.initials: LJ
authors.lastname: Schweren
authors.affiliation: From the Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; the Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands; the Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; the Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, the Netherlands; the Departments of Psychiatry and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, N.Y.; the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; and the Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, the Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.affiliation: From the Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; the Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands; the Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; the Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, the Netherlands; the Departments of Psychiatry and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, N.Y.; the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; and the Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, the Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Heslenfeld
authors.affiliation: From the Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; the Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands; the Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; the Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, the Netherlands; the Departments of Psychiatry and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, N.Y.; the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; and the Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, the Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Oosterlaan
authors.affiliation: From the Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; the Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands; the Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; the Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, the Netherlands; the Departments of Psychiatry and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, N.Y.; the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; and the Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, the Netherlands.
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.affiliation: From the Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; the Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands; the Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; the Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, the Netherlands; the Departments of Psychiatry and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, N.Y.; the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; and the Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, the Netherlands.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Buitelaar
authors.affiliation: From the Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; the Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands; the Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; the Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, the Netherlands; the Departments of Psychiatry and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, N.Y.; the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; and the Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, the Netherlands.
authors.forename: Catharina A
authors.initials: CA
authors.lastname: Hartman
mesh_terms: D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000473:pathology / Q000523:psychology; D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005625:Frontal Lobe / Q000473:pathology; D059647:Gene-Environment Interaction; D005838:Genotype; D066128:Gray Matter / Q000473:pathology*; D006179:Gyrus Cinguli / Q000473:pathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009929:Organ Size; D017397:Prefrontal Cortex / Q000473:pathology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D012720:Severity of Illness Index; D013315:Stress, Psychological / Q000235:genetics* / Q000473:pathology / Q000523:psychology; D055815:Young Adult
chemical_list: C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins