title: Interplay between stress response genes associated with attention-deficit hyperactivity disorder and brain volume.
abstract: The glucocorticoid receptor plays a pivotal role in the brain's response to stress; a haplotype of functional polymorphisms in the NR3C1 gene encoding this receptor has been associated with attention-deficit hyperactivity disorder (ADHD). The serotonin transporter (5-HTT) gene polymorphism 5-HTTLPR is known to influence the relation between stress exposure and ADHD severity, which may be partly because of its reported effects on glucocorticoid levels. We therefore investigated if NR3C1 moderates the relation of stress exposure with ADHD severity and brain structure, and the potential role of 5-HTTLPR. Neuroimaging, genetic and stress exposure questionnaire data were available for 539 adolescents and young adults participating in the multicenter ADHD cohort study NeuroIMAGE (average age: 17.2 years). We estimated the effects of genetic variation in NR3C1 and 5-HTT, stress exposure and their interactions on ADHD symptom count and gray matter volume. We found that individuals carrying the ADHD risk haplotype of NR3C1 showed significantly more positive relation between stress exposure and ADHD severity than non-carriers. This gene-environment interaction was significantly stronger for 5-HTTLPR L-allele homozygotes than for S-allele carriers. These two- and three-way interactions were reflected in the gray matter volume of the cerebellum, parahippocampal gyrus, intracalcarine cortex and angular gyrus. Our findings illustrate how genetic variation in the stress response pathway may influence the effects of stress exposure on ADHD severity and brain structure. The reported interplay between NR3C1 and 5-HTT may further explain some of the heterogeneity between studies regarding the role of these genes and hypothalamic-pituitary-adrenal axis activity in ADHD.
authors.affiliation: Department of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. d.van.der.meer01@gmail.com.|Centre for Cognitive Neuroimaging, Radboud University Medical Center, Nijmegen, the Netherlands. d.van.der.meer01@gmail.com.
authors.forename: D
authors.initials: D
authors.lastname: van der Meer
authors.affiliation: Department of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: P J
authors.initials: PJ
authors.lastname: Hoekstra
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Bralten
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: van Donkelaar
authors.affiliation: Clinical Neuropsychology Section, VU University Amsterdam, Amsterdam, the Netherlands.
authors.forename: D J
authors.initials: DJ
authors.lastname: Heslenfeld
authors.affiliation: Clinical Neuropsychology Section, VU University Amsterdam, Amsterdam, the Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Oosterlaan
authors.affiliation: Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA.|Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.|K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
authors.forename: S V
authors.initials: SV
authors.lastname: Faraone
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Franke
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre.|Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, the Netherlands.
authors.forename: J K
authors.initials: JK
authors.lastname: Buitelaar
authors.affiliation: Department of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: C A
authors.initials: CA
authors.lastname: Hartman
mesh_terms: D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000033:anatomy & histology* / Q000503:physiopathology*; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D008297:Male; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins
keywords: Attention-deficit hyperactivity disorder; HPA axis; gene-environment interaction; glucocorticoid receptor; gray matter volume; serotonin transporter