title: DRD4 VNTRs, observed stranger fear in preschoolers and later ADHD symptoms.
abstract: Fear of strangers is a developmental milestone in childhood that encompasses behavioral inhibition and decreased novelty seeking. Children with attention deficit/hyperactivity disorder (ADHD) often exhibit fearless and impulsive behaviors, similar to those observed in children with atypically low levels of stranger fear. It is currently unknown whether these behaviors share common underlying biological mechanisms. Polymorphisms in the dopamine receptor 4 gene (DRD4) have been implicated in the risk for developing ADHD symptoms in childhood. Here we investigate whether (1) DRD4 variable number tandem repeats (VNTRs) are associated with both stranger fear and ADHD symptoms, and (2) stranger fear in preschoolers mediates the link between DRD4 VNTRs and ADHD in later childhood. Stranger fear was observed in a large sample (N=589) of 3-year-old Caucasian children and ADHD symptoms were assessed by a validated, mother-rated questionnaire at 6 years. We found evidence that longer DRD4 variants were associated with increased ADHD symptoms at 6 years, and that this relationship was partially mediated by lower levels of observed stranger fear at 3 years. Our results suggest a common underlying neurobiological mechanism in the association between low stranger fear and ADHD symptoms; variation in DRD4 may be an important contributor to this mechanism.
authors.affiliation: School of Pedagogical and Educational Sciences, Erasmus University Rotterdam, The Netherlands; Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Irene
authors.initials: I
authors.lastname: Pappa
authors.affiliation: School of Pedagogical and Educational Sciences, Erasmus University Rotterdam, The Netherlands; Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Viara R
authors.initials: VR
authors.lastname: Mileva-Seitz
authors.affiliation: Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center-Sophia Children׳s Hospital, The Netherlands.
authors.forename: Eszter
authors.initials: E
authors.lastname: Szekely
authors.affiliation: Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center-Sophia Children׳s Hospital, The Netherlands.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Verhulst
authors.affiliation: Centre for Child and Family Studies, Leiden University, PO Box 9555, 2300 RB Leiden, The Netherlands.
authors.forename: Marian J
authors.initials: MJ
authors.lastname: Bakermans-Kranenburg
authors.affiliation: Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus University Medical Center-Sophia Children׳s Hospital, The Netherlands; Department of Pediatrics, Erasmus University Medical Center-Sophia Children׳s Hospital, The Netherlands.
authors.forename: Vincent W V
authors.initials: VW
authors.lastname: Jaddoe
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center-Sophia Children׳s Hospital, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center-Sophia Children׳s Hospital, The Netherlands.
authors.forename: Henning
authors.initials: H
authors.lastname: Tiemeier
authors.affiliation: School of Pedagogical and Educational Sciences, Erasmus University Rotterdam, The Netherlands; Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands; Centre for Child and Family Studies, Leiden University, PO Box 9555, 2300 RB Leiden, The Netherlands. Electronic address: vanijzen@fsw.leidenuniv.nl.
authors.forename: Marinus H
authors.initials: MH
authors.lastname: van IJzendoorn
mesh_terms: D001289:Attention Deficit Disorder with Hyperactivity / Q000175:diagnosis / Q000235:genetics* / Q000523:psychology*; D002648:Child; D002675:Child, Preschool; D005239:Fear / Q000523:psychology*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D006801:Humans; D008297:Male; D018598:Minisatellite Repeats / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D050638:Receptors, Dopamine D4 / Q000235:genetics*; D016037:Single-Blind Method
chemical_list: C493599:DRD4 protein, human; D050638:Receptors, Dopamine D4
keywords: Attention; Candidate gene; Dopamine receptor D4; Inhibitory control; Mediation; Social anxiety; Temperament