title: Methylation of NR3C1 and SLC6A4 and internalizing problems. The TRAILS study.
abstract: BACKGROUND
  The relationship between early adverse life events and later internalizing problems could be mediated by DNA methylation. Adversity has been associated with higher methylation levels in the glucocorticoid receptor gene (NR3C1) and the serotonin transporter gene (SLC6A4) in adolescents. We investigated cross-sectional and prospective associations of NR3C1 and SLC6A4 methylation with adolescents׳ clinical diagnoses of internalizing disorders and internalizing symptom scores.
  
  
  METHODS
  In a population sample (mean age=16.2) we measured DNA methylation in three regions of NR3C1 (NR3C1_1, N=454; NR3C1_2, N=904; NR3C1_3, N=412) and one region of SLC6A4 (N=939) at baseline. Internalizing problems were operationalized as clinical DSM-IV diagnoses, assessed at 3 year follow-up with a diagnostic interview, and internalizing symptom scores, assessed with Self-Report questionnaires at baseline and follow-up.
  
  
  RESULTS
  Only NR3C1_1 methylation was positively associated with risk of lifetime internalizing disorders, and with symptom scores at follow-up. However, after accounting for baseline symptom scores there was only a tendency for association with internalizing symptom scores at follow-up. There was no association between SLC6A4 methylation and risk of lifetime internalizing disorders. SLC6A4 methylation and internalizing symptom scores showed a tendency for association, also after accounting for baseline symptom scores.
  
  
  CONCLUSIONS
  There was no repeated measure of DNA methylation to study causality between methylation and internalizing problems. Gene expression data were not available.
  
  
  CONCLUSIONS
  Although the role of gene methylation in the development of internalizing problems remains unclear, our findings suggest that gene methylation, particularly of NR3C1, may be involved in the development of internalizing problems in adolescence.
authors.affiliation: Department of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Center, Sophia Children׳s Hospital, Rotterdam, The Netherlands. Electronic address: l.j.vanderknaap@erasmusmc.nl.
authors.forename: Lisette J
authors.initials: LJ
authors.lastname: van der Knaap
authors.affiliation: Department of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Center, Sophia Children׳s Hospital, Rotterdam, The Netherlands.
authors.forename: Floor V A
authors.initials: FV
authors.lastname: van Oort
authors.affiliation: Department of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Center, Sophia Children׳s Hospital, Rotterdam, The Netherlands.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Verhulst
authors.affiliation: Interdisciplinary Center Psychopathology and Emotion regulation (ICPE), Department of Psychiatry, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Albertine J
authors.initials: AJ
authors.lastname: Oldehinkel
authors.affiliation: Interdisciplinary Center Psychopathology and Emotion regulation (ICPE), Department of Psychiatry, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Harriëtte
authors.initials: H
authors.lastname: Riese
mesh_terms: D000293:Adolescent; D003430:Cross-Sectional Studies; D019175:DNA Methylation / Q000235:genetics*; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000235:genetics*; D011446:Prospective Studies; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins
keywords: Anxiety; DNA methylation; Depression; Internalizing problems; NR3C1; SLC6A4