title: Child abuse, depression, and methylation in genes involved with stress, neural plasticity, and brain circuitry.
abstract: OBJECTIVE
  To determine whether epigenetic markers predict dimensional ratings of depression in maltreated children.
  
  
  METHODS
  A genome-wide methylation study was completed using the Illumina 450K BeadChip array in 94 maltreated and 96 healthy nontraumatized children with saliva-derived DNA. The 450K BeadChip does not include any methylation sites in the exact location as sites in candidate genes previously examined in the literature, so a test for replication of prior research findings was not feasible.
  
  
  RESULTS
  Methylation in 3 genes emerged as genome-wide-significant predictors of depression: DNA-Binding Protein Inhibitor ID-3 (ID3); Glutamate Receptor, Ionotropic N-methyl-D-aspartate (NMDA) 1 (GRIN1); and Tubulin Polymerization Promoting Protein (TPPP) (p < 5.0 × 10(-7), all analyses). These genes are all biologically relevant with ID3 involved in the stress response, GRIN1 involved in neural plasticity, and TPPP involved in neural circuitry development. Methylation in CpG sites in candidate genes were not predictors of depression at significance levels corrected for whole genome testing, but maltreated and control children did have significantly different β values after Bonferroni correction at multiple methylation sites in these candidate genes (e.g., BDNF, NR3C1, FKBP5).
  
  
  CONCLUSIONS
  This study suggests that epigenetic changes in ID3, GRIN1, and TPPP genes, in combination with experiences of maltreatment, may confer risk for depression in children. The study adds to a growing body of literature supporting a role for epigenetic mechanisms in the pathophysiology of stress-related psychiatric disorders. Although epigenetic changes are frequently long lasting, they are not necessarily permanent. Consequently, interventions to reverse the negative biological and behavioral sequelae associated with child maltreatment are briefly discussed.
authors.affiliation: Child Mind Institute.
authors.forename: Natalie
authors.initials: N
authors.lastname: Weder
authors.affiliation: Yale University School of Medicine.
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Yale University School of Medicine.
authors.forename: Kevin
authors.initials: K
authors.lastname: Jensen
authors.affiliation: Yale University School of Medicine.
authors.forename: Bao Zhu
authors.initials: BZ
authors.lastname: Yang
authors.affiliation: Yale University School of Medicine; Merck Research Laboratories.
authors.forename: Arthur
authors.initials: A
authors.lastname: Simen
authors.affiliation: LiNC, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Andrea
authors.initials: A
authors.lastname: Jackowski
authors.affiliation: Yale University School of Medicine.
authors.forename: Deborah
authors.initials: D
authors.lastname: Lipschitz
authors.affiliation: Yale University School of Medicine.
authors.forename: Heather
authors.initials: H
authors.lastname: Douglas-Palumberi
authors.affiliation: Yale University School of Medicine.
authors.forename: Margrat
authors.initials: M
authors.lastname: Ge
authors.affiliation: Yale University School of Medicine.
authors.forename: Francheska
authors.initials: F
authors.lastname: Perepletchikova
authors.affiliation: University of Vermont, Vermont Center for Children, Youth, and Families.
authors.forename: Kerry
authors.initials: K
authors.lastname: O'Loughlin
authors.affiliation: University of Vermont, Vermont Center for Children, Youth, and Families.
authors.forename: James J
authors.initials: JJ
authors.lastname: Hudziak
authors.affiliation: Yale University School of Medicine.
authors.forename: Joel
authors.initials: J
authors.lastname: Gelernter
authors.affiliation: Child Mind Institute; Yale University School of Medicine. Electronic address: 06520.joan.kaufman@yale.edu.
authors.forename: Joan
authors.initials: J
authors.lastname: Kaufman
mesh_terms: D000293:Adolescent; D002648:Child; D002649:Child Abuse; D002675:Child, Preschool; D019175:DNA Methylation / Q000235:genetics; D003863:Depression / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics*; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics*; D009415:Nerve Net / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009473:Neuronal Plasticity / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism
chemical_list: C485668:GRIN1 protein, human; D051796:Inhibitor of Differentiation Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C118136:TPPP protein, human; C075640:ID3 protein, human
keywords: child abuse; depression; epigenetics; methylation