title: Longitudinal epigenetic variation of DNA methyltransferase genes is associated with vulnerability to post-traumatic stress disorder.
abstract: BACKGROUND
  Epigenetic differences exist between trauma-exposed individuals with and without post-traumatic stress disorder (PTSD). It is unclear whether these epigenetic differences pre-exist, or arise following, trauma and PTSD onset.
  
  
  METHODS
  In pre- and post-trauma samples from a subset of Detroit Neighborhood Health Study participants, DNA methylation (DNAm) was measured at DNA methyltransferase 1 (DNMT1), DNMT3A, DNMT3B and DNMT3L. Pre-trauma DNAm differences and changes in DNAm from pre- to post-trauma were assessed between and within PTSD cases (n = 30) and age-, gender- and trauma exposure-matched controls (n = 30). Pre-trauma DNAm was tested for association with post-trauma symptom severity (PTSS) change. Potential functional consequences of DNAm differences were explored via bioinformatic search for putative transcription factor binding sites (TFBS).
  
  
  RESULTS
  DNMT1 DNAm increased following trauma in PTSD cases (p = 0.001), but not controls (p = 0.067). DNMT3A and DNMT3B DNAm increased following trauma in both cases (DNMT3A: p = 0.009; DNMT3B: p < 0.001) and controls (DNMT3A: p = 0.002; DNMT3B: p < 0.001). In cases only, pre-trauma DNAm was lower at a DNMT3B CpG site that overlaps with a TFBS involved in epigenetic regulation (p = 0.001); lower pre-trauma DNMT3B DNAm at this site was predictive of worsening of PTSS post-trauma (p = 0.034). Some effects were attenuated following correction for multiple hypothesis testing.
  
  
  CONCLUSIONS
  DNAm among trauma-exposed individuals shows both longitudinal changes and pre-existing epigenetic states that differentiate individuals who are resilient versus susceptible to PTSD. These distinctive DNAm differences within DNMT loci may contribute to genome-wide epigenetic profiles of PTSD.
authors: Center for Molecular Medicine and Genetics,Wayne State University School of Medicine,Detroit, MI,USA.
authors: L
authors: L
authors: Sipahi
authors: Center for Molecular Medicine and Genetics,Wayne State University School of Medicine,Detroit, MI,USA.
authors: D E
authors: DE
authors: Wildman
authors: Department of Epidemiology,University of North Carolina Gillings School of Global Public Health,Chapel Hill, NC,USA.
authors: A E
authors: AE
authors: Aiello
authors: Department of Epidemiology, Mailman School of Public Health,Columbia University,New York, NY,USA.
authors: K C
authors: KC
authors: Koenen
authors: Department of Epidemiology, Mailman School of Public Health,Columbia University,New York, NY,USA.
authors: S
authors: S
authors: Galea
authors: Center for Molecular Medicine and Genetics,Wayne State University School of Medicine,Detroit, MI,USA.
authors: A
authors: A
authors: Abbas
authors: Center for Molecular Medicine and Genetics,Wayne State University School of Medicine,Detroit, MI,USA.
authors: M
authors: M
authors: Uddin
mesh_terms: D000328:Adult; D000368:Aged; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D013313:Stress Disorders, Post-Traumatic / Q000235:genetics*; D000097584:DNA Methyltransferase 3B
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C412484:DNMT3L protein, human; C000619380:DNMT1 protein, human