Frontiers in Behavioral Neuroscience (Apr 2013)

Differential Genetic and Epigenetic Regulation of Catechol-O-Methyl-Transferase (COMT) is Associated with Impaired Fear Inhibition in Posttraumatic Stress Disorder

  • Seth Davin Norrholm,
  • Tanja eJovanovic,
  • Alicia eSmith,
  • Elisabeth B Binder,
  • Elisabeth B Binder,
  • Torsten eKlengel,
  • Karen eConneely,
  • Kristina B. Mercer,
  • Jennifer S. Davis,
  • Kimberly eKerley,
  • Jennifer A. Winkler,
  • Charles F. Gillespie,
  • Bekh eBradley,
  • Kerry J Ressler

DOI
https://doi.org/10.3389/fnbeh.2013.00030
Journal volume & issue
Vol. 7

Abstract

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The catechol-O-methyltransferase (COMT) enzyme is critical for the catabolic regulation of synaptic dopamine, resulting in altered cortical functioning. The COMT Val158Met polymorphism has been implicated in human mental illness, with Met/Met homozygotes associated with increased susceptibility to posttraumatic stress disorder (PTSD). Our primary objective was to examine the intermediate phenotype of fear inhibition in PTSD stratified by COMT genotype (Met/Met, Val/Met, and Val/Val) and differential gene regulation via methylation status at CpG sites in the COMT promoter region. More specifically, we examined the potential interaction of COMT genotype and PTSD diagnosis on fear-potentiated startle during fear conditioning and extinction and COMT DNA methylation levels (as determined using genomic DNA isolated from whole blood) . Participants were recruited from medical and gynecological clinics of an urban hospital in Atlanta, Georgia. We found that individuals with the Met/Met genotype demonstrated higher fear-potentiated startle to the CS- (safety signal) and during extinction of the CS+ (danger signal) compared to Val/Met and Val/Val genotypes. The PTSD+ Met/Met genotype group had the greatest impairment in fear inhibition to the CS- (p=.006), compared to Val carriers. In addition, the Met/Met genotype was associated with DNA methylation at 4 CpG sites, 2 of which were associated with impaired fear inhibition to the safety signal. These results suggest that multiple differential mechanisms for regulating COMT function – at the level of protein structure via the Val158Met genotype and at the level of gene regulation via differential methylation - are associated with impaired fear inhibition in PTSD.

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