AUTHOR=Norrholm Seth D., Jovanovic Tanja , Smith Alicia , Binder Elisabeth B., Klengel Torsten , Conneely Karen , Mercer Kristina B., Davis Jennifer S., Kerley Kimberly , Winkler Jennifer A., Gillespie Charles F., Bradley Bekh , Ressler Kerry J.

TITLE=Differential Genetic and Epigenetic Regulation of catechol-O-methyltransferase is Associated with Impaired Fear Inhibition in Posttraumatic Stress Disorder

JOURNAL=Frontiers in Behavioral Neuroscience

VOLUME=Volume 7 - 2013

YEAR=2013

URL=https://www.frontiersin.org/journals/behavioral-neuroscience/articles/10.3389/fnbeh.2013.00030

DOI=10.3389/fnbeh.2013.00030

ISSN=1662-5153

ABSTRACT=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.