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Author Notes:

Correspondence: Seth Davin Norrholm, Mental Health Service Line, Atlanta VA Medical Center, 1670 Clairmont Road, MHSL 116A, Decatur, GA 30033, USA. e-mail: seth.norrholm@va.gov.

SDN and TJ have contributed equally to this work.

For authors' acknowledgments and disclosures, see the full article.

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Research Funding:

This research was supported by National Institute of Mental Health Grants MH071537 and MH096764 (PI, Kerry J. Ressler), MH085806 (PI, Alicia K. Smith), MH082256 (PI, Charles F. Gillespie), and MH070129 (PI, Tanja Jovanovic), the Howard Hughes Medical Institute (Kerry J. Ressler), and the Atlanta Clinical Translational Science Institute, the NIH National Centers for Research Resources (M01 RR00039), and the Burroughs Wellcome Fund (Kerry J. Ressler).

This work was funded in part by the Brain and Behavior Foundation (formerly NARSAD; Seth Davin Norrholm; and Tanja Jovanovic), and the Department of Defense (DOD)/Congressionally Directed Medical Research Program (CDMRP, Award # W81XWH-08-2-0170; PI, Seth Davin Norrholm).

This work was also supported by the Max Planck Society and the Doris Duke Charitable Foundation (Elisabeth Binder).

Keywords:

  • Behavioral Sciences
  • Neurosciences & Neurology
  • catechol-O-methyltransferase
  • fear-potentiated startle
  • posttraumatic stress disorder
  • epigenetic
  • methylation
  • trauma
  • POTENTIATED STARTLE PARADIGM
  • RAT PREFRONTAL CORTEX
  • DOPAMINE TRANSPORTER
  • VAL(158)MET GENOTYPE
  • BIPOLAR DISORDER
  • DNA METHYLATION
  • MESSENGER-RNA
  • COMT PROMOTER

Differential genetic and epigenetic regulation of catechol-O-methyltransferase is associated with impaired fear inhibition in posttraumatic stress disorder

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Journal Title:

Frontiers in Behavioral Neuroscience

Volume:

Volume 7, Number MAR

Publisher:

, Pages 30-30

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2013 Norrholm, Jovanovic, Smith, Binder, Klengel, Conneely, Mercer, Davis, Kerley, Winkler, Gillespie, Bradley and Ressler.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/).

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