Differential genetic and epigenetic regulation of catechol-O-methyltransferase is associated with impaired fear inhibition in posttraumatic stress disorder
Open accessAbstract
The catechol-O-methyltransferase (COMT) enzyme is critical for the catabolic regulation of synaptic dopamine, resulting in altered cortical functioning. The COMT Val(158)Met 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, GA, USA. 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 = 0.006), compared to Val carriers. In addition, the Met/Met genotype was associated with DNA methylation at four CpG sites, two 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 Val(158)Met genotype and at the level of gene regulation via differential methylation - are associated with impaired fear inhibition in PTSD.
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In PTSD, increased COMT methylation is associated with impaired fear inhibition, which affects stress responsivity via dopamine regulation.
“In PTSD, increased COMT methylation is associated with impaired fear inhibition, which affects stress responsivity via dopamine regulation”
From The clinical use of epigenetics in psychiatry: a narrative review of epigenetic mechanisms, key candidate genes, and precision psychiatry (2025) · cites this paper as [79]
The Results (Methylation) and Discussion report that higher COMT promoter methylation was associated with greater fear responses to a safety signal, consistent with impaired fear inhibition in the study’s traumatized participants. The Introduction describes COMT’s role in clearing dopamine, but the paper does not establish that the methylation-associated fear-inhibition difference affects stress responsivity through dopamine regulation. (LLM, conf=0.84)
Experimental — accuracy not yet measuredFear-conditioning paradigms afford the study of intermediate phenotypes, which may enhance the ability to elucidate complex gene × environment interactions.
“Fear-conditioning paradigms afford the study of intermediate phenotypes, which may enhance our ability to elucidate these complex interactions [see Ref. (36)].”
From Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors (2014) · cites this paper as [36]
Trauma-, stressor-, and anxiety-related disorders have a significant degree of heritability and genetic contributions include complex gene × environment interactions.
“trauma-, stressor-, and anxiety-related disorders have been shown to have a significant degree of heritability and more recently, it has become increasingly clear that genetic contributions include complex gene × environment interactions.”
From Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors (2014) · cites this paper as [36]
Increased 'fear load,' as measured by fear-potentiated startle, was related to the catechol-O-methyl-transferase (COMT) Val66Met polymorphism and a diagnosis of PTSD.
“For example, we recently showed that increased “fear load,” as measured by fear-potentiated startle was related to the catechol-O-methyl-transferase (COMT) Val66Met polymorphism and a diagnosis of PTSD (36).”
From Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors (2014) · cites this paper as [36]
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References 53 · Cited by 104
Research works printed but not linked: 1
- Institute of Medicine (2008). Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence. Washington, DC: The National Academies Press
- Authors
- Norrholm, S. D., Jovanovic, T., Smith, A. K., Binder, E., Klengel, T., Conneely, K., Mercer, K. B., Davis, J. S., Kerley, K., Winkler, J., Gillespie, C. F., Bradley, B., & Ressler, K. J.
- Affiliations
- Emory University (US)
- Max Planck Institute of Psychiatry (DE)
- Corresponding author
- Norrholm, Seth Davin
- ORCID
- Venue
- Frontiers in Behavioral Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2013
- Volume
- 7
- Pages
- 30-30
- ISSN
- 1662-5153 (ISSN-L)
- PMC
- PMC3622057
- OpenAlex
- W1964536180
- Cited by
- 104
- References
- 53
- Citations by year
- 2025: 6 · 2024: 3 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 5 · 2019: 8 · 2018: 10 · 2017: 8 · 2016: 10 · 2015: 13 · 2014: 17 · 2013: 10
- FWCI
- 18.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Behavioral Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Defense (W81XWH)
- American Foundation for Suicide Prevention
- National Alliance for Research on Schizophrenia and Depression
- Max-Planck-Gesellschaft
- National Institutes of Health (W81XWH, RR 00039, MH071537)
- National Institute of Mental Health (K23MH082256, MH082256, MH 071537, F32MH070129, K01MH085806, R01MH096764, R01MH071537, MH085806, MH096764, R56MH071537, MH070129)
- National Center for Research Resources (M01RR000039)
- Congressionally Directed Medical Research Programs (W81XWH-08-2-0170)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- catechol-O-methyltransferase, COMT Val158Met polymorphism, post-traumatic stress disorder, fear inhibition, fear-potentiated startle, fear extinction, fear conditioning, DNA methylation, CpG sites, epigenetic regulation, dopaminergic modulation, gene-environment interaction
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