Differential Genetic and Epigenetic Regulation of Catechol-O-Methyl-Transferase (COMT) is Associated with Impaired Fear Inhibition in Posttraumatic Stress Disorder
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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2013-04-01
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| Series: | Frontiers in Behavioral Neuroscience |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fnbeh.2013.00030/full |
| _version_ | 1819094228235452416 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Seth Davin Norrholm |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T23:24:04Z |
| format | Article |
| id | doaj.art-9dd960e5e64c40c59760d99c799b82f1 |
| institution | Directory Open Access Journal |
| issn | 1662-5153 |
| language | English |
| last_indexed | 2024-12-21T23:24:04Z |
| publishDate | 2013-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Behavioral Neuroscience |
| spelling | doaj.art-9dd960e5e64c40c59760d99c799b82f12022-12-21T18:46:43ZengFrontiers Media S.A.Frontiers in Behavioral Neuroscience1662-51532013-04-01710.3389/fnbeh.2013.0003046451Differential Genetic and Epigenetic Regulation of Catechol-O-Methyl-Transferase (COMT) is Associated with Impaired Fear Inhibition in Posttraumatic Stress DisorderSeth Davin Norrholm0Tanja eJovanovic1Alicia eSmith2Elisabeth B Binder3Elisabeth B Binder4Torsten eKlengel5Karen eConneely6Kristina B. Mercer7Jennifer S. Davis8Kimberly eKerley9Jennifer A. Winkler10Charles F. Gillespie11Bekh eBradley12Kerry J Ressler13Emory University School of MedicineEmory University School of MedicineEmory University School of MedicineEmory University School of MedicineMax-Planck Institute of PsychiatryMax-Planck Institute of PsychiatryEmory University School of MedicineEmory University School of MedicineEmory University School of MedicineEmory University School of MedicineEmory University School of MedicineEmory University School of MedicineEmory University School of MedicineEmory University School of MedicineThe 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.http://journal.frontiersin.org/Journal/10.3389/fnbeh.2013.00030/fullMethylationposttraumatic stress disorderepigeneticTraumacatechol-O-methyltransferasefear-potentiated startle |
| spellingShingle | 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 Differential Genetic and Epigenetic Regulation of Catechol-O-Methyl-Transferase (COMT) is Associated with Impaired Fear Inhibition in Posttraumatic Stress Disorder Frontiers in Behavioral Neuroscience Methylation posttraumatic stress disorder epigenetic Trauma catechol-O-methyltransferase fear-potentiated startle |
| title | Differential Genetic and Epigenetic Regulation of Catechol-O-Methyl-Transferase (COMT) is Associated with Impaired Fear Inhibition in Posttraumatic Stress Disorder |
| title_full | Differential Genetic and Epigenetic Regulation of Catechol-O-Methyl-Transferase (COMT) is Associated with Impaired Fear Inhibition in Posttraumatic Stress Disorder |
| title_fullStr | Differential Genetic and Epigenetic Regulation of Catechol-O-Methyl-Transferase (COMT) is Associated with Impaired Fear Inhibition in Posttraumatic Stress Disorder |
| title_full_unstemmed | Differential Genetic and Epigenetic Regulation of Catechol-O-Methyl-Transferase (COMT) is Associated with Impaired Fear Inhibition in Posttraumatic Stress Disorder |
| title_short | Differential Genetic and Epigenetic Regulation of Catechol-O-Methyl-Transferase (COMT) is Associated with Impaired Fear Inhibition in Posttraumatic Stress Disorder |
| title_sort | differential genetic and epigenetic regulation of catechol o methyl transferase comt is associated with impaired fear inhibition in posttraumatic stress disorder |
| topic | Methylation posttraumatic stress disorder epigenetic Trauma catechol-O-methyltransferase fear-potentiated startle |
| url | http://journal.frontiersin.org/Journal/10.3389/fnbeh.2013.00030/full |
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