Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Norrholm SD

PROVIDER: S-EPMC3622057 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Norrholm Seth Davin SD Jovanovic Tanja T Smith Alicia K AK Binder Elisabeth E Klengel Torsten T Conneely Karen K Mercer Kristina B KB Davis Jennifer S JS Kerley Kimberly K Winkler Jennifer J Gillespie Charles F CF Bradley Bekh B Ressler Kerry J KJ

Frontiers in behavioral neuroscience 20130410

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 differ ...[more]

PMID: 23596403

Similar Datasets

Project description:Epigenetic marks, including DNA methylation, are modifiable molecular factors that may underlie mental disorders, especially responses to trauma, including the development of and resilience to posttraumatic stress disorder (PTSD). Previous work has identified differential DNA methylation at CpG dinucleotide sites genomewide between trauma exposed individuals with and without PTSD, suggesting a role for epigenetic potential-the capacity to epigenetically regulate behavior and physiology in response to lived experiences. The human species is characterized by an increased period of adaptive plasticity during brain development. The evolutionary history of epigenetic potential in relation to adaptive plasticity is currently unknown. Using phylogenetic methods and functional annotation analyses, we trace the evolution of over 7000 CpG dinucleotides, including 203 associated with PTSD, during the descent of humans in during mammalian evolution and characterize the biological significance of this evolution. We demonstrate that few (7%) PTSD-associated CpG sites are unique to humans, while the vast majority of sites have deep evolutionary origins: 73 and 93% were unambiguously present in the last common ancestor of humans/orangutans and humans/chimpanzees, respectively. Genes proximal to evolved PTSD-associated CpG sites revealed significant enrichment for immune function during recent human evolution and regulation of gene expression during more ancient periods of human evolution. Additionally, 765 putative transcription factor binding motifs (TFBMs) were identified that overlap with PTSD-associated CpG sites. Elucidation of the evolutionary history of PTSD-associated CpG sites may provide insights into the function and origin of epigenetic potential in trauma responses, generally, and PTSD, specifically. The human capacity to respond to trauma with stable physiologic and behavioral changes may be due to epigenetic potentials that are shared among many mammalian species.

Project description:Fear conditioning is an established model for investigating posttraumatic stress disorder (PTSD). However, symptom triggers may vaguely resemble the initial traumatic event, differing on a variety of sensory and affective dimensions. We extended the fear-conditioning model to assess generalization of conditioned fear on fear processing neurocircuitry in PTSD. Military veterans (n=67) consisting of PTSD (n=32) and trauma-exposed comparison (n=35) groups underwent functional magnetic resonance imaging during fear conditioning to a low fear-expressing face while a neutral face was explicitly unreinforced. Stimuli that varied along a neutral-to-fearful continuum were presented before conditioning to assess baseline responses, and after conditioning to assess experience-dependent changes in neural activity. Compared with trauma-exposed controls, PTSD patients exhibited greater post-study memory distortion of the fear-conditioned stimulus toward the stimulus expressing the highest fear intensity. PTSD patients exhibited biased neural activation toward high-intensity stimuli in fusiform gyrus (P<0.02), insula (P<0.001), primary visual cortex (P<0.05), locus coeruleus (P<0.04), thalamus (P<0.01), and at the trend level in inferior frontal gyrus (P=0.07). All regions except fusiform were moderated by childhood trauma. Amygdala-calcarine (P=0.01) and amygdala-thalamus (P=0.06) functional connectivity selectively increased in PTSD patients for high-intensity stimuli after conditioning. In contrast, amygdala-ventromedial prefrontal cortex (P=0.04) connectivity selectively increased in trauma-exposed controls compared with PTSD patients for low-intensity stimuli after conditioning, representing safety learning. In summary, fear generalization in PTSD is biased toward stimuli with higher emotional intensity than the original conditioned-fear stimulus. Functional brain differences provide a putative neurobiological model for fear generalization whereby PTSD symptoms are triggered by threat cues that merely resemble the index trauma.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets