catechol-O-methyltransferase Allele Research Articles

Association of catechol-O-methyltransferase Val108/158 Met genetic polymorphism with schizophrenia, P50 sensory gating, and negative symptoms in a Chinese population

Catechol-O-methyltransferase (COMT), an enzyme involved in the degradation and inactivation of the neurotransmitter dopamine, is associated with the sensory gating phenomenon, protecting the cerebral cortex from information overload. The COMT Val108/158Met polymorphism is essential for prefrontal cortex processing capacity and efficiency. The current study was designed to investigate the role of COMT Val108/158Met polymorphism in development, sensory gating deficit, and symptoms of schizophrenia in Han Chinese population. P50 gating was determined in 139 schizophrenic patients and 165 healthy controls. Positive and Negative Syndrome Scale (PANSS) was used to assess the clinical symptomatology in 370 schizophrenic subjects. COMT Val108/158Met polymorphism was genotyped by PCR-restriction fragment length polymorphism (PCR-RFLP). No significant differences in COMT allele and genotype distributions were observed between schizophrenic patients and control groups. Although P50 deficits were present in patients, there was no evidence for an association between COMT Val108/158Met polymorphism and the P50 biomarker. Moreover, PANSS negative subscore was significantly higher in Val allele carriers than in Met/Met individuals. The present findings suggest that COMT Val108/158Met polymorphism may not contribute to the risk of schizophrenia and to the P50 deficits, but may contribute to the negative symptoms of schizophrenia among Han Chinese.

Epistatic interactions involving DRD2, DRD4, and COMT polymorphisms and risk of substance abuse in women with binge-purge eating disturbances

Substance abuse is common in individuals with bulimia-spectrum (binge-purge) eating disturbances, a co-occurrence that has been attributed to shared neurobiological substrates--notably alterations in dopaminergic activity. We examined the implications of variations of selected, dopamine-relevant polymorphisms (DRD2 Taq1A, DRD4 7R, and COMT) for risk of substance abuse in women with binge-purge eating syndromes. We genotyped 183 women (66.1% showing full-threshold BN and 33.9% showing sub-syndromic variants), and assessed lifetime presence of alcohol, cannabis, cocaine, and stimulant abuse or dependence using structured interviews. Tests for main and interaction effects of various allele combinations revealed that individuals who carried high function COMT and low-function DRD4 7R alleles (a combination expected to be associated with higher risk) did indeed show more lifetime substance abuse and, specifically, more cannabis abuse. Our findings suggest that a gene combination that, in theory, codes for low levels of dopaminergic neurotransmission coincides with sensitivity to substance abuse in a sample displaying binge-purge eating-disorder variants.

Association of Single Nucleotide Polymorphisms in Catechol-O-Methyltransferase and Serine-Threonine Protein Kinase Genes in the Pakistani Schizophrenic Population: A Study with Special Emphasis on Cannabis and Smokeless Tobacco.

Schizophrenia is a neuropsychiatric disorder in which abnormalities in the prefrontal cortex lead to impaired synthesis of dopamine. It is associated with hallucination, psychosis and hearing impairments. Many susceptible genes have been identified in schizophrenia such as catechol-O-methyltransferase (COMT) and serine/threonine kinase (AKT1). Single nucleotide polymorphisms (SNPs) in these genes have not been identified in Pakistan. Therefore, we investigated the allelic and genotypic frequencies in COMT and AKT1 genes in the Pakistani population. Polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) and DNA sequencing were used to identify SNPs in the genes. The present study shows that COMT Val and COMT Met allelic frequencies for the controls were p=0.52, q=0.48 and for the schizophrenic cases they were p=0.34, q=0.66 respectively. The distribution of polymorphism in COMT Val158Met genotype by Hardy-Weinberg equilibrium (HWE) was P=0.61 for controls and P=0.005 for cases. The data reveal that SNP rs1130214 T allele mutation was found neither in patients nor in controls in the 5' untranslated region (UTR). This proves that no association of AKT1 and positive association of COMT with schizophrenia exist in the population of Pakistan. Moreover, a study based on a single family showed COMT Met allele inheritance in schizophrenic offspring. This suggested that COMT allele alteration influences susceptibility to at least some forms of psychosis in the Pakistani population. Interestingly, according to our socio-economical survey, COMT genotype has no association with cannabis but it is strongly associated with tobacco. The Pakistani population with Val158Met SNP showed more susceptibility towards developing schizophrenia. This study highlights the genetic differences between Pakistani and other Caucasian populations.

Catechol-O-methyltransferase activity in erythrocytes from patients with eating disorders.

Abnormal feeding has been linked to disruptions in brain dopaminergic activity and recent studies have assessed the role of catechol-O-methyltransferase (COMT) in eating disorders. This is the first study to quantify the soluble catechol-O-methyltransferase (S-COMT) activity in erythrocytes from patients with anorexia nervosa (AN), bulimia nervosa (BN) and binge-eating disorder (BED) and the first study at all to evaluate the COMT on patients with BED. Forty blood samples from patients with AN, BN and BED and healthy controls were drawn to evaluate S-COMT activity in erythrocytes by high-performance liquid chromatography and mass spectrometry. Since several patients were being treated with fluoxetine 20mg, they were included in a different group (BN MED and BED MED). Liver homogenates from rats were used to evaluate baseline S-COMT activity in the presence of fluoxetine by the same in vitro procedures and assays. Erythrocyte S-COMT activity (pmol/mgprt/h) was significantly increased in patients with BN and BED (41.3±6.8 and 41.4±14, respectively) compared to control group (25.3±9.7). In fluoxetine-treated patients with BN, S-COMT activity (15.9±8.8) was decreased compared to the other BN group; however, in BED group, the difference between BED MED and BED was not observed. In patients with AN, no significant difference was found compared to controls. Patients with BN and BED presented higher S-COMT activity in erythrocytes, which is in agreement with previous studies on the literature addressing the high-activity COMT allele, Val158, as risk factor for eating disorders. Although in fluoxetine-treated patients with BN the activity of S-COMT was similar to the controls, this is not explained by a direct interaction between fluoxetine and S-COMT as verified in in vitro assays.

Endothelial function, folate pharmacogenomics, and neurocognition in psychotic disorders

Cardiovascular disease (CVD) is a well-described complication of schizophrenia, however, mechanisms connecting CVD with other facets of psychotic disorders, such as neurocognition, are not understood. The current study examined folate metabolism as a potential mechanism of CVD and neurocognitive deficits by: 1) using endothelial dysfunction as a biomarker of CVD, and 2) comparing enzymes associated with neurocognition, CVD, and critical to folate metabolism, methylenetetrahydrofolate reductase (MTHFR) and catechol-o-methyl transferase (COMT). Endothelial function was assessed in 147 participants with schizophrenia, schizoaffective disorder, and psychotic disorder not otherwise specified grouped by MTHFR and COMT allele status. Regression models were used to compare neurocognitive performance based on the Brief Assessment of Cognition in Schizophrenia (BACS). Overall, endothelial function predicted BACS composite z-scores after controlling for age, race, level of education, serum folate levels, and MTHFR/COMT risk allele status. Participants with at least one or more MTHFR and/or COMT risk alleles had lower BACS Composite and BACS Symbol Coding adjusted mean z-scores than those with both MTHFR CC and COMT Met/Met genotypes. Thus, endothelial dysfunction may contribute to the neurocognitive deficits seen in psychotic disorders. CVD interventions may not only reduce CVD-related morbidity, but also lessen progressive neurocognitive deficits reported in psychotic disorders.

Association of COMT and TPH-2 genes with DSM-5 based PTSD symptoms

BackgroundDopaminergic and serotonergic systems have been implicated in PTSD. The present study evaluated the association of four catechol-O-methyltransferase (COMT) gene loci, and the joint effect of COMT and tryptophan hydroxylase 2 (TPH2) genes on PTSD symptoms. MethodsSubjects included 200 Caucasian Armenian adults exposed to the 1988 Spitak earthquake from 12 multigenerational (3–5 generations) families. Instruments used included the UCLA PTSD Reaction Index based on DSM-5 criteria, and the Beck Depression Inventory. ResultsThe adjusted heritabilitiy of vulnerability to DSM-5 based PTSD symptoms was 0.60 (p<10−4). There was a significant association of the COMT allele rs4633C with total PTSD (p<0.03), and D category (p<0.04) (negative alterations in cognitions and mood) severity scores, but not with C category (avoidance) scores. There was no genetic correlation between C and D category severity scores. COMT allele rs4633C and the TPH-2 allele rs11178997T together accounted for 7% of the variance in PTSD severity scores (p<0.001). None of the COMT alleles were associated with depression. LimitationsThe ratings of earthquake exposure and prior trauma may have been subject to recall bias. The findings may not be generalizable to other ethnic/racial populations. ConclusionCOMT allele rs4633C may be causally related and/or is in linkage disequilibrium with gene(s) that are causally related to PTSD symptoms. Carriers of these COMT and the TPH-2 alleles may be at increased risk for PTSD. The findings provide biological support for dividing DSM-IV category C symptoms into DSM-5 categories C and D.

Association study of two steroid biosynthesis genes (COMT and CYP17) with Alzheimer's disease in the Italian population

The greater predisposition of women to Alzheimer's disease (AD), owing to the decrease in postmenopausal estrogen, may be influenced by polymorphic variation in genes regulating estrogen metabolism (e.g., COMT) and estrogen biosynthesis (e.g., CYP17). In order to better understand how the estrogen pathway genetic variation might affect AD onset, we conducted a case–control study of two single nucleotide polymorphisms (SNPs) of these two genes (COMT rs4680 and CYP17 rs743572) in a sample of AD patients of Italian origin. The COMT allele and genotype were found associated neither with AD onset nor with parameters of AD severity, such as cognitive impairment, age at onset, or disease duration. In contrast, CYP17 was found to affect the age at disease onset mainly in males and, as compared with noncarriers, people carrying the A2 (C) allele had a 2.2-fold increased risk for AD. These findings suggest that the CYP17 A2 allele influences AD susceptibility in a sex-specific way by acting not only on AD risk but also on the age at disease onset, an important parameter of AD severity.

Preliminary investigation of the influence of dopamine regulating genes on social working memory

Working memory (WM) refers to mental processes that enable temporary retention and manipulation of information, including information about other people (“social working memory”). Previous studies have demonstrated that nonsocial WM is supported by dopamine neurotransmission. Here, we investigated in 131 healthy adults whether dopamine is similarly involved in social WM by testing whether social and nonsocial WM are influenced by genetic variants in three genes coding for molecules regulating the availability of dopamine in the brain: catechol-O-methyltransferase (COMT), dopamine active transporter (DAT), and monoamine-oxidase A (MAOA). An advantage for the Met allele of COMT was observed in the two standard WM tasks and in the social WM task. However, the influence of COMT on social WM performance was not accounted for by its influence on either standard WM paradigms. There was no main effect of DAT1 or MAOA, but a significant COMT x DAT1 interaction on social WM performance. This study provides novel preliminary evidence of effects of genetic variants of the dopamine neurotransmitter system on social cognition. The results further suggest that the effects observed on standard WM do not explain the genetic effects on effortful social cognition.

COMT polymorphism influences decrease of ovarian follicles and emerges as a predictive factor for premature ovarian insufficiency.

BackgroundEstrogens are important factors in the female reproductive functions and are processed by a number of enzymes along their metabolic pathway. The COMT gene constitutes a crucial element in estrogen metabolism and is assumed to be involved in the development of Premature Ovarian Insufficiency (POI). This study aimed to determine whether the presence of the COMT Val/Met polymorphism (rs4680) is associated to the risk of developing POI.FindingsIn this case–control study, we evaluated 96 infertile women with POI and 120 fertile women as controls, after obtaining a detailed history of the disease and follicle-stimulating hormone measurements, besides karyotype determination and fragile-X premutation syndrome investigation. COMT (Val/Met) genotypes were identified by real time PCR (genotyping TaqMan assay), and the results were statistically analyzed. A statistically significant difference was found in the distribution of COMT genotypes (p = 0.003) and alleles (p = 0.015) between the POI patients and the control group.ConclusionWe were able to demonstrate a strong association between the COMT Val/Met polymorphism and the risk of premature ovarian insufficiency in the Brazilian women evaluated. However, further studies in larger populations are necessary to confirm these findings.

Polymorphisms of COMT Val158Met and DAT1 3′-UTR VNTR in Illicit Drug Use and Drug-Related Psychiatric Disorders

To investigate the involvement of COMT Val158Met and DAT1 3′-UTR VNTR genotypes in the pathogenesis of illicit drug use and drug-induced psychotic disorders (DIP), 187 substance users and 386 normal controls were recruited from Northern Taiwan. Substance users and normal controls significantly differed in allele frequencies of COMT Val158Met (p = 0.039) but not in allele frequencies of DAT1 3′-UTR VNTR (p = 0.879). However, neither allele frequencies of COMT Val158Met nor allele frequencies of DAT1 3′-UTR VNTR were associated with DIP. The findings should be confirmed in further studies of a larger sample size and a more homogenous patient group.

The association study between polymorphisms of catechol-O-methyltransferase gene and major depressive disorder

Objective To explore the association between catechol-O-methyltransferase (COMT) Val158Met gene (rs4680) polymorphisms and major depressive disorder (MDD) in Han Chinese. Methods Genotypes and allele frequencies of Val158Met polymorphisms of COMT gene were examined in 250 patients and 300 healthy controls by the method of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). t-test, Hardy Weinberg equilibrium and chi-square test were used to conduct statistical analysis. Results There were significant differences between patients and control group in COMT Val158Met genotypes and allele frequency distribution (χ2=20.268, 12.611, P<0.01). Subjects with Met allele had a higher risk than those with Val allele to develop MDD (OR=1.725, 95%CI 1.274-2.335). Conclusion This research suggests that COMT Val158Met polymorphisms are associated with the onset of MDD. Met allele is a risk factor of MDD. Key words: Major depressive disorder; Catechol-O-methyltransferase; Gene polymorphism

Effect of COMT Val158Met genotype on attention and response to methylphenidate following traumatic brain injury

Primary objective: To investigate whether COMT Val158Met allele status was associated with (i) attentional performance and (ii) response to methylphenidate (MP) following traumatic brain injury (TBI).Methods: Forty healthy controls and 32 patients with moderate–severe TBI (Mean time post-injury = 68 days) completed a baseline cognitive assessment. The TBI cohort then participated in a randomized, cross-over, double blind, placebo controlled 2-week MP trial. MP was administered at 0.3 mg/kg twice daily. TBI genotype distribution: val/val n = 11; val/met n = 14; met/met n = 7.Results: There were no significant differences across genotypes on baseline attentional measures. When compared with controls, the val/val group performed significantly more poorly on most measures. The met/met group performed more poorly than controls on measures of speed, but not in strategic control of attention. MP resulted in faster speed of information processing. Repeated measures mixed ANOVAs found only one significant drug × genotype interaction: (F(2,29) = 4.257, p = 0.024) the met/met group demonstrated a greater response to MP on the Symbol Digit Modalities Test.Conclusions: COMT allele status was not strongly associated with attentional performance or response to MP in the TBI sample. The met/met group, whilst performing slowly, had relatively preserved strategic control of attention.

Correlation of the COMT Val158Met polymorphism with latitude and a hunter-gather lifestyle suggests culture–gene coevolution and selective pressure on cognition genes due to climate

Dual-inheritance theory posits that the genotype has an impact on the evolution of human behavior and that cultural traits can be constrained by genetic imperatives. A large body of studies pro- vides evidence that the functional catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with executive function, working memory (WM), and intelligence. A survey of the popu- lation genetics database provides evidence that COMT gene frequencies vary across populations. The aim of the present study was to test the hypothesis that the COMT gene has an impact on cultural evo- lution, specifically on the adoption of an agricultural vs. a hunter-gatherer lifestyle. Statistically sig- nificant differences in COMT allele frequencies between hunter-gatherer and agricultural societies were found. Ethnic groups whose economy is based on farming have higher frequencies of the Met allele (symbol: A), whereas societies based on a hunter-gatherer economy have very low frequencies of the Met allele and a disproportionate predominance of the Val allele. Moreover, the frequency of the Met allele was positively correlated to the populations' IQ (r = 0.57). The FNBP1L gene (rs236330) is associated with childhood and adult intelligence and it varies in frequency across popu- lations. Frequency of rs236330 was also significantly correlated with the populations' IQ (r = 0.81). COMT and FNBP1L had fairly similar geographical distributions (r = 0.44) although the result did not reach statistical significance. The results suggest that the genotype of a population influences its cul- tural development in fairly specific and predictable ways. Met allele frequency was positively corre- lated with latitude (r = 0.56), suggesting selective pressure due to climate.

Polymorphism of catechol-o-methyltransferase and uterine leiomyoma

Uterine leiomyoma (ULM) is the most common gynecological benign tumor that is affecting around 20-50 % of women over the age of 30. Although its molecular pathogenesis is still unknown, ULM has a multifactorial etiology determined by both genetics and environmental factors. The present study was designed to find out whether Val158Met polymorphism in the catechol-o-methyltransferase (COMT) gene is associated with the risk of ULM. We analyzed COMT Val158Met polymorphism in 105 ULMs patients and 105 healthy subjects using a polymerase chain reaction-based restriction fragment length polymorphism assay. We found remarkably similar frequencies in ULM compared with controls for COMT Val158Met genotypes and alleles, and no association was found between ULM and this polymorphism (p = 0.46). The COMT 158 Met allele in patients with large (≥5 cm) fibroids was higher than in patients with small (<5 cm) fibroids, and significant association was found between fibroid size and COMT 158 Met allele (p = 0.011, OR 0.50, 95 %CI 0.28-0.90). Our results reflect that COMT Val158Met polymorphism is not associated with an increased risk of ULMs, but Val158Met polymorphism may be a risk factor for development of large fibroids in Turkish patients with ULM.

Dopamine-system genes, childhood abuse, and clinical manifestations in women with Bulimia-spectrum Disorders

ObjectiveWe explored interaction effects involving polymorphisms of targeted dopamine system genes and selected forms of childhood abuse (sexual, physical and emotional) acting upon severity of binge-eating and psychopathological symptoms in women with Bulimia-Spectrum Disorders (BSDs). MethodsWomen diagnosed with a BSD (n = 216) were assessed for childhood traumata, eating-disorder (ED) symptoms, and selected psychopathological features (sensation seeking, impulsivity, compulsivity and affective instability), and then provided blood samples for genotyping of main polymorphisms of dopamine-2 receptor (DRD2), dopamine transporter (DAT1) and catechol o-methyltransferase (COMT) genes. ResultsSensation Seeking was elevated in carriers of the low-function allele of the DRD2 Taq1A polymorphism who also reported childhood sexual abuse, relative to that in individuals showing other combinations of alleles and abuse exposures. In addition, carriers of a low-function allele of COMT scored higher on compulsivity, lower on impulsivity, and marginally lower on frequency of binge-eating than did individuals in whom the allele was absent. DiscussionOur results suggest that genes acting within the dopamine system may contribute, either directly or indirectly (i.e., in interaction with traumatic childhood experiences), to variations in the presentation of comorbid traits and, possibly, of bulimic symptoms.

COMT polymorphisms as predictors of cognitive dysfunction during manic and mixed episodes in bipolar I disorder

The dopaminergic system plays an important role in the prefrontal cortex (PFC) and is believed to mediate cognitive dysfunction (CD) in bipolar disorder (BD). The enzyme catechol-O-methyltransferase (COMT) is involved in the catabolism of dopamine in the PFC, and an association between COMT single nucleotide polymorphisms (SNPs) and BD has been reported. COMT SNPs have also been associated with executive and working memory performance in healthy subjects, patients with schizophrenia, and euthymic BD patients. The objective of this study was to investigate the association between COMT SNPs and acute CD during BD mood episodes. Seventy-two symptomatic, medication-free subjects with bipolar I disorder (BD-I) and 76 healthy controls were evaluated using neuropsychological tests, and genotyped for COMT SNPs rs4680 and rs165599. Patients undergoing mania and mixed episodes carrying the COMT allele G had better performance on executive function, memory, verbal fluency, and intelligence tests. Moreover, an interaction was detected between the COMT allele G and the Young Mania Rating Scale in BD CD. Allele G from COMT SNPs rs4680 and rs165599 may represent reliable state-dependent predictors of global CD during manic and mixed episodes in BD. Further studies in larger samples are necessary to confirm these findings.

Association Between Val158Met Functional Polymorphism in the COMT Gene and Risk of Preeclampsia in a Chinese Population

The catechol-O-methyltransferase (COMT) gene is a potential candidate in altering risk for preeclampsia due to the important enzymatic effects in the metabolism of steroid hormones. It contains a non-synonymous G-A base change at codon 158 in the membrane bound isoform, which leads to a valine-to-methionine amino acid substitution. In the soluble isoform the polymorphism rs4680 is located in codon 108. The variant allele is the Met (A) allele and the Val (G) allele is the wild type allele. Despite its previously reported association with preeclampsia in genotypes in three selected ethnic groups, further studies in other populations are required. We genotyped the Val158Met polymorphism in the COMT gene by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) analysis in a Chinese population. In the case-control study that included 187 patients with preeclampsia (cases) and 189 normal subjects (controls), the AA genotype and variant Met allele frequencies of Val158Met in the COMT gene were significantly higher in patients with preeclampsia than those in the control group (both p <0.05). The odds ratio for the risk of preeclampsia was 2.395 [95% confidence interval (CI): 1.061-5.408] in women homozygous for the variant COMT allele (χ(2) = 4.649, p = 0.031). Furthermore, it showed that obese women homozygous for the variant COMT allele (Met/Met) had higher diastolic blood pressure levels during pregnancy than wild-type homozygotes (Val/Val) (p = 0.034). Our study provided evidence in favor of COMT being a candidate gene for conferring genetic susceptibility to preeclampsia in a South West Chinese population.

Original article Association of monoamine oxidase B and catechol-O-methyltransferase polymorphisms with sporadic Parkinson’s disease in an Iranian population

Genetic polymorphisms have been shown to be involved in dopaminergic neurotransmission. This may influence susceptibility to Parkinson's disease (PD). We performed a case-control study of the association between PD susceptibility and a genetic polymorphism of MAOB and COMT, both separately and in combination, in Iranians. The study enrolled 103 Iranian patients with PD and 70 healthy individuals. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) methods were used for genotyping. Our data indicated that the MAOB genotype frequencies in PD patients did not differ significantly from the control group. However, the frequency of MAOB GG genotype was significantly lower in female patients. It has been shown that the distribution of MAOB allele A was slightly higher in PD patients. No statistically significant differences were found in the COMT allele and genotype distribution in PD patients in comparison to the controls. The combined haplotype of the MAOB A, A/A and COMT LL genotype showed a slight increase in the risk of PD in female patients in this Iranian population. The data may suggest that the MAOB and COMT genetic polymorphisms do not play any role in the pathogenesis of PD in Iranians. In addition, the combined haplotype of MAOB and COMT genes did not significantly affect the susceptibility to PD. Future studies involving larger control and case populations will undoubtedly lead to a more thorough understanding of the role of the polymorphisms involved in the dopamine pathway in PD.

Higher FKBP5, COMT, CHRNA5, and CRHR1 allele burdens are associated with PTSD and interact with trauma exposure: implications for neuropsychiatric research and treatment

ObjectiveThe study aim was to assess the cumulative burden of polymorphisms located within four genetic loci previously associated with posttraumatic stress disorder (PTSD) among outpatients at risk for PTSD.MethodsDiagnostic interviews were completed and DNA samples collected among 412 pain patients to determine if FKBP5 (rs9470080), COMT (rs4680), CHRNA5 (rs16969968), and CRHR1 (rs110402) single nucleotide polymorphisms were cumulatively associated with increased risk for PTSD.ResultsIn bivariate analyses, it was found that a count of specific PTSD risk alleles located within FKBP5, COMT, CHRNA5, and CRHR1 genetic loci (allele range = 0–6, mean count = 2.92, standard deviation = 1.36) was associated with lifetime (t [409] = 3.430, P = 0.001) and early onset PTSD (t [409] = 4.239, P = 0.000028). In logistic regression, controlling for demographic factors, personality traits, and trauma exposures, this risk allele count remained associated with both lifetime (odds ratio = 1.49, P = 0.00158) and early onset PTSD (odds ratio = 2.36, P = 0.000093). Interaction effects were also detected, whereby individuals with higher risk allele counts and higher trauma exposures had an increased risk of lifetime PTSD (allele count × high trauma, P = 0.026) and early onset PTSD (allele count × high trauma, P = 0.016) in these logistic regressions. Those with no or few risk alleles appeared resilient to PTSD, regardless of exposure history.ConclusionA cumulative risk allele count involving four single nucleotide polymorphisms located within the FKBP5, COMT, CHRNA5, and CRHR1 genes are associated with PTSD. Level of trauma exposure interacts with risk allele count, such that PTSD is increased in those with higher risk allele counts and higher trauma exposures. Since the single nucleotide polymorphisms studied encompass stress circuitry and addiction biology, these findings may have implications for neuropsychiatric research and treatment.

Nicotine normalizes event related potentials in COMT-Val-tg mice and increases gamma and theta spectral density.

Regulation of dopamine neurotransmission is essential for cognitive processes. In humans and rodents, the relationship between dopamine signaling and cognitive performance is described as a dose-dependent, inverted-U curve whereby excess or insufficiency of dopamine in prefrontal cortex has detrimental effects. Previous studies have indicated that prefrontal dopamine levels are associated with genetic variation in catechol-O-methyltransferase (COMT), a regulatory enzyme that controls dopamine availability. Furthermore, smokers who carry the high-activity COMT-Val allele are more prone to cognitive deficits and have an increased risk of smoking relapse. The present study employed transgenic mice expressing the human COMT-Val variant to determine the effects of the high-activity COMT allele on electrophysiological markers, including the P20, N40, and P80 components of the auditory event-related potential, as well as baseline and auditory event-related power and phase-synchrony in theta and gamma ranges. We also examined the effects of nicotine on these measures to investigate the potential effects of smoking on COMT-mediated electrophysiological activity. COMT-Val-tg mice displayed increased N40 latency and decreased P80 amplitude as well as reduced baseline theta and gamma power. Nicotine increased P20 and P80 amplitudes, decreased N40 amplitude, increased P20 and N40 latencies, and reduced P80 latency. Nicotine also increased the event-related power and phase synchrony, yielding an increase in signal-to-noise ratio across theta and gamma ranges. COMT activity specifically alters long-latency components of the event-related response. Nicotine restored normal event-related activity among COMT-Val-tg mice, suggesting one mechanism through which nicotine may normalize cognitive function among people with the high-activity allele.