catechol-O-methyltransferase Val158Met Polymorphism Research Articles

The Catechol-O-Methyltransferase (COMT) val158met Polymorphism Affects Brain Responses to Repeated Painful Stimuli

Despite the explosion of interest in the genetic underpinnings of individual differences in pain sensitivity, conflicting findings have emerged for most of the identified “pain genes”. Perhaps the prime example of this inconsistency is represented by catechol-O-methyltransferase (COMT), as its substantial association to pain sensitivity has been reported in various studies, but rejected in several others. In line with findings from behavioral studies, we hypothesized that the effect of COMT on pain processing would become apparent only when the pain system was adequately challenged (i.e., after repeated pain stimulation). In the present study, we used functional Magnetic Resonance Imaging (fMRI) to investigate the brain response to heat pain stimuli in 54 subjects genotyped for the common COMT val158met polymorphism (val/val = n 22, val/met = n 20, met/met = n 12). Met/met subjects exhibited stronger pain-related fMRI signals than val/val in several brain structures, including the periaqueductal gray matter, lingual gyrus, cerebellum, hippocampal formation and precuneus. These effects were observed only for high intensity pain stimuli after repeated administration. In spite of our relatively small sample size, our results suggest that COMT appears to affect pain processing. Our data demonstrate that the effect of COMT on pain processing can be detected in presence of 1) a sufficiently robust challenge to the pain system to detect a genotype effect, and/or 2) the recruitment of pain-dampening compensatory mechanisms by the putatively more pain sensitive met homozygotes. These findings may help explain the inconsistencies in reported findings of the impact of COMT in pain regulation.

Catechol‐O‐methyltransferase Val158Met and the risk of dyskinesias in Parkinson's disease

The A-allele of the catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with decreased enzymatic activity and higher dopamine availability. We studied 219 patients with PD who were free of dyskinesias at baseline and underwent thorough annual examinations. The A-allele of the COMT Val158Met polymorphism was related to an increased risk of developing dyskinesias during follow-up, in a dose-dependent manner (adjusted hazard ratios for the AG and AA genotypes [compared to GG]: 2.09 [95% confidence interval (CI), 1.07-4.06] and 2.81 [CI, 1.43-5.54], respectively). This finding suggests that genetic factors may affect susceptibility to dyskinesias in PD.

Serotonin-2a receptor and catechol-O-methyltransferase polymorphisms in panic disorder

Catechol-O-methyltransferase (COMT) and serotonin receptor 2A (5HTR2A) polymorphisms have been investigated for their possible role in panic disorder (PD). The aim of this study was to investigate the genotype distribution of the COMT val158met and 5HTR2A 102T/C polymorphisms in PD. COMT val158met is a polymorphism at codon 158 that results in variations in COMT enzymatic activity with high- (H) and low-activity (L) alleles. The 5HTR2A 102T/C polymorphism comprises a T-to-C mutation at position 102. The effects of symptom severity, gender, and age of onset were also investigated. The participants were 105 outpatients with PD and 130 controls. The severity of the symptoms of PD was assessed by the Panic and Agoraphobia Scale (PAS). Polymorphisms of the 5HTR2A and COMT genes were identified using polymerase chain reaction and restriction fragment length polymorphism analysis. A significant relationship was found between the COMT Val158Met polymorphism and PD. No significant differences were found in genotype distributions or allele frequencies of the 5HTR2A polymorphisms between the PD and control groups. There were no significant relationships between the COMT and 5HTR2A polymorphisms and age of onset, gender, presence of agoraphobia, or PAS scores in the PD group (p>0.05).

Influence of Serotonin Transporter Genotype and Catechol-O-Methyltransferase Val158Met Polymorphism on Recognition of Emotional Faces

Monoamines, such as serotonin, dopamine, and norepinephrine, play a crucial role in the regulation of emotion processing and mood. In this study, we investigated how polymorphisms of the serotonin transporter (5-HTT) and catechol-O-methyltransferase (COMT) influence emotion recognition abilities. We recruited 88 female undergraduate students and assessed 5-HTT genotype and the COMT Val158Met polymorphism. The subjects completed two computerized tasks: The Penn Emotion Recognition Test (ER40) and the Penn Emotion Acuity Test (PEAT). For the ER40, we found that s-allele carriers performed significantly worse in the recognition of happy faces, but did better in the recognition of fearful faces, compared with homozygous l-carriers of the 5-HTT gene. Neither 5-HTT nor COMT genotypes influenced the ability to discriminate between different intensities of sadness or happiness on the PEAT. Moreover, there was no significant interaction between the two polymorphisms in their effect on performance on the ER40 or the PEAT.

Influence of brain-derived neurotrophic factor and catechol O-methyl transferase polymorphisms on effects of meditation on plasma catecholamines and stress

Meditation may show differential effects on stress and plasma catecholamines based on genetic polymorphisms in brain-derived neurotrophic factor (BDNF) and catechol O-methyl transferase (COMT). Eighty adults (40 men, 40 women; mean age 26 years) who practiced meditation regularly and 57 healthy control adults (35 men, 22 women; mean age 26 years) participated. Plasma catecholamines (norepinephrine (NE), epinephrine (E), and dopamine (DA)) concentrations were measured, and a modified form of the Stress Response Inventory was administered. The results were analyzed using two-way analysis of covariance (ANCOVA) with control and meditation subjects, gene polymorphism as factors, and meditation duration as the covariate. Two-way ANCOVA showed a significant interaction between control and meditation subjects, and BDNF Val66Met polymorphism on DA/NE+DA/E (p = 0.042) and NE/E+NE/DA (p = 0.046) ratios. A significant interaction was found for control and meditation subjects with COMT Val158Met polymorphism and plasma NE concentrations (p = 0.009). Post hoc ANCOVA in the meditation group, adjusted for meditation duration, showed significantly higher plasma NE concentrations for COMT Met carriers than COMT Val/Val subjects (p = 0.025). Significant differences of stress levels were found between the control and meditation subjects in BDNF Val/Met (p < 0.001) and BDNF Met/Met (p = 0.003), whereas stress levels in the BDNF Val/Val genotype did not differ between the control and meditation groups. This is the first evidence that meditation produces different effects on plasma catecholamines according to BDNF or COMT polymorphisms.

Catechol-O-methyltransferase (COMT) Val158Met polymorphism and risk of osteoporotic fracture

Catechol-O-methyltransferase (COMT) is an estrogen degrading enzyme. The COMT Val158Met polymorphism is associated with bone mineral density. The aim of this study was to investigate associations between COMT Val158Met and osteoporotic fractures in Chinese Han patients. Case-control study of 320 patients with osteoporotic fractures and 320 healthy controls were conducted. The COMT Val158Met polymorphism was analyzed by polymerase chain reaction-restriction fragment length polymorphism assay. Patients with osteoporotic fracture had a significantly lower frequency of Val/Val genotype [odds ratio (OR) = 0.62, 95% confidence interval (CI) 0.39-0.99, P = 0.04] than controls. When stratified by the fracture type, there was a significantly lower frequency of Val/Val genotype in patients with vertebral fracture (OR = 0.58, 95% CI 0.36-0.94, P = 0.03) than controls. There was no significant difference in the distribution of each genotype between patients with hip fracture and the control group. Our findings suggest that COMT Val/Val genotype was associated with a lower risk of osteoporotic fracture in Chinese population, especially to vertebral fracture.

Catechol-O-Methyltransferase Genotype Is Associated with Self-Reported Increased Heart Rate Following Caffeine Consumption

Rationale: The mechanisms underlying the various acute effects of caffeine are not clear. Some of the physiological effects of caffeine may be mediated through increased catecholamines, which are metabolized by catechol-O-methyltransferase (COMT). A Val158Met polymorphism in COMT affects enzyme activity with Val/Val homozygotes having a 3–4-fold greater activity than Met/Met homozygotes. Objective: To determine whether the self-reported acute effects of caffeine are associated with the COMT Val158Met polymorphism (rs4680). Methods: Subjects were men (n=344) and women (n=801) aged 20–29 years who were participants of the Toronto Nutrigenomics and Health Study. Acute effects were assessed by questionnaire, and caffeine intake was assessed using a semiquantitative food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to determine if the likelihood of reporting an acute effect was associated with COMT genotype. Results: Among individuals consuming more than 200 mg/da...

Association of MAOA and COMT gene polymorphisms with palatable food intake in children

Several studies have implicated dopamine (DA) in appetite regulation. The enzymes catechol-o-methyltransferase (COMT) and monoamine oxidase A (MAOA) control DA availability and their genes have well-characterized functional variants. In this study, we examined three polymorphisms in these genes, T941G and MAOAu-VNTR in the MAOA gene and Val158Met in the COMT gene, to investigate how heritable variations in enzymes that determine DA levels might influence food intake and nutritional status. This investigation was a cross-sectional examination of 354 Brazilian children of three to four years old. Polymorphisms were analyzed by PCR-based methods. Means of dietary and anthropometric data were compared among genotypes by one-way analyses of variance or Kruskal Wallis tests. The MAOAu-VNTR and COMT Val158Met polymorphisms were associated with the amount of palatable food intake in boys. Presence of the MAOAu-VNTR⁎long allele was associated with higher intake of lipid-dense foods (LDF) when compared with the ⁎short allele (P=.009); the amount of sugar-dense foods (SDF) intake was also higher in males carriers of the MAOAu-VNTR⁎long allele than in carriers of the ⁎short allele (P=.034). In the girls' sample, MAOAu-VNTR polymorphism was not associated with food intake and nutritional status. Carriers of the COMT Val158Met⁎Val allele presented higher intake of LDF when compared with Met/Met homozygotes (P=.008). This study provides the first indication that genetic variants of enzymes that control DA availability might be involved in determination of the amount of palatable food intake in children.

No association between the Catechol-O-Methyltransferase (COMT) val158met polymorphism and cognitive improvement following cognitive remediation therapy (CRT) in schizophrenia

Cognitive deficits are rate limiters on recovery in schizophrenia that respond poorly to pharmacotherapy. Cognitive remediation therapy (CRT), a novel psychological therapy, has produced promising outcomes for cognition. However, little is known about the biological mechanisms that might underlie individual differences in CRT response. Catechol-O-Methyltransferase ( COMT) is associated specifically with prefrontal cognition. The COMT Val158Met polymorphism is known to have a functional effect on the rate of dopamine degradation, which may be related to cognitive treatment response. This study aimed to determine whether COMT genotype influences cognitive improvement following CRT in schizophrenia. Participants with schizophrenia were recruited from three randomised controlled trials of CRT compared to treatment as usual, and one CRT treatment only trial, each providing 40 CRT sessions. Eighty-seven participants (40%) agreed to participate in the genetic study, and provided DNA for COMT genotyping. Cognitive function and psychopathology were assessed at baseline, post-treatment and 3–6-month follow-up. People with the COMT Val/Met genotype performed more poorly on categories achieved at baseline on the Wisconsin Card Sorting Test (WCST) than those homozygous for the Val or Met allele. Cognitive function improved with CRT but there was no association between this cognitive improvement and COMT genotype, either in the CRT group or in the total sample. The COMT val158Met polymorphism does not appear to be a clinically useful biomarker of cognitive improvement following CRT in schizophrenia. A complex set of factors may influence cognitive change, however, such that the COMT genotype might still have a subtle effect on response to CRT or similar interventions.

Keine Assoziation zwischen Alexithymie und dem Catechol-O-Methyltransferase Val158Met-Polymorphismus

Reduced concentrations of dopamine in prefrontal brain structures may play a role in alexithymia. Dopamine degradation in the orbitofrontal cortex is regulated by catechol-O-methyltransferase (COMT), and a functional single nucleotide polymorphism of the COMT gene, Val158Met, has been related to psychiatric illness. This study examines the association between the COMT Val158Met gene polymorphism, and alexithymia. 120 healthy students and 120 patients with mental disorders were genotyped for the COMT Val158Met polymorphism. Additionally, the Toronto Alexithymia Scale (TAS-20) was administered. COMT genotype did not show a significant correlation with the TAS-20 in either group. COMT Val158Met polymorphism alone does not seem to be a major factor in alexithymia in healthy students. This is true even if patients with mental disorders covering a broader range of alexithymia are included. Thus, other genes, possibly interacting with cultural, environmental, and developmental factors, may be implicated.

Gender Effect of Catechol-O-Methyltransferase Val158Met Polymorphism on Suicidal Behavior

Genetic factors and catecholaminergic dysfunction have been suggested as the etiology of suicide. The catechol-O-methyltransferase (COMT) 158Val/Met polymorphism affects COMT activity; that is, the alleles encoding Val and Met are associated with relatively high and relatively low COMT activity, respectively. We aimed to identify the role of the COMT Val158Met polymorphism in suicidal attempt behavior. The COMT 158Val/Met polymorphisms were analyzed in 197 suicide attempters (male/female: 70/127), 170 control subjects (male/female: 85/85). All subjects were ethnic Korean. The Lethality Suicide Attempt Rating Scale (LSARS) and risk-rescue rating (RRR) system were explored. For the male subjects, there was a significant difference in genotype distributions and allele frequencies between control subjects and suicide attempters. That is, Val/Val genotype and Val carriers were more frequent in suicide attempters than in control subjects. For the female subjects, however, no significant difference was shown in genotype distributions and allele frequencies between control subjects and suicide attempters. There were no significant differences in LSARS and RRR according to the genotypes. The distribution of the COMT 158Val/Met polymorphism showed a biologically meaningful difference between control subjects and suicide attempters among the male subjects although selection bias should be considered.

Catechol-O-methyltransferase Val158Met polymorphism in breast cancer risk

We read with great interest in two recent articles about meta-analyses of the association between catechol-Omethyltransferase (COMT) Val158Met polymorphism and breast cancer risk [1, 2]. The study by Ding et al. [1] included 26 case–control studies with 16,693 breast cancer patients and 18,261 healthy controls. The authors found no significant association between COMT Val158Met polymorphism and breast cancer risk in all genetic models in overall, Asian and European populations. After two studies were excluded as their controls genotype frequencies were not in Hardy–Weinberg equilibrium, a marginally significant association with breast cancer risk was observed in European population under a recessive genetic model (Met/ Met vs. Met/Val and Val/Val: odds ratio(OR) = 0.90, 95% confidence interval (CI) 0.90–1.00, P = 0.06). They concluded that COMT Val158Met polymorphism might be a risk factor in the development of breast cancer. Actually, as the authors found a marginally significant decreased breast risk for Met/Met vs Met/Val and Val/Val among Europeans, it should be concluded that COMT Val158Met polymorphism might be a protective factor rather than a risk factor for breast cancer development. If so, the conclusion was fallacious, as it was contrary to the biological view that COMT Met/Met homozygote was usually considered as the risk genotype for breast cancer development. The other one by Mao et al. [2] consisted of 41 studies with 25,627 cases and 34,222 controls. The results suggested that COMT Val158Met polymorphism was not significantly associated with breast cancer risk in all genetic models in both overall and subgroup analyses (by ethnicity or menopausal status). The sensitivity analysis further strengthened their conclusions. The partial discrepancy between two studies drove us to seek the potential reasons. We compared the two studies with each other carefully and found some methodological issues in the study by Ding et al. [1]. First, the authors did not state whether there was a language limitation in the ‘‘Search strategy’’ section. Indeed, recruiting all related published or unpublished studies with no language restriction might be a proper strategy, thereby minimizing the potential language and publication biases. In addition, just searching PubMed database would have omitted many important data, and then caused the estimated effect imprecisely when performing a meta-analysis. Other databases such as EMBASE, ISI web of science, as well as non-English databases, should also be searched to reduce the selection bias. Second, the data presented by Ding et al. were not in accord with those provided by the original publications. The genotypes of Val/Val, Val/Met, and Met/Met in cases and controls should be 68/37/13 and 66/55/4 for the study by Huang et al. [3], 16/64/46 and 13/61/43 for the study by Bergman-Jungestrom et al. [4], 84/156/73 and 58/144/60 for the study by Ahsan et al. [5], 645/1,360/845 and 448/926/534 for the study by Dunning et al. [6], 287/521/ 240 and 277/549/266 for the study by Gaudet et al. [7], 731/1,569/844 and 1,243/2,669/1,569 in the study by MARIE-GENICA et al. [8], 44/82/28 and 52/85/29 for the study by Yadav et al. [9]. The country of origin should be B. Xi (&) W. Liu Institute of Maternal and Child Health Care, School of Public Health, Shandong University, Jinan 250012, China e-mail: xibo2010@sdu.edu.cn

The effects of catechol-O-methyl-transferase polymorphism Val158Met on functional connectivity in healthy young females: A resting EEG study

The catechol-O-methyl-transferase (COMT) gene has been linked to a wide spectrum of human phenotypes, including cognition, affective response, pain sensitivity, anxiety and psychosis. This study examined the modulatory effects of COMT Val158Met on neural interactions, indicated by connectivity strengths. Blood samples and resting state eyes-closed EEG signals were collected in 254 healthy young females. The COMT Val158Met polymorphism was decoded into 3 groups: Val/Val, Val/Met and Met/Met. The values of mutual information of 20 frontal-related channel pairs across delta, theta, alpha and beta frequencies were analyzed based on the time–frequency mutual information method. Our one-way ANOVA analyses revealed that the significant connection–frequency pairs were relatively left lateralized ( P < 0.01) and included F7–T3 and F7–C3 at delta frequency, and F3–F4, F7–T3, F7–C3, F7–P3, F3–C3, F3–F7 and F4–F8 at theta frequency. The F-test at F7–T3 and F7–C3 theta surpassed the statistical threshold of P < 0.003 (after Bonferroni correction). For all the above connection–frequency pairs, there was a dose-dependent trend in the connectivity strengths of the alleles as follows: Val/Val > Val/Met > Met/Met. Our analyses complemented previous literature regarding neural modulation by the COMT Val158Met polymorphism. The implication to the pathogenesis in schizophrenia was also discussed. Further studies are needed to clarify whether there is gender difference on this gene–brain interaction.

COMT Val158Met polymorphism, verbalizing of emotion and activation of affective brain systems

Genetic variation in the catechol-O-methyltransferase (COMT) Val158Met polymorphism has been shown to influence performance on cognitive and emotional tasks. Specifically, it has been suggested that the Met allele might be less advantageous than the Val allele with respect to emotional processing.This study addresses the question whether the presence of the Met allele is directly related to both lower emotional verbalizing proficiency and differences in brain activation during emotional processing. Specifically, we investigated whether COMT genotype would be associated with differences in activation in cortical midline structures during valence evaluation of words.Forty participants ranging from low to high on the verbalizing subscale of the Bermond–Vorst Alexithymia Questionnaire (BVAQ) were genotyped for the COMT Val158Met polymorphism. During fMRI, they evaluated the valence of emotional words.Met homozygotes reported more difficulties in verbalizing their feelings. In addition, the Met allele was associated with attenuated brain activation in posterior cingulate gyrus and precuneus during valence evaluation.We conclude that the Met allele modulates neural activation in regions associated with emotional awareness. Our findings may contribute to understanding the neural correlates of susceptibility for affective disorders.

The interaction between serotonin receptor 2A and catechol-O-methyltransferase gene polymorphisms is associated with the novelty-seeking subscale impulsiveness

Novelty seeking is a trait that has been consistently associated with problem behaviours. There is evidence for heritability of novelty seeking, but the molecular genetic basis of the trait is still widely unclear. The interaction between polymorphisms of catechol-O-methyltransferase (COMT) and serotonin receptor 2A genes was examined in relation to novelty seeking and its different subscales in healthy Finnish adults. A subsample of 1214 participants derived from a population-based sample was genotyped for the COMT Val158Met (rs4680) and HTR2A T102C (rs6313) genes. Novelty seeking was measured twice, with a 4-year interval, using Cloninger's Temperament and Character Inventory. The interaction between COMT Val158Met and HTR2A T102C polymorphisms was found to be associated with subscale impulsiveness. T/T carriers of HTR2A T102C polymorphism, that also had Met/Met genotype of COMT Val158Met single nucleotide polymorphism, scored significantly higher on impulsiveness than Val allele carriers (P=0.005). Our results suggest that the interaction between dopaminergic and serotonergic genes might underlie impulsiveness. Together with earlier research our results also stress the importance of considering novelty seeking as a heterogeneous trait with its subscales having different genetic backgrounds.

Catechol-O-methyltransferase (COMT) val158met Polymorphism as a Risk Factor for PTSD After Urban Violence

PTSD is a psychiatric disorder that requires a traumatic event as diagnostic criteria. Brazil has high rates of violence, and it is expected that urban victims of violence would be at risk to the development of PTSD. Studies have associated the COMT val158met polymorphism with diminished stress resilience, reduced ability to extinguish conditioned fear, and the development of PTSD after multiple traumatic experiences. The aim of this study was to identify, in a case-control study, whether the val158met polymorphism (rs4860) is associated with the development of PTSD in a group of victims of urban violence. To our knowledge, this is the first study that examines the association between PTSD and urban violence. The polymorphism of COMT in PTSD patients (n=65) as well as in victims of violence without PTSD (n=34) and in a community control group (n=335) were genotyped. We found a significant relationship between the met allele (p<0.02) and PTSD among cases (PTSD+)and victims of violence without PTSD (PTSD-; OR 2.57) and between cases and community control group (p<0.003) Further analysis with larger samples and another ethnic group should be necessary to confirm our findings.

Association of polymorphisms in genes involved in the dopaminergic pathway with blood pressure and uric acid levels in Chinese females

Since the high degree of heritability of physiological traits was demonstrated by twin and adoption studies, contemporary researchers in the fields of clinical medicine, behavioral science, and genetics have acknowledged the crucial role of genetic factors in human physiology. The study described herein explores the association between physiological parameters and the dopaminergic system using molecular genetic techniques. A total of 558 Taiwanese female volunteers, ranging from 16 to 17years, were recruited. Single nucleotide polymorphisms in genes involved in the dopaminergic pathway were selected for analysis. Systolic blood pressure and diastolic blood pressure were associated significantly with the catechol-O-methyltransferase (COMT) Val158Met polymorphism and the dopamine β-hydroxylase (DBH) C1021T polymorphism. Furthermore, plasma uric acid was associated significantly with the COMT Val158Met polymorphism. Our study suggests the possible involvement of genetic polymorphisms in COMT and DBH in the regulation of blood pressure and plasma uric acid.

COMT Val158Met polymorphism, cognitive stability and cognitive flexibility: an experimental examination

BackgroundDopamine in prefrontal cortex (PFC) modulates core cognitive processes, notably working memory and executive control. Dopamine regulating genes and polymorphisms affecting PFC - including Catechol-O-Methyltransferase (COMT) Val158Met - are crucial to understanding the molecular genetics of cognitive function and dysfunction. A mechanistic account of the COMT Val158Met effect associates the Met allele with increased tonic dopamine transmission underlying maintenance of relevant information, and the Val allele with increased phasic dopamine transmission underlying the flexibility of updating new information. Thus, consistent with some earlier work, we predicted that Val carriers would display poorer performance when the maintenance component was taxed, while Met carriers would be less efficient when rapid updating was required.MethodsUsing a Stroop task that manipulated level of required cognitive stability and flexibility, we examined reaction time performance of patients with schizophrenia (n = 67) and healthy controls (n = 186) genotyped for the Val/Met variation.ResultsIn both groups we found a Met advantage for tasks requiring cognitive stability, but no COMT effect when a moderate level of cognitive flexibility was required, or when a conflict cost measure was calculated.ConclusionsOur results do not support a simple stability/flexibility model of dopamine COMT Val/Met effects and suggest a somewhat different conceptualization and experimental operationalization of these cognitive components.

The COMT and DRD3 genes interacted in bipolar I but not bipolar II disorder

Objectives. Clarifying the association between bipolar I and bipolar II disorders at the genetic level is essential for improving our understanding of them. In this study, we evaluated the hypothesis that the dopaminergic polymorphisms are risk factors for bipolar disorders. We examined the association between the catechol-O-methyltransferase (COMT) Val158Met and dopamine D3 receptor (DRD3) Ser9Gly polymorphisms and bipolar I and II disorders, as well as possible interactions between these genes. Methods. Seven hundred and eleven participants were recruited: 205 with bipolar I, 270 with bipolar II, and 236 healthy controls. The genotypes of the COMT Val158Met and DRD3 Ser9Gly polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. Results. Logistic regression analyses showed a statistically significant main effect for the Met/Met genotype of the COMT Val158Met polymorphism (P=0.032) and a significant interaction effect for the Met/Met genotype of the COMT Val158Met and Ser/Ser genotypes of the DRD3 Ser9Gly polymorphism (P=0.001) predicted bipolar I patients. However, there was no association between the COMT Val158Met or DRD3 Ser9Gly and bipolar II. Conclusions. We provide initial evidence that the COMT Val158Met and DRD3 Ser9Gly genotypes interact in bipolar I and bipolar II disorders and that bipolar I and bipolar II are genetically distinct.

Effects of modafinil on the sleep EEG depend on Val158Met genotype of COMT.

Modafinil may promote wakefulness by increasing cerebral dopaminergic neurotransmission, which importantly depends on activity of catechol-O-methyltransferase (COMT) in prefrontal cortex. The effects of modafinil on sleep homeostasis in humans are unknown. Employing a novel sleep-pharmacogenetic approach, we investigated the interaction of modafinil with sleep deprivation to study dopaminergic mechanisms of sleep homeostasis. Placebo-controlled, double-blind, randomized crossover study. Sleep laboratory in temporal isolation unit. 22 healthy young men (23.4 +/- 0.5 years) prospectively enrolled based on genotype of the functional Val158Met polymorphism of COMT(10 Val/Val and 12 Met/Met homozygotes). 2 x 100 mg modafinil and placebo administered at 11 and 23 hours during 40 hours prolonged wakefulness. Subjective sleepiness and EEG markers of sleep homeostasis in wakefulness and sleep were equally affected by sleep deprivation in Val/Val and Met/Met allele carriers (placebo condition). Modafinil attenuated the evolution of sleepiness and EEG 5-8 Hz activity during sleep deprivation in both genotypes. In contrast to caffeine, modafinil did not reduce EEG slow wave activity (0.75-4.5 Hz) in recovery sleep, yet specifically increased 3.0-6.75 Hz and > 16.75 Hz activity in NREM sleep in the Val/Val genotype of COMT. The Val158Met polymorphism of COMT modulates the effects of modafinil on the NREM sleep EEG in recovery sleep after prolonged wakefulness. The sleep EEG changes induced by modafinil markedly differ from those of caffeine, showing that pharmacological interference with dopaminergic and adenosinergic neurotransmission during sleep deprivation differently affects sleep homeostasis.