The catechol o‐methyltransferase (COMT) val158met polymorphism modulates the association of serious life events (SLE) and impulsive aggression in female patients with borderline personality disorder (BPD)

Wagner S, Baskaya Ö, Anicker NJ, Dahmen N, Lieb K, Tadi? A. The catechol o‐methyltransferase (COMT) val¹⁵⁸met polymorphism modulates the association of serious life events (SLE) and impulsive aggression in female patients with borderline personality disorder (BPD). Objective: We analyzed i) the effects of serious life events (SLE) on impulsive aggression, and ii) modulating effects of the COMT Val¹⁵⁸Met polymorphism on the association between SLEs and impulsive aggression in borderline personality disorder (BPD). Method: One hundred and twelve female BPD patients from Germany were included in this study. Impulsive aggression was assessed by the Buss‐Durkee‐Hostility Inventory (BDHI). Results: Childhood sexual abuse was associated with lower BDHI sum score (P = 0.003). In COMT Val¹⁵⁸Val carriers, but not in Val/Met and Met/Met carriers, childhood sexual abuse and the cumulative number of SLEs were associated with lower BDHI sum scores (P < 0.05). Conclusion: This study analyzing a specific gene × environment interaction in female BPD patients suggests an association between SLEs and impulsive aggression, as well as a modulating effect of the COMT Val¹⁵⁸Val genotype on the relation between SLEs and impulsive aggression.     

COMT ValMet moderation of cannabis-induced psychosis: a momentary assessment study of 'switching on' hallucinations in the flow of daily life

Objective: A functional polymorphism in the catechol‐o‐methyltransferase gene (COMT Val¹⁵⁸Met) may moderate the psychosis‐inducing effects of cannabis. In order to extend this finding to dynamic effects in the flow of daily life, a momentary assessment study of psychotic symptoms in response to cannabis use was conducted. Method: The experience sampling technique was used to collect data on cannabis use and occurrence of symptoms in daily life in patients with a psychotic disorder (n = 31) and healthy controls (n = 25). Results: Carriers of the COMT Val¹⁵⁸Met Val allele, but not subjects with the Met/Met genotype, showed an increase in hallucinations after cannabis exposure, conditional on prior evidence of psychometric psychosis liability. Conclusion: The findings confirm that in people with psychometric evidence of psychosis liability, COMT Val¹⁵⁸Met genotype moderates the association between cannabis and psychotic phenomena in the flow of daily life.     

Neural correlates of subjective CS/UCS association in appetitive conditioning

Explicit knowledge of conditioned stimulus (CS)/unconditioned stimulus (UCS) associations is proposed as important factor in classical conditioning. However, while previous studies have focused on its roles in fear conditioning, it has been neglected in the context of appetitive conditioning. The present functional magnetic resonance study aimed to investigate neural activation and functional connectivity linked to subjective CS/UCS association in appetitive conditioning. In total, 85 subjects participated in an appetitive acquisition procedure in which a neutral stimulus (CS+) was paired with a monetary reward, while another neutral stimulus (CS‐) was never paired with the reward. Directly afterwards, subjective CS/UCS association was assessed by measuring the extent to which the CS+ was thought to be associated with the UCS compared to the CS‐. Close relationships were established between subjective CS/UCS association and activations in the primary visual cortex (V1) during the early phase of conditioning and in the striatum during the late conditioning phase. In addition, we observed inverse relationships between subjective CS/UCS association and both V1/ventromedial prefrontal cortex (vmPFC) and striatal/vmPFC connectivity. The results suggest the involvement of decoupling vmPFC connectivity in reward learning in general and the roles of attentional processes in the formation of the subjective CS/UCS association during the early phase and reward prediction during the late phase of appetitive conditioning.     

Prefrontal dopamine and the dynamic control of human long-term memory

Dopaminergic projections to the prefrontal cortex support higher-order cognitive functions, and are critically involved in many psychiatric disorders that involve memory deficits, including schizophrenia. The role of prefrontal dopamine in long-term memory, however, is still unclear. We used an imaging genetics approach to examine the hypothesis that dopamine availability in the prefrontal cortex selectively affects the ability to suppress interfering memories. Human participants were scanned via functional magnetic resonance imaging while practicing retrieval of previously studied target information in the face of interference from previously studied non-target information. This retrieval practice (RP) rendered the non-target information less retrievable on a later final test—a phenomenon known as retrieval-induced forgetting (RIF). In total, 54 participants were genotyped for the catechol-O-methyltransferase (COMT) Val^108/158Met polymorphism. The COMT Val^108/158Met genotype showed a selective and linear gene-dose effect on RIF, with the Met allele, which leads to higher prefrontal dopamine availability, being associated with greater RIF. Mirroring the behavioral pattern, the functional magnetic resonance imaging data revealed that Met allele carriers, compared with Val allele carriers, showed a greater response reduction in inhibitory control areas of the right inferior frontal cortex during RP, suggesting that they more efficiently reduced interference. These data support the hypothesis that the cortical dopaminergic system is centrally involved in the dynamic control of human long-term memory, supporting efficient remembering via the adaptive suppression of interfering memories.     

The flexible mind is associated with the catechol-O-methyltransferase (COMT) ValMet polymorphism: Evidence for a role of dopamine in the control of task-switching

Genetic variability related to the catechol-O-methyltransferase (COMT) gene (Val¹⁵⁸Met polymorphism) has received increasing attention as a possible modulator of cognitive control functions. Recent evidence suggests that the Val¹⁵⁸Met genotype may differentially affect cognitive stability and flexibility, in such a way that Val/Val homozygous individuals (who possess low prefrontal dopamine levels) may show more pronounced cognitive flexibility than Met/-carriers (who possess high prefrontal dopamine levels). To test this, healthy humans (n = 87), genotyped for the Val¹⁵⁸Met polymorphism at the COMT gene, performed a task-switching paradigm, which provides a relatively diagnostic index of cognitive flexibility. As predicted, Met/-carriers showed larger switching costs (i.e., less cognitive flexibility), F(1,85) = 4.28, p < 0.05, than Val/Val homozygous individuals. Our findings support the idea that low prefrontal dopamine levels promote cognitive flexibility.     

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

Background  

Dopamine 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.     

Executive attention in schizophrenic males and the impact of COMT Val108/158Met genotype on performance on the attention network test

Background: Executive control of attention in schizophrenia has recently been assessed by means of the Attention Network Test (ANT). In the past, for tasks assessing executive attention, findings in schizophrenia have been contradictory, among others suggesting a lack of increased stimulus interference effects. Attention and executive functioning are substantially influenced by candidate genes of schizophrenia, including the functional single-nucleotide polymorphism catechol-o-methyltransferase (COMT) Val^108/158Met, with task-dependent, specific effects of Met allele load on cognitive function. Therefore, we aimed at investigating executive attention in schizophrenic patients (SZP) as compared with healthy controls (HC), and to assess the specific impact of COMT Val^108/158Met on executive attention, using ANT. Methods: We applied ANT to 63 SZP and 40 HC. We calculated a general linear model to investigate the influence of affection status and the COMT Val^108/158Met genotype on executive attention as assessed by the ANT. Results: Multivariate analysis of variance revealed a significant effect of group on executive attention. SZP exhibited smaller conflict effects in the ANT. Met allele load significantly modulated executive attention efficiency, with homozygous Met individuals showing low overall reaction time but increased effects conflicting stimulus information in executive attention. Conclusions: Our data suggest a disease-related dissociation of executive attention with reduced conflict effects in SZP. Furthermore, they support the hypothesis of differential tonic-phasic dopamine activation and specific dopamine level effects in different cognitive tasks, which helps interpreting contradictory findings of Met allele load on cognitive performance. Disease status seems to modulate the impact of COMT Val^108/158Met on cognitive performance.     

COMT Val158Met polymorphism is related with interpersonal problem solving in schizophrenia

ObjectiveThe aim of this study was to investigate associations between COMT Val¹⁵⁸Met polymorphism, and interpersonal problem solving capacity and cognitive functions in schizophrenia.MethodsCOMT Val¹⁵⁸Met polymorphism was studied with ARMS-PCR method in 99 outpatients with schizophrenia. Brief Psychiatric Rating Scale was used to assess symptom severity. The Assessment of Interpersonal Problem Solving Skills (AIPSS) was used to evaluate problem solving capacity. Continuous Performance Test (CPT) and Wisconsin Card Sorting Test (WCST), were used to measure cognition.ResultsPatients with Met/Met genotype had higher AIPSS subscores for detecting the problem, than those with Val/Val at baseline (p = 0.02). Met allele was also found to be related with higher AIPSS-receiving skills (p = 0.04). Val allele was found to be related with more commission errors in CPT (p = 0.03). There was no relation between Val¹⁵⁸Met polymorphism and WCST and clinical measurements.ConclusionOur findings suggest that Val allele might be related to poor performance on detecting the interpersonal problems, and attention in schizophrenia.     

The 5‐HTTLPR polymorphism is associated with altered hemodynamic responses during appetitive conditioning

Background: Current models suggest that a variation in the promoter region of the serotonin transporter gene (5‐HTTLPR) is associated with altered amygdala reactivity not only towards negative but also towards positive stimuli, which has been neglected in the past. This association may possibly convey an elevated vulnerability for psychopathology like abuse, craving, and relapses. Since appetitive conditioning is a crucial mechanism in the pathogenesis of these psychiatric disorders, the identification of specific factors contributing to interindividual variation is important. Methods: In the present study (N = 86), an appetitive conditioning paradigm was conducted, in which a neutral stimulus (CS+) was associated with appetitive stimuli, while a second stimulus (CS?) predicted their absence. Subjects were genotyped according to the 5‐HTTLPR genotype. Results: As the main result, we report a significant association between the 5‐HTTLPR genotype and hemodynamic responses. Individuals with the s‐allele displayed elevated conditioned bilateral amygdala activity in contrast to l/l‐allele carriers. Further, increased hemodynamic responses in s‐allele carriers were also found in the extended emotional network including the orbitofrontal cortex, the thalamus, and the ventral striatum. Conclusion: The present findings indicate an association of the 5‐HTTLPR and altered conditioned responses in appetitive conditioning. Further, the findings contribute to the ongoing debate on 5‐HTTLPR dependent hemodynamic response patterns by emphasizing that s‐allele carriers are not exclusively biased towards fearful, but also towards positive stimuli. In conclusion, our results imply that s‐allele carriers might be better described as hyper‐reactive towards salient stimuli, which may convey vulnerability for the development of psychiatric disorders. Hum Brain Mapp 34:2549–2560, 2013. © 2012 Wiley Periodicals, Inc.     

COMT genotype affects brain white matter pathways in attention‐deficit/hyperactivity disorder

Increased dopamine availability may be associated with impaired structural maturation of brain white matter connectivity. This study aimed to derive a comprehensive, whole‐brain characterization of large‐scale axonal connectivity differences in attention‐deficit/hyperactivity disorder (ADHD) associated with catechol‐O‐methyltransferase gene (COMT) Val158Met polymorphism. Using diffusion tensor imaging, whole‐brain tractography, and an imaging connectomics approach, we characterized altered white matter connectivity in youth with ADHD who were COMT Val‐homozygous (N = 29) compared with those who were Met‐carriers (N = 29). Additionally, we examined whether dopamine transporter gene (DAT1) and dopamine D4 receptor gene (DRD4) polymorphisms were associated with white matter differences. Level of attention was assessed using the continuous performance test before and after an 8‐week open‐label trial of methylphenidate (MPH). A network of white matter connections linking 18 different brain regions was significantly weakened in youth with ADHD who were COMT Met‐carriers compared to those who were Val‐homozygous (P < 0.05, family‐wise error‐corrected). A measure of white matter integrity, fractional anisotropy, was correlated with impaired pretreatment performance in continuous performance test omission errors and response time variability, as well as with improvement in continuous performance test response time variability after MPH treatment. Altered white matter connectivity was exclusively based on COMT genotypes, and was not evident in DAT1 or DRD4. We demonstrated that white matter connectivity in youth with ADHD is associated with COMT Val158Met genotypes. The present findings suggest that different layers of dopamine‐related genes and interindividual variability in the genetic polymorphisms should be taken into account when investigating the human connectome. Hum Brain Mapp, 36:367–377, 2015. © 2014 Wiley Periodicals, Inc.     

Impact of catechol-O-methyltransferase Val(108/158) Met genotype on hippocampal and prefrontal gray matter volume

A variation in catechol-O-methyltransferase (COMT) gene (Val(108/158)Met) affects the physiological response of hippocampal-prefrontal circuits, predicts variation in human memory and is associated with increased risk for psychiatric disorders. Using optimized voxel-based morphometry we studied the effect of this functional polymorphism on the anatomy of the hippocampus, and the prefrontal cortex. Fifty-seven healthy participants were investigated (nine had Met/Met, 30 Val/Met, and 14 Val/Val). Voxel-based morphometry showed that individuals who are homozygous for the Val-COMT allele had greater gray matter volume of the prefrontal cortex bilaterally, whereas Met-COMT carriers were associated with increased tissue volume of the hippocampus bilaterally. This study provides evidence that the Val(108/158)Met polymorphism of the COMT gene might be responsible for individual variation in the human brain morphology.     

Association between Novelty Seeking of opiate-dependent patients and the catechol-O-methyltransferase ValMet polymorphism

Background

Candidate genes of the dopaminergic system have been reported as key elements in shaping human temperament. Catechol-O-methyltransferase (COMT) plays a vital role in dopamine inactivation, and the Val¹⁵⁸Met single nucleotide polymorphism (rs4680) in its gene has been recently associated with the Novelty Seeking (NS) temperament scale of the Temperament and Character Inventory in studies of healthy adults, as well as methamphetamine abusers.

Method

Our goal was to examine the association between temperament dimensions of the Temperament and Character Inventory and the COMT Val¹⁵⁸Met variation in a Hungarian sample of 117 heroin-dependent patients and 124 nondependent controls.

Results

Case-control analysis did not show any significant difference in allele or genotype distributions. However, dimensional approach revealed an association between the COMT Val¹⁵⁸Met and NS (P = .01): both controls and opiate users with Met/Met genotypes showed higher NS scores compared to those with the Val allele. The NS scores are also significantly higher among opiate users; however, no interaction was found between group status and COMT genotype.

Conclusion

Association of the COMT polymorphism and NS temperament scale has been shown for heroin-dependent patients and controls regardless of group status.     

COMT Val158Met polymorphism influences the susceptibility to framing in decision‐making: OFC‐amygdala functional connectivity as a mediator

Individuals tend to avoid risk in a gain frame, in which options are presented in a positive way, but seek risk in a loss frame, in which the same options are presented negatively. Previous studies suggest that emotional responses play a critical role in this “framing effect.” Given that the Met allele of COMT Val158Met polymorphism (rs4680) is associated with the negativity bias during emotional processing, this study investigated whether this polymorphism is associated with individual susceptibility to framing and which brain areas mediate this gene–behavior association. Participants were genotyped, scanned in resting state, and completed a monetary gambling task with options (sure vs risky) presented as potential gains or losses. The Met allele carriers showed a greater framing effect than the Val/Val homozygotes as the former gambled more than the latter in the loss frame. Moreover, the gene–behavior association was mediated by resting‐state functional connectivity (RSFC) between orbitofrontal cortex (OFC) and bilateral amygdala. Met allele carriers showed decreased RSFC, thereby demonstrating higher susceptibility to framing than Val allele carriers. These findings demonstrate the involvement of COMT Val158Met polymorphism in the framing effect in decision‐making and suggest RSFC between OFC and amygdala as a neural mediator underlying this gene–behavior association. Hum Brain Mapp 37:1880–1892, 2016. © 2016 Wiley Periodicals, Inc .     

Evidence that interactive effects of COMT and MTHFR moderate psychotic response to environmental stress

Peerbooms O, Rutten BPF, Collip D, Lardinois M, Lataster T, Thewissen V, Mafi Rad S, Drukker M, Kenis G, van Os J, Myin‐Germeys I, van Winkel R. Evidence that interactive effects of COMT and MTHFR moderate psychotic response to environmental stress. Objective: A functional interaction between Catechol‐O‐Methyltransferase (COMT) Val158Met and methylenetetrahydrofolate reductase (MTHFR) C677T has been shown to differentially affect cognition in patients with schizophrenia and healthy controls; the effect of COMT Val158Met × MTHFR interaction on resilience to stress in patients and controls remains to be examined. Method: A total of 98 patients with non‐affective psychotic disorder and 118 controls were genotyped for MTHFR C677T, MTHFR A1298C, and COMTVal158Met. Daily life reactivity to stress, modelled as the effect of daily life stress on psychotic experiences, was measured using the experience sampling method (ESM). Results: The MTHFR C677T genotype moderated the interaction between COMT Val158Met genotype and stress in patients (P < 0.0001), but not in controls (P = 0.68). Further examination of this interaction revealed that in patients with the MTHFR 677 T‐allele, COMT Met/Met individuals displayed the largest increases in psychotic symptoms in reaction to ESM stress [χ²(2) = 29.51; P < 0.0001], whereas in patients with the MTHFR 677 C/C genotype no significant COMT Val158Met × ESM stress interaction was apparent [χ²(2) = 3.65; P = 0.16]. No moderating effect of MTHFR A1298C was found. Conclusion: Stress reactivity associated with COMT Val158Met in patients with psychosis may crucially depend on MTHFR C677T genotype.     

Neuroticism and extraversion moderate neural responses and effective connectivity during appetitive conditioning

Classical appetitive conditioning constitutes a basic learning process through which environmental stimuli can be associated with reward. Previous studies showed that individual differences in neuroticism and extraversion influence emotional processing and have been shown to modulate neural activity in subcortical and prefrontal areas in response to emotional stimuli. However, the role of individual differences in appetitive conditioning has so far not been investigated in detail. The aim of this study was to assess the association between neuroticism and extraversion with neural activity and connectivity during appetitive conditioning. The conditioned stimulus (CS) was either a picture of a dish or a cup. One stimulus (CS+) was paired with a monetary reward and the other stimulus (CS?) was associated with its absence while hemodynamic activity was measured by means of functional magnetic resonance imaging. A significant negative correlation of neuroticism scores with amygdala activity was observed during appetitive conditioning. Further, extraversion was positively associated with responses in the hippocampus and the thalamus. In addition, effective connectivity between the amygdala as a seed region and the anterior cingulate cortex, the insula, and the thalamus was negatively correlated with neuroticism scores and positively correlated with extraversion scores. The results may indicate a neural correlate for the deficits in appetitive learning in subjects with high neuroticism scores and point to a facilitating effect of extraversion on reward‐related learning. Hum Brain Mapp 37:2992–3002, 2016. © 2016 Wiley Periodicals, Inc .     

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.     

COMT Val158Met-stress interaction in psychosis: role of background psychosis risk

Background: The interplay between the catechol‐O‐methyltransferase (COMT) Val158Met polymorphism and environmental stress may have etiological relevance for psychosis, but differential effects have been reported in healthy control and patient groups, suggesting that COMT Val158Met interactions with stress may be conditional on background genetic risk for psychotic disorder. Methods: Patients with a nonaffective psychotic disorder (n = 86) and control participants (n = 109) were studied with the experience sampling method (a structured diary technique) in order to assess stress, negative affect and momentary psychotic symptoms in the flow of daily life. Results: Multilevel analyses revealed significant three‐way interactions between group status (patient or control), COMT genotype and stress in the model of negative affect (χ²(2) = 13.26, P < 0.01) as well as in the model of momentary psychotic symptoms (χ²(2) = 6.92, P < 0.05). Exploration of the three‐way interaction revealed that in patients, COMT genotype moderated the association between stress and negative affect (χ²(4) = 11.50, P < 0.005), as well as the association between stress and momentary psychosis (χ²(4) = 12.79, P < 0.005). Met/Met genotype patients showed significantly increased psychotic and affective reactivity to stress in comparison to the Val/Met and Val/Val genotypes. In contrast, healthy controls did not display large or significant COMT Val158Met X stress interactions. Conclusions: Important differences exist in the effect of COMT Val158Met on stress reactivity, which may depend on background risk for psychotic disorder. Differential sensitivity to environmental stress occasioned by COMT Val158Met may be contingent on higher order interactions with genetic variation underlying psychotic disorder.     

Catechol-O-methyltransferase gene and obsessive-compulsive symptoms in patients with recent-onset schizophrenia: preliminary results

The catechol-O-methyltransferase (COMT) gene is a candidate gene for schizophrenia because of its role in the breakdown of dopamine in the prefrontal cortex. The COMT gene contains a functional polymorphism changing enzyme activity that has been associated with some neuropsychiatric (endo)phenotypes, e.g. cognitive performance and anxiety. In this study we investigated the association between the COMT Val(158)Met polymorphism and obsessive-compulsive symptoms in patients with schizophrenia. Severity of obsessive-compulsive symptoms in 77 male patients with recent-onset schizophrenia was assessed using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), and the COMT Val(158)Met polymorphism was genotyped for these patients. We found a significant effect of the COMT genotype on Y-BOCS scores: the Val/Val genotype was associated with the highest Y-BOCS scores, whereas patients with the Met/Met genotype had the lowest Y-BOCS scores. Our data suggest that the COMT high-activity Val allele is associated with more obsessive-compulsive symptoms in young patients with schizophrenia. These results support the hypothesis that the COMT Val(158)Met polymorphism may be a modifier gene for the symptomatology of schizophrenia.     

Catechol O-methyltransferase Val158Met polymorphism is associated with cognitive performance in nondemented adults

The catechol O-methyltransferase (COMT) gene is essential in the metabolic degradation of dopamine in the prefrontal cortex. In the present study, we examined the effect of a Val158Met polymorphism in the COMT gene on individual differences and changes in cognition (executive functions and visuospatial ability) in adulthood and old age. The participants were 292 nondemented men (initially aged 35-85 years) from a random sample of the population (i.e., the Betula study) tested at two occasions with a 5-year interval. Confirmatory factor analyses were used to test the underlying structure of three indicators of executive functions (verbal fluency, working memory, and Tower of Hanoi). Associations between COMT, age, executive functioning, and visuospatial (block design) tasks were examined using repeated-measures analyses of variance. Carriers of the Val allele (with higher enzyme activity) compared with carriers of the Met/Met genotype (with low enzyme activity) performed worse on executive functioning and visuospatial tasks. Individuals with the Val/Val genotype declined in executive functioning over the 5-year period, whereas carriers of the Met allele remained stable in performance. An Age x COMT interaction for visuospatial ability located the effect for middle-aged men only. This COMT polymorphism is a plausible candidate gene for executive functioning and fluid intelligence in nondemented middle-aged and older adults.     

Effect of COMT Val108/158Met Genotype on Risk for Polydipsia in Chronic Patients with Schizophrenia

Polydipsia is a serious condition often seen among patients with schizophrenia (SCZ). The cause of polydipsia is unknown; hence, it is hard to treat or manage. Animal studies showed that the drinking behavior is regulated by central dopaminergic neurotransmission at the hypothalamus. Meanwhile, the existence of a genetic predisposition to polydipsia in patients with SCZ has been suggested. The purpose of this study was to assess whether a functional polymorphism, Val^108/158Met in the gene for catechol-O-methyltransferase (COMT), is associated with susceptibility to polydipsia using a Japanese sample of SCZ. Our sample includes 330 chronic patients with SCZ (83 polydipsic patients and 247 non-polydipsic controls). The common COMT Val^108/158Met polymorphism was genotyped, and the differences in genotype distribution and allele frequency between cases and controls were evaluated using the χ ² test. A significant association between the COMT Val^108/158Met polymorphism and polydipsia was found (genotype distribution: χ ² = 13.0, df = 2, p = 0.001; allele frequency: χ ² = 7.50, df = 1, p = 0.006). The high-COMT activity group (Val/Val) was more frequent among patients with polydipsia compared with the low-COMT activity group (Val/Met + Met/Met) [odds ratio (OR) = 2.46]. The association survived after controlling for other possible confounding factors, including gender, age, age of onset, current antipsychotic dose, and smoking status. Our results suggest that the COMT Val^108/158Met genotype may confer susceptibility to polydipsia in SCZ. To our knowledge, this is the first association study between the COMT gene and polydipsia in SCZ. Further studies with larger sample sizes are warranted to confirm present findings.