catechol-O-methyltransferase Gene Research Articles

Schooling and variation in the COMT gene: the devil is in the details

Schooling is considered one of the major contributors to the development of intelligence within societies and individuals. Genetic variation might modulate the impact of schooling and explain, at least partially, the presence of individual differences in classrooms. We studied a sample of 1,502 children (mean age = 11.7 years) from Zambia. Approximately 57% of these children were enrolled in school, and the rest were not. To quantify genetic variation, we investigated a number of common polymorphisms in the catechol-O-methyltransferase (COMT) gene that controls the production of the protein thought to account for >60% of the dopamine degradation in the prefrontal cortex. Haplotype analyses generated results ranging from the presence to absence of significant interactions between a number of COMT haplotypes and indicators of schooling (i.e., in- vs. out-of-school and grade completed) in the prediction of nonverbal intelligence, depending on the parameter specification. However, an investigation of the distribution of corresponding p-values suggested that these positive results were false. Convincing evidence that the variation in the COMT gene is associated with individual differences in nonverbal intelligence either directly or through interactions with schooling was not found. p-values produced by the method of testing for haplotype effects employed here may be sensitive to parameter settings, invalid under default settings, and should be checked for validity through simulation.

The associations between the Val158Met in the catechol-O-methyltransferase (COMT) gene and the risk of uterine leiomyoma (ULM)

The Val158Met polymorphism of the COMT gene has been implicated in susceptibility to uterine leiomyoma (ULM), but the reported results were inconclusive. The aim of the study was to evaluate the Val158Met polymorphism of the COMT gene and the risk of ULM by meta-analysis. A comprehensive electronic search for relevant articles was conducted in Pubmed, Embase, CNKI, Wanfang, and Weipu databases. Statistical analysis was performed by using the Revman4.2 software and Stata10.0 software. A total of 7 articles including 12 case–control studies were identified in this meta-analysis. The results showed that the polymorphism was associated with decreased risk of ULM (Met/Met+Val/Met vs. Met/Met: OR=0.84, 95% CI=0.70–0.99, Z=2.07, p=0.04). In the subgroup analyses by ethnicity, significant decreased risk was found among the black populations (OR=0.68, 95% CI=0.48–0.97, Z=2.15, p=0.03). The current meta-analysis suggested that the Val158Met polymorphism in the COMT gene was associated with decreased risk of ULM, especially in the black population. Future studies are needed to validate our conclusions.

Role of COMT in ADHD: a Systematic Meta-Analysis

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable childhood-onset psychiatric disorder with significant genetic contribution. Considerable evidence has implicated involvement of dopaminergic system and the prefrontal cortex (PFC) in the pathomechanism of ADHD. The catechol-O-methyltransferase (COMT) gene is of particular interest for ADHD as its crucial role in the degradation of dopamine in the PFC. We summarized the reported findings investigating associations between COMT gene and ADHD and performed a meta-analysis of previous studies to assess the overall magnitude and significance of the association.

CB1 cannabinoid receptor-mediated aggressive behavior

This study examined the role of cannabinoid CB1 receptors (CB1r) in aggressive behavior. Social encounters took place in grouped and isolated mice lacking CB1r (CB1KO) and in wild-type (WT) littermates. Cognitive impulsivity was evaluated in the delayed reinforcement task (DRT). Gene expression analyses of monoaminooxidase-A (MAO-A), catechol-o-methyl-transferase (COMT), 5-hydroxytriptamine transporter (5-HTT) and 5-HT1B serotonergic receptor (5HT1Br) in the median and dorsal raphe nuclei (MnR and DR, respectively) and in the amygdala (AMY) were performed by real time-PCR. Double immunohistochemistry studies evaluated COMT and CB1r co-localization in the raphe nuclei and in the cortical (ACo), basomedian (BMA) and basolateral (BLA) amygdaloid nuclei. The behavioral effects of the CB1r agonist ACEA (1 and 2 mg/kg) on aggression were also evaluated in isolated OF1 mice. CB1KO mice housed in groups showed higher levels of offensive aggression. Isolation increased aggressive behavior only in WT. In grouped CB1KO mice COMT gene expression was significantly higher in the MnR and DR, while MAO-A gene expression was lower in the MnR. Gene expression of 5HT1Br, COMT and MAO-A was higher in the amygdala of CB1KO mice. CB1r double-immunohistochemistry revealed cytoplasmic-labeled COMT-ir cells in the raphe nuclei and in the ACo, BMA and BLA. CB1r immunolabeling was observed only in ACo, BMA and BLA, where it was localized in axons and buttons. The density of labeled processes increased in BLA. Acute administration of the CB1 agonist ACEA (2 mg/kg) significantly decreased the aggression levels of OF1 mice. These results suggest that CB1r plays an important role in social interaction and aggressive behavior.

Putative cortical dopamine levels affect cortical recruitment during planning

Planning, the decomposition of an ultimate goal into a number of sub-goals is critically dependent upon fronto-striatal dopamine (DA) levels. Here, we examined the extent to which the val158met polymorphism in the catechol O-methyltransferase (COMT) gene, which is thought to primarily alter cortical DA levels, affects performance and fronto-parietal activity during a planning task (Tower of London). COMT genotype was found to modulate activity in the left superior posterior parietal cortex (SPC) during planning, relative to subtracting, trials. Specifically, left SPC blood oxygenation level-dependent (BOLD) response was reduced in groups with putatively low or high cortical DA levels (COMT homozygotes) relative to those with intermediate cortical DA levels (COMT heterozygotes). These set of results are argued to occur either due to differences in neuronal processing in planning (and perhaps subtracting) caused by the COMT genotype and/or the cognitively heterogeneous nature of the TOL, which allows different cognitive strategies to be used whilst producing indistinguishable behavioural performance in healthy adults. The implications of this result for our understanding of COMT′s effect on cognition in health and disease are discussed.

Adipose tissue PCB levels and CYP1B1 and COMT genotypes in relation to breast cancer risk in postmenopausal Danish women

Exposure to PCBs may be an etiologic factor for breast cancer. The cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) enzymes are involved in estrogen metabolism and PCB metabolism, both of which may relate to breast cancer susceptibility. Polymorphisms in genes regulating these enzymes control efficiency. Our objective was to assess whether CYP1B1 and COMT gene polymorphisms modulate the effect of PCBs in breast cancer risk, among postmenopausal Danish women. Neither CYP1B1 Leu432Val polymorphisms nor adipose tissue PCBs were independently associated with breast cancer risk. When assessing the independent effect of the COMT Val158Met polymorphism, we observed reduced risk for breast cancer amongst hormone replacement therapy using women who were homozygous carriers of the variant allele compared with those carrying the wild-type variant (RR = 0.41; 95% CI: 0.29–0.89). We found no statistically significant interactions between any of the PCB groups and CYP1B1 or COMT polymorphisms on the risk of breast cancer.

No association of G‐protein‐coupled receptor kinase 5 or β‐adrenergic receptor polymorphisms with Takotsubo cardiomyopathy in a large Australian cohort

Takotsubo cardiomyopathy (TC) is an increasingly recognized syndrome in which patients present with chest pain and ST changes, and are observed to have reversible LV apical ballooning in the absence of angiographically significant coronary artery stenosis. Although the pathophysiology remains unclear, the syndrome occurs almost exclusively in women, and is often triggered by stress. Recent small studies have reported association of TC with functional variants in the G-protein-coupled receptor kinase 5 (GRK5) gene, as well as in the β1-adrenergic receptor (β1AR) and β2AR. We tested these associations in a larger cohort of 92 TC patients. In addition we examined for the association of polymorphisms in the oestrogen receptor α (ERα) and catechol-O-methyl transferase (COMT) with the occurrence of TC, by comparing the allele frequency of these variants in the TC cohort with that in previously genotyped large Caucasian cohorts. Ninety-two patients with TC were recruited from four Australian centres; they had an age range of 41-90 years (mean ± SD = 66.3 ± 9) and 89/92 were female. There were no significant differences in allelic frequency in the TC group vs. the historic control database for any of the loci. In the largest genotyped TC cohort in the literature, we have found no association of genetic variants in the ERα, β1AR, β2AR, or COMT genes, or with the previously implicated GRK5, with occurrence of the syndrome.

Distribution of the Val108/158Met polymorphism of the COMT gene in healthy Mexican population

Catechol-O-methyltransferase (COMT) inactivates the catecholamines adrenaline, noradrenaline and dopamine. On the other hand, some studies have reported that the enzymatic activity of COMT is partly genetically determined. With regard to the COMT gene, the most studied polymorphism is the functional variant Val108/158Met (rs4680), which results in substantial three- to four-fold variations in enzyme activity. To date, the rs4680 polymorphism of COMT has been associated with a number of disorders. In addition, this polymorphism has been found to have important differences in frequency according to the studied population. Therefore, the aim of the present study was to evaluate the frequency of a common single nucleotide polymorphism (SNP) Val108/158Met of the COMT gene in the Mexican population. Accordingly, we recruited 431 healthy volunteers. Our sample consisted of 111 healthy individuals from Mexico City and 320 individuals from the state of Tabasco, Mexico. We observed that Met was the most common allele, ranging from 57% (Tabasco) to 85% (Mexico City). In addition, we analyzed the frequency of Val108/158Met polymorphism of Caucasian (54% Met allele), Asian (29% Met allele) and African (34% Met allele) populations separately and also in comparison with Mexican (63% Met allele) population. In conclusion, the distribution of the Val108/158Met polymorphism distinguishes the Mexican population studied from other populations, but it is necessary to increase the size of the sample to get more conclusive results.

Apathy is associated with a single-nucleotide polymorphism in a dopamine-related gene

Dopaminergic neurotransmission is an important factor in the pathogenesis of apathy. In addition, the contribution of genetic factors to the regulation of brain dopaminergic activity is widely acknowledged. Therefore, we hypothesized that genes associated with brain dopaminergic activity may have some effects on apathy. In the current study, we evaluated the association between four functional single-nucleotide polymorphisms (SNPs) in specific genes related to dopaminergic neurotransmission and apathy in a general population. Participants in the health examination at the Shimane Institute of Health Science were recruited for this study (n=963). Apathy was assessed using the Japanese version of the apathy scale. SNPs were genotyped using the TaqMan method. In our population, 22.1% had apathy. We confirmed that apathy was associated with decreased cognitive function and depressive state. A significant association was found between an SNP in the catechol-O-methyltransferase (COMT) gene (rs4680) encoding the low-activity Met allele and apathy. This relationship was still significant after adjustment for confounding factors. Our study indicates an association between rs4680, an SNP in the COMT gene, and lower risk of apathy. Considering the function of rs4680, the current study suggests the importance of dopaminergic neurotransmission in the pathogenesis of apathy in a general population.

Common functional polymorphisms in SLC6A4 and COMT genes are associated with circadian phenotypes in a South American sample

The molecular study of circadian rhythms in humans could be an excellent approach to understand the relation between genes and behavior. It is possible that variations in genes involved in neurotransmission and/or synaptic plasticity, such as catechol-O-methyltransferase (COMT) and serotonin transporter (SLC6A4) could be of particular interest in understanding human circadian phenotypes. The aim of this study is to analyze the possible and novel associations of the functional polymorphisms in COMT and SLC6A4 genes (Val158Met and 5-HTTLPR) and circadian phenotypes in healthy Colombian subjects. 191 university students were genotyped for two functional polymorphisms in COMT and SLC6A4 genes (rs4680 and rs4795541). We applied two scales to measure phenotypic patterns of human circadian rhythms: Composite Scale of Morningness (CSM) and Epworth Sleepiness Scale (ESS). We found a significant association between 5-HTTLPR polymorphism and morning preference score (CSM) (p = 0.027) using an overdominant genotypic model and association of COMT Val158Met with daytime sleepiness (ESS scores) (p = 0.038) in a genotypic recessive model. These results were supported by differences in genotype frequencies between circadian typologies for SLC6A4 gene (p = 0.007) and categories of diurnal sleepiness for COMT gene (p = 0.032). Our results suggest, for the first time, a significant relationship between functional SLC6A4 and COMT polymorphisms with specific human circadian phenotypes: morning preference and diurnal sleepiness. These results need to be replicated in other populations. Further study of functional polymorphisms in other synaptic genes could be of relevance for the identification of novel candidate genes for circadian phenotypes, and related endophenotypes of neuropsychiatric importance, in healthy humans.

PTU-128 A Novel Association between Comt Gene Polymorphisms and Risk of Symptomatic Dysphagia in the Elderly

IntroductionGenetic variants of the enzyme Catechol-O-Methyl Transferase (COMT) have been associated with age related degeneration and changes in dopamine function. Further, COMT gene polymorphisms have been found to interact with...

Personality Traits of Schizophrenic Patients in Remission and Their First-Degree Relatives: A Dopaminergic and Glutamatergic Gene Polymorphism Study

Objective: The dopaminergic and glutamatergic systems are of major interest in the etiology of schizophrenia and supposed endophenotypes such as personality traits. In the present study, we investigated the association between the catechol-O-methyltransferase (COMT) gene P2 promoter rs2075507, Val/ Met (rs4680), the dopamine transporter gene (DAT1) VNTR and the glutamate transporter gene (SLC1A2) promoter -181A/C polymorphisms, and personality traits as well as symptomatic features in schizophrenia.Methods: There were 112 healthy subjects, 51 schizophrenic patients in remission for at least six months and 45 first-degree relatives of the patients enrolled in the study. The samples were genotyped for the COMT P2 promoter rs2075507, Val/Met, DAT1 VNTR and SLC1A2 promoter -181A/C polymorphisms and assessed with the Temperament and Character Inventory (TCI). Schizophrenia patients were also evaluated using the Operational Criteria Checklist for Psychotic Illness (OPCRIT) for each of the five factor-derived scales (negative symptoms, delusions, hallucinations, mania, and depression) and The Positive and Negative Symptom Scale.Results: Our findings demonstrate that schizophrenic patients, even after remission, had a different personality pattern from controls, showing higher scores in harm avoidance and self-transcendence and lower scores in novelty seeking, persistence, self-directedness and cooperativeness. First-degree relatives of patients also had profiles distinguishable from those of the patients only by intermediate levels of harm-avoidance and higher levels of cooperativeness. In the association of genotypes and personality, COMT Val/Met polymorphism was not associated with personality in patients or in healthy subjects. Another functional polymorphism in the COMT gene the P2 promoter rs2075507 G allele was associated with significantly higher novelty seeking scores in patients than was the A allele. DAT1 VNTR long alleles (10 or 11 repeats) were demonstrated to show a non-significant trend to association with higher self-transcendence scores than in those with the short alleles (3, 7, 8 or 9 repeats) in control samples and patients. In SLC1A2 promoter -181A/C polymorphism, the C allele was significantly associated with higher self-transcendence scores than in those with the A allele in healthy subjects. We did not find any associations between the psychotic symptom dimensions of patients and DAT1 VNTR, SLC1A2 promoter -181A/C and COMT Val/Met polymorphism; however, COMT P2 promoter rs2075507 polymorphism showed an association with the delusion and mania factor scores.Conclusions: Schizophrenia may be associated with different personality patterns from controls and some personality dimensions may be associated with the appearance of psychotic symptoms. The same genes may be responsible for the development of the disease, with personality patterns seen in at least one group of patients.

Association of OPRM1 and COMT Single-Nucleotide Polymorphisms With Hospital Length of Stay and Treatment of Neonatal Abstinence Syndrome

Neonatal abstinence syndrome (NAS) caused by in utero opioid exposure is a growing problem; genetic factors influencing the incidence and severity have not been previously examined. Single-nucleotide polymorphisms (SNPs) in the μ-opioid receptor (OPRM1), multidrug resistance (ABCB1), and catechol-o-methyltransferase (COMT) genes are associated with risk for opioid addiction in adults. To determine whether SNPs in the OPRM1, ABCB1, and COMT genes are associated with length of hospital stay and the need for treatment of NAS. Prospective multicenter cohort study conducted at 5 tertiary care centers and community hospitals in Massachusetts and Maine between July 2011 and July 2012. DNA samples were genotyped for SNPs, and then NAS outcomes were correlated with genotype. Eighty-six of 140 eligible mother-infant dyads were enrolled. Infants were eligible if they were 36 weeks' gestational age or older and exposed to methadone or buprenorphine in utero . Primary outcome measure was length of hospital stay, with between-group differences expressed as β and calculated with linear regression models. Secondary outcome measures included need for any medical treatment for NAS and treatment with 2 or more medications. Infants with the OPRM1 118A>G AG/GG genotype had shortened length of stay (β = -8.5 days; 95% CI, -14.9 to -2.1 days; P = .009) and were less likely to receive any treatment than AA infants (48% vs 72%; adjusted odds ratio, 0.76; 95% CI, 0.63-0.96; P = .006). The COMT 158A>G AG/GG genotype was associated with shortened length of stay (β = -10.8 days; 95% CI, -18.2 to -3.4 days; P = .005) and less treatment with 2 or more medications (18% vs 56%; adjusted odds ratio, 0.68; 95% CI, 0.55-0.86; P = .001) than the AA genotype. Associations with the ABCB1 SNPs were not significant. Among infants with NAS, variants in the OPRM1 and COMT genes were associated with a shorter length of hospital stay and less need for treatment. These preliminary findings may provide insight into the mechanisms underlying NAS.

The Influence of the Val158Met Catechol-O-Methyltransferase Polymorphism on the Personality Traits of Bipolar Patients

IntroductionCertain personality traits and genetic polymorphisms are contributing factors to bipolar disorder and its symptomatology, and in turn, this syndrome influences personality. The aim of the present study is to compare the personality traits of euthymic bipolar patients with healthy controls and to investigate the effect of the catechol-O-methyltransferase (COMT) Val158Met genotype on those traits. We recruited thirty seven bipolar I patients in euthymic state following a manic episode and thirty healthy controls and evaluated their personality by means of the Cloninger’s Temperament and Character Inventory (version TCI-R-140). We assessed the influence of the polymorphism Val158Met in the COMT gene on the personality of these patients. The patients scored higher than controls in harm avoidance (61.3±12.5 vs. 55.3±8.1) and self-transcendence (45.3±12.8 vs. 32.7±8.2) and scored lower than controls in self-directedness (68.8±13.3 vs. 79.3±8.1), cooperativeness (77.1±9.1 vs. 83.9±6.5) and persistence (60.4±15.1 vs. 67.1±8.9). The novelty seeking dimension associates with the Val158Met COMT genotype; patients with the low catabolic activity genotype, Met/Met, show a higher score than those with the high catabolic activity genotype, Val/Val.ConclusionsSuffering from bipolar disorder could have an impact on personality. A greater value in harm avoidance may be a genetic marker for a vulnerability to the development of a psychiatric disorder, but not bipolar disorder particularly, while a low value in persistence may characterize affective disorders or a subgroup of bipolar patients. The association between novelty seeking scores and COMT genotype may be linked with the role dopamine plays in the brain’s reward circuits.

Association of COMT gene polymorphisms with cerebral infarction in Han people of Tianjin

Background Catechol-O-methyltransferase (COMT) has a key function in the degradation of catecholamines and inactivating estrogen. A common polymorphism in the COMT gene is guanine-adenine (G-A) point mutation on rs4680, which causes a valine (Val) substitution to methionine (Met) in 108 and (or) 158 amino acid by this gene and is responsible for lowered activity of the enzyme. The Val/Met polymorphism has been recognized to be associated with psychiatric disorders, alcohol dependence and drug side effects, but few study has been done to examine the relationship with cerebral infarction (CI). The objective of this study is to investigate the relationship between the polymorphisms of COMT gene and CI. Methods The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to detect COMT Val158Met genotype in 181 CI patients and 148 cases of controls. Meanwhile the serum levels of glucose, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (ApoB) and ApoA in CI group were detected. Results The frequency of Val allele (78.45%) and Val/Val genotype (61.33%) in CI was significantly higher than that in the control group (68.24% and 45.95%, P 0.05) than that in the control group. The serum levels of glucose, TC, TG, LDL-C, HDL-C, ApoB, ApoA and the frequency of hypertension had no difference between Val/Val genotype and Val/Met + Met/Met genotypes ( P > 0.05, for all). Conclusion The frequencies of Val allele and Val/Val genotype can be considered as genetic risk factors of male CI patients. The effect of COMT on CI is not related to blood pressure, serum lipid and glucose.

Effect of the COMT val158met polymorphism on white matter connectivity in patients with major depressive disorder

Cortico-limbic network dysfunction and genetic polymorphism are considered to be associated with major depressive disorder (MDD). Using diffusion tensor imaging (DTI), we investigated the relationship between catechol-O-methyltransferase (COMT) gene polymorphisms and white matter tract integrity in patients with MDD. Eighty-six patients with MDD and 62 healthy controls participated in this study. DTI and genotyping for the COMT val158met gene (rs4680) polymorphism were conducted to determine the impact of COMT polymorphisms on white matter changes in patients with MDD. Voxel-wise statistical analyses of fractional anisotropy (FA) were performed using tract-based spatial statistics (TBSS). FAs of the MDD patient group were significantly decreased in bilateral frontal forceps minor, bilateral anterior cingulum, genu of corpus callosum, left posterior cingulum, right superior longitudinal fasciculus, and right posterior thalamic radiation compared with those of healthy controls. In the MDD patient group, mean FA in subjects with the GG allele was significantly decreased in left inferior longitudinal fasciculus, bilateral middle temporal gyrus, right frontal gyrus, and right cingulum bundle area compared with subjects with the AA/AG allele. These findings suggest cortico-limbic network dysfunction in MDD. Specifically, further FA reduction was evident in MDD patients with the valine homozygote group of the COMT gene. MDD may be associated with dysfunctional white matter changes, and the valine homozygote of COMT gene may contribute to further abnormalities in these pathological changes.

Pain modality- and sex-specific effects of COMT genetic functional variants

The enzyme catechol-O-methyltransferase (COMT) metabolizes catecholamine neurotransmitters involved in a number of physiological functions, including pain perception. Both human and mouse COMT genes possess functional polymorphisms contributing to interindividual variability in pain phenotypes such as sensitivity to noxious stimuli, severity of clinical pain, and response to pain treatment. In this study, we found that the effects of Comt functional variation in mice are modality specific. Spontaneous inflammatory nociception and thermal nociception behaviors were correlated the most with the presence of the B2 SINE transposon insertion residing in the 3′UTR mRNA region. Similarly, in humans, COMT functional haplotypes were associated with thermal pain perception and with capsaicin-induced pain. Furthermore, COMT genetic variations contributed to pain behaviors in mice and pain ratings in humans in a sex-specific manner. The ancestral Comt variant, without a B2 SINE insertion, was more strongly associated with sensitivity to capsaicin in female vs male mice. In humans, the haplotype coding for low COMT activity increased capsaicin-induced pain perception in women, but not men. These findings reemphasize the fundamental contribution of COMT to pain processes, and provide a fine-grained resolution of this contribution at the genetic level that can be used to guide future studies in the area of pain genetics.

Catechol-O-methyltransferase Val158Met polymorphism and risk of autism spectrum disorders

Autism spectrum disorders (ASD) are a family of childhood-onset neurodevelopmental disorders with complex genetic mechanisms underlying their aetiology. The aim of this case-control study was to evaluate the effect of the catechol-O-methyltransferase (COMT) gene Val158Met polymorphism on ASD risk in a Chinese Han population. The COMT gene Val158Met polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism in children (≤ 18 years old) with ASD and healthy control subjects. The frequency of the Val158/Val158 genotype in children with ASD (22/186; 11.8%) was significantly lower than in controls (38/186; 20.4%). When stratifying by select-item scores on the Autism Diagnostic Interview-Revised protocol, it was found that children with 'current overactivity' and 'ever overactivity' had a significantly lower frequency of the Val158/Val158 genotype than those without. There were no significant associations between the COMT gene Val158Met polymorphism and ASD subtypes. The COMT gene Val158Met polymorphism may be a biomarker for phenotypic variation in ASD, but these preliminary findings remain tentative, pending replication in larger, independent samples.

Catechol‐O‐methyltransferase gene val158met polymorphism and depressive symptoms during early childhood

Catechol-O-Methyltransferase (COMT) is a critical regulator of catecholamine levels in the brain. A functional polymorphism of the COMT gene, val158met, has been linked to internalizing symptoms (i.e., depression and anxiety) in adolescents and adults. We extended this research by investigating whether the val158met polymorphism was associated with childhood symptoms of depression and anxiety in two independent samples of young children (Ns = 476 and 409). In both samples, preschool-aged children were genotyped for the COMT val158met polymorphism. Symptoms of psychopathology were assessed via parent interviews and primary caregiver reports. In both samples, children homozygous for the val allele had higher levels of depressive symptoms compared to children with at least one copy of the met allele. Our findings extend previous research in older participants by showing links between the COMT val158met polymorphism and internalizing symptoms in early childhood.

Psychosis‐inducing effects of cannabis are related to both childhood abuse and COMT genotypes

To test whether the association between childhood abuse, cannabis use and psychotic experiences (PEs) was moderated by the COMT (catechol-O-methyltransferase) gene. Psychotic experiences (PEs), childhood abuse, cannabis use and COMT Val158Met genotypes were assessed in 533 individuals from the general population. Data were analysed hierarchically by means of multiple linear regression models. Childhood abuse showed a significant main effect on both positive (β = 0.09; SE = 0.04; P = 0.047) and negative PEs (β = 0.11; SE = 0.05; P = 0.038). A significant three-way interaction effect was found among childhood abuse, cannabis use and the COMT gene on positive PEs (β = -0.30; SE = 0.11; P = 0.006). This result suggests that COMT genotypes and cannabis use only influenced PE scores among individuals exposed to childhood abuse. Furthermore, exposure to childhood abuse and cannabis use increased PE scores in Val carriers. However, in individuals exposed to childhood abuse but who did not use cannabis, PEs increased as a function of the Met allele copies of the COMT gene. Cannabis use after exposure to childhood abuse may have opposite effects on the risk of PEs, depending on the COMT genotypes providing evidence for a qualitative interaction. Val carriers exposed to childhood abuse are vulnerable to the psychosis-inducing effects of cannabis.