Functional catechol-O-methyltransferase Polymorphism Research Articles

Association between the catechol-O-methyltransferase polymorphism Val158Met and Alzheimer's disease in a Japanese population.

Catechol-O-methyltransferase (COMT) plays an important role in dopamine degradation, which is associated with the pathophysiology of Alzheimer's disease (AD) and alcoholism. A functional COMT polymorphism, Val158Met (rs4680 G > A), affects the onset of AD and is associated with alcohol dependence through dopamine receptor sensitivity in the prefrontal cortex. The aim of this case-control study (398 cases and 149 controls) was to investigate whether Val158Met polymorphism influences the onset of AD stratified according to alcohol consumption and apolipoprotein E (APOE) status. We also used single photon-emission computed tomography (SPECT) to analyse 26 patients with AD with the polymorphism. As a function of APOE status, the genotypic frequencies of rs4680 in patients with AD did not differ from those in controls. We detected a significant association between high alcohol consumption in patients with AD (HAC-AD group) and the polymorphism in genotypic and allelic frequencies. Logistic regression analyses demonstrated that the presence of the APOE genotype with rs4680 increased the risk for HAC-AD synergistically. Hyperperfusion in the right sub-lobar insula of patients with the G/G genotype was found compared with that of patients with the G/A genotype. SPECT studies showed a relationship between the polymorphism and compensatory reactions for dysfunctions of dopaminergic neurotransmission in AD pathophysiology. Although genetic association between the polymorphism and the onset of AD in a Japanese population were not observed, the polymorphism affected the risk for HAC-AD.

Effects of a functional COMT polymorphism on brain anatomy and cognitive function in adults with velo-cardio-facial syndrome

Velo-cardio-facial syndrome (VCFS) is associated with deletions at chromosome 22q11, abnormalities in brain anatomy and function, and schizophrenia-like psychosis. Thus it is assumed that one or more genes within the deleted region are crucial to brain development. However, relatively little is known about how genetic variation at 22q11 affects brain structure and function. One gene on 22q11 is catechol-O-methyltransferase (COMT): an enzyme that degrades dopamine and contains a functional polymorphism (Val158Met) affecting enzyme activity. Here, we investigated the effect of COMT Val158Met polymorphism on brain anatomy and cognition in adults with VCFS. The COMT Val158Met polymorphism was genotyped for 26 adults with VCFS on whom DNA was available. We explored its effects on regional brain volumes using hand tracing approaches; on regional grey- and white-matter density using computerized voxel-based analyses; and measures of attention, IQ, memory, executive and visuospatial function using a comprehensive neuropsychological test battery. After corrections for multiple comparisons Val-hemizygous subjects, compared with Met-hemizygotes, had a significantly larger volume of frontal lobes. Also, Val-hemizygotes had significantly increased grey matter density in cerebellum, brainstem, and parahippocampal gyrus, and decreased white matter density in the cerebellum. No significant effects of COMT genotype on neurocognitive performance were found. COMT genotype effects on brain anatomy in VCFS are not limited to frontal regions but also involve other structures previously implicated in VCFS. This suggests variation in COMT activity is implicated in brain development in VCFS.

Schizotypal dimensions: An intermediate phenotype associated with the COMT high activity allele

Although catechol-O-methyltransferase (COMT) has long been suggested to be implicated in the pathogenesis of schizophrenia, association studies have generated discrepant results concerning the involvement of the COMT gene in schizophrenia. As several studies have suggested that schizotypal traits might be genetically related to schizophrenia, increased statistical power to detect gene effects could be obtained by using dimensional personality traits in unaffected relatives. We tested the hypothesis that the functional Val158Met COMT polymorphism might contribute to the variance of self-reported schizotypal scores in a sample of 106 unaffected subjects, composed of controls (N = 57), first-degree relatives of schizophrenic (N = 27) and of bipolar (N = 22) probands. We also looked for specific associations between COMT polymorphisms and the three dimensions of schizotypy (positive, negative, disorganized) assessed by the Schizotypal Personality Questionnaire (SPQ). We found that self-reported SPQ scores are related to COMT genotype (P = 0.01), with individuals homozygous for the high activity allele having the highest scores. This association is primarily due to specific associations with the positive (P = 0.001) and negative (P = 0.04) dimensions. Our data support the hypothesis that the functional COMT polymorphism could be involved in different psychotic dimensions. This confirms that studying specific schizotypal dimensions can help to identify the genes involved in the pathogenesis of psychosis.

Association Between a Functional COMT Polymorphism, Mental Retardation and Cognition in Qinba Area Children

Catechol-O-methyl transferase (COMT) plays an important role in the metabolism of neurotransmitters. Two alleles of the COMT gene as a result of a G/A transition in the exon 4 can lead to different COMT enzymatic activities. Much genetic research has revealed that this COMT functional polymorphism was related to human psychiatric disorders. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods were used to discern the relationships among the functional polymorphism of COMT, mental retardation (MR), and general cognitive ability of children. The results of the case-control analysis showed that there was no association between the frequencies of genotypes of COMT and MR ( x 2=0.776, P>0.05) or between the frequency of COMT alleles and MR ( x 2=0.335, P>0.05). COMT polymorphism was found in children whose intelligence quotient (IQ) was above 55. In normal children (IQ≥85), the frequencies of high-activity allele COMT H and the homozygote genotype COMT HH were 60.98% and 79.28%, respectively. Both were higher than those of the borderline group (46.67% and 70.67%, 0.10 > P>0.05). Therefore, the result of this study suggests that this functional polymorphism is not an important risk factor for MR, but the COMT HH genotype may have a positive effect on cognitive performance in normal children in the Qinba area.

A gender‐moderated effect of a functional COMT polymorphism on prefrontal brain morphology and function in velo‐cardio‐facial syndrome (22q11.2 deletion syndrome)

Caused by a microdeletion at the q11.2 locus of chromosome 22, velo-cardio-facial syndrome (also known as VCFS, 22q11 deletion syndrome, DiGeorge sequence, and conotruncal anomalies face syndrome) is associated with a distinctive physical, neurocognitive, and psychiatric phenotype. Increasing interest has centered on identifying the candidate genes within the deleted region that may contribute to this phenotype. One attractive candidate gene is catechol-O-methyltransferase (COMT) because it encodes for a protein that degrades dopamine. Variability in COMT activity is related to a Val158Met polymorphism that has been implicated in prefrontal lobe cognitive and neuropsychiatric function. We examined the effect of this polymorphism on prefrontal anatomy and frontally-mediated neuropsychological function in 58 children with VCFS, 26 who were hemizygous for the Met allele and 32 for the Val allele. We found an allele by gender interaction effect on the volumes of the dorsal prefrontal and orbital prefrontal cortices. We did not find significant allele or gender by allele effects on neuropsychological tasks, although girls with the Met allele tended to perform better on the Wisconsin card sorting task. These data suggest that this functional COMT polymorphism may play a gender-moderated role in determining the neuroanatomic phenotype of individuals with VCFS. Longitudinal evaluation of these children is essential in order to identify potential clinical implications of this allele by gender interaction.

Cognitive correlates of a functional COMT polymorphism in children with 22q11.2 deletion syndrome

Chromosome 22q11.2 deletion syndrome (22q11DS) is a common microdeletion syndrome associated with a markedly elevated risk of schizophrenia in adulthood. Cognitive impairments such as a low IQ and deficits in attention and executive function are common in childhood. The catechol O-methyltransferase (COMT) gene maps within the deleted region and is involved in the degradation of dopamine, a neurotransmitter thought to be important in cognition and the development of schizophrenia. Thus, we examined the correlation between neurocognitive deficits and a common polymorphism Val(158)Met in the COMT gene in a cohort of children with 22q11DS. Our results show that children with 22q11DS who have the Met allele have higher IQ and achievement scores and perform better on measures of prefrontal cognition, such as the Continuous Performance Task, as compared with those with the Val allele. These results confirm that the hemizygous COMT Val(158)Met genotype impacts upon cognition in children with 22q11DS.

Associations between theCOMT Val/Metpolymorphism, early life stress, and personality among healthy adults

Efforts to identify genetic factors that confer an increased risk for the expression of psychiatric symptoms have focused on polymorphisms in variety of candidate genes, including the catechol-O-methyltransferase (COMT) gene. Results from previous studies that have examined associations between the functional COMT polymorphism (Val158Met) and mental health have been mixed. In the present study, we examined the relationships between COMT, early life stress, and personality in a healthy adult sample. Consistent with previous studies, we hypothesized that individuals with the low-activity genotype would have higher neuroticism and lower extraversion and that this effect would be more pronounced in females. In addition, we extended the previous literature by investigating the potential influence of early life stress. A total of 486 healthy adults underwent genetic testing and personality assessment. Results revealed that individuals homozygous for the COMT low enzyme activity allele had lower extraversion on the NEO-FFI and demonstrated a trend toward greater neuroticism. These relationships were not influenced by sex or the presence of reported early life stress. The finding that COMT genotype was associated with extraversion, and more weakly with neuroticism, is consistent with previous studies. Future research to clarify the influence of sex and gene-environmental interactions is warranted.

The functional COMT polymorphism, Val158Met, is associated with logical memory and the personality trait intellect/imagination in a cohort of healthy 79 year olds

A polymorphism (Val158Met) in the gene for catechol- O-methyl transferase ( COMT) was previously associated with differences in cognitive ability and personality. Here we examine associations between this polymorphism and cognitive ability, cognitive aging, personality and mood in 460 relatively healthy people born in 1921. All had cognitive ability measured at age 11 in the Scottish Mental Survey of 1932, and again at age 79. COMT genotype was not associated with childhood IQ. At age 79, COMT genotype was significantly related to differences in verbal declarative memory (scores on the Logical Memory test; p = 0.028) and to scores on the personality trait of intellect/imagination ( p = 0.023), adjusted for sex and childhood IQ. In both cases the Val/Met heterozygotes had higher scores than both homozygous groups. There were trends toward the heterozygotes having higher scores on the personality traits of agreeableness and conscientiousness. The effect of COMT genotype on Logical Memory scores was independent of the effect of APOE genotype, and similar in effect size. Therefore, COMT genotype may contribute to differences in normal cognitive aging and to differences in some of the major personality traits in old age.

Association Between Catechol-O-Methyltransferase and Phobic Anxiety

The authors assessed the association between the catechol-O-methyltransferase (COMT) Val158Met polymorphism and scores on the phobic anxiety scale of the Crown-Crisp Experimental Index. A total of 1,234 women completed the Crown-Crisp Experimental Index phobic anxiety scale and were genotyped for the COMT polymorphism. The authors used unconditional logistic regression to compute odds ratios and 95% confidence intervals (CIs) to evaluate the association between the COMT genotype and phobic anxiety. The mean scores for the three genotypes were statistically significantly different. Compared to the COMT Met/Met genotype, the age-adjusted odds ratio for scoring >/=6 compared to scoring 0 or 1 were 1.15 (95% CI=0.71-1.85) and 1.99 (95% CI=1.17-3.40) for the COMT Val/Met and COMT Val/Val genotypes, respectively; a significant gene dosage effect was observed. Our results suggest that the functional COMT polymorphism is associated with the development of phobic anxiety.

No association between anxiety disorders and catechol- O-methyltransferase polymorphism

Several studies have shown that the morbidity risk for anxiety disorders is increased among the relatives of patients with obsessive–compulsive disorder (OCD). Recently, it was reported that a polymorphism of the catechol- O-methyltransferase (COMT) gene is significantly associated with OCD. The purpose of this study was to determine the association, if any, between the COMT polymorphism and anxiety disorders. We undertook an association study of the COMT polymorphism in 108 patients who met DSM-IV criteria for anxiety disorders and 135 healthy controls. All subjects were unrelated Japanese. The subdiagnostic groups did not differ significantly from the control group in either the genotypic or allelic frequencies. There were no statistically significant differences between the genotype and males, females, or a family history. The mean age of onset did not significantly differ among the genotypes. Our results suggest this functional COMT polymorphism does not make an important contribution to anxiety disorders in the Japanese population.