Showing papers on "Catechol-O-methyl transferase published in 2009"
TL;DR: The results indicate that genetically influenced variations in dopamine transmission modulate the response of brain regions involved in anticipation and reception of rewards and suggest that these responses may contribute to individual differences in reward-seeking behavior and in predisposition to neuropsychiatric disorders.
Abstract: In humans, dopamine neurotransmission is influenced by functional polymorphisms in the dopamine transporter (DAT1) and catechol-O-methyltransferase (COMT) genes. Here, we used event-related functional magnetic resonance imaging to directly investigate the neurofunctional effects of the Val158Met COMT and variable number of tandem repeat DAT1 polymorphisms on distinct components of the reward system in humans. The results revealed a main effect of COMT genotype in the ventral striatum and lateral prefrontal cortex during reward anticipation (P < 0.001, uncorrected) and in the orbitofrontal cortex at the time of reward delivery (P < 0.005), met/met individuals exhibiting the highest activation. The main effect of DAT1 genotype was seen in robust blood-oxygen-level-dependent response differences in the caudate nucleus and ventral striatum during reward anticipation (P < 0.001) and in the lateral prefrontal cortex and midbrain at the time of reward delivery, with carriers of the DAT1 9-repeat allele showing the highest activity. Moreover, an interaction between the COMT and DAT1 genes was found in the ventral striatum and lateral prefrontal cortex during reward anticipation and in the lateral prefrontal and orbitofrontal cortices as well as in the midbrain at the time of reward delivery, with carriers of the DAT1 9-repeat allele and COMT met/met allele exhibiting the highest activation, presumably reflecting functional change consequent to higher synaptic dopamine availability. Taken together, these results indicate that genetically influenced variations in dopamine transmission modulate the response of brain regions involved in anticipation and reception of rewards and suggest that these responses may contribute to individual differences in reward-seeking behavior and in predisposition to neuropsychiatric disorders.
369 citations
TL;DR: It is found that age-related cognitive performance is differentially affected by distinct genetic factors and their interactions with vascular health status, and younger age and COMT Met/Met genotype, associated with low COMT activity and higher prefrontal dopamine content, were independently linked to better performance in most of the tested domains.
Abstract: Several single nucleotide polymorphisms have been linked to neural and cognitive variation in healthy adults. We examined contribution of three polymorphisms frequently associated with individual differences in cognition (Catechol-O-Methyl-Transferase Val158Met, Brain-Derived-Neurotrophic-Factor Val66Met, and Apolipoprotein E epsilon4) and a vascular risk factor (hypertension) in a sample of 189 volunteers (age 18-82). Genotypes were determined from buccal culture samples, and cognitive performance was assessed in 4 age-sensitive domains?fluid intelligence, executive function (inhibition), associative memory, and processing speed. We found that younger age and COMT Met/Met genotype, associated with low COMT activity and higher prefrontal dopamine content, were independently linked to better performance in most of the tested domains. Homozygotes for Val allele of BDNF polymorphism exhibited better associative memory and faster speed of processing than the Met allele carriers, with greater effect for women and persons with hypertension. Carriers of ApoE epsilon4 allele evidenced steeper age-related increase in costs of Stroop color interference, but showed no negative effects on memory. The findings indicate that age-related cognitive performance is differentially affected by distinct genetic factors and their interactions with vascular health status.
155 citations
TL;DR: Evidence is reported that interacting functional variants in COMT affect gray matter regional volume in hippocampus and DLPFC, providing further in vivo validation of the biological impact of complex genetic variation in comT on neural systems relevant for the pathophysiology of schizophrenia and extending observations of nonlinear dependence of prefrontal neurons on extracellular dopamine to the domain of human brain structure.
132 citations
TL;DR: The results suggest that the COMT is unlikely to contribute to susceptibility to schizophrenia, although rs2075507 and rs737865 showed trends for significance in allele-wise analyses.
129 citations
TL;DR: MAOA in combination with COMT appears to regulate not only the stress response in laboratory experiments, but also seems to influence the stress-evoked onset of mood during normal, mild, stressful events, such as experienced in the peripartum period.
Abstract: Background: Polymorphisms of monoamine-related genes have been associated with depression following life events. The peripartum is a physiologically and psychologically challenging period, characterized by fluctuations in depressive symptoms, therefore facilitating prospective investigations in this gene x environment (G x E) interaction. Methods: Eighty nine pregnant women filled in two Edinburgh Postpartum Depression Scale (EPDS) questionnaires during pregnancy and two in the postpartum period. MAOA, COMT and 5-HTT polymorphisms were analyzed. Results: We found a significant interaction between the development of depressive symptoms in the course of pregnancy and polymorphisms in 5-HTT(p = 0.019): MAOA (p = 0.044) and COMT(p = 0.026), and MAOAxCOMT (p Conclusion: We found that MAOA in combination with COMT appears to regulate not only the stress response in laboratory experiments, but also seems to influence the stress-evoked onset of mood during normal, mild, stressful events, such as experienced in the peripartum period. These findings support the G x E concept for depression, but they underline the complexity of this concept as the cumulating effects of these polymorphic genes (i.e. MAOA + COMT) might be needed and the effects of these polymorphic genes becomes apparent in special environmental or physiological conditions (i.e. the peripartum period). We therefore suggest that G x E interactions become especially noticeable from longitudinal study designs in specific physiological or social challenging periods. (C)2009 Elsevier Inc. All rights reserved.
119 citations
TL;DR: Improved insight into how genetic variants within the COMT locus affect pain perception will contribute to improved understanding of the mechanisms involved in the development of common human pain disorders and may lead to improved strategies for pain treatment.
Abstract: Catechol-O-methyltransferase (COMT) is an enzyme that inactivates biologically-active catechols, including the important neurotransmitters dopamine, noradrenaline and adrenaline. These neurotransmitters are involved in numerous physiological processes, including modulation of pain. Genetic variation in the COMT gene has been implicated in variable response to various experimental painful stimuli, variable susceptibility to develop common pain conditions, as well as the variable need for opioids in the treatment of cancer pain. Increased insight into how genetic variants within the COMT locus affect pain perception will contribute to improved understanding of the mechanisms involved in the development of common human pain disorders and may lead to improved strategies for pain treatment. So far, a remarkable complex relationship between COMT genotypes or haplotypes and pain phenotypes has been revealed.
113 citations
TL;DR: Results add to a growing literature suggesting that inhibitory control is sensitive to variation in dopamine function, and suggest that this variation may be detectable at the level of individuals' genotypes.
106 citations
TL;DR: 2 year old children were examined and it was found that variation in the COMT gene influenced attention in a task involving looking to a sequence of visual stimuli, confirming that important aspects of cognitive development including attention depend on the interaction of genes and early environment.
105 citations
TL;DR: Predicting the strongest negative effect of high proline on brain function to occur in 22q11DS children who are carriers of the COMTmet allele is consistent with a model in which elevated proline negatively affects brain function by an increase in dopamine in the prefrontal cortex.
94 citations
TL;DR: It is demonstrated that COMT and DAT genes interact nonadditively to modulate cortical function during executive processing, and also, that this effect is significantly altered in schizophrenia, which may reflect abnormal dopamine function in the disorder.
Abstract: Dopamine has a crucial role in the modulation of neurocognitive function, and synaptic dopamine activity is normally regulated by the dopamine transporter (DAT) and catechol-O-methyltransferase (COMT). Perturbed dopamine function is a key pathophysiological feature of schizophrenia. Our objectives were (i) to examine epistasis between the DAT 3′ UTR variable number of tandem repeats (VNTR) and COMT Val158Met polymorphisms on brain activation during executive function, and (ii) to then determine the extent to which such interaction is altered in schizophrenia. Regional brain response was measured by using blood-oxygen-level-dependent fMRI during an overt verbal fluency task in 85 subjects (44 healthy volunteers and 41 patients with DSM-IV schizophrenia), and inferences were estimated by using an ANOVA in SPM5. There was a significant COMT × DAT nonadditive interaction effect on activation in the left supramarginal gyrus, irrespective of diagnostic group (Z-score = 4.3; family-wise error (FWE) p = 0.03), and in healthy volunteers alone (Z-score = 4.7; FWEp = 0.006). In this region, relatively increased activation was detected only when COMT Met-158/Met-158 subjects also carried the 9-repeat DAT allele, or when, reversely, Val-158/Val-158 subjects carried the 10/10-repeat genotype. Also, there was a significant diagnosis × COMT × DAT nonadditive interaction in the right orbital gyrus (Z-score = 4.3; FWEp = 0.04), where, only within patients, greater activation was only associated with a 9-repeat allele and Val-158 conjunction, and with a 10-repeat and Met-158 conjunction (Z-score = 4.3; FWE p = 0.04). These data demonstrate that COMT and DAT genes interact nonadditively to modulate cortical function during executive processing, and also, that this effect is significantly altered in schizophrenia, which may reflect abnormal dopamine function in the disorder.
89 citations
Journal Article•
TL;DR: It is suggested that the reduced frequency of the met allele in the non-affected relatives of FM patients acts as a 'protective' allele in this group and prevents the development of clinical FM.
Abstract: Objectives. Fibromyalgia syndrome (FM) is an idiopathic chronic pain syndrome characterised by widespread nonarticular musculoskeletal pain, generalised tender points, in the absence of inflammatory or structural musculoskeletal abnormalities, accompanied by a constellation of symptoms that include fatigue and disturbances of sleep and mood. Catechol-O-methyltransferase (COMT) is the major catecholamine-clearing pathway and involved in the mediation of pain perception in humans, and the hypothesized role of pain perception in FM. The association between Val/Met polymorphism at the COMT gene was evaluated in FM disorder. Methods. 209 FM female patients were compared with 152 of their non-affected relatives. DNA was obtained from all family members and extracted. We used the logistic based variant of the transmission disequilibrium test to assess association (and linkage) without confounding effect of population stratification. Results. We observed an association between FM and the COMT val 158 met polymorphism in a dose response effect of the COMT genotype and the number of pressure points reported. We also observed that non-affected relatives of FM patients had a reduced percentage of the COMT met allele. Conclusions. Our results are consistent with carriers of the COMT met/met genotype showing increased sensitivity to pain as one mechanism for the role of this gene in conferring risk for FM. We suggest that the reduced frequency of the met allele in the non-affected relatives acts as a 'protective' allele in this group and prevents the development of clinical FM.
TL;DR: A significant effect of gender on brain activations in the left amygdala and right temporal pole is found, where females demonstrated increased activations over males, particularly in females.
Abstract: The functional catechol- O -methyltransferase (COMT Val108/158Met) polymorphism has been shown to have an impact on tasks of executive function, memory and attention and recently, tasks with an affective component. As oestrogen reduces COMT activity, we focused on the interaction between gender and COMT genotype on brain activations during an affective processing task. We used functional MRI (fMRI) to record brain activations from 74 healthy subjects who engaged in a facial affect recognition task; subjects viewed and identified fearful compared to neutral faces. There was no main effect of the COMT polymorphism, gender or genotype×gender interaction on task performance. We found a significant effect of gender on brain activations in the left amygdala and right temporal pole, where females demonstrated increased activations over males. Within these regions, Val/Val carriers showed greater signal magnitude compared to Met/Met carriers, particularly in females. The COMT Val108/158Met polymorphism impacts on gender-related patterns of activation in limbic and paralimbic regions but the functional significance of any oestrogen-related COMT inhibition appears modest.
TL;DR: Smokers with val/val genotypes were more sensitive to the abstinence challenge than carriers of the met allele, with the greatest effects on BOLD signal and performance speed at the highest working memory load.
Abstract: Effect of abstinence challenge on brain function and cognition in smokers differs by COMT genotype
TL;DR: The COMT Val108/158Met polymorphism was shown to influence medial temporal lobe volumes in a linear-additive manner, mirroring its effect on dopamine catabolism, and support a model in which lower COMT activity, and a resulting elevation in extracellular dopamine levels, stimulates growth of medialporal lobe structures.
TL;DR: The results demonstrate the role of the COMT Val/Met polymorphism in the processing of reward, consistent with theoretical explanations that suggest the possible role of dopamine in the MFN and beta power increase generation.
TL;DR: Abnormal hippocampal and lateral ventricular volumes are among the most replicated endophenotypes for psychosis; however, the influences of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on these key brain regions must be very subtle if at all present.
Abstract: Background. Morphometric endophenotypes which have been proposed for psychotic disorders include lateral ventricular enlargement and hippocampal volume reductions. Genetic epidemiological studies support an overlap between schizophrenia and bipolar disorder, and COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes have been implicated in the aetiology of both these disorders. This study examined associations between these candidate genes and morphometric endophenotypes for psychosis. Method. A total of 383 subjects (128 patients with psychosis, 194 of their unaffected relatives and 61 healthy controls) from the Maudsley Family Psychosis Study underwent structural magnetic resonance imaging and genotyping. The effect of candidate genes on brain morphometry was examined using linear regression models adjusting for clinical group, age, sex and correlations between members of the same family. Results. The results showed no evidence of association between variation in COMT genotype and lateral ventricular, and left or right hippocampal volumes. Neither was there any effect of the BDNF, 5-HTTLPR, NRG1 and DTNBP1 genotypes on these regional brain volumes. Conclusions. Abnormal hippocampal and lateral ventricular volumes are among the most replicated endophenotypes for psychosis; however, the influences of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on these key brain regions must be very subtle if at all present.
TL;DR: The present study indicates that the interacting effects within the COMT gene polymorphisms may influence the disease status and response to risperidone in schizophrenia patients, however, the study needs to be replicated in a larger sample set for confirmation, followed by functional studies.
Abstract: Aim: We investigated the catechol-O-methyltrasferase (COMT) gene, which is a strong functional and positional candidate gene for schizophrenia and therapeutic response to antipsychotic medication. Materials & methods: Single-locus as well as detailed haplotype-based association analysis of the COMT gene with schizophrenia and antipsychotic treatment response was carried out using seven COMT polymorphisms in 398 schizophrenia patients and 241 healthy individuals from a homogeneous south Indian population. Further responsiveness to risperidone treatment was assessed in 117 schizophrenia patients using Clinical Global Impressions (CGI). A total of 69 patients with a CGI score of 2 or less met the criteria of good responders and 48 were patients who continued to have a score of 3 and above and were classified as poor responders to risperidone treatment. Results: The association of SNP rs4680 with schizophrenia did not remain significant after adjusting for multiple testing. Haplotype analysis showed highly si...
TL;DR: This study found that the COMT val158met polymorphism was not associated with 4-week fluoxetine therapeutic response; however, association analysis showed that patients with the comT(Val/Val) genotype had poorer responses in the eighth week and consistently showed significantly smaller reductions in HAM-D(21) scores in the eight week.
TL;DR: Previous studies suggesting that genes moderate ADHD treatment response are confirmed and expands to include larger samples, symptom reduction as well as side effects outcomes, and responses over full therapeutic dose ranges to assess differences in both gene and gene × dose interactive effects.
Abstract: Objective This study examines the potential role of candidate genes in moderating treatment effects of methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD). Method Eighty-two subjects with ADHD aged 6 to 17 years participated in a prospective, double-blind, placebo-controlled, multiple-dose, crossover titration trial of immediate release MPH three times daily. The subjects were assessed on a variety of parent and clinician ratings and a laboratory math test. Data reduction based on principal components analysis identified statistically derived efficacy and side effect outcomes. Results Attention-deficit/hyperactivity disorder symptom response was predicted by polymorphisms at the serotonin transporter ( SLC6A4 ) intron 2 VNTR ( p = .01), with a suggested trend for catechol-O-methyltransferase ( COMT ) ( p = .04). Gene × dose interactions were noted on math test outcomes for the dopamine D4 receptor ( DRD4 ) promoter ( p = .008), DRD4 exon 3 VNTR ( p = .006), and SLC6A4 promoter insertion/deletion polymorphism ( 5HTTLPR ) ( p = .02). Irritability was predicted by COMT ( p = .02). Vegetative symptoms were predicted by 5HTTLPR ( p = .003). No significant effects were noted for the dopamine transporter ( SLC6A3 ) or synaptosomal-associated protein 25 ( SNAP25 ). Conclusions This article confirms and expands previous studies suggesting that genes moderate ADHD treatment response. The ADHD outcomes are not unitary but reflect both behavioral and learning domains that are likely influenced by different genes. Future research should emphasize candidate gene and genome-wide association studies in larger samples, symptom reduction as well as side effects outcomes, and responses over full therapeutic dose ranges to assess differences in both gene and gene × dose interactive effects.
TL;DR: Frontotemporal function during verbal generation is modulated by variation in COMT genotype which is altered in schizophrenia, which may reflect the perturbation of central dopamine function associated with the disorder.
TL;DR: In this article, the authors investigated the impact of the related polymorphisms on PPI in healthy human volunteers and confirmed that PPI is influenced by genetic variation in the 5-HT 2A R gene.
TL;DR: The authors tested the hypothesis that a more informative COMT haplotype predicts normal cognitive development in a large population-based cohort of children enrolled in the Avon Longitudinal Study of Parents and Children, and found this three-SNP haplotype predicted both verbal inhibition and working memory.
Abstract: Objective: Genetic variants that contribute to the risk of psychiatric disorders may also affect normal variation in psychological function. Indeed, the behavioral effects of many genetic variants may be better understood as process-specific rather than disease-specific. A functional valine-to-methionine (Val 158 Met) polymorphism in the catechol- O -methyltransferase (COMT) gene has been associated with cognitive function and brain metabolic activity accompanying such tasks. Not all studies are consistent, and less is known about the effect of this polymorphism during development. The authors tested the hypothesis that a more informative COMT haplotype predicts normal cognitive development in a large population-based cohort of children enrolled in the Avon Longitudinal Study of Parents and Children. Method: Effects on verbal and performance IQ as well as verbal inhibition were assessed at age 8, and effects on working memory were assessed at age 10. From the five COMT single nucleotide polymorphisms (SNP...
TL;DR: It is suggested that COMT haplotype variation is associated primarily with the hyperactivity/impulsivity dimension of ADHD and point to the importance of testing this hypothesis in future studies.
Abstract: It has been suggested that symptoms of attention-deficit/hyperactivity disorder (ADHD) is related to low dopamine levels in the prefrontal cortex. The enzyme catechol O-methyltransferase (COMT), which degrades dopamine and other catecholamines, is important for monoamine signaling in this brain-region, but genetic studies of the functional Val158Met (rs4680) polymorphism in ADHD have been inconsistent. However, recently it was shown that also common synonymous COMT variants modulate total COMT enzymatic activity by affecting the expression of the gene [Nackley et al. (2006); Science 314(5807):1930-1933]. We therefore hypothesized that analysis of haplotypes could reveal more about the association between COMT and ADHD symptoms than the Val158Met polymorphism alone. SNPs rs6269, rs4633, rs4818, and rs4680, tagging the common putative functional COMT haplotypes, were genotyped in 435 adult subjects with a clinical diagnosis of ADHD and 383 controls and analyzed for association with ADHD and the hyperactivity/impulsivity and inattention dimensions from the Adult ADHD Self-Report Scale (ASRS). All markers showed a trend for association with the hyperactivity/impulsivity scale, peaking at marker rs6269 (P = 0.007). Haplotype analysis revealed that the rs6269 risk allele tags the suggested high COMT-activity haplotype, which is associated with the highest hyperactivity/impulsivity score in our sample (P = 0.01). Our results also suggest that there is a stepwise decreased hyperactivity/impulsivity score associated with the proposed mid and low activity haplotypes described previously. In conclusion, we suggest that COMT haplotype variation is associated primarily with the hyperactivity/impulsivity dimension of ADHD and point to the importance of testing this hypothesis in future studies.
TL;DR: The role of COMT functional variation in cognition is supported by imaging and cognitive studies showing that the COMT genotype more strongly predicts measures related to the manipulation of information rather than to its storage, which explains some of the discrepancies in the clinical genetic association data.
TL;DR: Tolcapone could be potentially useful in the treatment of conditions with deficient sensorimotor gating and working memory such as schizophrenia and prodromal states but only in a genotype-specific manner.
TL;DR: The ability of tolcapone to increase DA release in response to behaviorally salient stimuli and improve performance of the delayed spatial win-shift (DSWSh) task is characterized to suggest a generalized positive influence on cognition.
Abstract: Background and rationale
Genetic variations in catechol-O-methyl transferase (COMT) or administration of COMT inhibitors have a robust impact on cognition and executive function in humans. The COMT enzyme breaks down extracellular dopamine (DA) and has a particularly important role in the prefrontal cortex (PFC) where DA transporters are sparse. As such, the beneficial cognitive effects of the COMT inhibitor tolcapone are postulated to be the result of increased bioavailability of DA in the PFC. Furthermore, it has been shown previously that COMT inhibitors increase pharmacologically evoked DA but do not affect basal levels in the PFC.
TL;DR: Investigating whether additional minor single nucleotide polymorphisms (SNPs), accruing in 1 to 5% of the population, situated in the COMT transcript region contribute to haplotype-dependent enzymatic activity revealed that inclusion of allelic variants of these minor SNPs in APS or HPS haplotypes did not modify COMT function at the level of mRNA folding, RNA transcription, protein translation, or enzyme activity.
Abstract: Catechol-O-methyltransferase (COMT) is an enzyme that plays a key role in the modulation of catechol-dependent functions such as cognition, cardiovascular function, and pain processing. Three common haplotypes of the human COMT gene, divergent in two synonymous and one nonsynonymous (val(158)met) position, designated as low (LPS), average (APS), and high pain sensitive (HPS), are associated with experimental pain sensitivity and risk of developing chronic musculoskeletal pain conditions. APS and HPS haplotypes produce significant functional effects, coding for 3- and 20-fold reductions in COMT enzymatic activity, respectively. In the present study, we investigated whether additional minor single nucleotide polymorphisms (SNPs), accruing in 1 to 5% of the population, situated in the COMT transcript region contribute to haplotype-dependent enzymatic activity. Computer analysis of COMT ESTs showed that one synonymous minor SNP (rs769224) is linked to the APS haplotype and three minor SNPs (two synonymous: rs6267, rs740602 and one nonsynonymous: rs8192488) are linked to the HPS haplotype. Results from in silico and in vitro experiments revealed that inclusion of allelic variants of these minor SNPs in APS or HPS haplotypes did not modify COMT function at the level of mRNA folding, RNA transcription, protein translation, or enzymatic activity. These data suggest that neutral variants are carried with APS and HPS haplotypes, while the high activity LPS haplotype displays less linked variation. Thus, both minor synonymous and nonsynonymous SNPs in the coding region are markers of functional APS and HPS haplotypes rather than independent contributors to COMT activity.
TL;DR: It is suggested that the Val158Met SNP is involved in risk and protective genotypes for the vulnerability to schizophrenia in Spanish male population.
Abstract: The functional Val158Met polymorphism (rs4680) located at the gene that codes for the catechol-O-methyltransferase (COMT) has been extensively investigated in schizophrenia although current data are still controversial. Since COMT activity is sexually dimorphic, we carried out two independent studies in homogeneous samples of male and female Spanish schizophrenic patients. In males, we found an association between the homozygous Val genotype and the disorder, which resembled a recessive model (P = 0.022; odds ratio [OR] = 1.67). This Val homozygotes overrepresentation is produced at the expense of the heterozygous individuals decrease, whilst the Met homozygotes showed no differences when compared controls and patients. As a consequence, the heterozygous genotype in this sample had a protective effect (P = 0.03; OR = 0.65) and a strong deviation from Hardy–Weinberg equilibrium in male cases was observed (P = 0.006). In addition, a 2-SNP haplotype analysis (rs4818-Val158Met) confirmed there is an overrepresentation of the different homozygous Val genotypes in the male schizophrenic sample. Regarding females, we did not find any statistically significant association between COMT SNP and schizophrenia. In the light of this we suggest that the Val158Met SNP is involved in risk and protective genotypes for the vulnerability to schizophrenia in Spanish male population. © 2009 Wiley-Liss, Inc.
TL;DR: COMT (Val158 Met) polymorphism is not an independent risk factor for AD or MCI, but shows a synergistic effect with APOE ε4 allele that proves greater in women with AD.
Abstract: The aim of this study is to examine the influence of the catechol-O-methyltranferase (COMT) gene (polymorphism Val158 Met) as a risk factor for Alzheimer's disease (AD) and mild cognitive impairment of amnesic type (MCI), and its synergistic effect with the apolipoprotein E gene (APOE). A total of 223 MCI patients, 345 AD and 253 healthy controls were analyzed. Clinical criteria and neuropsychological tests were used to establish diagnostic groups. The DNA Bank of the University of the Basque Country (UPV-EHU) (Spain) determined COMT Val158 Met and APOE genotypes using real time polymerase chain reaction (rtPCR) and polymerase chain reaction (PCR), and restriction fragment length polymorphism (RFLPs), respectively. Multinomial logistic regression models were used to determine the risk of AD and MCI. Neither COMT alleles nor genotypes were independent risk factors for AD or MCI. The high activity genotypes (GG and AG) showed a synergistic effect with APOE e4 allele, increasing the risk of AD (OR = 5.96, 95%CI 2.74-12.94, p < 0.001 and OR = 6.71, 95%CI 3.36-13.41, p < 0.001 respectivily). In AD patients this effect was greater in women. In MCI patients such as synergistic effect was only found between AG and APOE e4 allele (OR = 3.21 95%CI 1.56-6.63, p = 0.02) and was greater in men (OR = 5.88 95%CI 1.69-20.42, p < 0.01). COMT (Val158 Met) polymorphism is not an independent risk factor for AD or MCI, but shows a synergistic effect with APOE e4 allele that proves greater in women with AD.
TL;DR: The authors examined the relationship between an interaction of COMT/MTHFR polymorphisms and volumes of putamen in depressed and nondepressed elders.
Abstract: Objective: Catechol-O-Methyltransferase (COMT) and Methylenetetrahydrofolate reductase (MTHFR) had been reported to relate to depression but with inconsistent results. The basal ganglia are also important in the pathophysiology of affective disorder via connections with limbic system and prefrontal cortex. The authors examined the relationship between an interaction of COMT/ MTHFR polymorphisms and volumes of putamen in depressed and nondepressed elders. Methods: Participants included 170 depressed and 83 nondepressed subjects aged 60 years or older. Subjects completed cross-sectional assessments, including clinical evaluation, brain magnetic resonance imaging (MRI) scan, and COMT Val158Met and MTHFR C677T genotyping. Putamen volumes were measured using 1.5-Tesla whole-body MRI system. Statistical models examined the relationship between COMT/MTHFR genotype, proportional volumes of putamen and depression while controlling for age and sex. Results: After controlling for covariates, depressed subjects with MTHFR C/C, both the right and left putamen have smaller volumes as the number of COMT 158Val increase. The left putamen volumes of depressed subjects with COMT Met/Met are smaller as the number of MTHFR 677T increase compared to nondepressed subjects. Conclusions: Our findings do not support a major role for COMT or MTHFR alone. However, an epigenetic interaction of COMT Val158Met and MTHFR C677T polymorphisms may contribute to putamen volumes differences between depressed and nondepressed subjects. Further studies with a larger sample size are necessary to support a genetically based role for basal ganglia structures in the etiopathogenesis of depression.