COMT Val158Met Research Articles

Vascular and dopaminergic contributors to mild parkinsonian signs in older adults.

Mild parkinsonian signs (MPS) are an underappreciated neurologic condition in older adults; we assessed associations of MPS with measures of dopaminergic (catechol-O-methyltransferase [COMT] genotype, an indicator of synaptic dopamine levels) and vascular (white matter hyperintensities [WMH], an indicator of cerebral small vessel disease) factors. In a cohort of older adults (mean age 82.6 years [SD 2.6]; 58.0% female; 38.8% black), we assessed cross-sectional associations of WMH volume and COMT Val158Met (rs4680) genotype (n = 35 Met/Met, n = 180 Val carriers) with MPS by regression models adjusted for demographic and health characteristics. Interactions between WMH and COMT were assessed and analyses were repeated stratified by COMT genotype (Met/Met related to higher synaptic dopamine vs Val carriers related to lower synaptic dopamine). MPS was present in 42.3% of our sample. WMH (odds ratio [OR] 1.16, confidence interval [CI] 1.05-1.27) but not COMT (Met/Met compared to Val carrier: OR 0.62, CI 0.27-1.42) was related to MPS. There was a significant interaction between WMH and COMT (p = 0.03). Stratified analyses reveled a strong association between WMH and MPS among COMT Val carriers (OR 1.23, CI 1.09-1.38), but not for Met/Met (OR 0.68, CI 0.45-1.02), independent of covariates. WMH had a direct relation with MPS. In contrast, COMT was not associated with MPS, but it did modify the effect of WMH on MPS. The dopaminergic system may provide compensation for the effects of WMH on MPS. These findings suggest that MPS has a vascular rather than dopaminergic origin in older adults, but both factors are important in MPS manifestation.

Task demands, tDCS intensity, and the COMT val158met polymorphism impact tDCS-linked working memory training gains

Working memory (WM) training paired with transcranial direct current stimulation (tDCS) can improve executive function in older adults. The unclear mechanism of tDCS likely depends on tDCS intensity, and task relevant genetic factors (e.g., for WM: COMT val158met, DAT, BDNF val66met). Higher tDCS intensity does not always lead to greater cognitive gains, and genetic polymorphisms may modulate tDCS-linked WM improvements. To evaluate these factors, 137 healthy older adults provided DNA samples and received Visual and Spatial WM training paired with tDCS (sham, 1, 1.5, 2 mA). After one session of tDCS, significant group differences in WM performance were predicted by COMT val158met status. One month after training, there was a significant interaction of tDCS intensity, COMT genotype, and WM task. Specifically, val/val homozygotes benefited most from 1.5 mA tDCS on Visual WM and from 1 mA tDCS on Spatial WM. For met/met homozygotes, 2 mA resulted in significantly poorer performance compared to 1.5 mA on Spatial WM. While this pattern was observed with relatively small sample sizes, these data indicate that variations in COMT val158met may predict the nature of WM improvement after initial and longitudinal tDCS. This contributes to our understanding of the underlying mechanism by which tDCS affects behaviour.

Investigation of the COMT Val158Met variant association with age of onset of psychosis, adjusting for cannabis use.

Objective COMT rs4680 (Val158Met) genotype moderates the effect of cannabis on the age of onset of psychosis (AoP). We investigated the association between rs4680 and AoP, after adjusting for relevant covariates, in a Canadian Caucasian sample.MethodsOne hundred and sixty‐nine subjects with psychosis were recruited. AoP, defined as age of DSM‐IV diagnosis was established using the Structured Clinical Interview for DSM‐IV. Cannabis use data were collected using a self‐report computerized questionnaire. DNA was extracted from saliva and genotyping of the COMT Val158Met polymorphism was done by SNaPshot and TaqMan assays. Logistic regression and Kaplan–Meier analysis results are reported.ResultsIn those who had used cannabis before 20 years of age, rs4680 had a trend level effect on AoP (median AoP: Val/Val < Val/Met < Met/Met 19.37, 20.95, 21.24 years, respectively; log‐rank test p = .051).ConclusionOur data are indicative of the need to further investigate the association between the COMT rs4680 variant and AoP in the context of adolescent cannabis use.

Lack of association between COMT Val158Met and ZDHHC8 rs175174 polymorphisms and susceptibility to schizophrenia in a Brazilian population.

Lack of association between COMT Val158Met and ZDHHC8 rs175174 polymorphisms and susceptibility to schizophrenia in a Brazilian population.

Catechol-O-Methyltransferase gene (val158met) polymorphisms and anxious symptoms in early childhood: The roles of hypothalamus-pituitary-adrenal axis reactivity and life stress.

Individual differences in hypothalamus-pituitary-adrenal (HPA) axis reactivity to stress (measured via salivary cortisol) have been widely implicated in the etiology of internalizing problems such as depression and anxiety. Literature suggests that stress during early childhood is an important source of contextual risk although its effects may be moderated by polymorphisms of neurotransmitter genes. The COMT val158met is one such polymorphism, and literature documents its link to internalizing problems. To extend these findings, and to better understand the role of this polymorphism in developmental risk, we investigated links between the val158met polymorphism and early-age cortisol response. Additionally, we investigated whether cortisol reactivity mediated the link between COMT and emerging internalizing symptoms. The study was conducted in a community sample of 409 preschoolers. Saliva samples were collected pre-stress task (baseline) and every 10min post-stress task for one-hour to asses cortisol response. Child anxious and depressive symptoms were tabulated based on parent-reports. Markers of early childhood stress included marital discord, socio-economic status and the UCLA Life Stress Interview. Findings indicated that the val158met polymorphism is associated with childhood cortisol response (p<0.05). A gene-environment interaction between val158met and life stress also predicted child anxiety symptoms (p<0.01). Finally, cortisol response mediated the main-effect of val158met on child anxiety symptoms (pathway ps<0.05). Analyses suggest that COMT val158met moderates the influence of early life stress on preschool-age symptoms of anxiety. Additionally, cortisol reactivity acts as a mechanistic mediator of the main-effect of COMT genotype on child anxious symptoms.

Joint Impact of Early Life Adversity and COMT Val158Met (rs4680) Genotypes on the Adult Cortisol Response to Psychological Stress.

Exposure to stress during critical periods of development can diminish stress reactivity by the hypothalamic-pituitary-adrenocortical axis. Genetic characteristics may further modify this effect of early adversity, leading to a gene by environment (G × E) interaction on stress reactivity in adulthood. Val-allele carriers of a common polymorphism of the COMT gene (Val158Met, rs4680) have rapid removal of catecholamines in the prefrontal cortex, limbic system, and reward centers. Carriers of the Val and Met alleles may therefore respond differently to the environment and differ in the long-term impact of exposure to early life adversity (ELA). We measured saliva cortisol reactivity to public speaking and mental arithmetic stress in 252 healthy young adults exposed to low, medium, and high levels of ELA and who were genotyped for the Val158Met polymorphism. Cortisol responses showed a G × E interaction (F(4,243) = 2.78, p = .028); simple effects tests showed that Met/Met carriers had progressively smaller cortisol responses with greater levels of ELA. In comparison, Val/Val homozygotes had blunted responses that did not vary with ELA exposure. Met/Met homozygotes seem sensitive to stressful events in childhood and adolescence, leading to environmental programming of the stress axis. Glucocorticoid responsivity may represent a common pathway revealing targeted genetic vulnerabilities to the long-term effects of early life stress. The results suggest that further G × E studies of ELA are warranted in relation to health behaviors and health outcomes in adulthood.

Depressive symptoms in schizophrenia and dopamine and serotonin gene polymorphisms

Although depressive symptoms seem to be frequent in schizophrenia they have received significantly less attention than other symptom domains. As impaired serotonergic and dopaminergic neurotransmission is implicated in the pathogenesis of depression and schizophrenia this study sought to investigate the putative association between several functional gene polymorphisms (SERT 5-HTTLPR, MAO-A VNTR, COMT Val158Met and DAT VNTR) and schizophrenia. Other objectives of this study were to closely examine schizophrenia symptom domains by performing factor analysis of the two most used instruments in this setting (Positive and negative syndrome scale - PANSS and Calgary depression rating scale - CDSS) and to examine the influence of investigated gene polymorphisms on the schizophrenia symptom domains, focusing on depressive scores. A total of 591 participants were included in the study (300 schizophrenic patients and 291 healthy volunteers). 192 (64%) of schizophrenic patients had significant depressive symptoms. Genotype distribution revealed no significant differences regarding all investigated polymorphisms except the separate gender analysis for MAO-A gene polymorphism which revealed significantly more allele 3 carriers in schizophrenic males. Factor analysis of the PANSS scale revealed the existence of five separate factors (symptom domains), while the CDSS scale revealed two distinct factors. Several investigated gene polymorphisms (mostly SERT and MAO-A, but also COMT) significantly influenced two factors from the PANSS (aggressive/impulsive and negative symptoms) and one from the CDSS scale (suicidality), respectively. Depressive symptoms in schizophrenic patients may be influenced by functional gene polymorphisms, especially those implicated in serotonergic neurotransmission.

Erratum to: Age differences in arterial and venous extra-cerebral blood flow in healthy adults: contributions of vascular risk factors and genetic variants.

Sufficient cerebral blood flow (CBF) and venous drainage are critical for normal brain function, and their alterations can affect brain aging. However, to date, most studies focused on arterial CBF (inflow) with little attention paid to the age differences in venous outflow. We measured extra-cerebral arterial and venous blood flow rates with phase-contrast MRI and assessed the influence of vascular risk factors and genetic polymorphisms (ACE insertion/deletion, COMT val158met, and APOEe4) in 73 adults (age 18–74 years). Advanced age, elevated vascular risk, ACE Deletion, and COMT met alleles were linked to lower in- and outflow, with no effects of APOE e4 noted. Lower age-related CBF rate was unrelated to brain volume and was observed only in val homozygotes of COMTval158met. Thus, in a disease-free population, age differences in CBF may be notable only in persons with high vascular risk and carriers of genetic variants associated with vasoconstriction and lower dopamine availability. It remains to be established if treatments targeting alleviation of the mutable factors can improve the course of cerebrovascular aging in spite of the immutable genetic influence.

Association between COMT Val158Met polymorphism and competition results of competitive swimmers

ABSTRACTRecent studies have shown the contribution of genetic determinants to athletes’ physical ability. However, despite the fact that cognitive abilities like self-control and stress-tolerance influence athletes’ competitive performance, few studies to date have investigated the association between genetic polymorphism, which is linked to cognitive ability and athletic performance. The present study investigated the link between single-nucleotide polymorphisms (SNPs), which are known to exert influences on dopaminergic neural function and competitive performance of swimmers. The results have revealed superior competitive performance in competitive swimmers with Met allele of catechol-O-methyltransferase Val158Met polymorphism than those with Val/Val genotype. The investigated SNPs of DRD2 and DRD3 were not associated with swimmer’s competitive performance. This finding indicates that genetic polymorphism linked to cognitive ability influences the athletes’ performance.

The association between well-being and the COMT gene: Dispositional gratitude and forgiveness as mediators

BackroundPrevious studies have demonstrated the contributions of genetic variants and positive psychological traits (e.g. gratitude and forgiveness) to well-being. However, little is known about how genes interact with positive traits to affect well-being. MethodsTo investigate to what extent the COMT Val158Met polymorphism modulates well-being and to what extent dispositional gratitude and forgiveness mediate the individual differences in well-being, 445 participants were recruited and required to complete a battery of questionnaires. ResultsWe found that individuals with a smaller number of the Met alleles reported greater well-being, less depressive symptoms, and greater tendencies for gratitude and forgiveness. Moreover, dispositional gratitude and forgiveness mediated the genotype effects on well-being and depressive symptoms. These results remained significant after controlling for non-genetic factors (socioeconomic status, religious beliefs, romantic relationship status, parenting style). LimitationThe sample size limits the generalizability of results. ConclusionThis study demonstrates the contribution of the COMT Val158Met polymorphism to individual differences in well-being and suggests a potential psychobiological pathway from dopaminergic and noradrenergic systems to happiness.

M93. No Association Between COMT Val158Met and Prepulse Inhibition: Findings From the Marine Resiliency Study

M93. No Association Between COMT Val158Met and Prepulse Inhibition: Findings From the Marine Resiliency Study

30. COMT Val158Met and MTHFR C677T Moderate Risk of Schizophrenia in Response to Childhood Trauma

30. COMT Val158Met and MTHFR C677T Moderate Risk of Schizophrenia in Response to Childhood Trauma

25. Cortical Information Processing in Patients With Schizophrenia is Modulated by Tolcapone: Role of COMT val158met Genotype

25. Cortical Information Processing in Patients With Schizophrenia is Modulated by Tolcapone: Role of COMT val158met Genotype

Polymorphism in xenobiotic and estrogen metabolizing genes, exposure to perfluorinated compounds and subsequent breast cancer risk: A nested case-control study in the Danish National Birth Cohort

In the present case-cohort study based on prospective data from Danish women, we aimed to estimate the main effect of polymorphisms in genes known to be involved in the steroid hormone metabolic pathway and xenobiotic metabolism on the risk of developing breast cancer. We also studied a possible effect measure modification between genotypes and levels of serum perfluoroalkylated substances (PFASs) on the risk to breast cancer. We have previously reported a weak association between serum PFASs levels and the risk of breast cancer for this study population of Danish pregnant nulliparous women as well as in a smaller case-control study of Greenlandic women.The study population consisted of 178 breast cancer cases and 233 controls (tabnulliparous and frequency matched on age) nested within the Danish National Birth Cohort (DNBC), which was established in 1996-2002. Blood samples were drawn at the time of enrollment (6-14 week of gestation). Serum levels of 10 perfluorocarboxylated acids (PFCAs), 5 perfluorosulfonated acids (PFSAs) and 1 sulfonamide (perflurooctane-sulfonamide, PFOSA) were measured. Genotyping was conducted for CYP1A1 (Ile462Val; rs1048943), CYP1B1 (Leu432Val; rs1056836), COMT (Val158Met; rs4680), CYP17A1 (A1→ A2; rs743572); CYP19A1 (C→T; rs10046) by the TaqMan allelic discrimination method.In overall, no significant associations were found between the investigated polymorphisms and the risk of breast cancer in this study among Danish women. The previously found association between PFOSA and risk of breast cancer did vary between different genotypes, with significantly increased risk confined to homozygous carriers of the following alleles: COMT (Met), CYP17 (A1) and CYP19 (C).Conclusion:Our results indicate that polymorphisms in COMT, CYP17 and CYP19 which are involved in estrogen biosynthesis and metabolism can modulate the potential effects of PFOSA exposure on the development of breast cancer.

Age differences in arterial and venous extra-cerebral blood flow in healthy adults: contributions of vascular risk factors and genetic variants.

Sufficient cerebral blood flow (CBF) and venous drainage are critical for normal brain function, and their alterations can affect brain aging. However, to date, most studies focused on arterial CBF (inflow) with little attention paid to the age differences in venous outflow. We measured extra-cerebral arterial and venous blood flow rates with phase-contrast MRI and assessed the influence of vascular risk factors and genetic polymorphisms (ACE insertion/deletion, COMT val158met, and APOEε4) in 73 adults (age 18-74years). Advanced age, elevated vascular risk, ACE Deletion, and COMT met alleles were linked to lower in- and outflow, with no effects of APOE ε4 noted. Lower age-related CBF rate was unrelated to brain volume and was observed only in val homozygotes of COMTval158met. Thus, in a disease-free population, age differences in CBF may be notable only in persons with high vascular risk and carriers of genetic variants associated with vasoconstriction and lower dopamine availability. It remains to be established if treatments targeting alleviation of the mutable factors can improve the course of cerebrovascular aging in spite of the immutable genetic influence.

Cannabis use, COMT, BDNF and age at first-episode psychosis

Although an interaction between COMT Val158Met and BDNF Val66Met polymorphisms with cannabis use has been proposed with respect to the risk of psychosis emergence, findings remain inconclusive. The aim of the present study was to evaluate the different possible associations between these polymorphisms and early cannabis use and the age at the first episode of psychosis. The relationship between age at psychosis onset and COMT Val158Met and BDNF Val66Met polymorphisms with early cannabis use as well as those factors associated with early cannabis use were investigated. Among 260 Caucasian first-episode psychosis patients, early cannabis use and the presence of the met-allele from the BDNF Val66Met polymorphism were significantly associated with age at psychosis onset. Furthermore, early cannabis use was significantly associated with male gender in the logistic regression analysis. These findings provide evidence of the important role of early cannabis use and the Val66Met BDNF polymorphism on age at psychosis onset and they point out to sex-specific differences in cannabis use patterns.

Influence of COMT Val158Met polymorphism on emotional decision-making: A sex-dependent relationship?

The biological underpinnings of sex-related differences in decision-making are still under-explored. The COMT gene is related to sexual dimorphism and with different choices made under uncertainty, albeit no study has specifically investigated a moderation effect of sex on the association between the COMT gene and the performance on decision-making paradigms. In this study, we investigated the influence of the COMT Val158Met polymorphism on Iowa Gambling Task (IGT) performance depending on sex in a healthy adult sample. Participants were 192 healthy adults (84 men and 108 women). The first 40 choices in the IGT were considered decisions under ambiguity and the last 60 choices decisions under risk. To test our moderation hypothesis we used a separate regressions approach. The results revealed a sex-dependent effect of COMT Va l158Met polymorphism on decision-making as measured by the IGT. Val/Val women showed the best performance in the last trials of the IGT. Therefore, the COMT Val158Met polymorphism may be considered a genetic marker underlying sex differences in decision-making.

The Role of Dopamine in Anticipatory Pursuit Eye Movements: Insights from Genetic Polymorphisms in Healthy Adults.

There is a long history of eye movement research in patients with psychiatric diseases for which dysfunctions of neurotransmission are considered to be the major pathologic mechanism. However, neuromodulation of oculomotor control is still hardly understood. We aimed to investigate in particular the impact of dopamine on smooth pursuit eye movements. Systematic variability in dopaminergic transmission due to genetic polymorphisms in healthy subjects offers a noninvasive opportunity to determine functional associations. We measured smooth pursuit in 110 healthy subjects genotyped for two well-documented polymorphisms, the COMT Val158Met polymorphism and the SLC6A3 3′-UTR-VNTR polymorphism. Pursuit paradigms were chosen to particularly assess the ability of the pursuit system to initiate tracking when target motion onset is blanked, reflecting the impact of extraretinal signals. In contrast, when following a fully visible target sensory, retinal signals are available. Our results highlight the crucial functional role of dopamine for anticipatory, but not for sensory-driven, pursuit processes. We found the COMT Val158Met polymorphism specifically associated with anticipatory pursuit parameters, emphasizing the dominant impact of prefrontal dopamine activity on complex oculomotor control. In contrast, modulation of striatal dopamine activity by the SLC6A3 3′-UTR-VNTR polymorphism had no significant functional effect. Though often neglected so far, individual differences in healthy subjects provide a promising approach to uncovering functional mechanisms and can be used as a bridge to understanding deficits in patients.

Does COMT val158met polymorphism influence P50 sensory gating, eye tracking or saccadic inhibition dysfunctions in schizophrenia?

Three electrophysiological endophenotypes are routinely studied in schizophrenia (SCZ): smooth pursuit eye movement (SPEM) dysfunction, deficits in P50 auditory-evoked potential inhibition, and saccadic inhibition deficits. The current study aimed to investigate the relationship between the COMT val158met polymorphism and these three endophenotypes. One hundred four SCZ patients (DSM-IV-R criteria) and 89 healthy controls were included in this study. P50 auditory-evoked potential inhibition, antisaccade paradigm and SPEM were analyzed. All individuals were genotyped for the COMT val158met. SCZ patients showed a higher rate of deficits measured by the SPEM, antisaccade and P50 inhibition paradigms without association with COMT val158met. However, in our control group, we have found an association between the Val polymorphism and the smoking status. More importantly, we have found a higher accuracy of saccades during the predictive pursuit task associated to the Met polymorphism in controls but not in SCZ patients who were receiving antidopaminergic medications. This result is in line with the hypothesis of the relationship between the Met polymorphism of the COMT gene, a higher level of dopamine in the prefrontal cortex and the role of the fronto-cerebellar loop in smooth predictive pursuit.

P.2.d.035 - The effect of COMT Val158Met genotype on neural response and performance during spatial working memory in remitted patients with bipolar disorder

P.2.d.035 - The effect of COMT Val158Met genotype on neural response and performance during spatial working memory in remitted patients with bipolar disorder