Effect Of catechol-O-methyltransferase Research Articles

0205 Catechol-O-methyltransferase Genotype, but not Dopamine Receptor D2 Genotype, Modulates Slow Wave Sleep

Abstract Introduction Slow wave sleep (SWS), a putative marker of sleep homeostasis, robustly increases following total sleep deprivation (TSD). The neurotransmitter dopamine is substantively involved in sleep-wake regulation. Single nucleotide polymorphisms (SNP) in the dopaminergic genes of dopamine receptor D2 (DRD2) and catechol-O-methyltransferase (COMT) have been found to alter dopamine availability primarily in the striatum and prefrontal cortex (PFC), respectively. Here, we investigate if these SNPs are associated with changes in SWS at baseline and following TSD. Methods N=105 healthy adults (ages 26.5±5.0; 55 females) completed one of three 4-day/3-night in-laboratory studies with 10h baseline sleep opportunity (22:00–08:00), 38h TSD period, and 10h recovery sleep opportunity. Sleep periods were recorded polysomnographically and visually scored according to AASM criteria. DNA isolated from whole blood was assayed for DRD2 (C957T, rs6277) and COMT (Val158Met, rs4680) genotypes using real-time PCR. For each genotype, SWS duration was analyzed using mixed-effects ANOVA with fixed effects for genotype, night (baseline vs. recovery), and their interaction, controlling for study, and a random effect over subjects on the intercept. Results DRD2 genotypes (25 C/C, 52 C/T, 28 T/T) and COMT genotypes (23 Val/Val, 58 Val/Met, 24 Met/Met) were in Hardy-Weinberg Equilibrium. As expected, SWS was substantially increased during recovery sleep compared to baseline. There was no main effect of DRD2 (F[2,102]=2.78, p=0.07), nor interaction of DRD2 by night (F[2,102]=1.45, p=0.24). However, there was a significant main effect of COMT on SWS duration (F[2,102]=3.20, p=0.04), without interaction of COMT by night (F[2,102]=1.43, p=0.24). Compared to Met allele carriers, Val homozygotes displayed reduced SWS duration during both baseline and recovery sleep. Conclusion The DRD2 T allele is associated with decreased dopamine D2 receptors and decreased dopaminergic signaling in the striatum relative to the C allele. The COMT Val allele is associated with increased enzymatic activity and decreased dopaminergic signaling in the PFC relative to the Met allele. Our results indicate that compared to striatal dopamine, PFC dopamine may be a more prominent mediator of SWS regulation, with less PFC dopamine corresponding to less SWS. This needs to be confirmed in a larger sample. Support (if any) CDMRP W81XWH1610319; USAMRDC W81XWH1810100; ONR N000141310302; NIH R21CA16769; ARO W911NF2210223.

Catechol-O-Methyltransferase Effects on Smoking: A Review and Proof of Concept of Sex-Sensitive Effects.

This article reviews recent research on how catechol-O-methyltransferase (COMT) may impact cigarette smoking behavior, and how effects may be sex-sensitive. Preliminary data are presented on sex-sensitive effects of COMT on response to short-term abstinence in individuals who smoke. Although research is mixed, functional variants in the COMT gene have been linked with smoking behavior, cessation outcomes and nicotine abstinence-related symptoms. Our proof-of-concept preliminary data from a human laboratory study of individuals who smoke cigarettes found that those with the high COMT enzyme activity genotype (Val/Val) reported more severe smoking urges and withdrawal symptoms following overnight abstinence than Met carriers. These effects were present in women, but not in men and were abstinent-dependent, in that they dissipated following nicotine administration. The preliminary data showing sex-sensitive pharmacogenetic effects may shed light on mechanisms contributing to sex differences in barriers to smoking cessation or potential sex-specific treatment options.

Influence of COMT (rs4680) and DRD2 (rs1076560, rs1800497) Gene Polymorphisms on Safety and Efficacy of Methylphenidate Treatment in Children with Fetal Alcohol Spectrum Disorders

Fetal alcohol spectrum disorders (FASD) in a course of high prenatal alcohol exposure (hPAE) are among the most common causes of developmental disorders. The main reason for pharmacological treatment of FASD children is attention deficit hyperactivity disorder (ADHD), and methylphenidate (MPH) is the drug of choice. The aim of the study was to assess whether children born of hPAE with ADHD, with or without morphological FASD, differ in terms of catechol-O-methyltransferase (COMT) and dopamine receptor D2 (DRD2) gene polymorphisms, and if genetic predisposition affects response and safety of MPH treatment. The polymorphisms of COMT (rs4680) and DRD2 (rs1076560, rs1800497) were analyzed in DNA samples. A borderline significance was found for the correlation between MPH side effects and the G allele of COMT (rs4680) (p = 0.04994) in all ADHD children. No effect of COMT (rs4680) and DRD2 (rs1076560, rs1800497) polymorphisms and the treatment efficacy was observed. The analyzed DRD2 and COMT gene polymorphisms seem to play no role in MPH efficacy in ADHD children with hPAE, while low-activity COMT (Met158) variant carriers may be more intolerant to MPH. The MPH treatment is effective in ADHD independent of FASD, although the ADHD-FASD variant requires higher doses to be successful. These results may help in optimization and individualization in child psychiatry.

Distinct roles for dopamine clearance mechanisms in regulating behavioral flexibility

Dopamine plays a crucial role in adaptive behavior, and dysfunctional dopamine is implicated in multiple psychiatric conditions characterized by inflexible or inconsistent choices. However, the precise relationship between dopamine and flexible decision making remains unclear. One reason is that, while many studies have focused on the activity of dopamine neurons, efficient dopamine signaling also relies on clearance mechanisms, notably the dopamine transporter (DAT), which predominates in striatum, and catechol-O-methyltransferase (COMT), which predominates in cortex. The exact locus, extent, and timescale of the effects of DAT and COMT are uncertain. Moreover, there is limited data on how acute disruption of either mechanism affects flexible decision making strategies mediated by cortico-striatal networks. To address these issues, we combined pharmacological modulation of DAT and COMT with electrochemistry and behavior in mice. DAT blockade, but not COMT inhibition, regulated sub-second dopamine release in the nucleus accumbens core, but surprisingly neither clearance mechanism affected evoked release in prelimbic cortex. This was not due to a lack of sensitivity, as both amphetamine and atomoxetine changed the kinetics of sub-second release. In a multi-step decision making task where mice had to respond to reversals in either reward probabilities or the choice sequence to reach the goal, DAT blockade selectively impaired, and COMT inhibition improved, performance after reward reversals, but neither manipulation affected the adaptation of choices after action-state transition reversals. Together, our data suggest that DAT and COMT shape specific aspects of behavioral flexibility by regulating different aspects of the kinetics of striatal and cortical dopamine, respectively.

Interaction of Catechol-O-methyltransferase Val158 Met polymorphism and sex influences association of parietal intrinsic functional connectivity and immediate verbal memory.

IntroductionSex differences modulate catechol‐O‐methyltransferase (COMT) genotype effect at a synaptic dopamine level, which influences brain function as well as cognitive performance. In this study, we investigated how COMT Val158Met polymorphism and sex affect intrinsic functional connectivity and memory.MethodsIntrinsic functional networks were extracted using independent component analysis of resting‐state functional magnetic resonance imaging data from 186 healthy young COMT‐genotyped participants. The association of these functional networks and memory function was tested to investigate whether the effect of COMT × sex interaction influences the association of intrinsic functional connectivity and memory performance. Quadratic curve fit estimation was used to examine the relationship between functional connectivity and speculative dopamine level among groups.ResultsCOMT MM/MV carriers, relative to VV carriers, showed increased functional connectivity in left superior parietal lobule and right inferior frontal gyrus. Further, male MM/MV carriers showed significant higher mean functional connectivity in left inferior parietal lobule relative to male VV carriers and female MM/MV carriers, which was associated with worse immediate verbal recall performance. Additionally, the relationship between inferior parietal lobule functional connectivity and speculative dopamine level among groups fits the quadratic curve.ConclusionsThese findings suggest that the interaction of COMT genotype and sex might regulate synaptic dopaminergic concentrations and influence the association of intrinsic functional connectivity and immediate verbal memory in left inferior parietal lobule.

Catechol-O-methyltransferase Val158Met Genotype and Early-Life Family Adversity Interactively Affect Attention-Deficit Hyperactivity Symptoms Across Childhood.

Attention-deficit hyperactivity disorder (ADHD) is among the most commonly diagnosed psychiatric disorders of childhood. The dopaminergic system has been shown to have substantial effects on its etiology, with both functional Catechol-O-methyltransferase (COMT) Val158Met genotype and early-life environmental adversity involved in the risk of inattention and hyperactivity/impulsivity symptoms. In this prospective longitudinal study, we examined for the first time the impact of proximal and distal early-life family adversity and COMT Val158Met polymorphism gene – both the direct and the interactive effects, on children’s ADHD symptoms across childhood. Data came from the Family Life Project, a prospective longitudinal study of 1,292 children and families in high poverty from birth to 11 years. In infancy, data regarding socioeconomic (SES)-risk-factors, observed-caregiving behaviors, and DNA genotyping were collected. In early and middle childhood teachers rated the occurrence and severity of the child’s ADHD symptoms. Multilevel growth curve models revealed independent effects of COMT, early-life SES-risk and negative caregiving on ADHD symptoms in early and middle childhood. Significant gene-environment interactions were found, indicating that overall, carriers of at least one COMT158Met allele were more sensitive to early-life adversity, showing higher inattention and hyperactivity/impulsivity symptoms severity in childhood when exposed to high SES-risk factors in infancy, compared to Val-Val carriers. Findings provide new insights into the complex etiology of ADHD and underline the need for further investigation of the neuronal mechanisms underlying gene-environment interactions. Findings might have implications for prevention and intervention strategies with a focus on early-life family relationships in genetically at-risk children.

Low catechol-O-methyltransferase and stress potentiate functional pain and depressive behavior, especially in female mice

Low levels of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, and stress, which potentiates catecholamine release from sympathetic nerves, are fundamental to chronic functional pain syndromes and comorbid depression, which predominantly affect females. Here, we sought to examine the independent and joint contributions of low COMT and stress to chronic functional pain and depression at the behavioral and molecular level. Male and female C57BL/6 mice received sustained systemic delivery of the COMT inhibitor OR486 over 14 days and underwent a swim stress paradigm on days 8 to 10. Pain and depressive-like behavior were measured over 14 days, and brain-derived neurotrophic factor (BDNF; a factor involved in nociception and depression) and glucocorticoid receptor (GR; a stress-related receptor) expression were measured on day 14. We found that stress potentiates the effect of low COMT on functional pain and low COMT potentiates the effect of stress on depressive-like behavior. The joint effects of low COMT and stress on functional pain and depressive-like behavior were significantly greater in females vs males. Consistent with behavioral data, we found that stress potentiates COMT-dependent increases in spinal BDNF and low COMT potentiates stress-dependent decreases in hippocampal BDNF in females, but not males. Although low COMT increases spinal GR and stress increases hippocampal GR expression, these increases are not potentiated in the OR486 + stress group and are not sex-specific. These results suggest that genetic and environmental factors that enhance catecholamine bioavailability cause abnormalities in BDNF signaling and increase risk of comorbid functional pain and depression, especially among females.

Age-specific associations among functional COMT Val158Met polymorphism, resting parasympathetic nervous control and generalized anxiety disorder

The functional Val158Met polymorphism (rs4680) of the Catechol-O-Methyltransferase (COMT) gene has been implicated in generalized anxiety disorder (GAD); however, the underlying neural mechanisms remain unexamined. Recent evidence reveals that low resting parasympathetic (vagal) control is an endophenotypic predictor of anxiety, while the effect of COMT rs4680 differs at different ages. Thus, we examined whether the COMT Val158Met variant could increase the risk of GAD through decreased resting parasympathetic nervous control in an age-specific manner. COMT rs4680 polymorphism was genotyped in 1,655 Han Chinese adults (1,142 healthy subjects and 513 patients with GAD; age: 20–65). High-frequency power (HF) of heart rate variability (HRV) was used to measure resting state parasympathetic nervous regulation. Non-genetic factors, such as gender, smoking status, medication use and comorbidity conditions, were treated as covariates. After adjusting for relevant covariates, there was a significant age x COMT genotype interaction on resting HF of HRV. In younger adults, Met allele carriers had a significantly lower HF index; however, older adults exhibited the opposite pattern, with Val/Val homozygotes exhibiting decreased HF values. Moreover, reduced HF-HRV is associated with increased risk of GAD. Finally, pathway analysis revealed a significant indirect effect of COMT on the risk of GAD via reduced resting HF-HRV, in the aforementioned age-dependent manner. Our findings are the first to demonstrate that COMT Val158Met polymorphism is associated with risk of GAD via reduced resting parasympathetic nervous control, an age-specific risk pathway.

The impact of Catechol-O-methyl transferase knockdown on the cell proliferation of hormone-responsive cancers

Estrogen (E2) plays a central role in the development and progression of hormone-responsive cancers. Estrogen metabolites exhibit either stimulatory or inhibitory roles on breast and prostate cells. The catechol metabolite 4-hydroxyestradiol (4-OHE2) enhances cell proliferation, while 2-methoxyestradiol (2 ME) possesses anticancer activity. The major metabolizing enzyme responsible for detoxifying the deleterious metabolite 4-OHE2 and forming the anticancer metabolite 2 ME is Catechol-O-Methyl Transferase (COMT). The current work investigated the relationship between the expression level of COMT and the cell proliferation of hormone-responsive cancers. The results showed that COMT silencing enhanced the cell proliferation of ER-α positive cancer cells MCF-7 and PC-3 but not the cells that lack ER-α expression as MDA-MB231 and DU-145. The data generated from our study provides a better understanding of the effect of COMT on critical signaling pathways involved in the development and progression of breast cancer (BC) and prostate cancer (PC) including ER-α, p21cip1, p27kip1, NF-κB (P65) and CYP19A1. These findings suggest that COMT enzyme plays a tumor suppressor role in hormone receptor-positive tumors which opens the door for future studies to validate COMT expression as a novel biomarker for the prediction of cancer aggressiveness and treatment efficacy.

The Effects of COMT Polymorphism on Cortical Thickness and Surface Area Abnormalities in Children with ADHD.

The catechol-O-methyltransferase (COMT) gene is associated with frontal cortex development and the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). However, how the COMT gene impacts brain structure and behavior in ADHD remains unknown. In the present study, we identify the effect of COMT on cortical thickness and surface area in children with ADHD and children with typically developing (TD) using a machine learning approach. In a sample of 39 children with ADHD and 34 age- and IQ-matched TD children, we found that cortical thickness and surface area differences were predominantly observed in the frontal cortex. Furthermore, a path analysis revealed that a COMT genotype affected abnormal development of the frontal cortex in terms of both cortical thickness and surface area and was associated with working memory changes in children with ADHD. Our study confirms that the role of COMT in ADHD is not restricted to the development of behavior but may also affect the cortical thickness and surface area. Thus, our findings may help to improve the understanding of the neuroanatomic basis for the relationship between the COMT genotype and ADHD pathogenesis.

1.30 The Effects of Catechol-O-Methyltransferase (COMT) Polymorphism on Cortical Thickness and Surface Area Abnormalities in Children With ADHD

The catechol-O-methyltransferase (COMT) gene is associated with frontal cortex development and the pathophysiology of ADHD. However, how the COMT gene impacts brain structure and behavior in ADHD remains unknown. In the present study, we identify the effect of COMT on cortical thickness and surface area in children with ADHD and children with typical development (TD) by use of a machine-learning approach.

Interacting Effect of Catechol-O-Methyltransferase (COMT) and Monoamine Oxidase A (MAOA) Gene Polymorphisms, and Stressful Life Events on Aggressive Behavior in Chinese Male Adolescents.

Numerous studies have demonstrated that both catechol-O-methyltransferase (COMT) gene and monoamine oxidase A (MAOA) gene have been involved in aggressive behavior, as have stressful life events (SLEs). However, most of available evidence was based upon single gene or single gene–environment design, which is limited in accounting for the variance of aggressive behavior, a complex phenotype. This study examined the possible gene × gene × environment interactions between SLE (interpersonal problems and academic pressure) and two genetic polymorphisms (MAOA T941G and COMT Ala22/72Ser) correlated with aggressive behaviors in a sample of 658 Chinese male adolescents. Mothers and teachers reported on adolescents’ aggressive behavior using Achenbach’s Child Behavior Checklist and Teacher Report Form, respectively. Adolescents completed Self-Rating Life Events Checklist. Saliva samples were collected for DNA analysis. The results revealed no main effects of MAOA T941G and COMT Ala22/72Ser polymorphisms on male adolescents’ aggressive behaviors. However, a two-way interactive effect of interpersonal problems and MAOA T941G genotype on teacher-reported aggressive behavior was observed: adolescents with lower activity of MAOA T allele, but not those with MAOA G allele, exhibited greater aggressive behavior with an increase in interpersonal problems. A three-way interaction among COMT Ala22/72Ser and MAOA T941G polymorphisms, and SLE in the academic pressure on aggressive behavior was also identified. Among adolescents with lower activity of COMT GT/TT genotype and MAOA T allele, the higher level of academic pressure was significantly linked with an amplification of aggressive behavior, whereas this association didn’t exist among those with other genotypes. The present study presents the first evidence of COMT × MAOA × SLE interaction effect on male adolescents’ aggressive behavior, highlights the importance of considering distinct domains of stressful events and information bias when examining the effect of MAOA and COMT on aggressive behavior, and thereby contributes to MAOA gene-aggression and COMT gene-aggression literature.

Sex-specific effects of COMT Val158Met polymorphism on corpus callosum structure: A whole-brain diffusion-weighted imaging study.

BackgroundGenetic polymorphisms play a significant role in determining brain morphology, including white matter structure and may thus influence the development of brain functions. The main objective of this study was to examine the effect of Val158Met (rs4680) polymorphism of Catechol‐O‐Methyltransferase (COMT) gene on white matter connectivity in healthy adults.MethodsWe used a whole‐brain diffusion‐weighted imaging method with Tract‐Based Spatial Statistics (TBSS) analysis to examine white matter structural integrity in intrinsic brain networks on a sample of healthy subjects (N = 82).ResultsResults revealed a sex‐specific effect of COMT on corpus callosum (CC): in males only, Val homozygotes had significantly higher fractional anisotropy (FA) compared to Met‐carriers. Volume‐of‐interest analysis showed a genotype by sex interaction on FA in genu and rostral midbody of CC, whereby Val males demonstrated higher FA than Met females.ConclusionsThese results demonstrate the key effect of genes by sex interaction, rather than their individual contribution, on the corpus callosum anatomy.

Nonlinear modulation of interacting between COMT and depression on brain function

BackgroundThe catechol-O-methyltransferase (COMT) gene is related to dopamine degradation and has been suggested to be involved in the pathogenesis of major depressive disorder (MDD). However, how this gene affects brain function properties in MDD is still unclear. MethodsFifty patients with MDD and 35 cognitively normal participants underwent a resting-state functional magnetic resonance imaging scan. A voxelwise and data-drive global functional connectivity density (gFCD) analysis was used to investigate the main effects and the interactions of disease states and COMT rs4680 gene polymorphism on brain function. ResultsWe found significant group differences of the gFCD in bilateral fusiform area (FFA), post-central and pre-central cortex, left superior temporal gyrus (STG), rectal and superior temporal gyrus and right ventrolateral prefrontal cortex (vlPFC); abnormal gFCDs in left STG were positively correlated with severity of depression in MDD group. Significant disease×COMT interaction effects were found in the bilateral calcarine gyrus, right vlPFC, hippocampus and thalamus, and left SFG and FFA. Further post-hoc tests showed a nonlinear modulation effect of COMT on gFCD in the development of MDD. Interestingly, an inverted U-shaped modulation was found in the prefrontal cortex (control system) but U-shaped modulations were found in the hippocampus, thalamus and occipital cortex (processing system). ConclusionOur study demonstrated nonlinear modulation of the interaction between COMT and depression on brain function. These findings expand our understanding of the COMT effect underlying the pathophysiology of MDD.

COMT and BDNF Gene Variants Help to Predict Alcohol Consumption in Alcohol-dependent Patients.

The neurobiology of alcohol dependence (AD) involves alterations in neurotransmitters and the stress response. We hypothesized that an interaction between functional variants of dopaminergic and neurotrophic genes may influence drinking in AD. The relationship between alcohol consumption and single-nucleotide polymorphisms, Val66Met in the brain-derived neurotrophic factor (BDNF), and Val158Met in the catechol-O-methyltransferase (COMT), was analyzed among 281 alcohol-dependent individuals. Individuals carrying both the COMT Met158Met genotype and the BDNF Val66Val genotype drank more than those with other variants of these genes (P = 0.039). Those who had a family history of AD also drank more than those without a family history (P = 0.048). Patients with both Met/Met genotype in the COMT Val158Met polymorphism and Val/Val genotype in the BDNF Val66Met polymorphism suffered from more health problems than those carrying other variants (P = 0.030) and had lower motivation to change drinking patterns (P = 0.031). Patients carrying both the BDNF Val66Val and COMT Met158Met variants had higher alcohol consumption. These effects may be influenced by the effects of BDNF and COMT on dopamine responses to alcohol. Motivation-enhancing strategies might benefit the group of patients identified by genotyping in this study, and also treatment aimed at reducing alcohol consumption.

Executive control in schizophrenia: a preliminary study on the moderating role of COMT Val158Met for comorbid alcohol and substance use disorders

Background: A functional polymorphism in the catechol-O-methyltransferase (COMT) gene (Val158Met) appears to influence cognition in people with alcohol/substance use disorders (AUD/SUD) and in those with psychosis.Methods: To explore the potential moderating effect of these factors, a cross-sectional study was conducted, randomly recruiting subjects with DSM-IV diagnosis of schizophrenia. AUD/SUD was rigorously assessed, as well as COMT Val158Met polymorphism. Executive control functioning was measured using the Intra-Extra Dimensional Set Shift (IED). The effect of a possible interaction between comorbid AUD/SUD and COMT Val158Met polymorphism on IED scores was explored.Results: Subjects with schizophrenia, comorbid AUD/SUD, and MetMet carriers for SNP rs4680 of the COMT gene showed worse performance on IED completed stages scores, as compared with individuals with ValVal genotype. However, among subjects without AUD/SUD, those with the MetMet variant performed better than people carrying ValVal genotype.Conclusions: This study is the first to date examining the impact of COMT on cognition in a highly representative sample of people with schizophrenia and comorbid AUD/SUD. Differential moderating effects of COMT Val/Met genotype variations may similarly influence executive functions in people with schizophrenia and comorbid AUD/SUD.

Executive function performance and change in aging is predicted by apolipoprotein E, intensified by catechol-O-methyltransferase and brain-derived neurotrophic factor, and moderated by age and lifestyle

Recent studies have reported several genetic, health, and aging interaction effects in predicting cognitive performance and change. We used an accelerated longitudinal design to examine interactions among genetic, lifestyle, and aging for executive function (EF) in non-demented older adults (n = 634; age range = 53–95 years). The polymorphisms were apolipoprotein E (APOE), catechol-O-methyltransferase (COMT), and brain-derived neurotrophic factor (BDNF). We tested (1) independent and additive effects of APOE, COMT, and BDNF and (2) APOE effect modification for COMT + BDNF, on EF performance and 9-year change as separated by age and lifestyle activities. First, APOE ε4+ carriers had poorer EF performance and steeper 9-year decline. Second, APOE ε4+ carriers with (1) BDNF Met/Met genotype and (2) increasing allelic risk in the COMT + BDNF risk panel had poorer EF performance; these effects were moderated by lifestyle activities (composite of everyday social, physical, and cognitive activities). Examining APOE effect modification for COMT + BDNF risk panel effects with other moderating factors may help identify complex neurobiological and genetic underpinnings of polygenic phenotypes such as EF in aging.

Interaction Effects of BDNF and COMT Genes on Resting-State Brain Activity and Working Memory.

Catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) genes have been found to interactively influence working memory (WM) as well as brain activation during WM tasks. However, whether the two genes have interactive effects on resting-state activities of the brain and whether these spontaneous activations correlate with WM are still unknown. This study included behavioral data from WM tasks and genetic data (COMT rs4680 and BDNF Val66Met) from 417 healthy Chinese adults and resting-state fMRI data from 298 of them. Significant interactive effects of BDNF and COMT were found for WM performance as well as for resting-state regional homogeneity (ReHo) in WM-related brain areas, including the left medial frontal gyrus (lMeFG), left superior frontal gyrus (lSFG), right superior and medial frontal gyrus (rSMFG), right medial orbitofrontal gyrus (rMOFG), right middle frontal gyrus (rMFG), precuneus, bilateral superior temporal gyrus, left superior occipital gyrus, right middle occipital gyrus, and right inferior parietal lobule. Simple effects analyses showed that compared to other genotypes, subjects with COMT-VV/BDNF-VV had higher WM and lower ReHo in all five frontal brain areas. The results supported the hypothesis that COMT and BDNF polymorphisms influence WM performance and spontaneous brain activity (i.e., ReHo).

Commonly-occurring polymorphisms in the COMT, DRD1 and DRD2 genes influence different aspects of motor sequence learning in humans

Performing sequences of movements is a ubiquitous skill that involves dopamine transmission. However, it is unclear which components of the dopamine system contribute to which aspects of motor sequence learning. Here we used a genetic approach to investigate the relationship between different components of the dopamine system and specific aspects of sequence learning in humans. In particular, we investigated variations in genes that code for the catechol-O-methyltransferase (COMT) enzyme, the dopamine transporter (DAT) and dopamine D1 and D2 receptors (DRD1 and DRD2). COMT and the DAT regulate dopamine availability in the prefrontal cortex and the striatum, respectively, two key regions recruited during learning, whereas dopamine D1 and D2 receptors are thought to be involved in long-term potentiation and depression, respectively. We show that polymorphisms in the COMT, DRD1 and DRD2 genes differentially affect behavioral performance on a sequence learning task in 161 Caucasian participants. The DRD1 polymorphism predicted the ability to learn new sequences, the DRD2 polymorphism predicted the ability to perform a previously learnt sequence after performing interfering random movements, whereas the COMT polymorphism predicted the ability to switch flexibly between two sequences. We used computer simulations to explore potential mechanisms underlying these effects, which revealed that the DRD1 and DRD2 effects are possibly related to neuroplasticity. Our prediction-error algorithm estimated faster rates of connection strengthening in genotype groups with presumably higher D1 receptor densities, and faster rates of connection weakening in genotype groups with presumably higher D2 receptor densities. Consistent with current dopamine theories, these simulations suggest that D1-mediated neuroplasticity contributes to learning to select appropriate actions, whereas D2-mediated neuroplasticity is involved in learning to inhibit incorrect action plans. However, the learning algorithm did not account for the COMT effect, suggesting that prefrontal dopamine availability might affect sequence switching via other, non-learning, mechanisms. These findings provide insight into the function of the dopamine system, which is relevant to the development of treatments for disorders such as Parkinson’s disease. Our results suggest that treatments targeting dopamine D1 receptors may improve learning of novel sequences, whereas those targeting dopamine D2 receptors may improve the ability to initiate previously learned sequences of movements.

Epistasis between COMT Val158Met and DRD3 Ser9Gly polymorphisms and cognitive function in schizophrenia: genetic influence on dopamine transmission.

To assess the relationship between cognitive function, a proposed schizophrenia endophenotype, and two genetic polymorphisms related to dopamine function, catechol-O-methyl transferase (COMT) Val158Met and dopamine receptor 3 (DRD3) Ser9Gly. Fifty-eight outpatients with schizophrenia/schizoaffective disorder and 88 healthy controls underwent neurocognitive testing and genotyping. Analyses of covariance (ANCOVAs) using age, sex, and years of education as covariates compared cognitive performance for the proposed genotypes in patients and controls. ANCOVAs also tested for the epistatic effect of COMT and DRD3 genotype combinations on cognitive performance. For executive functioning, COMT Val/Val patients performed in a similar range as controls (30.70-33.26 vs. 35.53-35.67), but as COMT Met allele frequency increased, executive functioning worsened. COMT Met/Met patients carrying the DRD3 Ser/Ser genotype performed poorest (16.184 vs. 27.388-31.824). Scores of carriers of this COMT/DRD3 combination significantly differed from all DRD3 Gly/Gly combinations (p < 0.05), from COMT Val/Met DRD3 Ser/Gly (p = 0.02), and from COMT Val/Val DRD3 Ser/Ser (p = 0.01) in patients. It also differed significantly from all control scores (p < 0.001). Combined genetic polymorphisms related to dopamine neurotransmission might influence executive function in schizophrenia. Looking at the effects of multiple genes on a single disease trait (epistasis) provides a comprehensive and more reliable way to determine genetic effects on endophenotypes.