Sample records for val158met comt polymorphism

  1. The association between COMT Val158Met polymorphism and migraine risk: A meta-analysis.

    PubMed

    Liao, Yao-Jun; Jiang, Jing-Ru; Jin, San-Qing

    2017-05-01

    Background The COMT Val158Met polymorphism has long been regarded as a risk factor for migraine. The possible association between COMT Val158Met polymorphism and migraine has been evaluated in several studies, but the results are not consistent. Therefore, we conduct this meta-analysis to address these issues. Methods The WEB OF SCIENCE and EMBASE databases were searched for eligible studies. The odds ratio (OR) with the corresponding 95% confidence interval (CI) was calculated to estimate the strength of the association between COMT Val158Met polymorphism and migraine. Results Five studies with 979 cases and 1870 controls were ultimately included in the present meta-analysis. The overall data showed no significant association between COMT Val158Met polymorphism and migraine in the multiplicative model (OR = 0.97, 95% CI: 0.78-1.21, p = 0.805) and dominant model (OR = 1.05, 95% CI: 0.75-1.48, p = 0.773), neither in the additive model (OR = 0.97, 95% CI: 0.77-1.23, p = 0.817) nor in the recessive model (OR = 0.88, 95% CI: 0.71-1.09, p = 0.246). In subgroup analysis, both for Caucasian and Asian populations, no statistically significant associations were observed in any genetic models. Conclusions Our meta-analysis suggested that the COMT Val158Met polymorphism was not associated with migraine risk.

  2. Association between the Catechol O-Methyltransferase (COMT) Val158met Polymorphism and Different Dimensions of Impulsivity

    PubMed Central

    Malloy-Diniz, Leandro Fernandes; Lage, Guilherme Menezes; Campos, Simone Becho; de Paula, Jonas Jardim; de Souza Costa, Danielle; Romano-Silva, Marco Aurélio; de Miranda, Débora Marques; Correa, Humberto

    2013-01-01

    Background Impulsivity is a multidimensional construct which has been associated with dopaminergic neurotransmission. Nonetheless, until this moment, few studies addressed the relationship between different types of impulsivity and the single nucleotide polymorphism caused by a substitution of valine (val) with methionine (met) in the 158 codon of the Catechol-o-Methyltransferase gene (COMT-val158met). The present study aimed to investigate the association between val158met COMT polymorphism and impulsive behavior measured by two neuropsychological tests. Methodology/Principal Findings We administered two neuropsychological tests, a Continuous Performance Task and the Iowa Gambling Task were applied to 195 healthy participants to characterize their levels of motor, attentional and non-planning impulsivity. Then, subjects were grouped by genotype, and their scores on impulsivity measures were compared. There were no significant differences between group scores on attentional and motor impulsivity. Those participants who were homozygous for the met allele performed worse in the Iowa Gambling Task than val/val and val/met subjects. Conclusions/Significance Our results suggest that met allele of val158met COMT polymorphism is associated with poor performance in decision-making/cognitive impulsivity task. The results reinforce the hypothesis that val and met alleles of the val158met polymorphism show functional dissociation and are related to different prefrontal processes. PMID:24039968

  3. Association between the COMT Val158Met polymorphism and fibromyalgia susceptibility and fibromyalgia impact questionnaire score: a meta-analysis.

    PubMed

    Lee, Young Ho; Kim, Jae-Hoon; Song, Gwan Gyu

    2015-01-01

    The aim of this study was to explore whether the catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with susceptibility to fibromyalgia and fibromyalgia impact questionnaire (FIQ) score in fibromyalgia patients. We conducted a meta-analysis of the associations of the COMT Val158Met polymorphism with fibromyalgia risk as well as FIQ score in fibromyalgia patients. A total of 993 fibromyalgia patients and 778 controls from 10 studies on the COMT Val158Met polymorphism and 538 fibromyalgia patients from 5 studies on the COMT Val158Met polymorphism and FIQ score were included in this meta-analysis. The meta-analysis revealed an association between fibromyalgia and the COMT Met/Met + Val/Met genotype in all study subjects (odds ratio (OR) 1.635, 95 % confidence interval (CI) 1.029-2.597, p = 0.037). However, stratification by ethnicity indicated no association between the Met/Met + Val/Met genotype and fibromyalgia in the European and Turkish populations (OR 1.202, 95 % CI 0.876-1.649, p = 0.255; OR 2.132, 95 % CI 0.764-5.949, p = 0.148, respectively). Analysis using other genetic models showed no association between the COMT Val158Met polymorphism and fibromyalgia. The meta-analysis also revealed that the FIQ score was significantly higher in individuals with the COMT Met/Met genotype than in those with the Val/Val genotype [weighted mean difference (WMD) = 14.39, 95 % CI 3.316-25.48, p = 0.011] and the Val/Met genotype (WMD = 5.108, 95 % CI 2.212-4.891, p = 0.021). This meta-analysis identified an association between fibromyalgia risk and the COMT Val158Met polymorphism as well as the FIQ score in fibromyalgia patients.

  4. Modulation of the COMT Val(158)Met polymorphism on resting-state EEG power.

    PubMed

    Solís-Ortiz, Silvia; Pérez-Luque, Elva; Gutiérrez-Muñoz, Mayra

    2015-01-01

    The catechol-O-methyltransferase (COMT) Val(158)Met polymorphism impacts cortical dopamine (DA) levels and may influence cortical electrical activity in the human brain. This study investigated whether COMT genotype influences resting-state electroencephalogram (EEG) power in the frontal, parietal and midline regions in healthy volunteers. EEG recordings were conducted in the resting-state in 13 postmenopausal healthy woman carriers of the Val/Val genotype and 11 with the Met/Met genotype. The resting EEG spectral absolute power in the frontal (F3, F4, F7, F8, FC3 and FC4), parietal (CP3, CP4, P3 and P4) and midline (Fz, FCz, Cz, CPz, Pz and Oz) was analyzed during the eyes-open and eyes-closed conditions. The frequency bands considered were the delta, theta, alpha1, alpha2, beta1 and beta2. EEG data of the Val/Val and Met/Met genotypes, brain regions and conditions were analyzed using a general linear model analysis. In the individuals with the Met/Met genotype, delta activity was increased in the eyes-closed condition, theta activity was increased in the eyes-closed and in the eyes-open conditions, and alpha1 band, alpha2 band and beta1band activity was increased in the eyes-closed condition. A significant interaction between COMT genotypes and spectral bands was observed. Met homozygote individuals exhibited more delta, theta and beta1 activity than individuals with the Val/Val genotype. No significant interaction between COMT genotypes and the resting-state EEG regional power and conditions were observed for the three brain regions studied. Our findings indicate that the COMT Val(158)Met polymorphism does not directly impact resting-state EEG regional power, but instead suggest that COMT genotype can modulate resting-state EEG spectral power in postmenopausal healthy women.

  5. Modulation of the COMT Val158Met polymorphism on resting-state EEG power

    PubMed Central

    Solís-Ortiz, Silvia; Pérez-Luque, Elva; Gutiérrez-Muñoz, Mayra

    2015-01-01

    The catechol-O-methyltransferase (COMT) Val158Met polymorphism impacts cortical dopamine (DA) levels and may influence cortical electrical activity in the human brain. This study investigated whether COMT genotype influences resting-state electroencephalogram (EEG) power in the frontal, parietal and midline regions in healthy volunteers. EEG recordings were conducted in the resting-state in 13 postmenopausal healthy woman carriers of the Val/Val genotype and 11 with the Met/Met genotype. The resting EEG spectral absolute power in the frontal (F3, F4, F7, F8, FC3 and FC4), parietal (CP3, CP4, P3 and P4) and midline (Fz, FCz, Cz, CPz, Pz and Oz) was analyzed during the eyes-open and eyes-closed conditions. The frequency bands considered were the delta, theta, alpha1, alpha2, beta1 and beta2. EEG data of the Val/Val and Met/Met genotypes, brain regions and conditions were analyzed using a general linear model analysis. In the individuals with the Met/Met genotype, delta activity was increased in the eyes-closed condition, theta activity was increased in the eyes-closed and in the eyes-open conditions, and alpha1 band, alpha2 band and beta1band activity was increased in the eyes-closed condition. A significant interaction between COMT genotypes and spectral bands was observed. Met homozygote individuals exhibited more delta, theta and beta1 activity than individuals with the Val/Val genotype. No significant interaction between COMT genotypes and the resting-state EEG regional power and conditions were observed for the three brain regions studied. Our findings indicate that the COMT Val158Met polymorphism does not directly impact resting-state EEG regional power, but instead suggest that COMT genotype can modulate resting-state EEG spectral power in postmenopausal healthy women. PMID:25883560

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

    PubMed

    Costa, Danielle de Souza; Bechara, Antoine; de Paula, Jonas Jardim; Romano-Silva, Marco Aurélio; Correa, Humberto; Lage, Guilherme Menezes; Miranda, Débora Marques de; Malloy-Diniz, Leandro Fernandes

    2016-12-30

    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 Val 158 Met 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 l 158 Met 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 Val 158 Met polymorphism may be considered a genetic marker underlying sex differences in decision-making. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  7. The effect of the COMT val(158)met polymorphism on neural correlates of semantic verbal fluency.

    PubMed

    Krug, Axel; Markov, Valentin; Sheldrick, Abigail; Krach, Sören; Jansen, Andreas; Zerres, Klaus; Eggermann, Thomas; Stöcker, Tony; Shah, N Jon; Kircher, Tilo

    2009-12-01

    Variation in the val(158)met polymorphism of the COMT gene has been found to be associated with cognitive performance. In functional neuroimaging studies, this dysfunction has been linked to signal changes in prefrontal areas. Given the complex modulation and functional heterogeneity of frontal lobe systems, further specification of COMT gene-related phenotypes differing in prefrontally mediated cognitive performance are of major interest. Eighty healthy individuals (54 men, 26 women; mean age 23.3 years) performed an overt semantic verbal fluency task while brain activation was measured with functional magnetic resonance imaging (fMRI). COMT val(158)met genotype was determined and correlated with brain activation measured with fMRI during the task. Although there were no differences in performance, brain activation in the left inferior frontal gyrus [Brodmann area 10] was positively correlated with the number of val alleles in the COMT gene. COMT val(158)met status modulates brain activation during the language production on a semantic level in an area related to executive functions.

  8. COMT val158met and 5-HTTLPR Genetic Polymorphisms Moderate Executive Control in Cannabis Users

    PubMed Central

    Verdejo-García, Antonio; Beatriz Fagundo, Ana; Cuenca, Aida; Rodriguez, Joan; Cuyás, Elisabet; Langohr, Klaus; de Sola Llopis, Susana; Civit, Ester; Farré, Magí; Peña-Casanova, Jordi; de la Torre, Rafael

    2013-01-01

    The adverse effects of cannabis use on executive functions are still controversial, fostering the need for novel biomarkers able to unveil individual differences in the cognitive impact of cannabis consumption. Two common genetic polymorphisms have been linked to the neuroadaptive impact of Δ9-tetrahydrocannabinol (THC) exposure and to executive functions in animals: the catechol-O-methyltransferase (COMT) gene val158met polymorphism and the SLC6A4 gene 5-HTTLPR polymorphism. We aimed to test if these polymorphisms moderate the harmful effects of cannabis use on executive function in young cannabis users. We recruited 144 participants: 86 cannabis users and 58 non-drug user controls. Both groups were genotyped and matched for genetic makeup, sex, age, education, and IQ. We used a computerized neuropsychological battery to assess different aspects of executive functions: sustained attention (CANTAB Rapid Visual Information Processing Test, RVIP), working memory (N-back), monitoring/shifting (CANTAB ID/ED set shifting), planning (CANTAB Stockings of Cambridge, SOC), and decision-making (Iowa Gambling Task, IGT). We used general linear model-based analyses to test performance differences between cannabis users and controls as a function of genotypes. We found that: (i) daily cannabis use is not associated with executive function deficits; and (ii) COMT val158met and 5-HTTLPR polymorphisms moderate the link between cannabis use and executive performance. Cannabis users carrying the COMT val/val genotype exhibited lower accuracy of sustained attention, associated with a more strict response bias, than val/val non-users. Cannabis users carrying the COMT val allele also committed more monitoring/shifting errors than cannabis users carrying the met/met genotype. Finally, cannabis users carrying the 5-HTTLPR s/s genotype had worse IGT performance than s/s non-users. COMT and SLC6A4 genes moderate the impact of cannabis use on executive functions. PMID:23449176

  9. The COMT Val158Met Polymorphism Is Associated With Response to Add-on Dextromethorphan Treatment in Bipolar Disorder.

    PubMed

    Lee, Sheng-Yu; Chen, Shiou-Lan; Wang, Tzu-Yun; Chang, Yun-Hsuan; Chen, Po See; Huang, San-Yuan; Tzeng, Nian-Sheng; Wang, Liang-Jen; Lee, I Hui; Chen, Kao Ching; Yang, Yen Kuang; Lu, Ru-Band

    2017-02-01

    We previously conducted a randomized, double-blind, controlled, 12-week study evaluating the effect of add-on dextromethorphan (DM), a noncompetitive N-methyl-D-aspartate receptor antagonist, on patients with bipolar disorder (BD) treated using valproate (VPA), which showed negative clinical differences. The genetic variation between each individual may be responsible for interindividual differences. The catechol-O-methyltransferase (COMT) gene has been a candidate gene for BD. In the current study, we investigated whether the COMT Val158Met polymorphism predicts treatment response to VPA + add-on DM and to VPA + placebo. Patients with BD (n = 309) undergoing regular VPA treatments were randomly assigned to groups given either add-on DM (30 mg/d) (n = 102), DM (60 mg/d) (n = 101), or placebo (n = 106) for 12 weeks. The Hamilton Depression Rating Scale and Young Mania Rating Scale were used to evaluate clinical response during weeks 0, 1, 2, 4, 8, and 12. The genotypes of the COMT Val158Met polymorphism were determined using polymerase chain reaction plus restriction fragment length polymorphism analysis. To adjust for within-subject dependence over repeated assessments, multiple linear regression with generalized estimating equation methods was used. When stratified by the COMT Val158Met genotypes, significantly greater decreases in Hamilton Depression Rating Scale scores were found in the VPA + DM (30 mg/d) group in patients with the Val/Met genotype (P = 0.008). We conclude that the COMT Val158Met polymorphism may influence responses to DM (30 mg/d) by decreasing depressive symptoms in BD patients.

  10. The influence of COMT Val158Met genotype on the character dimension cooperativeness in healthy females

    PubMed Central

    Baeken, Chris; Claes, Stephan; De Raedt, Rudi

    2014-01-01

    Objectives Although the Val158Met catechol-O-methyltransferase (COMT) gene has been linked with the temperament dimension Novelty Seeking (NS), new insights in this polymorphism might point to a major role for character features as well. Given that individual life experiences may influence Val158 and Met158 allele carriers differently it has been suggested that the character trait cooperativeness could be implicated. Case report A homogeneous group of eighty right-handed Caucasian healthy female university students were assessed with the TCI and genotyped for the COMT Val158Met polymorphism (rs4680). Gene determination showed that eighteen were Val158 homozygotes, forty-four Val/Met158 heterozygotes, and eighteen were Met158 homozygotes. All were within the same age range and never documented to have suffered from any neuropsychiatric illness. Bonferroni corrected non-parametric analyses showed that only for the character scale cooperativeness Val158 homozygotes displayed significant higher scores when compared to Met158 homozygotes. No significant differences on cooperativeness scores were found between Val158 and Val/Met158 carriers or between Met158 and Val/Met158 carriers. No differences were observed for the COMT Val158Met polymorphism and the other temperament and character scales. Conclusions Our findings support the assumption that the Val158Met single nucleotide polymorphism (SNP) influences character traits and not only temperament. Our results add to the notion that Val158 homozygotes are considered to be helpful and empathic and it suggest that these cooperativeness character traits are related to the dopaminergic system. PMID:25161818

  11. The effects of gender and COMT Val158Met polymorphism on fearful facial affect recognition: a fMRI study.

    PubMed

    Kempton, Matthew J; Haldane, Morgan; Jogia, Jigar; Christodoulou, Tessa; Powell, John; Collier, David; Williams, Steven C R; Frangou, Sophia

    2009-04-01

    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 genotypexgender 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.

  12. The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism

    PubMed Central

    Klebe, Stephan; Golmard, Jean-Louis; Nalls, Michael A; Saad, Mohamad; Singleton, Andrew B; Bras, Jose M; Hardy, John; Simon-Sanchez, Javier; Heutink, Peter; Kuhlenbäumer, Gregor; Charfi, Rim; Klein, Christine; Hagenah, Johann; Gasser, Thomas; Wurster, Isabel; Lesage, Suzanne; Lorenz, Delia; Deuschl, Günther; Durif, Franck; Pollak, Pierre; Damier, Philippe; Tison, François; Durr, Alexandra; Amouyel, Philippe; Lambert, Jean-Charles; Tzourio, Christophe; Maubaret, Cécilia; Charbonnier-Beaupel, Fanny; Tahiri, Khadija; Vidailhet, Marie; Martinez, Maria; Brice, Alexis; Corvol, Jean-Christophe

    2013-01-01

    The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD. PMID:23408064

  13. Association between Catechol-O-Methyltransferase Val158Met (158G/A) Polymorphism and Suicide Susceptibility: A Meta-analysis.

    PubMed

    Sadeghiyeh, Tahereh; Hosseini Biouki, Fatemeh; Mazaheri, Mahta; Zare-Shehneh, Masoud; Neamatzadeh, Hossein; Poursharif, Zahra

    2017-06-24

    Common functional Val158Met polymorphism in the Catechol-O-methyltransferase (COMT) gene may have an impact on an individual's susceptibility to suicide, but individually published results are inconclusive. Therefore, we performed this meta-analysis to provide a more precise estimation of the association between COMT 158G/A (COMT Val158Met) polymorphism and suicide susceptibility. A cross-sectional study. This systematic review and meta-analysis is a comprehensive literature search of PubMed, Scopus, Web of Science and Google Scholar databases was conducted on case-control studies published up to Mar 2017. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. We identified 14 eligible case-control studies, including 2353 suicide attempters and 2593 controls. The pooled results indicated that COMT 158G/A (COMT Val158Met) polymorphism was not significantly associated with increased overall suicide risk. The same results were revealed based on ethnicity, Hardy-Weinberg equilibrium (HWE) status and genotyping technique. However, there was significant association between COMT Val158Met polymorphism and suicide risk among females under the homozygote (AA vs. GG: OR=1.829, 95% CI=1.158-2.889, P=0.010) and recessive (AA vs. AG +GG: OR = 1.787, 95% CI=1.195, 2.671, P=0.005) models, but not among males. COMT 158G/A (COMT Val158Met) polymorphism was associated with suicide susceptibility only in females.

  14. Association of Catechol-O-methyltransferase polymorphism Val158Met and mammographic density: A meta-analysis.

    PubMed

    Kallionpää, Roope A; Uusitalo, Elina; Peltonen, Juha

    2017-08-15

    The Val158Met polymorphism in catechol-O-methyltransferase (COMT) enzyme reduces the methylation of catechol estrogens, which may affect mammographic density. High mammographic density is a known risk factor of breast cancer. Our aim was to perform meta-analysis of the effect of COMT Val158Met polymorphism on mammographic density. Original studies reporting data on mammographic density, stratified by the presence of COMT Val158Met polymorphism, were identified and combined using genetic models Met/Val vs. Val/Val, Met/Met vs. Val/Val, Val/Met+Met/Met vs. Val/Val (dominant model) and Met/Met vs. Val/Met+Val/Val (recessive model). Subgroup analyses by breast cancer status, menopausal status and use of hormone replacement therapy (HRT) were also performed. Eight studies were included in the meta-analysis. The overall effect in percent mammographic density was -1.41 (CI -2.86 to 0.05; P=0.06) in the recessive model. Exclusion of breast cancer patients increased the effect size to -1.93 (CI -3.49 to -0.37; P=0.02). The results suggested opposite effect of COMT Val158Met for postmenopausal users of HRT versus premenopausal women or postmenopausal non-users of HRT. COMT Val158Met polymorphism may be associated with mammographic density at least in healthy women. Menopausal status and HRT should be taken into account in future studies to avoid masking of the underlying effects. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. COMT Val158Met Polymorphism and Symptom Improvement Following a Cognitively-Focused Intervention for Irritable Bowel Syndrome

    PubMed Central

    Han, Claire J.; Kohen, Ruth; Jun, Sangeun; Jarrett, Monica E.; Cain, Kevin C.; Burr, Robert; Heitkemper, Margaret M.

    2016-01-01

    Background Our nurse-delivered Comprehensive Self-Management (CSM) program, a cognitive behavioral therapy intervention, is effective in reducing gastrointestinal and psychological distress symptoms in patients with irritable bowel syndrome (IBS). Findings from non-IBS studies indicate that the catechol-O-methyltransferase (COMT) Val158Met polymorphism may moderate the efficacy of cognitive behavioral therapy. It is unknown whether this COMT polymorphism is associated with symptom improvements in patients with IBS. Objective We tested whether this COMT Val158Met polymorphism influences the efficacy of our two-month CSM intervention. Methods We analyzed data from two published randomized controlled trials of CSM. The combined European-American sample included 149 women and 23 men with IBS (CSM, n =111; Usual Care [UC], n = 61). The primary outcomes were daily reports of abdominal pain, depression, anxiety, and feeling stressed measured three and six months after randomization. Secondary outcomes were additional daily symptoms, retrospective psychological distress, IBS quality of life, and cognitive beliefs about IBS. The interaction between COMT Val158Met polymorphism and treatment group (CSM vs. UC) in a generalized estimating equation model tested the main objective. Results At three months, participants with at least one Val allele benefited more from CSM than did those with the Met/Met genotype (p = .01 for anxiety and feeling stressed, and p < .16 for abdominal pain and depression). The moderating effect of genotype was weaker at six months. Discussion Persons with at least one Val allele may benefit more from CSM than those homozygous for the Met allele. Future studies with larger and more racially diverse samples are needed to confirm these findings. RCT Registration Parent studies were registered at ClinicalTrials.gov (NCT00167635 and NCT00907790). PMID:28252569

  16. The roles of COMT val158met status and aviation expertise in flight simulator performance and cognitive ability.

    PubMed

    Kennedy, Q; Taylor, J L; Noda, A; Adamson, M; Murphy, G M; Zeitzer, J M; Yesavage, J A

    2011-09-01

    The polymorphic variation in the val158met position of the catechol-O-methyltransferase (COMT) gene is associated with differences in executive performance, processing speed, and attention. The purpose of this study is: (1) replicate previous COMT val158met findings on cognitive performance; (2) determine whether COMT val158met effects extend to a real-world task, aircraft navigation performance in a flight simulator; and (3) determine if aviation expertise moderates any effect of COMT val158met status on flight simulator performance. One hundred seventy two pilots aged 41-69 years, who varied in level of aviation training and experience, completed flight simulator, cognitive, and genetic assessments. Results indicate that although no COMT effect was found for an overall measure of flight performance, a positive effect of the met allele was detected for two aspects of cognitive ability: executive functioning and working memory performance. Pilots with the met/met genotype benefited more from increased levels of expertise than other participants on a traffic avoidance measure, which is a component of flight simulator performance. These preliminary results indicate that COMT val158met polymorphic variation can affect a real-world task.

  17. The Roles of COMT val158met Status and Aviation Expertise in Flight Simulator Performance and Cognitive Ability

    PubMed Central

    Taylor, J. L.; Noda, A.; Adamson, M.; Murphy, G. M.; Zeitzer, J. M.; Yesavage, J. A.

    2011-01-01

    The polymorphic variation in the val158met position of the catechol-O-methyltransferase (COMT) gene is associated with differences in executive performance, processing speed, and attention. The purpose of this study is: (1) replicate previous COMT val158met findings on cognitive performance; (2) determine whether COMT val158met effects extend to a real-world task, aircraft navigation performance in a flight simulator; and (3) determine if aviation expertise moderates any effect of COMT val158met status on flight simulator performance. One hundred seventy two pilots aged 41–69 years, who varied in level of aviation training and experience, completed flight simulator, cognitive, and genetic assessments. Results indicate that although no COMT effect was found for an overall measure of flight performance, a positive effect of the met allele was detected for two aspects of cognitive ability: executive functioning and working memory performance. Pilots with the met/met genotype benefited more from increased levels of expertise than other participants on a traffic avoidance measure, which is a component of flight simulator performance. These preliminary results indicate that COMT val158met polymorphic variation can affect a real-world task. PMID:21193954

  18. The modulatory influence of the functional COMT Val158Met polymorphism on lexical decisions and semantic priming.

    PubMed

    Reuter, Martin; Montag, Christian; Peters, Kristina; Kocher, Anne; Kiefer, Markus

    2009-01-01

    The role of the prefrontal Cortex (PFC) in higher cognitive functions - including working memory, conflict resolution, set shifting and semantic processing - has been demonstrated unequivocally. Despite the great heterogeneity among tasks measuring these phenotypes, due in part to the different cognitive sub-processes implied and the specificity of the stimulus material used, there is agreement that all of these tasks recruit an executive control system located in the PFC. On a biochemical level it is known that the dopaminergic system plays an important role in executive control functions. Evidence comes from molecular genetics relating the functional COMT Val158Met polymorphism to working memory and set shifting. In order determine whether this pattern of findings generalises to linguistic and semantic processing, we investigated the effects of the COMT Val158Met polymorphism in lexical decision making using masked and unmasked versions of the semantic priming paradigm on N = 104 healthy subjects. Although we observed strong priming effects in all conditions (masked priming, unmasked priming with short/long stimulus asynchronies (SOAs), direct and indirect priming), COMT was not significantly related to priming, suggesting no reliable influence on semantic processing. However, COMT Val158Met was strongly associated with lexical decision latencies in all priming conditions if considered separately, explaining between 9 and 14.5% of the variance. Therefore, the findings indicate that COMT mainly influences more general executive control functions in the PFC supporting the speed of lexical decisions.

  19. COMT Val(158)Met genotype determines the direction of cognitive effects produced by catechol-O-methyltransferase inhibition.

    PubMed

    Farrell, Sarah M; Tunbridge, Elizabeth M; Braeutigam, Sven; Harrison, Paul J

    2012-03-15

    Catechol-O-methyltransferase (COMT) metabolizes dopamine. The COMT Val(158)Met polymorphism influences its activity, and multiple neural correlates of this genotype on dopaminergic phenotypes, especially working memory, have been reported. COMT activity can also be regulated pharmacologically by COMT inhibitors. The inverted-U relationship between cortical dopamine signaling and working memory predicts that the effects of COMT inhibition will differ according to COMT genotype. Thirty-four COMT Met(158)Met (Met-COMT) and 33 COMT Val(158)Val (Val-COMT) men were given a single 200-mg dose of the brain-penetrant COMT inhibitor tolcapone or placebo in a randomized, double-blind, between-subjects design. They completed the N-back task of working memory and a gambling task. In the placebo group, Met-COMT subjects outperformed Val-COMT subjects on the 2- back, and they were more risk averse. Tolcapone had opposite effects in the two genotype groups: it worsened N-back performance in Met-COMT subjects but enhanced it in Val-COMT subjects. Tolcapone made Met-COMT subjects less risk averse but Val-COMT subjects more so. In both tasks, tolcapone reversed the baseline genotype differences. Depending on genotype, COMT inhibition can enhance or impair working memory and increase or decrease risky decision making. To our knowledge, the data are the clearest demonstration to date that the direction of effect of a drug can be influenced by a polymorphism in its target gene. The results support the inverted-U model of dopamine function. The findings are of translational relevance, because COMT inhibitors are used in the adjunctive treatment of Parkinson's disease and are under evaluation in schizophrenia and other disorders. Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  20. COMT val108/158 met genotype affects neural but not cognitive processing in healthy individuals.

    PubMed

    Dennis, Nancy A; Need, Anna C; LaBar, Kevin S; Waters-Metenier, Sheena; Cirulli, Elizabeth T; Kragel, James; Goldstein, David B; Cabeza, Roberto

    2010-03-01

    The relationship between cognition and a functional polymorphism in the catechol-O-methlytransferase (COMT) gene, val108/158met, is one of debate in the literature. Furthermore, based on the dopaminergic differences associated with the COMT val108/158met genotype, neural differences during cognition may be present, regardless of genotypic differences in cognitive performance. To investigate these issues the current study aimed to 1) examine the effects of COMT genotype using a large sample of healthy individuals (n = 496-1218) and multiple cognitive measures, and using a subset of the sample (n = 22), 2) examine whether COMT genotype effects medial temporal lobe (MTL) and frontal activity during successful relational memory processing, and 3) investigate group differences in functional connectivity associated with successful relational memory processing. Results revealed no significant group difference in cognitive performance between COMT genotypes in any of the 19 cognitive measures. However, in the subset sample, COMT val homozygotes exhibited significantly decreased MTL and increased prefrontal activity during both successful relational encoding and retrieval, and reduced connectivity between these regions compared with met homozygotes. Taken together, the results suggest that although the COMT val108/158met genotype has no effect on cognitive behavioral measures in healthy individuals, it is associated with differences in neural process underlying cognitive output.

  1. Modification of depression by COMT val158met polymorphism in children exposed to early severe psychosocial deprivation

    PubMed Central

    Drury, Stacy S; Theall, Katherine P; Smyke, Anna T; Keats, Bronya JB; Egger, Helen L; Nelson, Charles A; Fox, Nathan A; Marshall, Peter J; Zeanah, Charles H

    2014-01-01

    Objective To examine the impact of the Catechol-O-Methyltransferase (COMT) val158met allele on depressive symptoms in young children exposed to early severe social deprivation as a result of being raised in institutions. Methods 136 children from the Bucharest Early Intervention Project (BEIP) were randomized before 31 months of age to either care as usual (CAU) in institutions or placement in newly created foster care (FCG). At 54 months of age, a psychiatric assessment using the Preschool Age Psychiatric Assessment (PAPA) was completed. DNA was collected and genotyped for the COMT val158met polymorphism. Multivariate analysis examined the relationship between COMT alleles and depressive symptoms. Results Mean level of depressive symptoms was lower among participants with the met allele compared to those with two copies of the val allele (p <0.05). Controlling for group and gender, the rate of depressive symptoms was significantly lower among participants with the met/met or the met/val genotype (adjusted relative risk (aRR) = 0.67, 95% CI = 0.45, 0.99) compared to participants with the val/val genotype, indicating an intermediate impact for heterozygotes consistent with the biological impact of this polymorphism. The impact of genotype within groups differed significantly. There was a significant protective effect of the met allele on depressive symptoms within the CAU group, however there was no relationship seen within the FCG group. Conclusions This is the first study, to our knowledge, to find evidence of a gene × environment interaction in the setting of early social deprivation. These results support the hypothesis that individual genetic differences may explain some of the variability in recovery amongst children exposed to early severe social deprivation. PMID:20403637

  2. Val158Met polymorphism in the COMT gene is associated with hypersomnia and mental health-related quality of life in a Colombian sample.

    PubMed

    Jiménez, Karen M; Pereira-Morales, Angela J; Forero, Diego A

    2017-03-22

    The identification of genes that are risk factors for major depressive disorder remains a main task for global psychiatric research. The Catechol-O-methyltransferase (COMT) gene has been an important candidate risk factor for several psychiatric disorders. Previous studies have shown that a functional polymorphism (Val158Met) in this gene has an effect on several brain circuits and endophenotypes of psychiatric relevance. The aim of this study was to explore the association of a functional polymorphism in the COMT gene with psychological distress, sleep problems and health-related quality of life. Two hundred seventy young Colombian subjects (mean age: 21.3 years; range: 18-57 years) completed the Patient Health Questionnaire-9, the Perceived Stress Scale, the Oviedo Sleep Questionnaire and the 12-Item Short-Form Health Survey and were genotyped for the Val158Met polymorphism (rs4680) in the COMT gene. A linear regression analysis, adjusting for potential confounding factors, was carried out. Subjects that were Met carriers (Val/Met and Met/Met genotypes) showed higher scores for hypersomnia (p=0.001) and lower scores for mental health-related quality of life (p=0.007), these associations remained significant after correcting for multiple testing. These findings support the hypothesis of a broad effect of the Val158Met polymorphism in the COMT gene on several dimensions of behavior and neuropsychiatric symptoms. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Association of the Catechol-O-Methyltransferase (COMT) Val158Met Polymorphism and Anxiety-Related Traits: A Meta-Analysis

    PubMed Central

    Lee, Lewina O.; Prescott, Carol A.

    2014-01-01

    Objectives The main goals of this study were: (i) to examine genotypic association of the COMT val158met polymorphism with anxiety-related traits via a meta-analysis; (ii) to examine sex and ethnicity as moderators of the association, and (iii) to evaluate whether the association differed by particular anxiety traits. Methods Association studies of the COMT val18met polymorphism and anxiety traits were identified from the PubMed or PsycInfo databases, conference abstracts and listserv postings. Exclusion criteria were: (a) pediatric samples, (b) exclusively clinical samples, and (c) samples selected for a non-anxiety phenotype. Standardized mean differences in anxiety between genotypes were aggregated to produce mean effect sizes across all available samples, and for subgroups stratified by sex and ethnicity (Caucasians vs. Asians). Construct-specific analysis was conducted to evaluate the association of COMT with neuroticism, harm avoidance, and behavioral inhibition. Results Twenty seven eligible studies (N=15,979) with available data were identified. Overall findings indicate sex-specific and ethnic-specific effects: Val homozygotes had higher neuroticism than Met homozygotes in studies of Caucasian males ( ES¯=0.13, 95%CI: 0.02 – 0.25, p = 0.03), and higher harm avoidance in studies of Asian males ( ES¯=0.43, 95%CI: 0.14 – 0.72, p = 0.004). No significant associations were found in women and effect sizes were diminished when studies were aggregated across ethnicity or anxiety traits. Conclusions: This meta-analysis provides evidence for sex and ethnicity differences in the association of the COMT val158met polymorphism with anxiety traits. Our findings contribute to current knowledge on the relation between prefrontal dopaminergic transmission and anxiety. PMID:24300663

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

    PubMed

    Carrà, Giuseppe; Nicolini, Gabriella; Crocamo, Cristina; Lax, Annamaria; Amidani, Francesca; Bartoli, Francesco; Castellano, Filippo; Chiorazzi, Alessia; Gamba, Giulia; Papagno, Costanza; Clerici, Massimo

    2017-07-01

    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. 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. 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. 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.

  5. MTHFR 677C --> T genotype disrupts prefrontal function in schizophrenia through an interaction with COMT 158Val --> Met.

    PubMed

    Roffman, Joshua L; Gollub, Randy L; Calhoun, Vince D; Wassink, Thomas H; Weiss, Anthony P; Ho, Beng C; White, Tonya; Clark, Vincent P; Fries, Jill; Andreasen, Nancy C; Goff, Donald C; Manoach, Dara S

    2008-11-11

    Understanding how risk genes cumulatively impair brain function in schizophrenia could provide critical insights into its pathophysiology. Working memory impairment in schizophrenia has been associated with abnormal dopamine signaling in the prefrontal cortex, which is likely under complex genetic control. The catechol-O-methyltransferase (COMT) 158Val --> Met polymorphism (rs4680), which affects the availability of prefrontal dopamine signaling, consistently stratifies prefrontal activation during working memory performance. However, the low-dopamine COMT 158Val allele does not confer increased risk for schizophrenia, and its effects on prefrontal function are not specific to the disorder. In the setting of other genetic variants influencing prefrontal dopamine signaling, COMT 158Val --> Met genotype may exert disease-specific effects. A second polymorphism, methylenetetrahydrofolate reductase (MTHFR) 677C --> T (rs1801133), has been associated with overall schizophrenia risk and executive function impairment in patients, and may influence dopamine signaling through mechanisms upstream of COMT effects. We found that the hypofunctional 677T variant was associated with decreased working memory load-dependent activation in the prefrontal and insular cortices in 79 schizophrenia patients, but not in 75 demographically matched healthy controls. Further, significant MTHFR x COMT genotype interactions were observed, which differed by diagnostic group: Reduced prefrontal activation was associated with the 677T and 158Val alleles in patients, but with 677C/C and 158Met/Met genotype in controls. These findings are consistent with epistatic effects of the COMT and MTHFR polymorphisms on prefrontal dopamine signaling, and suggest that in schizophrenia patients, the MTHFR 677T allele exacerbates prefrontal dopamine deficiency. The findings also suggest the importance of weighing COMT effects on prefrontal function within the context of MTHFR genotype.

  6. The COMT Val/Met polymorphism modulates effects of tDCS on response inhibition.

    PubMed

    Nieratschker, Vanessa; Kiefer, Christoph; Giel, Katrin; Krüger, Rejko; Plewnia, Christian

    2015-01-01

    Transcranial direct current stimulation (tDCS) is increasingly discussed as a new option to support the cognitive rehabilitation in neuropsychiatric disorders. However, the therapeutic impact of tDCS is limited by high inter-individual variability. Genetic factors most likely contribute to this variability by modulating the effects of tDCS. We aimed to investigate the influence of the COMT Val(108/158)Met polymorphism on cathodal tDCS effects on executive functioning. Cathodal tDCS was applied to the left dorsolateral prefrontal cortex (dlPFC) during the performance of a parametric Go/No-Go test. We demonstrate an impairing effect of cathodal tDCS to the dlPFC on response inhibition. This effect was only found in individuals homozygous for the Val-allele of the COMT Val(108/158)Met polymorphism. No effects of stimulation on executive functions in Met-allele carriers were detected. Our data indicate that i) cathodal, excitability reducing tDCS, interferes with inhibitory cognitive control, ii) the left dlPFC is critically involved in the neuronal network underlying the control of response inhibition, and iii) the COMT Val(108/158)Met polymorphism modulates the impact of cathodal tDCS on inhibitory control. Together with our previous finding that anodal tDCS selectively impairs set-shifting abilities in COMT Met/Met homozygous individuals, these results indicate that genetic factors modulate effects of tDCS on cognitive performance. Therefore, future tDCS research should account for genetic variability in the design and analysis of neurocognitive as well as therapeutic applications to reduce the variability of results and facilitate individualized neurostimulation approaches. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. COMT Val158Met polymorphism influences the susceptibility to framing in decision-making: OFC-amygdala functional connectivity as a mediator.

    PubMed

    Gao, Xiaoxue; Gong, Pingyuan; Liu, Jinting; Hu, Jie; Li, Yue; Yu, Hongbo; Gong, Xiaoliang; Xiang, Yang; Jiang, Changjun; Zhou, Xiaolin

    2016-05-01

    Individuals tend to avoid risk in a gain frame, in which options are presented in a positive way, but seek risk in a loss frame, in which the same options are presented negatively. Previous studies suggest that emotional responses play a critical role in this "framing effect." Given that the Met allele of COMT Val158Met polymorphism (rs4680) is associated with the negativity bias during emotional processing, this study investigated whether this polymorphism is associated with individual susceptibility to framing and which brain areas mediate this gene-behavior association. Participants were genotyped, scanned in resting state, and completed a monetary gambling task with options (sure vs risky) presented as potential gains or losses. The Met allele carriers showed a greater framing effect than the Val/Val homozygotes as the former gambled more than the latter in the loss frame. Moreover, the gene-behavior association was mediated by resting-state functional connectivity (RSFC) between orbitofrontal cortex (OFC) and bilateral amygdala. Met allele carriers showed decreased RSFC, thereby demonstrating higher susceptibility to framing than Val allele carriers. These findings demonstrate the involvement of COMT Val158Met polymorphism in the framing effect in decision-making and suggest RSFC between OFC and amygdala as a neural mediator underlying this gene-behavior association. Hum Brain Mapp 37:1880-1892, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  8. COMT Val158Met and 5-HT1A-R -1019 C/G polymorphisms: effects on the negative symptom response to clozapine.

    PubMed

    Bosia, Marta; Lorenzi, Cristina; Pirovano, Adele; Guglielmino, Carmelo; Cocchi, Federica; Spangaro, Marco; Bramanti, Placido; Smeraldi, Enrico; Cavallaro, Roberto

    2015-01-01

    Clozapine is still considered the gold standard for treatment-resistant schizophrenia patients; however, up to 40% of patients do not respond adequately. Identifying potential predictors of clinical response to this last-line antipsychotic could represent an important goal for treatment. Among these, functional polymorphisms involved in dopamine system modulation, known to be disrupted in schizophrenia, may play a role. We examined the COMT Val158Met polymorphism, which plays a key role in dopamine regulation at the prefrontal level, and the 5-HT1A-R -1019 C/G polymorphism, a target of clozapine activity involved in the interaction between the serotonin and dopamine systems. 107 neuroleptic-refractory, biologically unrelated Italian patients (70 males and 37 females) with a DSM-IV diagnosis of schizophrenia who were being treated with clozapine were recruited. Psychopathology was assessed by the Positive and Negative Symptoms Scale (PANSS) at the beginning of treatment, and at weeks 8 and 12. Genomic DNA was extracted from venous blood samples. COMT rs4680 (Val158Met) and 5-HT1A-R rs6295 (-1019 C/G) polymorphisms were analyzed by PCR-based restriction fragment length and direct sequencing, respectively. We found a significant effect of COMT and 5-HT1A-R on the PANSS Negative Subscale variation, with greater improvement among COMT Val/Val and 5-HT1A-R G/G subjects. The findings support the hypothesis that COMT rs4680 and 5-HT1A-R rs6295 polymorphisms could influence the negative symptom response to clozapine, probably through modulation of the dopaminergic system.

  9. COMT Val158Met polymorphism moderates the association between PTSD symptom severity and hippocampal volume.

    PubMed

    Hayes, Jasmeet P; Logue, Mark W; Reagan, Andrew; Salat, David; Wolf, Erika J; Sadeh, Naomi; Spielberg, Jeffrey M; Sperbeck, Emily; Hayes, Scott M; McGlinchey, Regina E; Milberg, William P; Verfaellie, Mieke; Stone, Annjanette; Schichman, Steven A; Miller, Mark W

    2017-03-01

    Memory-based alterations are among the hallmark symptoms of posttraumatic stress disorder (PTSD) and may be associated with the integrity of the hippocampus. However, neuroimaging studies of hippocampal volume in individuals with PTSD have yielded inconsistent results, raising the possibility that various moderators, such as genetic factors, may influence this association. We examined whether the catechol-O-methyltransferase (COMT) Val158Met polymorphism, which has previously been shown to be associated with hippocampal volume in healthy individuals, moderates the association between PTSD and hippocampal volume. Recent war veterans underwent structural MRI on a 3 T scanner. We extracted volumes of the right and left hippocampus using FreeSurfer and adjusted them for individual differences in intracranial volume. We assessed PTSD severity using the Clinician-Administered PTSD Scale. Hierarchical linear regression was used to model the genotype (Val158Met polymorphism) × PTSD severity interaction and its association with hippocampal volume. We included 146 white, non-Hispanic recent war veterans (90% male, 53% with diagnosed PTSD) in our analyses. A significant genotype × PTSD symptom severity interaction emerged such that individuals with greater current PTSD symptom severity who were homozygous for the Val allele showed significant reductions in left hippocampal volume. The direction of proposed effects is unknown, thus precluding definitive assessment of whether differences in hippocampal volume reflect a consequence of PTSD, a pre-existing characteristic, or both. Our findings suggest that the COMT polymorphism moderates the association between PTSD and hippocampal volume. These results highlight the role that the dopaminergic system has in brain structure and suggest a possible mechanism for memory disturbance in individuals with PTSD.

  10. COMT Val158Met polymorphism moderates the association between PTSD symptom severity and hippocampal volume

    PubMed Central

    Hayes, Jasmeet P.; Logue, Mark W.; Reagan, Andrew; Salat, David; Wolf, Erika J.; Sadeh, Naomi; Spielberg, Jeffrey M.; Sperbeck, Emily; Hayes, Scott M.; McGlinchey, Regina E.; Milberg, William P.; Verfaellie, Mieke; Stone, Annjanette; Schichman, Steven A.; Miller, Mark W.

    2017-01-01

    Background Memory-based alterations are among the hallmark symptoms of posttraumatic stress disorder (PTSD) and may be associated with the integrity of the hippocampus. However, neuroimaging studies of hippocampal volume in individuals with PTSD have yielded inconsistent results, raising the possibility that various moderators, such as genetic factors, may influence this association. We examined whether the catechol-O-methyltransferase (COMT) Val158Met polymorphism, which has previously been shown to be associated with hippocampal volume in healthy individuals, moderates the association between PTSD and hippocampal volume. Methods Recent war veterans underwent structural MRI on a 3 T scanner. We extracted volumes of the right and left hippocampus using FreeSurfer and adjusted them for individual differences in intracranial volume. We assessed PTSD severity using the Clinician-Administered PTSD Scale. Hierarchical linear regression was used to model the genotype (Val158Met polymorphism) × PTSD severity interaction and its association with hippocampal volume. Results We included 146 white, non-Hispanic recent war veterans (90% male, 53% with diagnosed PTSD) in our analyses. A significant genotype × PTSD symptom severity interaction emerged such that individuals with greater current PTSD symptom severity who were homozygous for the Val allele showed significant reductions in left hippocampal volume. Limitations The direction of proposed effects is unknown, thus precluding definitive assessment of whether differences in hippocampal volume reflect a consequence of PTSD, a pre-existing characteristic, or both. Conclusion Our findings suggest that the COMT polymorphism moderates the association between PTSD and hippocampal volume. These results highlight the role that the dopaminergic system has in brain structure and suggest a possible mechanism for memory disturbance in individuals with PTSD. PMID:28234210

  11. Modulating effect of COMT Val(158)Met polymorphism on interference resolution during a working memory task.

    PubMed

    Jaspar, Mathieu; Dideberg, Vinciane; Bours, Vincent; Maquet, Pierre; Collette, Fabienne

    2015-04-01

    Genetic variability related to the catechol-O-methyltransferase (COMT) gene has received increasing attention in the last 15years, in particular as a potential modulator of the neural substrates underlying inhibitory processes and updating in working memory (WM). In an event-related functional magnetic resonance imaging (fMRI) study, we administered a modified version of the Sternberg probe recency task (Sternberg, 1966) to 43 young healthy volunteers, varying the level of interference across successive items. The task was divided into two parts (high vs. low interference) to induce either proactive or reactive control processes. The participants were separated into three groups according to their COMT Val(158)Met genotype [Val/Val (VV); Val/Met (VM); Met/Met (MM)]. The general aim of the study was to determine whether COMT polymorphism has a modulating effect on the neural substrates of interference resolution during WM processing. Results indicate that interfering trials were associated with greater involvement of frontal cortices (bilateral medial frontal gyrus, left precentral and superior frontal gyri, right inferior frontal gyrus) in VV homozygous subjects (by comparison to Met allele carriers) only in the proactive condition of the task. In addition, analysis of peristimulus haemodynamic responses (PSTH) revealed that the genotype-related difference observed in the left SFG was specifically driven by a larger increase in activity from the storage to the recognition phase of the interfering trials in VV homozygous subjects. These results confirm the impact of COMT genotype on inhibitory processes during a WM task, with an advantage for Met allele carriers. Interestingly, this impact on frontal areas is present only when the level of interference is high, and especially during the transition from storage to recognition in the left superior frontal gyrus. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. The influence of COMT Val¹⁵⁸Met genotype on the character dimension cooperativeness in healthy females.

    PubMed

    Baeken, Chris; Claes, Stephan; De Raedt, Rudi

    2014-07-01

    Although the Val(158)Met catechol-O-methyltransferase (COMT) gene has been linked with the temperament dimension Novelty Seeking (NS), new insights in this polymorphism might point to a major role for character features as well. Given that individual life experiences may influence Val(158) and Met(158) allele carriers differently it has been suggested that the character trait cooperativeness could be implicated. A homogeneous group of eighty right-handed Caucasian healthy female university students were assessed with the TCI and genotyped for the COMT Val(158)Met polymorphism (rs4680). Gene determination showed that eighteen were Val(158) homozygotes, forty-four Val/Met(158) heterozygotes, and eighteen were Met(158) homozygotes. All were within the same age range and never documented to have suffered from any neuropsychiatric illness. Bonferroni corrected non-parametric analyses showed that only for the character scale cooperativeness Val(158) homozygotes displayed significant higher scores when compared to Met(158) homozygotes. No significant differences on cooperativeness scores were found between Val(158) and Val/Met(158) carriers or between Met(158) and Val/Met(158) carriers. No differences were observed for the COMT Val(158)Met polymorphism and the other temperament and character scales. Our findings support the assumption that the Val(158)Met single nucleotide polymorphism (SNP) influences character traits and not only temperament. Our results add to the notion that Val(158) homozygotes are considered to be helpful and empathic and it suggest that these cooperativeness character traits are related to the dopaminergic system.

  13. COMT Val158Met polymorphism is associated with post-traumatic stress disorder and functional outcome following mild traumatic brain injury

    PubMed Central

    Winkler, Ethan A.; Yue, John K.; Ferguson, Adam R.; Temkin, Nancy R.; Stein, Murray B.; Barber, Jason; Yuh, Esther L.; Sharma, Sourabh; Satris, Gabriela G.; McAllister, Thomas W.; Rosand, Jonathan; Sorani, Marco D.; Lingsma, Hester F.; Tarapore, Phiroz E.; Burchard, Esteban G.; Hu, Donglei; Eng, Celeste; Wang, Kevin K.W.; Mukherjee, Pratik; Okonkwo, David O.; Diaz-Arrastia, Ramon; Manley, Geoffrey T.

    2017-01-01

    Mild traumatic brain injury (mTBI) results in variable clinical trajectories and outcomes. The source of variability remains unclear, but may involve genetic variations, such as single nucleotide polymorphisms (SNPs). A SNP in catechol-o-methyltransferase (COMT) is suggested to influence development of post-traumatic stress disorder (PTSD), but its role in TBI remains unclear. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val158Met polymorphism is associated with PTSD and global functional outcome as measured by the PTSD Checklist – Civilian Version and Glasgow Outcome Scale Extended (GOSE), respectively. Results in 93 predominately Caucasian subjects with mTBI show that the COMT Met158 allele is associated with lower incidence of PTSD (univariate odds ratio (OR) of 0.25, 95% CI [0.09–0.69]) and higher GOSE scores (univariate OR 2.87, 95% CI [1.20–6.86]) 6-months following injury. The COMT Val158Met genotype and PTSD association persists after controlling for race (multivariable OR of 0.29, 95% CI [0.10–0.83]) and pre-existing psychiatric disorders/substance abuse (multivariable OR of 0.32, 95% CI [0.11–0.97]). PTSD emerged as a strong predictor of poorer outcome on GOSE (multivariable OR 0.09, 95% CI [0.03–0.26]), which persists after controlling for age, GCS, and race. When accounting for PTSD in multivariable analysis, the association of COMT genotype and GOSE did not remain significant (multivariable OR 1.73, 95% CI [0.69–4.35]). Whether COMT genotype indirectly influences global functional outcome through PTSD remains to be determined and larger studies in more diverse populations are needed to confirm these findings. PMID:27769642

  14. COMT Val158Met polymorphism is associated with post-traumatic stress disorder and functional outcome following mild traumatic brain injury.

    PubMed

    Winkler, Ethan A; Yue, John K; Ferguson, Adam R; Temkin, Nancy R; Stein, Murray B; Barber, Jason; Yuh, Esther L; Sharma, Sourabh; Satris, Gabriela G; McAllister, Thomas W; Rosand, Jonathan; Sorani, Marco D; Lingsma, Hester F; Tarapore, Phiroz E; Burchard, Esteban G; Hu, Donglei; Eng, Celeste; Wang, Kevin K W; Mukherjee, Pratik; Okonkwo, David O; Diaz-Arrastia, Ramon; Manley, Geoffrey T

    2017-01-01

    Mild traumatic brain injury (mTBI) results in variable clinical trajectories and outcomes. The source of variability remains unclear, but may involve genetic variations, such as single nucleotide polymorphisms (SNPs). A SNP in catechol-o-methyltransferase (COMT) is suggested to influence development of post-traumatic stress disorder (PTSD), but its role in TBI remains unclear. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val 158 Met polymorphism is associated with PTSD and global functional outcome as measured by the PTSD Checklist - Civilian Version and Glasgow Outcome Scale Extended (GOSE), respectively. Results in 93 predominately Caucasian subjects with mTBI show that the COMT Met 158 allele is associated with lower incidence of PTSD (univariate odds ratio (OR) of 0.25, 95% CI [0.09-0.69]) and higher GOSE scores (univariate OR 2.87, 95% CI [1.20-6.86]) 6-months following injury. The COMT Val 158 Met genotype and PTSD association persists after controlling for race (multivariable OR of 0.29, 95% CI [0.10-0.83]) and pre-existing psychiatric disorders/substance abuse (multivariable OR of 0.32, 95% CI [0.11-0.97]). PTSD emerged as a strong predictor of poorer outcome on GOSE (multivariable OR 0.09, 95% CI [0.03-0.26]), which persists after controlling for age, GCS, and race. When accounting for PTSD in multivariable analysis, the association of COMT genotype and GOSE did not remain significant (multivariable OR 1.73, 95% CI [0.69-4.35]). Whether COMT genotype indirectly influences global functional outcome through PTSD remains to be determined and larger studies in more diverse populations are needed to confirm these findings. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. The divergent impact of catechol-O-methyltransferase (COMT) Val158Met genetic polymorphisms on executive function in adolescents with discrete patterns of childhood adversity.

    PubMed

    Zhang, Huihui; Li, Jie; Yang, Bei; Ji, Tao; Long, Zhouting; Xing, Qiquan; Shao, Di; Bai, Huayu; Sun, Jiwei; Cao, Fenglin

    2018-02-01

    Catechol-O-methyltransferase (COMT) Val 158 Met functional polymorphisms play a crucial role in the development of executive function (EF), but their effect may be moderated by environmental factors such as childhood adversity. The present study aimed at testing the divergent impact of the COMT Val 158 Met genotype on EF in non-clinical adolescents with discrete patterns of childhood adversity. A total of 341 participants completed the Childhood Trauma Questionnaire, the self-reported version of the Behavior Rating Inventory of Executive Function, and self-administered questionnaires on familial function. The participants' COMT Val 158 Met genotype was determined. Associations among the variables were explored using latent class analysis and general linear models. We found that Val/Val homozygotes showed significantly worse performance on behavioral shift, relative to Met allele carriers (F=5.921, p=0.015, Partial η 2 =0.018). Moreover, three typical patterns of childhood adversity, namely, low childhood adversity (23.5%), childhood neglect (59.8%), and high childhood adversity (16.7%), were found. Both childhood neglect and high childhood adversity had a negative impact on each aspect of EF and on global EF performance. Importantly, these results provided evidence for significant interaction effects, as adolescents with the Val/Val genotype showed inferior behavioral shift performance than Met carriers (F=6.647, p=0.010, Partial η 2 =0.020) in the presence of high childhood adversity. Furthermore, there were no differences between the genotypes for childhood neglect and low childhood adversity. Overall, this is the first study to show that an interaction between the COMT genotype and childhood adversity affects EF in non-clinical adolescents. These results suggest that the COMT genotype may operate as a susceptibility gene vulnerable to an adverse environment. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. COMT Val(108/158)Met polymorphism effects on emotional brain function and negativity bias.

    PubMed

    Williams, Leanne M; Gatt, Justine M; Grieve, Stuart M; Dobson-Stone, Carol; Paul, Robert H; Gordon, Evian; Schofield, Peter R

    2010-11-15

    Biases toward processing negative versus positive information vary as a function of level of awareness, and are modulated by monoamines. Excessive biases are associated with individual differences in mood and emotional stability, and emotional disorder. Here, we examined the impact of the catechol-O-methyltransferase (COMT) Val(108/158)Met polymorphism, involved in dopamine and norepinephrine catabolism, on both emotional brain function and self-reported negativity bias. COMT genotyping and self-reported level of negativity bias were completed for 46 healthy participants taking part in the Brain Resource International Database. Functional MRI was undertaken during perception of facial expressions of fear and happiness presented under unmasked (consciously identified) and masked (to prevent conscious detection) conditions. Structural MR images were also acquired. A greater number of COMT Met alleles predicted increased activation in brainstem, amygdala, basal ganglia and medial prefrontal regions for conscious fear, but decreased activation for conscious happiness. This pattern was also apparent for brainstem activation for the masked condition. Effects were most apparent for females. These differences could not be explained by gray matter variations. The Met-related profile of activation, particularly prefrontally, predicted greater negativity bias associated with risk for emotional disorder. The findings suggest that the COMT Met allele modulates neural substrates of negative versus positive emotion processing. This effect may contribute to negativity biases, which confer susceptibility for emotional disorders. Copyright 2010 Elsevier Inc. All rights reserved.

  17. Genetic contribution of catechol-O-methyltransferase polymorphism (Val158Met) in children with chronic tension-type headache.

    PubMed

    Fernández-de-las-Peñas, César; Ambite-Quesada, Silvia; Rivas-Martínez, Inés; Ortega-Santiago, Ricardo; de-la-Llave-Rincón, Ana Isabel; Fernández-Mayoralas, Daniel M; Pareja, Juan A

    2011-10-01

    Our aim was to investigate the relationship between Val158Met polymorphisms, headache, and pressure hypersensitivity in children with chronic tension-type headache (CTTH). A case-control study with blinded assessor was conducted. Seventy children with CTTH associated with pericranial tenderness and 70 healthy children participated. After amplifying Val158Met polymorphism by polymerase chain reactions, we assessed genotype frequencies and allele distributions. We classified children according to their Val158Met polymorphism: Val/Val, Val/Met, Met/Met. Pressure pain thresholds (PPT) were bilaterally assessed over the temporalis, upper trapezius, second metacarpal, and tibialis anterior muscles. The distribution of Val158Met genotypes was not significantly different (p = 0.335), between children with CTTH and healthy children, and between boys and girls (p = 0.872). Children with CTTH with the Met/Met genotype showed a longer headache history compared with those with Met/Val (p = 0.001) or Val/Val (p = 0.002) genotype. Children with CTTH with Met/Met genotype showed lower PPT over upper trapezius and temporalis muscles than children with CTTH with Met/Val or Val/Val genotype (p < 0.01). The Val158Met catechol-O-methyltransferase (COMT) polymorphism does not appear to be involved in predisposition to suffer from CTTH in children; nevertheless, this genetic factor may be involved in the phenotypic expression, as pressure hypersensitivity was greater in those CTTH children with the Met/Met genotype.

  18. The impact of the Catechol-O-methyltransferase Val158Met polymorphism on survival in the general population – the HUNT study

    PubMed Central

    Hagen, Knut; Stovner, Lars J; Skorpen, Frank; Pettersen, Elin; Zwart, John-Anker

    2007-01-01

    Background The catechol-O-methyltransferase (COMT) gene contains a functional polymorphism, Val158Met which has been related to common diseases like cancer, psychiatric illness and myocardial infarction. Whether the Val158Met polymorphism is associated with survival has not been evaluated in the general population. The aim of this prospective study was to evaluate the impact of codon 158 COMT gene polymorphism on survival in a population-based cohort. Methods The sample comprised 2979 non-diabetic individuals who participated in the Nord-Trøndelag Health Study (HUNT) in the period 1995–97. The subjects were followed up with respect to mortality throughout year 2004. Results 212 men and 183 women died during the follow up. No association between codon 158 COMT gene polymorphism and survival was found. The unadjusted relative risk of death by non-ischemic heart diseases with Met/Met or Met/Val genotypes was 3.27 (95% confidence interval, 1.19–9.00) compared to Val/Val genotype. When we adjusted for age, gender, smoking, coffee intake and body mass index the relative risk decreased to 2.89 (95% confidence interval, 1.04–8.00). Conclusion During 10 year of follow-up, the Val158Met polymorphism had no impact on survival in a general population. Difference in mortality rates from non-ischemic heart diseases may be incidental and should be evaluated in other studies. PMID:17577421

  19. Catechol-O-Methyltransferase Val158Met Polymorphism Associates with Individual Differences in Sleep Physiologic Responses to Chronic Sleep Loss

    PubMed Central

    Goel, Namni; Banks, Siobhan; Lin, Ling; Mignot, Emmanuel; Dinges, David F.

    2011-01-01

    Background The COMT Val158Met polymorphism modulates cortical dopaminergic catabolism, and predicts individual differences in prefrontal executive functioning in healthy adults and schizophrenic patients, and associates with EEG differences during sleep loss. We assessed whether the COMT Val158Met polymorphism was a novel marker in healthy adults of differential vulnerability to chronic partial sleep deprivation (PSD), a condition distinct from total sleep loss and one experienced by millions on a daily and persistent basis. Methodology/Principal Findings 20 Met/Met, 64 Val/Met, and 45 Val/Val subjects participated in a protocol of two baseline 10h time in bed (TIB) nights followed by five consecutive 4 h TIB nights. Met/Met subjects showed differentially steeper declines in non-REM EEG slow-wave energy (SWE)—the putative homeostatic marker of sleep drive—during PSD, despite comparable baseline SWE declines. Val/Val subjects showed differentially smaller increases in slow-wave sleep and smaller reductions in stage 2 sleep during PSD, and had more stage 1 sleep across nights and a shorter baseline REM sleep latency. The genotypes, however, did not differ in performance across various executive function and cognitive tasks and showed comparable increases in subjective and physiological sleepiness in response to chronic sleep loss. Met/Met genotypic and Met allelic frequencies were higher in whites than African Americans. Conclusions/Significance The COMT Val158Met polymorphism may be a genetic biomarker for predicting individual differences in sleep physiology—but not in cognitive and executive functioning—resulting from sleep loss in a healthy, racially-diverse adult population of men and women. Beyond healthy sleepers, our results may also provide insight for predicting sleep loss responses in patients with schizophrenia and other psychiatric disorders, since these groups repeatedly experience chronically-curtailed sleep and demonstrate COMT

  20. Analysis of the Association between Catechol-O-Methyltransferase Val158Met and Male Sexual Orientation.

    PubMed

    Yu, Wei; Tu, Dan; Hong, Fuchang; Wang, Jing; Liu, Xiaoli; Cai, Yumao; Xu, Ruiwei; Zhao, Guanglu; Wang, Feng; Pan, Hong; Wu, Shinan; Feng, Tiejian; Wang, Binbin

    2015-09-01

    Male sexual orientation is thought to have a genetic component. However, previous studies have failed to generate positive results from among candidate genes. Catechol-O-methyltransferase (COMT), located on chromosome 22, has six exons, spans 27 kb, and encodes a protein of 271 amino acids. COMT has an important role in regulating the embryonic levels of catecholamine neurotransmitters (such as dopamine, norepinephrine, and epinephrine) and estrogens. COMT is also thought to be related to sexual orientation. This study aimed to investigate the relationship between the COMT Val158Met variant and male sexual orientation. We performed association analysis of the COMT gene single nucleotide polymorphism, Val158Met, in 409 homosexual cases and 387 heterosexual control Chinese men. COMT polymorphism status was determined using a polymerase chain reaction-based assay. Polymerase chain reaction was performed to genotype the COMT Val158Met polymorphism. The frequency differences of the genotype and alleles distribution between the male homosexual and control groups. Significant differences, both in genotype and alleles, between male homosexual individuals and controls indicated a genetic component related to male homosexuality. The Val allele recessive model could be an interrelated genetic model of the cause of male homosexuality. The COMT Val158Met variant might be associated with male sexual orientation and a recessive model was suggested. © 2015 International Society for Sexual Medicine.

  1. COMT Val158Met Polymorphism, Executive Dysfunction, and Sexual Risk Behavior in the Context of HIV Infection and Methamphetamine Dependence

    PubMed Central

    Bousman, C. A.; Cherner, M.; Atkinson, J. H.; Heaton, R. K.; Grant, I.; Everall, I. P.; HNRC Group, The

    2010-01-01

    Catechol-O-methyltransferease (COMT) metabolizes prefrontal cortex dopamine (DA), a neurotransmitter involved in executive behavior; the Val158Met genotype has been linked to executive dysfunction, which might increase sexual risk behaviors favoring HIV transmission. Main and interaction effects of COMT genotype and executive functioning on sexual risk behavior were examined. 192 sexually active nonmonogamous men completed a sexual behavior questionnaire, executive functioning tests, and were genotyped using blood-derived DNA. Main effects for executive dysfunction but not COMT on number of sexual partners were observed. A COMT x executive dysfunction interaction was found for number of sexual partners and insertive anal sex, significant for carriers of the Met/Met and to a lesser extent Val/Met genotypes but not Val/Val carriers. In the context of HIV and methamphetamine dependence, dopaminergic overactivity in prefrontal cortex conferred by the Met/Met genotype appears to result in a liability for executive dysfunction and potentially associated risky sexual behavior. PMID:20069120

  2. Interaction between COMT Val(158)Met polymorphism and childhood adversity affects reward processing in adulthood.

    PubMed

    Boecker-Schlier, Regina; Holz, Nathalie E; Buchmann, Arlette F; Blomeyer, Dorothea; Plichta, Michael M; Jennen-Steinmetz, Christine; Wolf, Isabella; Baumeister, Sarah; Treutlein, Jens; Rietschel, Marcella; Meyer-Lindenberg, Andreas; Banaschewski, Tobias; Brandeis, Daniel; Laucht, Manfred

    2016-05-15

    Accumulating evidence suggests that altered dopamine transmission may increase the risk of mental disorders such as ADHD, schizophrenia or depression, possibly mediated by reward system dysfunction. This study aimed to clarify the impact of the COMT Val(158)Met polymorphism in interaction with environmental variation (G×E) on neuronal activity during reward processing. 168 healthy young adults from a prospective study conducted over 25years participated in a monetary incentive delay task measured with simultaneous EEG-fMRI. DNA was genotyped for COMT, and childhood family adversity (CFA) up to age 11 was assessed by a standardized parent interview. At reward delivery, a G×E revealed that fMRI activation for win vs. no-win trials in reward-related regions increased with the level of CFA in Met homozygotes as compared to Val/Met heterozygotes and Val homozygotes, who showed no significant effect. During the anticipation of monetary vs. verbal rewards, activation decreased with the level of CFA, which was also observed for EEG, in which the CNV declined with the level of CFA. These results identify convergent genetic and environmental effects on reward processing in a prospective study. Moreover, G×E effects during reward delivery suggest that stress during childhood is associated with higher reward sensitivity and reduced efficiency in processing rewarding stimuli in genetically at-risk individuals. Together with previous evidence, these results begin to define a specific system mediating interacting effects of early environmental and genetic risk factors, which may be targeted by early intervention and prevention. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Genetic Correlates of Maladaptive Beliefs: COMT VAL(158)MET and Irrational Cognitions Linked Depending on Distress.

    PubMed

    Podina, Ioana; Popp, Radu; Pop, Ioan; David, Daniel

    2015-11-01

    Maladaptive/irrational beliefs are significant cognitive vulnerability mechanisms in psychopathology. They are more likely to be associated with a genetic vulnerability marker under conditions of emotional distress when irrational beliefs are more salient. Therefore, in the current study we investigated the COMT Val(158)Met gene variation in relation to irrational beliefs, assuming this relationship depended on the level of emotional distress. Two hundred and sixty-seven genotyped volunteers were assessed for core/general maladaptive beliefs, as well as trait emotional distress. We focused on context-independent measures of irrational beliefs and emotional distress in the absence of a stressor. As expected, the relationship between COMT Val(158)Met and irrational beliefs depended on the level of emotional distress (f(2)=.314). The COMT Val(158)Met-irrationality association was significant only when individuals fell in the average to above average range of emotional distress. Furthermore, within this range the Met allele seemed to relate to higher irrational beliefs. These results were significant for overall irrational beliefs and its subtypes, but not for rational beliefs, the functional counterpart of irrationality. In light of the study's limitations, the results should be considered as preliminary. If replicable, these findings have potential implications for therapygenetics, changing the view that COMT Val(158)Met might be of greater relevance when treatment modality does not rely on cognitive variables. Copyright © 2015. Published by Elsevier Ltd.

  4. The catechol-O-methyltransferase (COMT) Val158Met genotype modulates working memory-related dorsolateral prefrontal response and performance in bipolar disorder.

    PubMed

    Miskowiak, K W; Kjaerstad, H L; Støttrup, M M; Svendsen, A M; Demant, K M; Hoeffding, L K; Werge, T M; Burdick, K E; Domschke, K; Carvalho, A F; Vieta, E; Vinberg, M; Kessing, L V; Siebner, H R; Macoveanu, J

    2017-05-01

    Cognitive dysfunction affects a substantial proportion of patients with bipolar disorder (BD), and genetic-imaging paradigms may aid in the elucidation of mechanisms implicated in this symptomatic domain. The Val allele of the functional Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene is associated with reduced prefrontal cortex dopamine and exaggerated working memory-related prefrontal activity. This functional magnetic resonance imaging (fMRI) study investigated for the first time whether the COMT Val158Met genotype modulates prefrontal activity during spatial working memory in BD. Sixty-four outpatients with BD in full or partial remission were stratified according to COMT Val158Met genotype (ValVal [n=13], ValMet [n=34], and MetMet [n=17]). The patients completed a spatial n-back working memory task during fMRI and the Cambridge Neuropsychological Test Automated Battery (CANTAB) Spatial Working Memory test outside the scanner. During high working memory load (2-back vs 1-back), Val homozygotes displayed decreased activity relative to ValMet individuals, with Met homozygotes displaying intermediate levels of activity in the right dorsolateral prefrontal cortex (dlPFC) (P=.016). Exploratory whole-brain analysis revealed a bilateral decrease in working memory-related dlPFC activity in the ValVal group vs the ValMet group which was not associated with differences in working memory performance during fMRI. Outside the MRI scanner, Val carriers performed worse in the CANTAB Spatial Working Memory task than Met homozygotes (P≤.006), with deficits being most pronounced in Val homozygotes. The association between Val allelic load, dlPFC activity and WM impairment points to a putative role of aberrant PFC dopamine tonus in the cognitive impairments in BD. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Facial emotion recognition in schizophrenia: An exploratory study on the role of comorbid alcohol and substance use disorders and COMT Val158Met.

    PubMed

    Carrà, Giuseppe; Nicolini, Gabriella; Lax, Annamaria; Bartoli, Francesco; Castellano, Filippo; Chiorazzi, Alessia; Gamba, Giulia; Bava, Mattia; Crocamo, Cristina; Papagno, Costanza

    2017-11-01

    To explore whether facial emotion recognition (FER), impaired in both schizophrenia and alcohol and substance use disorders (AUDs/SUDs), is additionally compromised among comorbid subjects, also considering the role of catechol-O-methyltransferase (COMT) Val158Met. We conducted a cross-sectional study, randomly recruiting 67 subjects with a DSM-IV-TR diagnosis of schizophrenia, and rigorously assessing AUDs/SUDs and COMT Val158Met polymorphism. FER was assessed using the Ekman 60 Faces Test- EK-60F. As a whole, the sample scored significantly lower than normative data on EK-60F. However, subjects with comorbid AUDs/SUDs did not perform worse on EK-60F than those without, who had a better performance on EK-60F if they carried the COMT Val/Met variant. This study is the first to date examining the impact of AUDs/SUDs and COMT variants on FER in an epidemiologically representative sample of subjects with schizophrenia. Our findings do not suggest an additional impairment from comorbid AUDs/SUDs on FER among subjects with schizophrenia, whilst COMT Val158Met, though based on a limited sample, might have a role just among those without AUDs/SUDs. Based on our results, additional research is needed also exploring differential roles of various substances. Copyright © 2017 John Wiley & Sons, Ltd.

  6. The effect of COMT Val158 Met genotype on decision-making and preliminary findings on its interaction with the 5-HTTLPR in healthy females.

    PubMed

    van den Bos, Ruud; Homberg, Judith; Gijsbers, Ellen; den Heijer, Esther; Cuppen, Edwin

    2009-02-01

    Poor decision-making is inherent to several psychiatric conditions for which a genetic basis may exist. We previously showed that healthy female volunteers homozygous for the short allele (s/s) of the serotonin transporter length polymorphic region (5-HTTLPR) chose more often cards from disadvantageous decks in the Iowa Gambling Task (IGT), which measures decision-making, than long (l) allele carriers. The 5-HTTLPR and catechol-O-methyltransferase (COMT) Val(158) Met polymorphism affect the same set of neuronal structures. Therefore, we explored the effect of the (COMT) Val(158) Met polymorphism on IGT performance and its interaction with the 5-HTTLPR in the same subjects in this study. We observed that subjects homozygous for methionine (Met/Met) chose more disadvantageously than subjects homozygous for valine (Val/Val). s/s-Met/Met-subjects appeared to show the poorest IGT performance of all possible combinations of 5-HTTLPR and COMT allelic variants. Using the Expectancy-Valence model, no differences were found for the three different 5-HTTLPR or COMT genotypes regarding (i) attention to wins versus losses, (ii) updating rate, or (iii) response consistency. However, subjects with at least one Met-allele were paying more attention to wins than subjects with no Met-alleles. We discuss whether a common neuronal mechanism relates to s- and Met-allele-related deficits in updating and/or processing of choice outcome to guide subsequent choices in this gamble-based test.

  7. Cathecol-O-methyl transferase Val158Met genotype is not a risk factor for conversion disorder.

    PubMed

    Armagan, E; Almacıoglu, M L; Yakut, T; Köse, A; Karkucak, M; Köksal, O; Görükmez, O

    2013-03-19

    Alterations in catechol-O-methyltransferase (COMT) activity are involved in various types of neurological disorders. We examined a possible association between the COMT Val158Met polymorphism and conversion disorder in a study of 48 patients with conversion disorder and 48 control patients. In the conversion disorder group, 31 patients were Val/Met heterozygotes, 15 patients were Val/Val homozygotes and 2 patients were Met/Met homozygotes. In the control group, 32 patients were Val/Met heterozygotes and 16 patients were Val/Val homozygotes. There was no significant difference between the groups. We conclude that the COMT Val158Met genotype is quite common in Turkey and that it is not a risk factor for conversion disorder in the Turkish population.

  8. COMT Val(158)Met genotype and cannabis use in people with an At Risk Mental State for psychosis: Exploring Gene x Environment interactions.

    PubMed

    Nieman, Dorien H; Dragt, Sara; van Duin, Esther D A; Denneman, Nadine; Overbeek, Jozefien M; de Haan, Lieuwe; Rietdijk, Judith; Ising, Helga K; Klaassen, Rianne M C; van Amelsvoort, Thérèse; Wunderink, Lex; van der Gaag, Mark; Linszen, Don H

    2016-07-01

    Epidemiological and retrospective studies suggest a cannabis x catechol-O-methyltransferase (COMT) Val(158)Met interaction effect on development of psychosis. The aim of this study was to examine this interaction and its association with severity of subclinical symptoms in people with an At Risk Mental State (ARMS) for psychosis. Severity of symptoms, cannabis use and genotype were assessed at baseline in 147 help-seeking young adults who met the ARMS criteria and agreed to participate in the Dutch Early Detection and Intervention (EDIE-NL) trial. Cannabis use and COMT Val-allele showed an interaction effect in ARMS subjects. Subjects who were weekly cannabis users at some point prior to entering the study showed more severe positive symptoms. This effect increased if they were carriers of the COMT Val-allele and even more so if they were homozygous for the Val-allele. Our results suggest that the COMT Val(158)Met polymorphism moderates the effect of regular cannabis use on severity of subclinical psychotic symptoms. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. No association between catechol-o-methyltransferase Val108/158Met polymorphism and schizophrenia or its clinical symptomatology in a Mexican population.

    PubMed

    Tovilla-Zárate, Carlos; Medellín, Beatriz Camarena; Fresán, Ana; López-Narváez, Lilia; Castro, Thelma Beatriz Gonzalez; Juárez Rojop, Isela; Ramírez-Bello, Julián; Genis, Alma; Nicolini, Humberto

    2013-02-01

    The gene coding for catecol-o-methyltransferase (COMT), participant in the metabolism of catecholamines, has long been implicated as a candidate gene for schizophrenia. We determined the relation of the COMT Val108/158Met polymorphism with schizophrenia or its symptomatology (negative, disorganized and psychotic dimension). We conducted a case-control study comprising 186 patients with schizophrenia and 247 controls. The diagnosis of schizophrenia was established using the DSM-IV criteria for this illness. The clinical symptomatology was assessed through the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms. No significant differences were found in the distribution of alleles (χ2 = 0.01, df = 1, p = 0.90) or genotypes (χ2 = 1.66, df = 2, p = 0.43) between schizophrenic patients and the control group. Multivariate analysis showed that the COMT Val108/158Met polymorphism has no influence in the clinical symptomatology of schizophrenia. Our results showed no association between COMT Val108/158Met and schizophrenia or evidence for an association between COMT and the clinical symptomatology of this illness. This suggests that the COMT gene may not contribute to the risk for schizophrenia among the Mexican population.

  10. Interaction between catechol-O-methyltransferase (COMT) Val158Met genotype and genetic vulnerability to schizophrenia during explicit processing of aversive facial stimuli.

    PubMed

    Lo Bianco, L; Blasi, G; Taurisano, P; Di Giorgio, A; Ferrante, F; Ursini, G; Fazio, L; Gelao, B; Romano, R; Papazacharias, A; Caforio, G; Sinibaldi, L; Popolizio, T; Bellantuono, C; Bertolino, A

    2013-02-01

    Emotion dysregulation is a key feature of schizophrenia, a brain disorder strongly associated with genetic risk and aberrant dopamine signalling. Dopamine is inactivated by catechol-O-methyltransferase (COMT), whose gene contains a functional polymorphism (COMT Val158Met) associated with differential activity of the enzyme and with brain physiology of emotion processing. The aim of the present study was to investigate whether genetic risk for schizophrenia and COMT Val158Met genotype interact on brain activity during implicit and explicit emotion processing. A total of 25 patients with schizophrenia, 23 healthy siblings of patients and 24 comparison subjects genotyped for COMT Val158Met underwent functional magnetic resonance imaging during implicit and explicit processing of facial stimuli with negative emotional valence. We found a main effect of diagnosis in the right amygdala, with decreased activity in patients and siblings compared with control subjects. Furthermore, a genotype × diagnosis interaction was found in the left middle frontal gyrus, such that the effect of genetic risk for schizophrenia was evident in the context of the Val/Val genotype only, i.e. the phenotype of reduced activity was present especially in Val/Val patients and siblings. Finally, a complete inversion of the COMT effect between patients and healthy subjects was found in the left striatum during explicit processing. Overall, these results suggest complex interactions between genetically determined dopamine signalling and risk for schizophrenia on brain activity in the prefrontal cortex during emotion processing. On the other hand, the effects in the striatum may represent state-related epiphenomena of the disorder itself.

  11. Age-Dependent Effects of Catechol-O-Methyltransferase (COMT) Gene Val158Met Polymorphism on Language Function in Developing Children.

    PubMed

    Sugiura, Lisa; Toyota, Tomoko; Matsuba-Kurita, Hiroko; Iwayama, Yoshimi; Mazuka, Reiko; Yoshikawa, Takeo; Hagiwara, Hiroko

    2017-01-01

    The genetic basis controlling language development remains elusive. Previous studies of the catechol-O-methyltransferase (COMT) Val158Met genotype and cognition have focused on prefrontally guided executive functions involving dopamine. However, COMT may further influence posterior cortical regions implicated in language perception. We investigated whether COMT influences language ability and cortical language processing involving the posterior language regions in 246 children aged 6-10 years. We assessed language ability using a language test and cortical responses recorded during language processing using a word repetition task and functional near-infrared spectroscopy. The COMT genotype had significant effects on language performance and processing. Importantly, Met carriers outperformed Val homozygotes in language ability during the early elementary school years (6-8 years), whereas Val homozygotes exhibited significant language development during the later elementary school years. Both genotype groups exhibited equal language performance at approximately 10 years of age. Val homozygotes exhibited significantly less cortical activation compared with Met carriers during word processing, particularly at older ages. These findings regarding dopamine transmission efficacy may be explained by a hypothetical inverted U-shaped curve. Our findings indicate that the effects of the COMT genotype on language ability and cortical language processing may change in a narrow age window of 6-10 years. © The Author 2016. Published by Oxford University Press.

  12. Modification of Depression by COMT val[superscript 158]Met Polymorphism in Children Exposed to Early Severe Psychosocial Deprivation

    ERIC Educational Resources Information Center

    Drury, Stacy S.; Theall, Katherine P.; Smyke, Anna T.; Keats, Bronya J. B.; Egger, Helen L.; Nelson, Charles A.; Fox, Nathan A.; Marshall, Peter J.; Zeanah, Charles H.

    2010-01-01

    Objective: To examine the impact of the catechol-O-methyltransferase (COMT) val[superscript 158]met allele on depressive symptoms in young children exposed to early severe social deprivation as a result of being raised in institutions. Methods: One hundred thirty six children from the Bucharest Early Intervention Project (BEIP) were randomized…

  13. Influence of BDNF and COMT polymorphisms on emotional decision making.

    PubMed

    Kang, Jee In; Namkoong, Kee; Ha, Ra Yeon; Jhung, Kyungun; Kim, Yang Tae; Kim, Se Joo

    2010-06-01

    Decision making is an important brain function. Although little is known about the genetic basis of decision making, it has been suggested that it is mediated by the modulation of neurotransmitter systems. We investigated how the BDNF Val66Met and COMT Val158Met polymorphisms affect emotional decision making using the Iowa Gambling Task (IGT). One hundred sixty-eight healthy Korean college students (93 males, 75 females) with a complete dataset were included in the data analysis. The IGT and genotyping for the polymorphisms of BDNF Val66Met and COMT Val158Met were performed. Both Met/Met and Val/Met of the BDNF Val66Met polymorphism were significantly associated with a lower mean score of blocks 3-5 of the IGT and with less improvement from block 1 to block 3-5 than the Val/Val. However, the BDNF was not significantly associated with the score of block 1, and the COMT Val158Met polymorphism produced no significant effect on IGT performance. No interaction effect was observed between the BDNF and the COMT for the IGT. These findings suggest the BDNF Val66Met may affect the emotional decision making performance. (c) 2010 Elsevier Ltd. All rights reserved.

  14. Perceived Stress in Adults Aged 65 to 90: Relations to Facets of Time Perspective and COMT Val158Met Polymorphism

    PubMed Central

    Rönnlund, Michael; Åström, Elisabeth; Adolfsson, Rolf; Carelli, Maria G.

    2018-01-01

    This study examined the relation between perceived stress and time perspective (views of past, present, future) in a population-based sample of older adults (65–90 years, N = 340). The Perceived Questionnaire (PSQ index) was used to measure stress and the Swedish version of the Zimbardo Time Perspective Inventory (S-ZTPI) was used to operationalize time perspective. Unlike the original inventory, S-ZTPI separates positive and negative aspects of a future time perspective and we hypothesized that the Future Negative (FN) scale would be important to account for variations in stress. Additionally, associations with Catechol-O-methyltransferase (COMT) Val158Met polymorphism were examined, motivated by prior associations of this single nucleotide polymorphism (SNP) with stress (or “anxiety”) related personality traits. In line with the hypotheses, FN was the strongest predictor of PSQ index scores in multiple regression analyses. In a related vein, the dichotomization of the unitary Future scale increased the association between PSQ scores and a measure of deviations from a balanced time perspective, i.e., the difference between a proposed optimal and observed ZTPI profile. Finally, higher levels of stress as well as higher scores on FN were observed in COMT Val/Val carriers, at least among men. This suggests a shared dopaminergic genetic influence on these variables. Collectively, the results demonstrate that perceived stress is closely linked to time perspective and highlight the need to take negative aspects of a future temporal orientation into account to understand this relation. PMID:29623060

  15. Perceived Stress in Adults Aged 65 to 90: Relations to Facets of Time Perspective and COMT Val158Met Polymorphism.

    PubMed

    Rönnlund, Michael; Åström, Elisabeth; Adolfsson, Rolf; Carelli, Maria G

    2018-01-01

    This study examined the relation between perceived stress and time perspective (views of past, present, future) in a population-based sample of older adults (65-90 years, N = 340). The Perceived Questionnaire (PSQ index) was used to measure stress and the Swedish version of the Zimbardo Time Perspective Inventory (S-ZTPI) was used to operationalize time perspective. Unlike the original inventory, S-ZTPI separates positive and negative aspects of a future time perspective and we hypothesized that the Future Negative (FN) scale would be important to account for variations in stress. Additionally, associations with Catechol-O-methyltransferase ( COMT ) Val 158 Met polymorphism were examined, motivated by prior associations of this single nucleotide polymorphism (SNP) with stress (or "anxiety") related personality traits. In line with the hypotheses, FN was the strongest predictor of PSQ index scores in multiple regression analyses. In a related vein, the dichotomization of the unitary Future scale increased the association between PSQ scores and a measure of deviations from a balanced time perspective, i.e., the difference between a proposed optimal and observed ZTPI profile. Finally, higher levels of stress as well as higher scores on FN were observed in COMT Val/Val carriers, at least among men. This suggests a shared dopaminergic genetic influence on these variables. Collectively, the results demonstrate that perceived stress is closely linked to time perspective and highlight the need to take negative aspects of a future temporal orientation into account to understand this relation.

  16. COMT ValMet moderation of cannabis-induced psychosis: a momentary assessment study of 'switching on' hallucinations in the flow of daily life.

    PubMed

    Henquet, C; Rosa, A; Delespaul, P; Papiol, S; Fananás, L; van Os, J; Myin-Germeys, I

    2009-02-01

    A functional polymorphism in the catechol-o-methyltransferase gene (COMT Val(158)Met) may moderate the psychosis-inducing effects of cannabis. In order to extend this finding to dynamic effects in the flow of daily life, a momentary assessment study of psychotic symptoms in response to cannabis use was conducted. The experience sampling technique was used to collect data on cannabis use and occurrence of symptoms in daily life in patients with a psychotic disorder (n = 31) and healthy controls (n = 25). Carriers of the COMT Val(158)Met Val allele, but not subjects with the Met/Met genotype, showed an increase in hallucinations after cannabis exposure, conditional on prior evidence of psychometric psychosis liability. The findings confirm that in people with psychometric evidence of psychosis liability, COMT Val(158)Met genotype moderates the association between cannabis and psychotic phenomena in the flow of daily life.

  17. COMT Val158Met and MTHFR C677T moderate risk of schizophrenia in response to childhood adversity.

    PubMed

    Debost, J-C; Debost, M; Grove, J; Mors, O; Hougaard, D M; Børglum, A D; Mortensen, P B; Petersen, L

    2017-07-01

    Mesolimbic dopamine sensitization has been hypothesized to be a mediating factor of childhood adversity (CA) on schizophrenia risk. Activity of catechol-O-methyltransferase (COMT) Val158Met increases mesolimbic dopamine signaling and may be further regulated by methylenetetrahydrofolate reductase (MTHFR) C677T. This study investigates the three-way interaction between CA, COMT, and MTHFR. We conducted a nested case-control study on individuals born after 1981, linking population-based registers to study the three-way interaction. We included 1699 schizophrenia cases and 1681 controls, and used conditional logistic regression to report incidence rate ratios (IRRs). Childhood adversity was robustly associated with schizophrenia. No main genetic effects were observed. MTHFR C677T increased schizophrenia risk in a dose-dependent manner per MTHFR T allele (P = 0.005) consequent upon CA exposure. After inclusion of the significant (P = 0.03) COMT × MTHFR × CA interaction, the risk was further increased per high-activity COMT Val allele. Hence, exposed COMT Val/Val and MTHFR T/T carriers had an IRR of 2.76 (95% CI, 1.66-4.61). Additional adjustments for ancestry and parental history of mental illness attenuated the results with the interaction being only marginally significant. MTHFR C677T and COMT Val158Met interact with CA to increase risk of schizophrenia. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Association between COMT Val158Met and psychiatric disorders: A comprehensive meta-analysis.

    PubMed

    Taylor, Steven

    2018-03-01

    Catechol-O-methyltransferase (COMT) Val158Met is widely regarded as potentially important for understanding the genetic etiology of many different psychiatric disorders. The present study appears to be the first comprehensive meta-analysis of COMT genetic association studies to cover all psychiatric disorders for which there were available data, published in any language, and with an emphasis on investigating disorder subtypes (defined clinically or by demographic or other variables). Studies were included if they reported one or more datasets (i.e., some studies examined more than one clinical group) in which there were sufficient information to compute effect sizes. A total of 363 datasets were included, consisting of 56,998 cases and 74,668 healthy controls from case control studies, and 2,547 trios from family based studies. Fifteen disorders were included. Attention-deficit hyperactivity disorder and panic disorder were associated with the Val allele for Caucasian samples. Substance-use disorder, defined by DSM-IV criteria, was associated with the Val allele for Asian samples. Bipolar disorder was associated with the Met allele in Asian samples. Obsessive-compulsive disorder tended to be associated with the Met allele only for males. There was suggestive evidence that the Met allele is associated with an earlier age of onset of schizophrenia. Results suggest pleiotropy and underscore the importance of examining subgroups-defined by variables such as age of onset, sex, ethnicity, and diagnostic system-rather than examining disorders as monolithic constructs. © 2017 Wiley Periodicals, Inc.

  19. Gender effects of the COMT Val 158 Met genotype on verbal fluency in healthy adults.

    PubMed

    Soeiro-De-Souza, Marcio Gerhardt; Bio, Danielle Soares; David, Denise Petresco; Missio, Giovani; Lima, Bruno; Fernandes, Fernando; Machado-Vieira, Rodrigo; Moreno, Ricardo Alberto

    2013-09-01

    Cognitive performance in healthy individuals is associated with gender differences in specific tests; a female advantage has been demonstrated in language tests, whereas a male advantage has been demonstrated in spatial relation examinations. The prefrontal cortex (PFC) mediates important cognitive domains and is influenced by dopamine (DA) activity. The single nucleotide polymorphism (SNP) rs4680 in the catechol‑O‑methyltransferase (COMT) gene results in an amino acid substitution from valine (Val) to methionine (Met). The Met allele has been demonstrated to decrease COMT enzyme activity and improve PFC cognitive function. COMT regulates DA activity in the PFC and exhibits gender effects. The aim of the present study was to investigate the gender‑specific effects of the COMT genotype on cognition in healthy young adults. Seventy‑six healthy subjects were genotyped for COMT rs4680 and submitted to an extensive range of neuropsychological tests assessing aspects of PFC function. The COMT Met allele influenced the performance of executive function. The results revealed gender effects of the COMT rs4680 Met allele on verbal fluency, with positive effects in males and negative effects in females. This suggested that DA activity affects cognitive function in different ways, according to gender.

  20. Differential Effects of the Catechol-O-Methyltransferase Val158Met Genotype on the Cognitive Function of Schizophrenia Patients and Healthy Japanese Individuals

    PubMed Central

    Tsuchimine, Shoko; Yasui-Furukori, Norio; Kaneda, Ayako; Kaneko, Sunao

    2013-01-01

    Background The functional polymorphism Val158Met in the catechol-O-methyltransferase (COMT) gene has been associated with differences in prefrontal cognitive functions in patients with schizophrenia and healthy individuals. Several studies have indicated that the Met allele is associated with better performance on measures of cognitive function. We investigated whether the COMT Val158Met genotype was associated with cognitive function in 149 healthy controls and 118 patients with schizophrenia. Methods Cognitive function, including verbal memory, working memory, motor speed, attention, executive function and verbal fluency, was assessed by the Brief Assessment of Cognition in Schizophrenia (BACS-J). We employed a one-way analysis of variance (ANOVA) and a multiple regression analysis to determine the associations between the COMT Val158Met genotype and the BACS-J measurements. Results The one-way ANOVA revealed a significant difference in the scores on the Tower of London, a measure of executive function, between the different Val158Met genotypes in the healthy controls (p = 0.023), and a post-hoc analysis showed significant differences between the scores on the Tower of London in the val/val genotype group (18.6 ± 2.4) compared to the other two groups (17.6 ± 2.7 for val/met and 17.1 ± 3.2 for met/met; p = 0.027 and p = 0.024, respectively). Multiple regression analyses revealed that executive function was significantly correlated with the Val158Met genotype (p = 0.003). However, no evidence was found for an effect of the COMT on any cognitive domains of the BACS-J in the patients with schizophrenia. Conclusion These data support the hypothesis that the COMT Val158Met genotype maintains an optimal level of dopamine activity. Further studies should be performed that include a larger sample size and include patients on and off medication, as these patients would help to confirm our findings. PMID:24282499

  1. The interaction between cannabis use and the Val158Met polymorphism of the COMT gene in psychosis: A transdiagnostic meta - analysis.

    PubMed

    Vaessen, Thomas Stephanus Johannes; de Jong, Lea; Schäfer, Annika Theresia; Damen, Thomas; Uittenboogaard, Aniek; Krolinski, Pauline; Nwosu, Chinyere Vicky; Pinckaers, Florentina Maria Egidius; Rotee, Iris Leah Marije; Smeets, Antonius Petrus Wilhelmus; Ermiş, Ayşegül; Kennedy, James L; Nieman, Dorien H; Tiwari, Arun; van Os, Jim; Drukker, Marjan

    2018-01-01

    Neither environmental nor genetic factors are sufficient to predict the transdiagnostic expression of psychosis. Therefore, analysis of gene-environment interactions may be productive. A meta-analysis was performed using papers investigating the interaction between cannabis use and catechol-O-methyl transferase (COMT) polymorphism Val158Met (COMTVal158Met). PubMed, Embase, PsychInfo. All observational studies assessing the interaction between COMTVal158Met and cannabis with any psychosis or psychotic symptoms measure as an outcome. A meta-analysis was performed using the Meta-analysis of Observational Studies in Epidemiology guidelines and forest plots were generated. Thirteen articles met the selection criteria: 7 clinical studies using a case-only design, 3 clinical studies with a dichotomous outcome, and 3 studies analysing a continuous outcome of psychotic symptoms below the threshold of psychotic disorder. The three study types were analysed separately. Validity of the included studies was assessed using "A Cochrane Risk of Bias Assessment Tool: for Non-Randomized Studies of Interventions". For case-only studies, a significant interaction was found between cannabis use and COMTVal158Met, with an OR of 1.45 (95% Confidence Interval = 1.05-2.00; Met/Met as the risk genotype). However, there was no evidence for interaction in either the studies including dichotomous outcomes (B = -0.51, 95% Confidence Interval -1.72, 0.70) or the studies including continuous outcomes (B = -0.04 95% Confidence Interval -0.16-0.08). A substantial part of the included studies used the case-only design, which has lower validity and tends to overestimate true effects. The interaction term between cannabis use and COMTVal158Met was only statistically significant in the case-only studies, but not in studies using other clinical or non-clinical psychosis outcomes. Future additional high quality studies might change current perspectives, yet currently evidence for the interaction remains

  2. The Flexible Mind Is Associated with the Catechol-O-Methyltransferase (COMT) Val[superscript 158]Met Polymorphism: Evidence for a Role of Dopamine in the Control of Task-Switching

    ERIC Educational Resources Information Center

    Colzato, Lorenza S.; Waszak, Florian; Nieuwenhuis, Sander; Posthuma, Danielle; Hommel, Bernhard

    2010-01-01

    Genetic variability related to the catechol-O-methyltransferase (COMT) gene Val[superscript 128]Met polymorphism) has received increasing attention as a possible modulator of cognitive control functions. Recent evidence suggests that the Val[superscript 128]Met genotype may differentially affect cognitive stability and flexibility, in such a way…

  3. The Mediating Effect of Prefrontal Asymmetry on the Relationship between the COMT Val158Met SNP and Trait Consummatory Positive Affect

    PubMed Central

    Katz, Andrea C.; Sarapas, Casey; Bishop, Jeffrey R.; Patel, Shitalben R.; Shankman, Stewart A.

    2014-01-01

    The Val158Met rs4680 polymorphism in the COMT gene regulates dopamine catabolism in the prefrontal cortex (PFC). Dopamine’s involvement in reward experience suggests those with the Met variant may exhibit trait-level sensitivity to reward due to more post-synaptic dopamine in the PFC. A physiological mediator of this association may be greater relative left asymmetry in the PFC, a putative biomarker for trait positive emotionality. Electroencephalograms of 120 participants were measured during a task that assesses two aspects of reward processing: pre-reward anticipation and post-reward consummatory affect. Participants provided genetics samples and completed the Temporal Experience of Pleasure Scale, which assesses trait-level anticipatory and consummatory positive affect. Met carriers had higher TEPS-Consummatory scores. This effect was mediated by greater relative left activation in the post-reward phase of the task. No effects were observed for the pre-reward phase. Results suggest that frontal asymmetry is an endophenotype between COMT genotype and trait reward responsivity. PMID:25195915

  4. Association of Catechol-O-Methyltransferase (COMT) Polymorphism and Academic Achievement in a Chinese Cohort

    ERIC Educational Resources Information Center

    Yeh, Ting-Kuang; Chang, Chun-Yen; Hu, Chung-Yi; Yeh, Ting-Chi; Lin, Ming-Yeh

    2009-01-01

    Catechol-O-methyltransferase (COMT) is a methylation enzyme that catalyzes the degradation pathway and inactivation of dopamine. It is accepted widely as being involved in the modulation of dopaminergic physiology and prefrontal cortex (PFC) function. The COMT Val158Met polymorphism is associated with variation in COMT activity. COMT 158Met allele…

  5. The impact of the Val158Met catechol-O-methyltransferase genotype on neural correlates of sad facial affect processing in patients with bipolar disorder and their relatives.

    PubMed

    Lelli-Chiesa, G; Kempton, M J; Jogia, J; Tatarelli, R; Girardi, P; Powell, J; Collier, D A; Frangou, S

    2011-04-01

    The Met allele of the catechol-O-methyltransferase (COMT) valine-to-methionine (Val158Met) polymorphism is known to affect dopamine-dependent affective regulation within amygdala-prefrontal cortical (PFC) networks. It is also thought to increase the risk of a number of disorders characterized by affective morbidity including bipolar disorder (BD), major depressive disorder (MDD) and anxiety disorders. The disease risk conferred is small, suggesting that this polymorphism represents a modifier locus. Therefore our aim was to investigate how the COMT Val158Met may contribute to phenotypic variation in clinical diagnosis using sad facial affect processing as a probe for its neural action. We employed functional magnetic resonance imaging to measure activation in the amygdala, ventromedial PFC (vmPFC) and ventrolateral PFC (vlPFC) during sad facial affect processing in family members with BD (n=40), MDD and anxiety disorders (n=22) or no psychiatric diagnosis (n=25) and 50 healthy controls. Irrespective of clinical phenotype, the Val158 allele was associated with greater amygdala activation and the Met158 allele with greater signal change in the vmPFC and vlPFC. Signal changes in the amygdala and vmPFC were not associated with disease expression. However, in the right vlPFC the Met158 allele was associated with greater activation in all family members with affective morbidity compared with relatives without a psychiatric diagnosis and healthy controls. Our results suggest that the COMT Val158Met polymorphism has a pleiotropic effect within the neural networks subserving emotional processing. Furthermore the Met158 allele further reduces cortical efficiency in the vlPFC in individuals with affective morbidity.

  6. COMT Val158Met Genotype Selectively Alters Prefrontal [18F]Fallypride Displacement and Subjective Feelings of Stress in Response to a Psychosocial Stress Challenge

    PubMed Central

    Lataster, Johan; Ceccarini, Jenny; Kenis, Gunther; Booij, Linda; Pruessner, Jens; Van Laere, Koen; van Winkel, Ruud; van Os, Jim; Myin-Germeys, Inez

    2013-01-01

    Catechol-O-methyltransferase (COMT) plays an essential role in degradation of extracellular dopamine in prefrontal regions of the brain. Although a polymorphism in this gene, COMT Val158Met, affects human behavior in response to stress little is known about its effect on dopaminergic activity associated with the human stress response, which may be of interest for stress-related psychiatric disorders such as psychosis. We aimed to investigate the effect of variations in COMT genotype on in vivo measures of stress-induced prefrontal cortex (PFC) dopaminergic processing and subjective stress responses. A combined sample of healthy controls and healthy first-degree relatives of psychosis patients (n = 26) were subjected to an [18F]fallypride Positron Emission Tomography scan. Psychosocial stress during the scan was induced using the Montreal Imaging Stress Task and subjective stress was assessed every 12 minutes. Parametric t-maps, generated using the linear extension of the simplified reference region model, revealed an effect of COMT genotype on the spatial extent of [18F]fallypride displacement. Detected effects of exposure to psychosocial stress were unilateral and remained restricted to the left superior and right inferior frontal gyrus, with Met-hetero- and homozygotes showing less [18F]fallypride displacement than Val-homozygotes. Additionally, Met-hetero- and homozygotes experienced larger subjective stress responses than Val-homozygotes. The direction of the effects remained the same when the data was analyzed separately for controls and first-degree relatives. The human stress response may be mediated in part by COMT-dependent dopaminergic PFC activity, providing speculation for the neurobiology underlying COMT-dependent differences in human behaviour following stress. Implications of these results for stress-related psychopathology and models of dopaminergic functioning are discussed. PMID:23799032

  7. COMT Val158Met genotype selectively alters prefrontal [18F]fallypride displacement and subjective feelings of stress in response to a psychosocial stress challenge.

    PubMed

    Hernaus, Dennis; Collip, Dina; Lataster, Johan; Ceccarini, Jenny; Kenis, Gunther; Booij, Linda; Pruessner, Jens; Van Laere, Koen; van Winkel, Ruud; van Os, Jim; Myin-Germeys, Inez

    2013-01-01

    Catechol-O-methyltransferase (COMT) plays an essential role in degradation of extracellular dopamine in prefrontal regions of the brain. Although a polymorphism in this gene, COMT Val(158)Met, affects human behavior in response to stress little is known about its effect on dopaminergic activity associated with the human stress response, which may be of interest for stress-related psychiatric disorders such as psychosis. We aimed to investigate the effect of variations in COMT genotype on in vivo measures of stress-induced prefrontal cortex (PFC) dopaminergic processing and subjective stress responses. A combined sample of healthy controls and healthy first-degree relatives of psychosis patients (n = 26) were subjected to an [(18)F]fallypride Positron Emission Tomography scan. Psychosocial stress during the scan was induced using the Montreal Imaging Stress Task and subjective stress was assessed every 12 minutes. Parametric t-maps, generated using the linear extension of the simplified reference region model, revealed an effect of COMT genotype on the spatial extent of [(18)F]fallypride displacement. Detected effects of exposure to psychosocial stress were unilateral and remained restricted to the left superior and right inferior frontal gyrus, with Met-hetero- and homozygotes showing less [(18)F]fallypride displacement than Val-homozygotes. Additionally, Met-hetero- and homozygotes experienced larger subjective stress responses than Val-homozygotes. The direction of the effects remained the same when the data was analyzed separately for controls and first-degree relatives. The human stress response may be mediated in part by COMT-dependent dopaminergic PFC activity, providing speculation for the neurobiology underlying COMT-dependent differences in human behaviour following stress. Implications of these results for stress-related psychopathology and models of dopaminergic functioning are discussed.

  8. The interaction between cannabis use and the Val158Met polymorphism of the COMT gene in psychosis: A transdiagnostic meta – analysis

    PubMed Central

    Schäfer, Annika Theresia; Damen, Thomas; Uittenboogaard, Aniek; Krolinski, Pauline; Nwosu, Chinyere Vicky; Pinckaers, Florentina Maria Egidius; Rotee, Iris Leah Marije; Ermiş, Ayşegül; Kennedy, James L.; Nieman, Dorien H.; Tiwari, Arun; van Os, Jim

    2018-01-01

    Background Neither environmental nor genetic factors are sufficient to predict the transdiagnostic expression of psychosis. Therefore, analysis of gene-environment interactions may be productive. Objective A meta-analysis was performed using papers investigating the interaction between cannabis use and catechol-O-methyl transferase (COMT) polymorphism Val158Met (COMTVal158Met). Data sources PubMed, Embase, PsychInfo. Study eligibility criteria All observational studies assessing the interaction between COMTVal158Met and cannabis with any psychosis or psychotic symptoms measure as an outcome. Study appraisal and synthesis methods A meta-analysis was performed using the Meta-analysis of Observational Studies in Epidemiology guidelines and forest plots were generated. Thirteen articles met the selection criteria: 7 clinical studies using a case-only design, 3 clinical studies with a dichotomous outcome, and 3 studies analysing a continuous outcome of psychotic symptoms below the threshold of psychotic disorder. The three study types were analysed separately. Validity of the included studies was assessed using "A Cochrane Risk of Bias Assessment Tool: for Non-Randomized Studies of Interventions". Results For case-only studies, a significant interaction was found between cannabis use and COMTVal158Met, with an OR of 1.45 (95% Confidence Interval = 1.05–2.00; Met/Met as the risk genotype). However, there was no evidence for interaction in either the studies including dichotomous outcomes (B = -0.51, 95% Confidence Interval -1.72, 0.70) or the studies including continuous outcomes (B = -0.04 95% Confidence Interval -0.16–0.08). Limitation A substantial part of the included studies used the case-only design, which has lower validity and tends to overestimate true effects. Conclusion The interaction term between cannabis use and COMTVal158Met was only statistically significant in the case-only studies, but not in studies using other clinical or non-clinical psychosis

  9. Catechol-O-Methyltransferase Val158Met Polymorphism on Striatum Structural Covariance Networks in Alzheimer's Disease.

    PubMed

    Chang, Chiung-Chih; Tsai, Shih-Jen; Chen, Nai-Ching; Huang, Chi-Wei; Hsu, Shih-Wei; Chang, Ya-Ting; Liu, Mu-En; Chang, Wen-Neng; Tsai, Wan-Chen; Lee, Chen-Chang

    2018-06-01

    The catechol-O-methyltransferase enzyme metabolizes dopamine in the prefrontal axis, and its genetic polymorphism (rs4680; Val158Met) is a known determinant of dopamine signaling. In this study, we investigated the possible structural covariance networks that may be modulated by this functional polymorphism in patients with Alzheimer's disease. Structural covariance networks were constructed by 3D T1 magnetic resonance imaging. The patients were divided into two groups: Met-carriers (n = 91) and Val-homozygotes (n = 101). Seed-based analysis was performed focusing on triple-network models and six striatal networks. Neurobehavioral scores served as the major outcome factors. The role of seed or peak cluster volumes, or a covariance strength showing Met-carriers > Val-homozygotes were tested for the effect on dopamine. Clinically, the Met-carriers had higher mental manipulation and hallucination scores than the Val-homozygotes. The volume-score correlations suggested the significance of the putaminal seed in the Met-carriers and caudate seed in the Val-homozygotes. Only the dorsal-rostral and dorsal-caudal putamen interconnected peak clusters showed covariance strength interactions (Met-carriers > Val-homozygotes), and the peak clusters also correlated with the neurobehavioral scores. Although the triple-network model is important for a diagnosis of Alzheimer's disease, our results validated the role of the dorsal-putaminal-anchored network by the catechol-O-methyltransferase Val158Met polymorphism in predicting the severity of cognitive and behavior in subjects with Alzheimer's disease.

  10. Stressful life events, perceived stress, and 12-month course of geriatric depression: direct effects and moderation by the 5-HTTLPR and COMT Val158Met polymorphisms.

    PubMed

    Zannas, Anthony S; McQuoid, Douglas R; Steffens, David C; Chrousos, George P; Taylor, Warren D

    2012-07-01

    Although the relation between stressful life events (SLEs) and risk of major depressive disorder is well established, important questions remain about the effects of stress on the course of geriatric depression. Our objectives were (1) to examine how baseline stress and change in stress is associated with course of geriatric depression and (2) to test whether polymorphisms of serotonin transporter (5-HTTLPR) and catechol-O-methyltransferase (COMT Val158Met) genes moderate this relation. Two-hundred and sixteen depressed subjects aged 60 years or older were categorized by remission status (Montgomery-Asberg depression rating scale≤6) at 6 and 12 months. At 6 months, greater baseline numbers of self-reported negative and total SLEs and greater baseline perceived stress severity were associated with lower odds of remission. At 12 months, only baseline perceived stress predicted remission. When we examined change in stress, 12-month decrease in negative SLEs and level of perceived stress were associated with improved odds of 12-month remission. When genotype data were included, COMT Val158Met genotype did not influence these relations. However, when compared with 5-HTTLPR L/L homozygotes, S allele carriers with greater baseline numbers of negative SLEs and with greater decrease in negative SLEs were more likely to remit at 12 months. This study demonstrates that baseline SLEs and perceived stress severity may influence the 12-month course of geriatric depression. Moreover, changes in these stress measures over time correlate with depression outcomes. 5-HTTLPR S carriers appear to be more susceptible to both the effects of enduring stress and the benefit of interval stress reduction.

  11. Catechol-O-methyltransferase Val(158)Met association with parahippocampal physiology during memory encoding in schizophrenia.

    PubMed

    Di Giorgio, A; Caforio, G; Blasi, G; Taurisano, P; Fazio, L; Romano, R; Ursini, G; Gelao, B; Bianco, L Lo; Papazacharias, A; Sinibaldi, L; Popolizio, T; Bellomo, A; Bertolino, A

    2011-08-01

    Catechol-O-methyltransferase (COMT) Val158Met has been associated with activity of the mesial temporal lobe during episodic memory and it may weakly increase risk for schizophrenia. However, how this variant affects parahippocampal and hippocampal physiology when dopamine transmission is perturbed is unclear. The aim of the present study was to compare the effects of the COMT Val158Met genotype on parahippocampal and hippocampal physiology during encoding of recognition memory in patients with schizophrenia and in healthy subjects. Using blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI), we studied 28 patients with schizophrenia and 33 healthy subjects matched for a series of sociodemographic and genetic variables while they performed a recognition memory task. We found that healthy subjects had greater parahippocampal and hippocampal activity during memory encoding compared to patients with schizophrenia. We also found different activity of the parahippocampal region between healthy subjects and patients with schizophrenia as a function of the COMT genotype, in that the predicted COMT Met allele dose effect had an opposite direction in controls and patients. Our results demonstrate a COMT Val158Met genotype by diagnosis interaction in parahippocampal activity during memory encoding and may suggest that modulation of dopamine signaling interacts with other disease-related processes in determining the phenotype of parahippocampal physiology in schizophrenia. © Cambridge University Press 2010

  12. Catechol-O-Methyltransferase "Val[superscript 158]Met" Genotype, Parenting Practices and Adolescent Alcohol Use: Testing the Differential Susceptibility Hypothesis

    ERIC Educational Resources Information Center

    Laucht, Manfred; Blomeyer, Dorothea; Buchmann, Arlette F.; Treutlein, Jens; Schmidt, Martin H.; Esser, Gunter; Jennen-Steinmetz, Christine; Rietschel, Marcella; Zimmermann, Ulrich S.; Banaschewski, Tobias

    2012-01-01

    Background: Recently, first evidence has been reported for a gene-parenting interaction (G x E) with regard to adolescent alcohol use. The present investigation set out to extend this research using the catechol-O-methyltransferase ("COMT") "Val[superscript 158]Met" polymorphism as a genetic susceptibility factor. Moreover, the current study…

  13. Does adult ADHD interact with COMT val (158) met genotype to influence working memory performance?

    PubMed

    Biehl, Stefanie C; Gschwendtner, Kathrin M; Guhn, Anne; Müller, Laura D; Reichert, Susanne; Heupel, Julia; Reif, Andreas; Deckert, Jürgen; Herrmann, Martin J; Jacob, Christian P

    2015-03-01

    Both attention-deficit/hyperactivity disorder (ADHD) and catechol-O-methyltransferase (COMT) genotype have been linked to altered dopaminergic transmission and possible impairment in frontal lobe functioning. This study offers an investigation of a possible interaction between ADHD diagnosis and COMT genotype on measures of working memory and executive function. Thirty-five adults with ADHD, who were recruited from the ADHD outpatient clinic at the Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, and thirty-five matched healthy controls completed the Digit Span test and the Stroop Color Word Test. While there were no main effects of ADHD or COMT, the two factors interacted on both Digit Span subtests with the two groups' met/met carriers showing significantly different performance on the Digit Span Forward subtest and the val/val carriers showing significantly different performance on the Digit Span Backward subtest. Findings provide preliminary support for a differential impact of COMT genotype on working memory measures in adult patients with ADHD compared to healthy controls.

  14. The Val/Met functional polymorphism in COMT confers susceptibility to bipolar disorder: evidence from an association study and a meta-analysis.

    PubMed

    Zhang, Zhao; Lindpaintner, Klaus; Che, Ronglin; He, Zangdong; Wang, Peng; Yang, Ping; Feng, Guoyin; He, Lin; Shi, Yongyong

    2009-10-01

    The COMT gene is considered as one of the prominent candidate genes for susceptibility to BP, and most studies focused a functional polymorphism in the gene: the Val/Met polymorphism (rs4680). However, results from these studies are sometimes contradictory, due to small sample size or heterogeneity. In this study, we first investigate the possible association between the Val/Met polymorphism in COMT and bipolar disorder in the Han population, which has never been done before. Then a systematic meta-analysis was conducted to determine if the low-activity allele (Met) increases the risk of BP in different ethnic groups. A total of 478 BP patients and 469 healthy subjects were recruited in our case/control study. MIX software package was employed to perform the meta-analysis on 19 studies after careful search and selection. We observed statistically-significant differences in allele (p = 0.00060) and genotype (p = 0.00203) frequencies between patients and controls in our samples. The meta-analysis also provided a significant pooled OR for association of the Met allele in rs4680 with BP in the total population (p = 0.0223) and in the Asian population (p = 0.0232). Although a significant pooled OR was also found for the Caucasian population (p = 0.0409) after one of the studies as discussed below was removed, the role for Val/Met polymorphism in BP in Caucasian ethnicity was not yet to be confirmed. In conclusion, the low-activity allele (Met) of rs4680 in COMT gene possibly confers risk for bipolar disorder in the Han population, while it needs further evidence for concluding its association with BP in the Caucasian population.

  15. The Role of the Catechol-o-methyltransferase (COMT) Gene Val158Met in Aggressive Behavior, A Review of Genetic Studies

    PubMed Central

    Qayyum, Arqam; Zai, Clement C.; Hirata, Yuko; Tiwari, Arun K.; Cheema, Sheraz; Nowrouzi, Behdin; Beitchman, Joseph H.; Kennedy, James L.

    2015-01-01

    Aggressive behaviors have become a major public health problem, and early-onset aggression can lead to outcomes such as substance abuse, antisocial personality disorder among other issues. In recent years, there has been an increase in research in the molecular and genetic underpinnings of aggressive behavior, and one of the candidate genes codes for the catechol-O-methyltransferase (COMT). COMT is involved in catabolizing catecholamines such as dopamine. These neurotransmitters appear to be involved in regulating mood which can contribute to aggression. The most common gene variant studied in the COMT gene is the Valine (Val) to Methionine (Met) substitution at codon 158. We will be reviewing the current literature on this gene variant in aggressive behavior. PMID:26630958

  16. Association of MAOA and COMT gene polymorphisms with palatable food intake in children.

    PubMed

    Galvão, Ananda C S; Krüger, Raquel C; Campagnolo, Paula D B; Mattevi, Vanessa S; Vitolo, Márcia R; Almeida, Silvana

    2012-03-01

    Several studies have implicated dopamine (DA) in appetite regulation. The enzymes catechol-o-methyltransferase (COMT) and monoamine oxidase A (MAOA) control DA availability and their genes have well-characterized functional variants. In this study, we examined three polymorphisms in these genes, T941G and MAOAu-VNTR in the MAOA gene and Val158Met in the COMT gene, to investigate how heritable variations in enzymes that determine DA levels might influence food intake and nutritional status. This investigation was a cross-sectional examination of 354 Brazilian children of three to four years old. Polymorphisms were analyzed by PCR-based methods. Means of dietary and anthropometric data were compared among genotypes by one-way analyses of variance or Kruskal Wallis tests. The MAOAu-VNTR and COMT Val158Met polymorphisms were associated with the amount of palatable food intake in boys. Presence of the MAOAu-VNTR*long allele was associated with higher intake of lipid-dense foods (LDF) when compared with the *short allele (P=.009); the amount of sugar-dense foods (SDF) intake was also higher in males carriers of the MAOAu-VNTR *long allele than in carriers of the *short allele (P=.034). In the girls' sample, MAOAu-VNTR polymorphism was not associated with food intake and nutritional status. Carriers of the COMT Val158Met*Val allele presented higher intake of LDF when compared with Met/Met homozygotes (P=.008). This study provides the first indication that genetic variants of enzymes that control DA availability might be involved in determination of the amount of palatable food intake in children. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. The COMT Val/Met polymorphism is associated with reading related skills and consistent patterns of functional neural activation

    PubMed Central

    Landi, Nicole; Frost, Stephen J.; Mencl, W. Einar; Preston, Jonathan L.; Jacobsen, Leslie K.; Lee, Maria; Yrigollen, Carolyn; Pugh, Kenneth R.; Grigorenko, Elena L.

    2013-01-01

    In both children and adults there is large variability in reading skill, with approximately 5–10% of individuals characterized as having reading disability; these individuals struggle to learn to read despite adequate intelligence and opportunity. Although it is well established that a substantial portion of this variability is attributed to the genetic differences between individuals, specifics of the connections between reading and the genome are not understood. This article presents data that suggest that variation in the COMT gene, which has previously been associated with variation in higher-order cognition, is associated with reading and reading-related skills, both at the level of brain and behavior. In particular, we found that the COMT Val/Met polymorphism at rs4680, which results in the substitution of the ancestral Valine (Val) by Methionine (Met), was associated with better performance on a number of critical reading measures and with patterns of functional neural activation that have been linked to better readers. We argue that this polymorphism, known for its broad effects on cognition, may modulate (likely through frontal lobe function) reading skill. PMID:23278923

  18. Catechol-O-methyltransferase (COMT) gene modulates private self-consciousness and self-flexibility.

    PubMed

    Wang, Bei; Ru, Wenzhao; Yang, Xing; Yang, Lu; Fang, Pengpeng; Zhu, Xu; Shen, Guomin; Gao, Xiaocai; Gong, Pingyuan

    2016-08-01

    Dopamine levels in the brain influence human consciousness. Inspired by the role of Catechol-O-methyltransferase (COMT) in inactivating dopamine in the brain, we investigated to what extent COMT could modulate individual's self-consciousness dispositions and self-consistency by genotyping the COMT Val158Met (rs4680) polymorphism and measuring self-consciousness and self-consistency and congruence in a college student population. The results indicated that COMT Val158Met polymorphism significantly modulated the private self-consciousness. The individuals with Val/Val genotype, corresponding to lower dopamine levels in the brain, were more likely to be aware of their feelings and beliefs. The results also indicated that this polymorphism modulated one's self-flexibility. The individuals with Val/Val genotype showed higher levels of stereotype in self-concept compared with those with Met/Met genotype. These findings suggest that COMT is a predictor of the individual differences in self-consciousness and self-flexibility. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. The COMT Val/Met polymorphism is associated with reading-related skills and consistent patterns of functional neural activation.

    PubMed

    Landi, Nicole; Frost, Stephen J; Mencl, W Einar; Preston, Jonathan L; Jacobsen, Leslie K; Lee, Maria; Yrigollen, Carolyn; Pugh, Kenneth R; Grigorenko, Elena L

    2013-01-01

    In both children and adults there is large variability in reading skill, with approximately 5-10% of individuals characterized as having reading disability; these individuals struggle to learn to read despite adequate intelligence and opportunity. Although it is well established that a substantial portion of this variability is attributed to the genetic differences between individuals, specifics of the connections between reading and the genome are not understood. This article presents data that suggest that variation in the COMT gene, which has previously been associated with variation in higher-order cognition, is associated with reading and reading-related skills, at the level of both brain and behavior. In particular, we found that the COMT Val/Met polymorphism at rs4680, which results in the substitution of the ancestral Valine (Val) by Methionine (Met), was associated with better performance on a number of critical reading measures and with patterns of functional neural activation that have been linked to better readers. We argue that this polymorphism, known for its broad effects on cognition, may modulate (likely through frontal lobe function) reading skill. © 2012 Blackwell Publishing Ltd.

  20. Association analysis of COMT/MTHFR polymorphisms and major depressive disorder in Chinese Han population.

    PubMed

    Shen, Xinhua; Wu, Yanfeng; Guan, Tiefeng; Wang, Xiaoquan; Qian, Mincai; Lin, Min; Shen, Zhongxia; Sun, Jushui; Zhong, Hua; Yang, Jianhong; Li, Liang; Yuan, Yonggui

    2014-06-01

    In several previous biochemical and genetic studies, the Val158Met polymorphism of the gene encoding catechol-O-methyltransferase (COMT) and the C677T polymorphism of Methylenetetrahydrofolate reductase (MTHFR) have been suggested to be involved in the pathogenesis as well as the treatment response of major depressive disorder (MDD), but the results have been inconsistent. In this study, we investigate the association of COMT/MTHFR and their interactions with MDD and antidepressant response in Chinese Han population. Three hundred and sixty eight depressed patients who met DSM-IV criteria for MDD were recruited for the study. Two hundred and nineteen normal controls were recruited from the local community. Patients and normal controls were genotyped for the functional COMT val158met and MTHFR C677T polymorphisms. Patients were characterized for clinical response to antidepressant treatment as measured by intra-individual changes of Hamilton Depression (HAMD-17) scores over 6 weeks. The T allele (OR=1.81; CI95%=1.40-2.34, P<0.001) and C/T genotype (OR=3.66; CI95% =2.53-5.28, P<0.001) of MTHFR C677T were significantly different between case and control groups. The COMT Met/Val genotype was more common among depressed individuals than among controls (OR=1.52, CI95%=1.04-2.21, P=0.02). There is disequilibrium in age and sex between case and control groups. Though we control the two variables in the statistic analysis, to be more accurate, we need to increase sample size in further study. Individuals with the genotype COMT Met/Val and MTHFR C/T have more probability of suffering from MDD. However, there is no association between gene polymorphism and treatment response. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Genetic Contributions to Age-Related Decline in Executive Function: A 10-Year Longitudinal Study of COMT and BDNF Polymorphisms

    PubMed Central

    Erickson, Kirk I.; Kim, Jennifer S.; Suever, Barbara L.; Voss, Michelle W.; Francis, B. Magnus; Kramer, Arthur F.

    2008-01-01

    Genetic variability in the dopaminergic and neurotrophic systems could contribute to age-related impairments in executive control and memory function. In this study we examined whether genetic polymorphisms for catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) were related to the trajectory of cognitive decline occurring over a 10-year period in older adults. A single nucleotide polymorphism in the COMT (Val158/108Met) gene affects the concentration of dopamine in the prefrontal cortex. In addition, a Val/Met substitution in the pro-domain for BDNF (Val66Met) affects the regulated secretion and trafficking of BDNF with Met carriers showing reduced secretion and poorer cognitive function. We found that impairments over the 10-year span on a task-switching paradigm did not vary as a function of the COMT polymorphism. However, for the BDNF polymorphism the Met carriers performed worse than Val homozygotes at the first testing session but only the Val homozygotes demonstrated a significant reduction in performance over the 10-year span. Our results argue that the COMT polymorphism does not affect the trajectory of age-related executive control decline, whereas the Val/Val polymorphism for BDNF may promote faster rates of cognitive decay in old age. These results are discussed in relation to the role of BDNF in senescence and the transforming impact of the Met allele on cognitive function in old age. PMID:18958211

  2. Count on dopamine: influences of COMT polymorphisms on numerical cognition

    PubMed Central

    Júlio-Costa, Annelise; Antunes, Andressa M.; Lopes-Silva, Júlia B.; Moreira, Bárbara C.; Vianna, Gabrielle S.; Wood, Guilherme; Carvalho, Maria R. S.; Haase, Vitor G.

    2013-01-01

    Catechol-O-methyltransferase (COMT) is an enzyme that is particularly important for the metabolism of dopamine. Functional polymorphisms of COMT have been implicated in working memory and numerical cognition. This is an exploratory study that aims at investigating associations between COMT polymorphisms, working memory, and numerical cognition. Elementary school children from 2th to 6th grades were divided into two groups according to their COMT val158met polymorphism [homozygous for valine allele (n = 61) vs. heterozygous plus methionine homozygous children or met+ group (n = 94)]. Both groups were matched for age and intelligence. Working memory was assessed through digit span and Corsi blocks. Symbolic numerical processing was assessed through transcoding and single-digit word problem tasks. Non-symbolic magnitude comparison and estimation tasks were used to assess number sense. Between-group differences were found in symbolic and non-symbolic numerical tasks, but not in working memory tasks. Children in the met+ group showed better performance in all numerical tasks while val homozygous children presented slower development of non-symbolic magnitude representations. These results suggest COMT-related dopaminergic modulation may be related not only to working memory, as found in previous studies, but also to the development of magnitude processing and magnitude representations. PMID:23966969

  3. The Role of Catechol-O-Methyl Transferase Val(108/158)Met Polymorphism (rs4680) in the Effect of Green Tea on Resting Energy Expenditure and Fat Oxidation: A Pilot Study

    PubMed Central

    Hursel, Rick; Janssens, Pilou L. H. R.; Bouwman, Freek G.; Mariman, Edwin C.; Westerterp-Plantenga, Margriet S.

    2014-01-01

    Introduction Green tea(GT) is able to increase energy expenditure(EE) and fat oxidation(FATox) via inhibition of catechol-O-methyl transferase(COMT) by catechins. However, this does not always appear unanimously because of large inter-individual variability. This may be explained by different alleles of the functional COMT Val108/158Met polymorphism that are associated with COMT enzyme activity; high-activity enzyme, COMTH(Val/Val genotype), and low-activity COMTL(Met/Met genotype). Methods Fourteen Caucasian subjects (BMI: 22.2±2.3 kg/m2, age: 21.4±2.2 years) of whom 7 with the COMTH-genotype and 7 with the COMTL-genotype were included in a randomized, cross-over study in which EE and substrate oxidation were measured with a ventilated-hood system after decaffeinated GT and placebo(PL) consumption. Results At baseline, EE, RQ, FATox and carbohydrate oxidation(CHOox) did not differ between groups. Significant interactions were observed between COMT genotypes and treatment for RQ, FATox and CHOox (p<0.05). After GT vs. PL, EE(GT: 62.2 vs. PL: 35.4 kJ.3.5 hrs; p<0.01), RQ(GT: 0.80 vs. PL: 0.83; p<0.01), FATox(GT: 18.3 vs. PL: 15.3 g/d; p<0.001) and CHOox(GT: 18.5 vs. PL: 24.3 g/d; p<0.001) were significantly different for subjects carrying the COMTH genotype, but not for subjects carrying the COMTL genotype (EE, GT: 60.3 vs. PL: 51.7 kJ.3.5 hrs; NS), (RQ, GT: 0.81 vs. PL: 0.81; NS), (FATox, GT: 17.3 vs. PL: 17.0 g/d; NS), (CHOox, GT: 22.1 vs. PL: 21.4 g/d; NS). Conclusion Subjects carrying the COMTH genotype increased energy expenditure and fat-oxidation upon ingestion of green tea catechins vs, placebo, whereas COMTL genotype carriers reacted similarly to GT and PL ingestion. The differences in responses were due to the different responses on PL ingestion, but similar responses to GT ingestion, pointing to different mechanisms. The different alleles of the functional COMT Val108/158Met polymorphism appear to play a role in the inter-individual variability for EE

  4. Motor Impulsivity in Parkinson Disease: Associations with COMT and DRD2 polymorphisms

    PubMed Central

    Ziegler, David A.; Ashourian, Paymon; Wonderlick, Julien S.; Sarokhan, Alison K.; Prelec, Drazen; Scherzer, Clemens R.; Corkin, Suzanne

    2017-01-01

    Parkinson disease (PD) is an age-related degenerative disease of the brain, characterized by motor, cognitive, and psychiatric symptoms. Neurologists and neuroscientists now understand that several symptoms of the disease, including hallucinations and impulse control behaviors, stem from the dopaminergic medications used to control the motor aspects of PD. Converging evidence from animals and humans suggests that individual differences in the genes that affect the dopamine system influence the response of PD patients to dopaminergic medication. In this study, we tested the hypothesis that patients taking dopamine replacement therapy who carry candidate alleles that increase dopamine signaling exhibit greater amounts of motor impulsivity. We examined the relation between inhibitory ability (measured by the Stop Signal Task) and polymorphisms of COMT Val158Met and DRD2 C957T in patients with idiopathic PD. On the Stop Signal Task, carriers of COMT Val/Met and Met/Met genotypes were more impulsive than Val/Val carriers, but we did not find a link between DRD2 polymorphisms and inhibitory ability. These results support the hypothesis that the Met allele of COMT confers an increased risk for behavioral impulsivity in PD patients, whereas DRD2 polymorphisms appear to be less important in determining whether PD patients exhibit a dopamine overdose in the form of motor impulsivity. PMID:24749760

  5. Association between Val66Met brain-derived neurotrophic factor (BDNF) gene polymorphism and post-treatment relapse in alcohol dependence.

    PubMed

    Wojnar, Marcin; Brower, Kirk J; Strobbe, Stephen; Ilgen, Mark; Matsumoto, Halina; Nowosad, Izabela; Sliwerska, Elzbieta; Burmeister, Margit

    2009-04-01

    The purpose of this study was to examine relationships between genetic markers of central serotonin (5-HT) and dopamine function, and risk for post-treatment relapse, in a sample of alcohol-dependent patients. The study included 154 patients from addiction treatment programs in Poland, who met DSM-IV criteria for alcohol dependence. After assessing demographics, severity of alcohol use, suicidality, impulsivity, depression, hopelessness, and severity of alcohol use at baseline, patients were followed for approximately 1 year to evaluate treatment outcomes. Genetic polymorphisms in several genes (TPH2, SLC6A4, HTR1A, HTR2A, COMT, and BDNF) were tested as predictors of relapse (defined as any drinking during follow-up) while controlling for baseline measures. Of 154 eligible patients, 123 (80%) completed follow-up and 48% (n = 59) of these individuals relapsed. Patients with the Val allele in the Val66Met BDNF polymorphism and the Met allele in the Val158Met COMT polymorphism were more likely to relapse. Only the BDNF Val/Val genotype predicted post-treatment relapse [odds ratio (OR) = 2.62; p = 0.019], and time to relapse (OR = 2.57; p = 0.002), after adjusting for baseline measures and other significant genetic markers. When the analysis was restricted to patients with a family history of alcohol dependence (n = 73), the associations between the BDNF Val/Val genotype and relapse (OR = 5.76, p = 0.0045) and time to relapse (hazard ratio = 4.93, p = 0.001) were even stronger. The Val66Met BDNF gene polymorphism was associated with a higher risk and earlier occurrence of relapse among patients treated for alcohol dependence. The study suggests a relationship between genetic markers and treatment outcomes in alcohol dependence. Because a large number of statistical tests were conducted for this study and the literature on genetics and relapse is so novel, the results should be considered as hypothesis generating and need to be replicated in independent studies.

  6. Association between Val66Met Brain-Derived Neurotrophic Factor (BDNF) Gene Polymorphism and Post-Treatment Relapse in Alcohol Dependence

    PubMed Central

    Wojnar, Marcin; Brower, Kirk J.; Strobbe, Stephen; Ilgen, Mark; Matsumoto, Halina; Nowosad, Izabela; Sliwerska, Elzbieta; Burmeister, Margit

    2009-01-01

    Background The purpose of this study was to examine relationships between genetic markers of central serotonin and dopamine function, and risk for post-treatment relapse, in a sample of alcohol-dependent patients. Methods The study included 154 patients from addiction treatment programs in Poland, who met DSM-IV criteria for alcohol dependence. After assessing demographics, severity of alcohol use, suicidality, impulsivity, depression, hopelessness, and severity of alcohol use at baseline, patients were followed for approximately one year to evaluate treatment outcomes. Genetic polymorphisms in several genes (TPH2, SLC6A4, HTR1A, HTR2A, COMT, BDNF) were tested as predictors of relapse (defined as any drinking during follow-up) while controlling for baseline measures. Results Of 154 eligible patients, 123 (80%) completed follow-up and 48% (n = 59) of these individuals relapsed. Patients with the Val allele in the Val66Met BDNF polymorphism and the Met allele in the Val158Met COMT polymorphism were more likely to relapse. Only the BDNF Val/Val genotype predicted post-treatment relapse (OR = 2.62; p = 0.019), and time to relapse (OR = 2.57; p = 0.002), after adjusting for baseline measures and other significant genetic markers. When the analysis was restricted to patients with a family history of alcohol dependence (n = 73), the associations between the BDNF Val/Val genotype and relapse (OR = 5.76, p = 0.0045) and time to relapse (HR = 4.93, p = 0.001) were even stronger. Conclusions The Val66Met BDNF gene polymorphism was associated with a higher risk and earlier occurrence of relapse among patients treated for alcohol dependence. The study suggests a relationship between genetic markers and treatment outcomes in alcohol dependence. Because a large number of statistical tests were conducted for this study and the literature on genetics and relapse is so novel, the results should be considered as hypothesis generating and need to be replicated in independent studies

  7. Cortical Dopamine Transmission as Measured with the [11C]FLB 457 – Amphetamine PET Imaging Paradigm Is Not Influenced by COMT Genotype

    PubMed Central

    Narendran, Rajesh; Tumuluru, Divya; May, Maureen A.; Chowdari, Kodavali V.; Himes, Michael L.; Fasenmyer, Kelli; Frankle, W. Gordon; Nimgaonkar, Vishwajit L.

    2016-01-01

    Basic investigations link a Val158Met polymorphism (rs4680) in the catechol-O-methyltransferase (COMT) gene to not only its enzymatic activity, but also to its dopaminergic tone in the prefrontal cortex. Previous PET studies have documented the relationship between COMT Val158Met polymorphism and D1 and D2/3 receptor binding potential (BP), and interpreted them in terms of dopaminergic tone. The use of baseline dopamine D1 and D2/3 receptor binding potential (BPND) as a proxy for dopaminergic tone is problematic because they reflect both endogenous dopamine levels (a change in radiotracer's apparent affinity) and receptor density. In this analysis of 31 healthy controls genotyped for the Val158Met polymorphism (Val/Val, Val/Met, and Met/Met), we used amphetamine-induced displacement of [11C]FLB 457 as a direct measure of dopamine release. Our analysis failed to show a relationship between COMT genotype status and prefrontal cortical dopamine release. COMT genotype was also not predictive of baseline dopamine D2/3 receptor BPND. PMID:27322568

  8. An experimental study of catechol-o-methyltransferase Val158Met moderation of delta-9-tetrahydrocannabinol-induced effects on psychosis and cognition.

    PubMed

    Henquet, Cécile; Rosa, Araceli; Krabbendam, Lydia; Papiol, Sergi; Fananás, Lourdes; Drukker, Marjan; Ramaekers, Johannes G; van Os, Jim

    2006-12-01

    Observational studies have suggested that psychometric psychosis liability and a functional polymorphism in the catechol-O-methyltransferase (COMT Val(158)Met) gene moderate the psychosis-inducing effect of cannabis. To replicate and extend this finding, a double-blind, placebo-controlled cross-over design was used in which patients with a psychotic disorder (n=30), relatives of patients with a psychotic disorder (n=12), and healthy controls (n=32) were exposed to Delta-9-tetrahydrocannabinol (Delta-9-THC, the principal component of cannabis) or placebo, followed by cognitive assessment and assessment of current psychotic experiences. Previous expression of psychometric psychosis liability was also assessed. Models of current psychotic experiences and cognition were examined with multilevel random regression analyses to assess (i) main effects of genotype and condition, (ii) interactions between condition and genotype, and (iii) three-way interactions between condition, genotype, and psychometric psychosis liability. Carriers of the Val allele were most sensitive to Delta-9-THC-induced psychotic experiences, but this was conditional on prior evidence of psychometric psychosis liability. Delta-9-THC impacted negatively on cognitive measures. Carriers of the Val allele were also more sensitive to Delta-9-THC-induced memory and attention impairments compared to carriers of the Met allele. Experimental effects of Delta-9-THC on cognition and psychosis are moderated by COMT Val(158)Met genotype, but the effects may in part be conditional on the additional presence of pre-existing psychosis liability. The association between cannabis and psychosis may represent higher order gene-environment and gene-gene interactions.

  9. BDNF and COMT polymorphisms have a limited association with episodic memory performance or engagement in complex cognitive activity in healthy older adults.

    PubMed

    Stuart, Kimberley; Summers, Mathew James; Valenzuela, Michael J; Vickers, James C

    2014-04-01

    Cognitive decline is a major factor in lowering the quality of life in older populations, and contributes substantially to social, economic, and health costs. As humans age, cognitive function decreases differentially, and individual differences in cognitive ageing are likely attributed to a range of causes, including environmental and genetic influences. The current study included 360 participants (240 females and 120 males) aged between 50 and 79years from the Tasmanian Healthy Brain Project. The brain-derived neurotrophic factor (BDNF) Val66Met and Catechol-O-Methyltransferase (COMT) Val158Met polymorphisms were examined for their association with visual and auditory episodic memory performance. The polymorphisms were also investigated for their association with reported life-long engagement in complex cognitive activity using a retrospective questionnaire. Relative to the demographic variables, the gene variations were found to have no association with episodic memory performance, with the exception of the COMT polymorphism on a single measure of auditory memory (RAVLT). Several other studies also demonstrated that these polymorphisms have no, small, or inconsistent effects on memory function. The BDNF Val66Met and COMT Val158Met polymorphisms were also found to be of little significance to active engagement in complex cognitive activity throughout most of the lifespan. An association was detected between BDNF Val66Met and engagement in cognitive activity in early life (p=.04, d=.23), however this did not reach significance when adjusted for multiple comparisons. The biological mechanisms that underlie engagement in cognitive activity are elusive, thus the potential relationship between BDNF Val66Met genotype and early life cognitive engagement warrants further investigation. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

  10. COMT Val(158)Met and 5HTTLPR functional loci interact to predict persistence of anxiety across adolescence: results from the Victorian Adolescent Health Cohort Study.

    PubMed

    Olsson, C A; Byrnes, G B; Anney, R J L; Collins, V; Hemphill, S A; Williamson, R; Patton, G C

    2007-10-01

    We investigated whether a composite genetic factor, based on the combined actions of catechol-O-methyltransferase (COMT) (Val(158)Met) and serotonin transporter (5HTTLPR) (Long-Short) functional loci, has a greater capacity to predict persistence of anxiety across adolescence than either locus in isolation. Analyses were performed on DNA collected from 962 young Australians participating in an eight-wave longitudinal study of mental health and well-being (Victorian Adolescent Health Cohort Study). When the effects of each locus were examined separately, small dose-response reductions in the odds of reporting persisting generalized (free-floating) anxiety across adolescence were observed for the COMT Met(158) [odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.76-0.95, P = 0.004] and 5HTTLPR Short alleles (OR = 0.88, CI = 0.79-0.99, P = 0.033). There was no evidence for a dose-response interaction effect between loci. However, there was a double-recessive interaction effect in which the odds of reporting persisting generalized anxiety were more than twofold reduced (OR = 0.45, CI = 0.29-0.70, P < 0.001) among carriers homozygous for both the COMT Met(158) and the 5HTTLPR Short alleles (Met(158)Met + Short-Short) compared with the remaining cohort. The double-recessive effect remained after multivariate adjustment for a range of psychosocial predictors of anxiety. Exploratory stratified analyses suggested that genetic protection may be more pronounced under conditions of high stress (insecure attachments and sexual abuse), although strata differences did not reach statistical significance. By describing the interaction between genetic loci, it may be possible to describe composite genetic factors that have a more substantial impact on psychosocial development than individual loci alone, and in doing so, enhance understanding of the contribution of constitutional processes in mental health outcomes.

  11. The role of maternal stress during pregnancy, maternal discipline, and child COMT Val158Met genotype in the development of compliance.

    PubMed

    Kok, Rianne; Bakermans-Kranenburg, Marian J; van Ijzendoorn, Marinus H; Velders, Fleur P; Linting, Mariëlle; Jaddoe, Vincent W V; Hofman, Albert; Verhulst, Frank C; Tiemeier, Henning

    2013-07-01

    Maternal discipline is an important predictor of child committed compliance. Maternal stress can affect both parenting and child development. In a large population-based cohort study (N = 613) we examined whether maternal discipline mediated the association between maternal stress during pregnancy and child compliance, and whether COMT or DRD4 polymorphisms moderated the association between maternal discipline and child compliance. Family-related and general stress were measured through maternal self-report and genetic material was collected through cord blood sampling at birth. Mother-child dyads were observed at 36 months in disciplinary tasks in which the child was not allowed to touch attractive toys. Maternal discipline and child compliance were observed in two different tasks and independently coded. The association between family stress during pregnancy and child committed compliance was mediated by maternal positive discipline. Children with more COMT Met alleles seemed more susceptible to maternal positive discipline than children with more COMT Val alleles. Copyright © 2012 Wiley Periodicals, Inc.

  12. Catechol-o-methyl transferase (COMT) val158met polymorphism and adolescent cortical development in patients with childhood-onset schizophrenia, their non-psychotic siblings, and healthy controls

    PubMed Central

    Raznahan, Armin; Greenstein, Deanna; Lee, Yohan; Long, Robert; Clasen, Liv; Gochman, Pete; Addington, Anjene; Giedd, Jay N.; Rapoport, Judith L.; Gogtay, Nitin

    2012-01-01

    Non-psychotic individuals at increased risk for schizophrenia show alterations in fronto-striatal dopamine signaling and cortical gray matter maturation reminiscent of those seen in schizophrenia. It remains unclear however if variations in dopamine signaling influence rates of structural cortical maturation in typically developing individuals, and whether such influences are disrupted in patients with schizophrenia and their non-psychotic siblings. We sought to address these issues by relating a functional Val→Met polymorphism within the gene encoding catechol-o-methyltransferase (COMT)—a key enzymatic regulator of cortical dopamine levels—to longitudinal structural neuroimaging measures of cortical gray matter thickness. We included a total of 792 magnetic resonance imaging brain scans, acquired between ages 9 and 22 years from patients with childhood-onset schizophrenia (COS), their non-psychotic full siblings, and matched healthy controls. Whereas greater Val allele dose (which confers enhanced dopamine catabolism and is proposed to aggravate cortical deficits in schizophrenia) accelerated adolescent cortical thinning in both schizophrenia probands and their siblings, it attenuated cortical thinning in healthy controls. This similarity between COS patients and their siblings was accompanied by differences between the two groups in the timing and spatial distribution of disrupted COMT influences on cortical maturation. Consequently, whereas greater Val “dose” conferred persistent dorsolateral prefrontal cortical deficits amongst affected probands by adulthood, cortical thickness differences associated with varying Val dose in non-psychotic siblings resolved over the age-range studied. These findings suggest that cortical abnormalities in pedigrees affected by schizophrenia may be contributed to by a disruption of dopaminergic infleunces on cortical maturation. PMID:21620981

  13. Stressful life events and catechol-O-methyl-transferase (COMT) gene in bipolar disorder.

    PubMed

    Hosang, Georgina M; Fisher, Helen L; Cohen-Woods, Sarah; McGuffin, Peter; Farmer, Anne E

    2017-05-01

    A small body of research suggests that gene-environment interactions play an important role in the development of bipolar disorder. The aim of the present study is to contribute to this work by exploring the relationship between stressful life events and the catechol-O-methyl-transferase (COMT) Val 158 Met polymorphism in bipolar disorder. Four hundred eighty-two bipolar cases and 205 psychiatrically healthy controls completed the List of Threatening Experiences Questionnaire. Bipolar cases reported the events experienced 6 months before their worst depressive and manic episodes; controls reported those events experienced 6 months prior to their interview. The genotypic information for the COMT Val 158 Met variant (rs4680) was extracted from GWAS analysis of the sample. The impact of stressful life events was moderated by the COMT genotype for the worst depressive episode using a Val dominant model (adjusted risk difference = 0.09, 95% confidence intervals = 0.003-0.18, P = .04). For the worst manic episodes no significant interactions between COMT and stressful life events were detected. This is the first study to explore the relationship between stressful life events and the COMT Val 158 Met polymorphism focusing solely on bipolar disorder. The results of this study highlight the importance of the interplay between genetic and environmental factors for bipolar depression. © 2017 Wiley Periodicals, Inc.

  14. COMT and MTHFR polymorphisms interaction on cognition in schizophrenia: an exploratory study.

    PubMed

    Kontis, Dimitrios; Theochari, Eirini; Fryssira, Helen; Kleisas, Spyridon; Sofocleous, Christalena; Andreopoulou, Angeliki; Kalogerakou, Stamatina; Gazi, Anthia; Boniatsi, Lucia; Chaidemenos, Alexandros; Tsaltas, Eleftheria

    2013-03-14

    The investigation of the catechol-O-methyltransferase (COMT-[rs4680]) and methylenetetrahydrofolate reductase (MTHFR-[rs1801133]) polymorphisms' interaction might shed light into the pathogenetic mechanisms of the cognitive dysfunction in schizophrenia. In an exploratory study, we hypothesized that the MTHFR 677T allele which has been related to a hypoactive MTHFR enzyme would augment the unfavorable effects of COMT Val158 homozygosity which has been associated with COMT enzyme hyperfunction. 90 schizophrenia patients and 55 healthy volunteers were assessed on psychomotor speed, pattern and spatial recognition memory (SRM), spatial working memory (SWM), attentional flexibility and planning (Stockings of Cambridge-SOC). IQ scores in a random subgroup of patients were also measured. A significant COMT×MTHFR interaction on SWM (p=0.048) and planning (p=0.026) was revealed in both groups. Among COMT-Val/Val participants, MTHFR-C/C made more SWM errors (p=0.033) and solved fewer SOC problems (p=0.025) than MTHFR-T carriers. In patients, there was a significant COMT×MTHFR interaction on full scale IQ (p=0.035): among COMT-Met carriers, MTHFR-T carriers performed significantly worse than MTHFR-C/C (p=0.021), which was driven by a COMT×MTHFR interaction involving performance IQ (p=0.047). In conclusion, COMT and MTHFR polymorphisms interacted on cognition, suggesting that the MTHFR enzyme activity might moderate the effects of the COMT enzyme. In contrast to our initial hypothesis, the MTHFR T-allele attenuated the cognitive effects of COMT Val homozygosity. In this preliminary study, we propose that dopaminergic and intracellular methylation mechanisms could interact on cognitive deficits in schizophrenia. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  15. The interaction of early life experiences with COMT val158met affects anxiety sensitivity.

    PubMed

    Baumann, C; Klauke, B; Weber, H; Domschke, K; Zwanzger, P; Pauli, P; Deckert, J; Reif, A

    2013-11-01

    The pathogenesis of anxiety disorders is considered to be multifactorial with a complex interaction of genetic factors and individual environmental factors. Therefore, the aim of this study was to examine gene-by-environment interactions of the genes coding for catechol-O-methyltransferase (COMT) and monoamine oxidase A (MAOA) with life events on measures related to anxiety. A sample of healthy subjects (N = 782; thereof 531 women; mean age M = 24.79, SD = 6.02) was genotyped for COMT rs4680 and MAOA-uVNTR (upstream variable number of tandem repeats), and was assessed for childhood adversities [Childhood Trauma Questionnaire (CTQ)], anxiety sensitivity [Anxiety Sensitivity Index (ASI)] and anxious apprehension [Penn State Worry Questionnaire (PSWQ)]. Main and interaction effects of genotype, environment and gender on measures related to anxiety were assessed by means of regression analyses. Association analysis showed no main gene effect on either questionnaire score. A significant interactive effect of childhood adversities and COMT genotype was observed: Homozygosity for the low-active met allele and high CTQ scores was associated with a significant increment of explained ASI variance [R(2) = 0.040, false discovery rate (FDR) corrected P = 0.04]. A borderline interactive effect with respect to MAOA-uVNTR was restricted to the male subgroup. Carriers of the low-active MAOA allele who reported more aversive experiences in childhood exhibited a trend for enhanced anxious apprehension (R(2) = 0.077, FDR corrected P = 0.10). Early aversive life experiences therefore might increase the vulnerability to anxiety disorders in the presence of homozygosity for the COMT 158met allele or low-active MAOA-uVNTR alleles. © 2013 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  16. The influence of the COMT genotype in the underlying functional brain activity of context processing in schizophrenia and in relatives.

    PubMed

    Lopez-Garcia, Pilar; Cristobal-Huerta, Alexandra; Young Espinoza, Leslie; Molero, Patricio; Ortuño Sanchez-Pedreño, Felipe; Hernández-Tamames, Juan Antonio

    2016-11-03

    Context processing deficits have been shown to be present in chronic and first episode schizophrenia patients and in their relatives. This cognitive process is linked to frontal functioning and is highly dependent on dopamine levels in the prefrontal cortex (PFC). The catechol-O-methyltransferase (COMT) enzyme plays a prominent role in regulating dopamine levels in PFC. Genotypic variations in the functional polymorphism Val(158)Met COMT appear to have an impact in dopamine signaling in the PFC of healthy subjects and schizophrenia patients. We aimed to explore the effect of the Val(158)Met COMT polymorphism on brain activation during the performance of a context processing task in healthy subjects, schizophrenia spectrum patients and their healthy relatives. 56 participants performed the Dot Probe Expectancy task (DPX) during the fMRI session. Subjects were genotyped and only the Val and Met homozygotes participated in the study. Schizophrenia spectrum patients and their relatives showed worse performance on context processing measures than healthy control subjects. The Val allele was associated with more context processing errors in healthy controls and in relatives compared to patients. There was a greater recruitment of frontal areas (supplementary motor area/cingulate gyrus) during context processing in patients relative to healthy controls. Met homozygotes subjects activated more frontal areas than Val homozygotes subjects. The Val(158)Met COMT polymorphism influences context processing and on its underlying brain activation, showing less recruitment of frontal areas in the subjects with the genotype associated to lower dopamine availability in PFC. Copyright © 2016. Published by Elsevier Inc.

  17. Association between COMT, PTSD, and Increased Smoking Following Hurricane Exposure in an Epidemiologic Sample

    PubMed Central

    Nugent, Nicole R.; Koenen, Karestan C.; Ruggiero, Kenneth J.; Acierno, Ron; Galea, Sandro; Kilpatrick, Dean G.; Gelernter, Joel

    2009-01-01

    Background Tobacco smoking has been found to increase after the experience of a traumatic event and has been associated with posttraumatic stress disorder (PTSD). Initiation and persistence of cigarette smoking is moderately heritable; two recent investigations have implicated the COMT Val158Met (also known as rs4680) polymorphism in smoking age of initiation, dependence, as well as in quantity and frequency of smoking. Method To examine a possible association of COMT Val158Met and posttrauma increases in cigarette smoking, we studied 614 adults from the 2004 Florida Hurricane Study who returned saliva DNA samples via mail. Results PTSD was strongly associated with increased smoking. Moreover, each COMT Val158Met ‘Met’ allele predicted a 2.10 fold risk of smoking post-hurricane independent of PTSD; follow-up analyses revealed that this finding was primarily driven by European-American males. Conclusions This study represents the first genetic association study (to our knowledge) of smoking behavior following an acute stressor. PMID:20070134

  18. Catechol-O-methyltransferase (COMT) influences the connectivity of the prefrontal cortex at rest

    PubMed Central

    Tunbridge, Elizabeth M.; Farrell, Sarah M.; Harrison, Paul J.; Mackay, Clare E.

    2013-01-01

    Catechol-O-methyltransferase (COMT) modulates dopamine in the prefrontal cortex (PFC) and influences PFC dopamine-dependent cognitive task performance. A human COMT polymorphism (Val158Met) alters enzyme activity and is associated with both the activation and functional connectivity of the PFC during task performance, particularly working memory. Here, we used functional magnetic resonance imaging and a data-driven, independent components analysis (ICA) approach to compare resting state functional connectivity within the executive control network (ECN) between young, male COMT Val158 (n = 27) and Met158 (n = 28) homozygotes. COMT genotype effects on grey matter were assessed using voxel-based morphometry. COMT genotype significantly modulated functional connectivity within the ECN, which included the head of the caudate, and anterior cingulate and frontal cortical regions. Val158 homozygotes showed greater functional connectivity between a cluster within the left ventrolateral PFC and the rest of the ECN (using a threshold of Z > 2.3 and a family-wise error cluster significance level of p < 0.05). This difference occurred in the absence of any alterations in grey matter. Our data show that COMT Val158Met affects the functional connectivity of the PFC at rest, complementing its prominent role in the activation and functional connectivity of this region during cognitive task performance. The results suggest that genotype-related differences in prefrontal dopaminergic tone result in neuroadaptive changes in basal functional connectivity, potentially including subtle COMT genotype-dependent differences in the relative coupling of task-positive and task-negative regions, which could in turn contribute to its effects on brain activation, connectivity, and behaviour. PMID:23228511

  19. COMT genotype, gambling activity, and cognition.

    PubMed

    Grant, Jon E; Leppink, Eric W; Redden, Sarah A; Odlaug, Brian L; Chamberlain, Samuel R

    2015-09-01

    Neuropsychological studies of adults with problem gambling indicate impairments across multiple cognitive domains. Catechol-O-methyltransferase (COMT) plays a unique role in the regulation of dopamine in the prefrontal cortex, and has been implicated in the cognitive dysfunction evident in problem gambling. This study examined adults with varying levels of gambling behavior to determine whether COMT genotype was associated with differences in gambling symptoms and cognitive functioning. 260 non-treatment-seeking adults aged 18-29 years with varying degrees of gambling behavior provided saliva samples for genotyping COMT val158met (rs4680). All subjects underwent clinical evaluations and neurocognitive assessment of decision-making, working memory, and impulsivity. The Val/Val COMT genotype was associated with the largest percentage of subjects with gambling disorder (31.8%), a rate significantly different from the Val/Met (13.2%) group (p = 0.001). The Val/Val COMT group was also associated with significantly more gambling disorder diagnostic criteria being met, greater frequency of gambling behavior, and significantly worse cognitive performance on the Cambridge Gamble Task (risk adjustment and delay aversion) and the Spatial Working Memory task (total errors). This study adds to the growing literature on the role of COMT in impulsive behaviors by showing that the Val/Val genotype was associated with specific clinical and cognitive elements among young adults who gamble, in the absence of differences on demographic measures and other cognitive domains. Future work should consider using genotyping to explore whether certain polymorphisms predict subsequent development of impulsive behaviors including gambling disorder, and treatment outcomes. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Modulation of brain structure by catechol-O-methyltransferase Val(158) Met polymorphism in chronic cannabis users.

    PubMed

    Batalla, Albert; Soriano-Mas, Carles; López-Solà, Marina; Torrens, Marta; Crippa, José A; Bhattacharyya, Sagnik; Blanco-Hinojo, Laura; Fagundo, Ana B; Harrison, Ben J; Nogué, Santiago; de la Torre, Rafael; Farré, Magí; Pujol, Jesús; Martín-Santos, Rocío

    2014-07-01

    Neuroimaging studies have shown that chronic consumption of cannabis may result in alterations in brain morphology. Recent work focusing on the relationship between brain structure and the catechol-O-methyltransferase (COMT) gene polymorphism suggests that functional COMT variants may affect brain volume in healthy individuals and in schizophrenia patients. We measured the influence of COMT genotype on the volume of four key regions: the prefrontal cortex, neostriatum (caudate-putamen), anterior cingulate cortex and hippocampus-amygdala complex, in chronic early-onset cannabis users and healthy control subjects. We selected 29 chronic cannabis users who began using cannabis before 16 years of age and matched them to 28 healthy volunteers in terms of age, educational level and IQ. Participants were male, Caucasians aged between 18 and 30 years. All were assessed by a structured psychiatric interview (PRISM) to exclude any lifetime Axis-I disorder according to Diagnostic and Statistical Manual for Mental Disorders-Fourth Edition. COMT genotyping was performed and structural magnetic resonance imaging data was analyzed by voxel-based morphometry. The results showed that the COMT polymorphism influenced the volume of the bilateral ventral caudate nucleus in both groups, but in an opposite direction: more copies of val allele led to lesser volume in chronic cannabis users and more volume in controls. The opposite pattern was found in left amygdala. There were no effects of COMT genotype on volumes of the whole brain or the other selected regions. Our findings support recent reports of neuroanatomical changes associated with cannabis use and, for the first time, reveal that these changes may be influenced by the COMT genotype. © 2013 The Authors, Addiction Biology © 2013 Society for the Study of Addiction.

  1. COMT met allele differentially predicts risk versus severity of aberrant eating in a large community sample.

    PubMed

    Donofry, Shannon D; Roecklein, Kathryn A; Wildes, Jennifer E; Miller, Megan A; Flory, Janine D; Manuck, Stephen B

    2014-12-15

    Prefrontal dopamine (DA) transmission participates in the reinforcement of reward-driven behaviors like eating. Because catechol-O-methyltransferase (COMT) degrades DA and is expressed in the prefrontal cortex, variation in the COMT gene may modulate eating behavior. Previous studies have shown that the met allele of the COMT val158met single nucleotide polymorphism (SNP) is associated with Bulimia Nervosa (BN). The specific aim of this study was to test whether the met allele increased risk for, and severity of, eating disorder symptomatology in community volunteers. Caucasian adults (N=1003; 51.2% female) from the University of Pittsburgh Adult Health and Behavior Project (AHAB) were genotyped and completed the Eating Disorders Inventory (EDI). Logistic and Poisson regression analyses assessed genotype-dependent presence and severity of eating disorder symptomatology. The met allele was significantly associated with the presence of symptoms on the Bulimia subscale and the severity of Body Dissatisfaction scores. All EDI subscales significantly predicted BMI. To our knowledge, these are the first data indicating that the COMT met allele increases risk for some symptoms of disordered eating, while increasing severity of others, in a community sample. These novel findings may have important implications for understanding the etiology of heterogeneous disordered eating phenotypes. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  2. Gene-gene interaction between COMT and MAOA potentially predicts the intelligence of attention-deficit hyperactivity disorder boys in China.

    PubMed

    Qian, Qiu-Jin; Yang, Li; Wang, Yu-Feng; Zhang, Hao-Bo; Guan, Li-Li; Chen, Yun; Ji, Ning; Liu, Lu; Faraone, S V

    2010-05-01

    The catechol-O-methyltransferase (COMT) gene contains a functional polymorphism (Val158Met) affecting the activity of the enzyme, and the monoamine oxidase A (MAOA) gene contains a VNTR polymorphism (MAOA-uVNTR) that affects the transcription of the gene. COMT and MAOA each contribute to the enzymatic degradation of dopamine and noradrenaline. Prefrontal cortical (PFC) function, which plays an important role in individual cognitive abilities, including intelligence, is modulated by dopamine. Since our previous association studies between attention deficit hyperactivity disorder (ADHD) and these two functional polymorphisms consistently showed the low activity alleles were preferentially transmitted to inattentive ADHD boys, the goal of the present study was to test the hypothesis that the interaction between COMT Val158Met and MAOA-uVNTR may affect the intelligence in a clinical sample of Chinese male ADHD subjects (n = 264). We found that the COMT x MAOA interaction significantly predicted full scale (FSIQ) and performance (PIQ) IQ scores (P = 0.039, 0.011); the MAOA-uVNTR significantly predicted FSIQ, PIQ and verbal IQ (VIQ) (P = 0.009, 0.019, 0.038); COMT Val158Met independently had no effect on any of the IQ scores. Only the COMT x MAOA interaction for PIQ remained significant after a Bonferroni correction. Among all combined genotypes, the valval-3R genotype predicted higher intelligence, (average 106.7 +/- 1.6, 95% C.I. 103.7-109.8 for FSIQ), and the valval-4R predicted lower intelligence (average 98.0 +/- 2.3, 95% C.I. 93.5-102.6 for FSIQ). These results suggest that there is an inverted U-shaped relationship between intelligence and dopaminergic activity in our sample. Our finding that gene-gene interaction between COMT and MAOA predicts the intelligence of ADHD boys in China is intriguing but requires replication in other samples.

  3. Neuropsychological correlates of transcription factor AP-2Beta, and its interaction with COMT and MAOA in healthy females.

    PubMed

    Schabram, Ina; Eggermann, Thomas; Siegel, Steven J; Gründer, Gerhard; Zerres, Klaus; Vernaleken, Ingo

    2013-01-01

    The transcription factor AP-2β has been shown to impact clinical and neuropsychological properties. Apparently, it regulates the transcription of genes that code for molecules which are part of the catecholaminergic transmission system. This investigation focuses on possible effects of the transcription factor AP-2β intron 2 polymorphism on cognitive performance parameters. This hypothesis-driven investigation examined the effects and interactions of the transcription factor AP-2β intron 2 polymorphism, the Val158Met catechol-O-methyltransferase (COMT) polymorphism, and the variable number of tandem repeat polymorphism of monoamine oxidase A (MAOA) on cognitive performance parameters within a group of 200 healthy women (age: mean ± SD, 23.93 ± 3.33 years). The AP-2β polymorphism significantly influenced cognitive performance (in particular, the Trail Making Test part B), whereas the MAOA and COMT polymorphisms did not. However, there was an interaction effect of the AP-2β × MAOA × COMT genotypes on the decision bias β of the degraded-stimulus version of the continuous performance task. Only the Val158Met COMT polymorphism showed an influence on personality questionnaires (openness and self-transcendence; NEO Five-Factor Inventory, Temperament and Character Inventory). The transcription factor AP-2β intron 2 polymorphism had more influence on cognition than the MAOA and COMT polymorphisms. Possibly, the AP-2β genotype might influence cognition through pathways other than those that regulate MAOA and COMT transcription. Interactions of transcription factor AP-2β, COMT, and MAOA polymorphisms suggest higher leverage effects of transcription factor AP-2β in subjects with high dopamine availability. Copyright © 2013 S. Karger AG, Basel.

  4. Child Exposure to Serious Life Events, COMT, and Aggression: Testing Differential Susceptibility Theory

    ERIC Educational Resources Information Center

    Hygen, Beate Wold; Belsky, Jay; Stenseng, Frode; Lydersen, Stian; Guzey, Ismail Cuneyt; Wichstrøm, Lars

    2015-01-01

    Both genetic and environmental factors contribute to individual differences in aggression. Catechol-O-methyltransferase Val158Met (COMT), a common, functional polymorphism, has been implicated in aggression and aggression traits, as have childhood experiences of adversity. It is unknown whether these effects are additive or interactional and, in…

  5. Differences in Cognitive Outcomes After ECT Depending on BDNF and COMT Polymorphisms.

    PubMed

    Bennett, Daniel Mark; Currie, James; Fernie, Gordon; Perrin, Jennifer S; Reid, Ian C

    2016-12-01

    The study aimed to explore cognitive outcomes after electroconvulsive therapy (ECT) depending on which version of common single nucleotide polymorphisms the patient expressed for brain-derived neurotrophic factor (BDNF) and catechol-O-methyltransferase (COMT). A total of 87 patients from the clinical ECT service in Aberdeen, Scotland, were included in the study. Cognitive function testing (using Spatial Recognition Memory task from the Cambridge Neuropsychological Test Automated Battery and Mini-Mental State Examination) and mood ratings (Montgomery-Åsberg Depression Rating Scale) were performed before ECT, after 4 treatments, at the end of ECT and 1 and 3 months after the end of treatment. These scores were compared depending on BDNF and COMT variant at each time point using the Student t test and using a time series generalized least squares random effects model. No differences were found between the val and met versions of the BDNF or COMT polymorphism in either cognitive or mood outcomes at any time point during ECT treatment or up to 3 months of follow-up. This study did not detect significant differences in cognitive or mood outcomes between patients who have the val66val or met versions of the BDNF polymorphism. Our results suggest that these polymorphisms will not be helpful in clinical practice for predicting cognitive outcomes after ECT.

  6. Does COMT genotype influence the effects of d-amphetamine on executive functioning?

    PubMed Central

    Wardle, Margaret C.; Hart, Amy B.; Palmer, Abraham A.; de Wit, Harriet

    2012-01-01

    In a widely cited study, Mattay et al. (2003) reported that amphetamine (0.25 mg/kg oral, or 17mg for a 68kg individual) impaired behavioral and brain indices of executive functioning, measured using the Wisconsin Card Sorting Task (WCST) and N-Back working memory task, in 6 individuals homozygous for the met allele of the val158met polymorphism in the catechol-O-methyltransferase (COMT) gene, whereas it improved executive functioning in 10 individuals homozygous for the more active val allele. We attempted to replicate their behavioral findings in a larger sample, using similar executive functioning tasks and a broader range of amphetamine doses. Over four sessions, n = 200 healthy normal adults received oral placebo, d-amphetamine 5mg, 10mg, and 20mg (average of 0.07, 0.15 and 0.29 mg/kg), under counterbalanced double-blind conditions, and completed WCST and N-back tests of executive functioning. Amphetamine had typical effects on blood pressure and processing speed but did not affect executive functioning. COMT genotype (val158met) was not related to executive functioning under placebo or amphetamine conditions, even when we compared only the homozygous val/val and met/met genotypes at the highest dose of amphetamine (20 mg). Thus, we were not able to replicate the behavioral interaction between COMT and amphetamine seen in Mattay et al. (Mattay et al., 2003). We discuss possible differences between the studies and the implications of our findings for the use of COMT genotyping to predict clinical responses to dopaminergic drugs, and the use of intermediate phenotypes in genetic research. PMID:23231539

  7. Catechol-O-methyltransferase (COMT) genotype biases neural correlates of empathy and perceived personal distress in schizophrenia.

    PubMed

    Poletti, Sara; Radaelli, Daniele; Cavallaro, Roberto; Bosia, Marta; Lorenzi, Cristina; Pirovano, Adele; Smeraldi, Enrico; Benedetti, Francesco

    2013-02-01

    The catechol-O-methyltransferase (COMT) Val(108/158)Met polymorphism (rs4680) influences enzyme activity with valine (Val) allele associated with higher enzymatic activity. Several studies suggest that factors influencing dopaminergic transmission could control response to stressful situations. Empathy is an essential element of human behavior, requires the ability to adopt another person's perspective, and has been found to be dysfunctional in schizophrenia. Twenty-eight schizophrenic patients underwent functional magnetic resonance imaging performing an empathy task. Perceived empathy has been evaluated with the Interpersonal Reactivity Index. An effect of COMT on perceived distress subscale has been shown, with methionine (Met)/Met subjects reporting lower rates of stress compared with Val/Val. Moreover, imaging results showed an effect of genotype on empathy processing in the anterior cingulate with Val/Val subjects showing the lowest activation. This is the first study of the effect of rs4680 on interpersonal distress and neural correlates of empathy in schizophrenia. We found a decrease in neural responses in areas that ensure a cognitive control of emotion that is paralleled by perceived distress in interpersonal situation; this functional pattern seems to be influenced by rs4680 COMT polymorphism. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Perception of emotion in facial stimuli: The interaction of ADRA2A and COMT genotypes, and sex.

    PubMed

    Tamm, Gerly; Kreegipuu, Kairi; Harro, Jaanus

    2016-01-04

    Emotional facial stimuli are important social signals that are essential to be perceived and recognized in order to make appropriate decisions and responses in everyday communication. The ability to voluntarily guide attention to perceive and recognize emotions, and react to them varies largely across individuals, and has a strong genetic component (Friedman et al., 2008). Two key genetic variants of the catecholamine system that have been related to emotion perception and attention are the catechol-O-methyl transferase genetic variant (COMT Val158Met) and the α2A-receptor gene promoter polymorphism (ADRA2A C-1291G) accordingly. So far, the interaction of the two with sex in emotion perception has not been studied. Multilevel modeling method was applied to study how COMT Val158Met, ADRA2A C-1291G and sex are associated with measures of emotion perception in a large sample of young adults. Participants (n=506) completed emotion recognition and behavioral emotion detection tasks. It was found that COMT Val158Met genotype in combination with the ADRA2A C-1291G and sex predicts emotion detection, and perception of valence and arousal. In simple visual detection, the ADRA2A C-1291G G-allele leads to slower detection of a highly arousing face (scheming), which is modulated by each additional COMT Val158Met Met-allele and male sex predicting faster responses. The combination of G-allele, Met-allele and male sex also predicts higher perceived negativity in sad faces. No effects of C-1291G, Val158Met, and sex were found on verbal emotion recognition. Applying the findings to study the interplay between catecholamine-O-methyl transferase activity and α2A-receptors in emotion perception disorders (such as ADHD, autism and schizophrenia) in men and women would be the next step towards understanding individual differences in emotion perception. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. How to consistently link extraversion and intelligence to the catechol-O-methyltransferase (COMT) gene: on defining and measuring psychological phenotypes in neurogenetic research.

    PubMed

    Wacker, Jan; Mueller, Erik M; Hennig, Jürgen; Stemmler, Gerhard

    2012-02-01

    The evidence for associations between genetic polymorphisms and complex behavioral/psychological phenotypes (traits) has thus far been weak and inconsistent. Using the well-studied Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene as an example, we demonstrate that using theoretical models to guide phenotype definition and measuring the phenotypes of interest with a high degree of specificity reveals strong gene-behavior associations that are consistent with prior work and that would have otherwise gone unnoticed. Only after statistically controlling for irrelevant portions of phenotype variance did we observe strong (Cohen's d = 0.33-0.70) and significant associations between COMT Val158Met and both cognitive and affective traits in a healthy male sample (N = 201) in Study 1: Carriers of the Met allele scored higher in fluid intelligence (reasoning) but lower in both crystallized intelligence (general knowledge) and the agency facet of extraversion. In Study 2, we conceptually replicated the association of COMT Val158Met with the agency facet of extraversion after partialing irrelevant phenotype variance in a female sample (N = 565). Finally, through reanalysis of a large published data set we showed that Met allele carriers also scored higher in indicators of fluid intelligence after partialing verbal fluency. Because the Met allele codes for a less efficient variant of the enzyme COMT, resulting in higher levels of extrasynaptic prefrontal dopamine, these observations provide further support for a role for dopamine in both intelligence and extraversion. More importantly, the present findings have important implications for the definition of psychological phenotypes in neurogenetic research.

  10. Association of COMT and PRODH gene variants with intelligence quotient (IQ) and executive functions in 22q11.2DS subjects.

    PubMed

    Carmel, Miri; Zarchi, Omer; Michaelovsky, Elena; Frisch, Amos; Patya, Miriam; Green, Tamar; Gothelf, Doron; Weizman, Abraham

    2014-09-01

    The 22q11.2 deletion syndrome (22q11.2DS) carries the highest genetic risk factor for the development of schizophrenia. We investigated the association of genetic variants in two schizophrenia candidate genes with executive function (EF) and IQ in 22q11.2DS individuals. Ninety two individuals with 22q11.2 deletion were studied for the genetic association between COMT and PRODH variants and EF and IQ. Subjects were divided into children (under 12 years old), adolescents (between 12 and 18 years old) and adults (older than 18 years), and genotyped for the COMT Val158Met (rs4680) and PRODH Arg185Trp (rs4819756) polymorphisms. The participants underwent psychiatric evaluation and EF assessment. Our main finding is a significant influence of the COMT Val158Met polymorphism on both IQ and EF performance. Specifically, 22q11.2DS subjects with Met allele displayed higher IQ scores in all age groups compared to Val carriers, reaching significance in both adolescents and adults. The Met allele carriers performed better than Val carriers in EF tasks, being statistically significant in the adult group. PRODH Arg185Trp variant did not affect IQ or EF in our 22q11.2DS cohort. In conclusion, functional COMT variant, but not PRODH, affects IQ and EF in 22q11.2DS subjects during neurodevelopment with a maximal effect at adulthood. Future studies should monitor the cognitive performance of the same individuals from childhood to old age. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Catechol-O-methyltransferase gene variation: impact on amygdala response to aversive stimuli.

    PubMed

    Domschke, Katharina; Baune, Bernhard T; Havlik, Linda; Stuhrmann, Anja; Suslow, Thomas; Kugel, Harald; Zwanzger, Peter; Grotegerd, Dominik; Sehlmeyer, Christina; Arolt, Volker; Dannlowski, Udo

    2012-05-01

    The functional catechol-O-methyltransferase (COMT) val158met polymorphism has been found to be associated with anxiety disorders and depression as well as with neural correlates of emotional processing, with, however, contradictory results. Thus, the aim of the present study was to re-evaluate the impact of the COMT val158met variant on neural activation correlates of emotional face processing in a sample of healthy probands. In 85 healthy subjects genotyped for the COMT val158met polymorphism, amygdala responses were assessed by means of fMRI. Participants were presented with anger- and fear-relevant faces in a robust emotion-processing paradigm. For exploratory reasons, a supplementary whole-brain analysis of the allele-dose model and a gender-stratified analysis were conducted. The COMT 158val allele showed an allele-dose effect on increased predominantly left-sided amygdala activity in response to fearful/angry facial stimuli (p(uncorrected)=.00004). This effect was independent from the distribution of the frequently studied 5-HTTLPR polymorphism for which a linear effect of S-alleles on amygdala responsiveness was replicated. The influence of COMT 158val alleles was only discerned in the female subgroup of probands. The whole-brain analysis suggested associations of the COMT 158val allele with increased activity in areas of the ventral visual stream and the lateral prefrontal cortex. The present results provide further support for a-potentially female-specific-role of the COMT val158met polymorphism in the genetic and neural underpinnings of anxiety- and depression-related intermediate phenotypes and may aid in further clarifying the differential role of COMT genotype driven dopaminergic tonus in the processing of emotionally salient stimuli. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Predictors of heroin relapse: Personality traits, impulsivity, COMT gene Val158met polymorphism in a 5-year prospective study in Shanghai, China.

    PubMed

    Su, Hang; Li, Zhibin; Du, Jiang; Jiang, Haifeng; Chen, Zhikang; Sun, Haiming; Zhao, Min

    2015-12-01

    Relapse is a typical feature of heroin addiction and rooted in genetic and psychological determinants. The aim of this study was to evaluate the effect of personality traits, impulsivity, and COMT gene polymorphism (rs4680) on relapse to heroin use during 5-year follow up. 564 heroin dependent patients were enrolled in compulsory drug rehabilitation center. 12 months prior to their release, personality traits were measured by BIS-11 (Barratt Impulsiveness Scale-11) and Temperament and Character Inventory (TCI). The COMT gene rs4680 polymorphism was genotyped using a DNA sequence detection system. The heroin use status was evaluated for 5 years after discharged. Among the 564 heroin-dependent patients, 500 were followed for 5 years after discharge and 53.0% (n = 265) were considered as relapsed to heroin use according to a strict monitor system. Univariate analysis showed that age, having ever been in methadone maintenance treatment (MMT), the total scores and non-planning scores of BIS-11, and the COMT rs4680 gene variants were different between relapse and abstinent groups. Logistic regression analysis showed higher BIS total score, having ever been in MMT and younger first heroin use age are the predictors of relapse to heroin use during 5 years follow-up, and the COMT rs4680 gene had an interaction with BIS scores. Our findings indicated that the impulsive personality traits, methadone use history, and onset age could predict relapse in heroin-dependent patients during 5 year's follow up. The COMT gene showed a moderational effect in part the relationship of impulsivity with heroin relapse. © 2015 Wiley Periodicals, Inc.

  13. Genetic moderation of the effects of cannabis: catechol-O-methyltransferase (COMT) affects the impact of Δ9-tetrahydrocannabinol (THC) on working memory performance but not on the occurrence of psychotic experiences.

    PubMed

    Tunbridge, Elizabeth M; Dunn, Graham; Murray, Robin M; Evans, Nicole; Lister, Rachel; Stumpenhorst, Katharina; Harrison, Paul J; Morrison, Paul D; Freeman, Daniel

    2015-11-01

    Cannabis use can induce cognitive impairments and psychotic experiences. A functional polymorphism in the catechol-O-methyltransferase (COMT) gene (Val(158)Met) appears to influence the immediate cognitive and psychotic effects of cannabis, or ∆(9)-tetrahydrocannabinol (THC), its primary psychoactive ingredient. This study investigated the moderation of the impact of experimentally administered THC by COMT. Cognitive performance and psychotic experiences were studied in participants without a psychiatric diagnosis, using a between-subjects design (THC vs. placebo). The effect of COMT Val(158)Met genotype on the cognitive and psychotic effects of THC, administered intravenously in a double-blind, placebo-controlled manner to 78 participants who were vulnerable to paranoia, was examined. The results showed interactive effects of genotype and drug group (THC or placebo) on working memory, assayed using the Digit Span Backwards task. Specifically, THC impaired performance in COMT Val/Val, but not Met, carriers. In contrast, the effect of THC on psychotic experiences, measured using the Community Assessment of Psychic Experiences (CAPE) positive dimension, was unaffected by COMT genotype. This study is the largest to date examining the impact of COMT genotype on response to experimentally administered THC, and the first using a purely non-clinical cohort. The data suggest that COMT genotype moderates the cognitive, but not the psychotic, effects of acutely administered THC. © The Author(s) 2015.

  14. Aggressive behavior in schizophrenia is associated with the low enzyme activity COMT polymorphism: a replication study.

    PubMed

    Strous, Rael D; Nolan, Karen A; Lapidus, Raya; Diaz, Libna; Saito, Takuya; Lachman, Herbert M

    2003-07-01

    We have previously reported that increased aggressive behavior in schizophrenic patients may be associated with a polymorphism at codon 158 of the catechol O-methyltransferase (COMT) gene that encodes a low enzyme activity variant. The finding has been replicated by one group, but not others. The discordant findings could be due to statistical errors or methodological issues in the assessment of aggressive/violent behavior. Consequently, additional studies are needed. Patients with schizophrenia (SZ) were assessed for violent behavior using the Lifetime History of Aggression (LHA) scale, an 11-item questionnaire that includes Aggression, Self-Directed Aggression, and Consequences/Antisocial Behavior subscales. DNA was genotyped for the COMT 158 polymorphism, as well as a functional polymorphism in the monoamine oxidase A (MAOA) gene promoter. Similar to our previously reported findings, a statistically significant association was found between aggressive behavior in SZ and the COMT 158 polymorphism; mean LHA scores were higher in subjects homozygous for 158Met, the low enzyme activity COMT variant (F(2,105) = 5.616, P = 0.005). Analysis of the major LHA subscales revealed that the association with 158Met was due to high scores on the Aggression, and Self-Directed Aggression subscales, but not the Consequences/Antisocial Behavior subscale. No significant association was detected for the MAOA gene alone. Our findings provide further support that COMT is a modifying gene that plays a role in determining interindividual variability in the proclivity for outward and self-directed aggressive behavior found in some schizophrenic patients. Copyright 2003 Wiley-Liss, Inc.

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

    PubMed

    Liu, Jinting; Gong, Pingyuan; Gao, Xiaoxue; Zhou, Xiaolin

    2017-05-01

    Previous 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. To 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. We 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). The sample size limits the generalizability of results. This 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. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Analysis of functional polymorphisms in three synaptic plasticity-related genes (BDNF, COMT AND UCHL1) in Alzheimer's disease in Colombia.

    PubMed

    Forero, Diego A; Benítez, Bruno; Arboleda, Gonzalo; Yunis, Juan J; Pardo, Rodrigo; Arboleda, Humberto

    2006-07-01

    In recent years, it has been proposed that synaptic dysfunction may be an important etiological factor for Alzheimer's disease (AD). This hypothesis has important implications for the analysis of AD genetic risk in case-control studies. In the present work, we analyzed common functional polymorphisms in three synaptic plasticity-related genes (brain-derived neurotrophic factor, BDNF Val66Met; catechol-O-methyl transferase, COMT Val158; ubiquitin carboxyl-terminal hydroxylase, UCHL1 S18Y) in a sample of 102 AD cases and 168 age and sex matched controls living in Bogotá, Colombia. There was not association between UCHL1 polymorphism and AD in our sample. We have found an initial association with BDNF polymorphism in familial cases and with COMT polymorphism in male and sporadic patients. These initial associations were lost after Bonferroni correction for multiple testing. Unadjusted results may be compatible with the expected functional effect of variations in these genes on pathological memory and cognitive dysfunction, as has been implicated in animal and cell models and also from neuropsychological analysis of normal subjects carriers of the AD associated genotypes. An exploration of functional variants in these and in other synaptic plasticity-related genes (a synaptogenomics approach) in independent larger samples will be important to discover new genes associated with AD.

  17. Interactive effects of the COMT gene and training on individual differences in supervisory control of unmanned vehicles.

    PubMed

    Parasuraman, Raja; Kidwell, Brian; Olmstead, Ryan; Lin, Ming-Kuan; Jankord, Ryan; Greenwood, Pamela

    2014-06-01

    We examined whether a gene known to influence dopamine availability in the prefrontal cortex is associated with individual differences in learning a supervisory control task. Methods are needed for selection and training of human operators who can effectively supervise multiple unmanned vehicles (UVs). Compared to the valine (Val) allele, the methionine (Met) allele of the COMT gene has been linked to superior executive function, but it is not known whether it is associated with training-related effects in multi-UV supervisory control performance. Ninety-nine healthy adults were genotyped for the COMT Val158Met single nucleotide polymorphism (rs4680) and divided into Met/Met, Val/Met, and Val/Val groups. Participants supervised six UVs in an air defense mission requiring them to attack incoming enemy aircraft and protect a no-fly zone from intruders in conditions of low and high task load (numbers of enemy aircraft). Training effects were examined across four blocks of trials in each task load condition. Compared to the Val/Met and Val/Val groups, Met/Met individuals exhibited a greater increase in enemy targets destroyed and greater reduction in enemy red zone incursions across training blocks. Individuals with the COMT Met/Met genotype can acquire skill in executive function tasks, such as multi-UV supervisory control, to a higher level and/or faster than other genotype groups. Potential applications of this research include the development of individualized training methods for operators of multi-UV systems and selecting personnel for complex supervisory control tasks.

  18. Genetic and vascular modifiers of age-sensitive cognitive skills: effects of COMT, BDNF, ApoE, and hypertension.

    PubMed

    Raz, Naftali; Rodrigue, Karen M; Kennedy, Kristen M; Land, Susan

    2009-01-01

    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. (c) 2009 APA, all rights reserved.

  19. COMT haplotypes modulate associations of antenatal maternal anxiety and neonatal cortical morphology.

    PubMed

    Qiu, Anqi; Tuan, Ta Anh; Ong, Mei Lyn; Li, Yue; Chen, Helen; Rifkin-Graboi, Anne; Broekman, Birit F P; Kwek, Kenneth; Saw, Seang-Mei; Chong, Yap-Seng; Gluckman, Peter D; Fortier, Marielle V; Holbrook, Joanna Dawn; Meaney, Michael J

    2015-02-01

    Exposure to antenatal maternal anxiety and complex genetic variations may shape fetal brain development. In particular, the catechol-O-methyltransferase (COMT) gene, located on chromosome 22q11.2, regulates catecholamine signaling in the prefrontal cortex and is implicated in anxiety, pain, and stress responsivity. This study examined whether individual single-nucleotide polymorphisms (SNPs) of the COMT gene and their haplotypes moderate the association between antenatal maternal anxiety and in utero cortical development. A total of 146 neonates were genotyped and underwent MRI shortly after birth. Neonatal cortical morphology was characterized using cortical thickness. Antenatal maternal anxiety was assessed using the State-Trait Anxiety Inventory at week 26 of pregnancy. Individual COMT SNPs (val158met, rs737865, and rs165599) modulated the association between antenatal maternal anxiety and the prefrontal and parietal cortical thickness in neonates. Based on haplotype trend regression analysis, findings also showed that among rs737865-val158met-rs165599 haplotypes, the A-val-G (AGG) haplotype probabilities modulated positive associations of antenatal maternal anxiety with cortical thickness in the right ventrolateral prefrontal cortex and the right superior parietal cortex and precuneus. In contrast, the G-met-A (GAA) haplotype probabilities modulated negative associations of antenatal maternal anxiety with cortical thickness in bilateral precentral gyrus and the dorsolateral prefrontal cortex. These results suggest that the association between maternal anxiety and in utero neurodevelopment is modified through complex genetic variation in COMT. Such genetic moderation may explain, in part, the variation in phenotypic outcomes in offspring associated with maternal emotional well-being.

  20. The functional BDNF Val66Met polymorphism affects functions of pre-attentive visual sensory memory processes.

    PubMed

    Beste, Christian; Schneider, Daniel; Epplen, Jörg T; Arning, Larissa

    2011-01-01

    The brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is involved in nerve growth and survival. Especially, a single nucleotide polymorphism (SNP) in the BDNF gene, Val66Met, has gained a lot of attention, because of its effect on activity-dependent BDNF secretion and its link to impaired memory processes. We hypothesize that the BDNF Val66Met polymorphism may have modulatory effects on the visual sensory (iconic) memory performance. Two hundred and eleven healthy German students (106 female and 105 male) were included in the data analysis. Since BDNF is also discussed to be involved in the pathogenesis of depression, we additionally tested for possible interactions with depressive mood. The BDNF Val66Met polymorphism significantly influenced iconic-memory performance, with the combined Val/Met-Met/Met genotype group revealing less time stability of information stored in iconic memory than the Val/Val group. Furthermore, this stability was positively correlated with depressive mood exclusively in the Val/Val genotype group. Thus, these results show that the BDNF Val66Met polymorphism has an effect on pre-attentive visual sensory memory processes. Copyright © 2010 Elsevier Ltd. All rights reserved.

  1. Association of COMT (Val158Met) and BDNF (Val66Met) Gene Polymorphisms with Anxiety, ADHD and Tics in Children with Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Gadow, Kenneth D.; Roohi, Jasmin; Devincent, Carla J.; Kirsch, Sarah; Hatchwell, Eli

    2009-01-01

    The aim of the study is to examine rs4680 ("COMT") and rs6265 ("BDNF") as genetic markers of anxiety, ADHD, and tics. Parents and teachers completed a DSM-IV-referenced rating scale for a total sample of 67 children with autism spectrum disorder (ASD). Both "COMT" (p = 0.06) and "BDNF" (p = 0.07) genotypes were marginally significant for teacher…

  2. BDNF val66met Polymorphism Affects Aging of Multiple Types of Memory

    PubMed Central

    Kennedy, Kristen M.; Reese, Elizabeth D.; Horn, Marci M.; Sizemore, April N.; Unni, Asha K.; Meerbrey, Michael E.; Kalich, Allan G.; Rodrigue, Karen M.

    2014-01-01

    The BDNF val66met polymorphism (rs6265) influences activity-dependent secretion of brain-derived neurotrophic factor in the synapse, which is crucial for learning and memory. Individuals homozygous or heterozygous for the met allele have lower BDNF secretion than val homozygotes and may be at risk for reduced declarative memory performance, but it remains unclear which types of declarative memory may be affected and how aging of memory across the lifespan is impacted by the BDNF val66met polymorphism. This cross-sectional study investigated the effects of BDNF polymorphism on multiple indices of memory (item, associative, prospective, subjective complaints) in a lifespan sample of 116 healthy adults aged 20-93 years. Advancing age showed a negative effect on item, associative and prospective memory, but not on subjective memory complaints. For item and prospective memory, there were significant age x BDNF group interactions, indicating the adverse effect of age on memory performance across the lifespan was much stronger in the BDNF met carriers than for the val homozygotes. BDNF met carriers also endorsed significantly greater subjective memory complaints, regardless of age, and showed a trend (p < .07) toward poorer associative memory performance compared to val homozygotes. These results suggest that genetic predisposition to the availability of brain-derived neurotrophic factor, by way of the BDNF val66met polymorphism, exerts an influence on multiple indices of episodic memory – in some cases in all individuals regardless of age (subjective memory and perhaps associative memory), in others as an exacerbation of age-related differences in memory across the lifespan (item and prospective memory). PMID:25264352

  3. No association between catechol-O-methyltransferase (COMT) genotype and attention deficit hyperactivity disorder (ADHD) in Japanese children.

    PubMed

    Yatsuga, Chiho; Toyohisa, Daiki; Fujisawa, Takashi X; Nishitani, Shota; Shinohara, Kazuyuki; Matsuura, Naomi; Ikeda, Shinobu; Muramatsu, Masaaki; Hamada, Akinobu; Tomoda, Akemi

    2014-08-01

    This study ascertained the association between attention deficit/hyperactivity disorder (ADHD) in Japanese children and a polymorphism of catechol-O-methyltransferase (COMT), a dopamine-control gene. The secondary aim of the study was the evaluation of a putative association between methylphenidate (MPH) effect/adverse effects and the COMT genotype. To ascertain the distribution of the Val158Met variant of COMT, 50 children meeting ADHD inclusion criteria were compared with 32 healthy children. Clinical improvement and the occurrence of adverse effects were measured before and 3 months after MPH administration in children with ADHD, and analyzed for genotype association. Wechsler Intelligence Scale for Children-Third Edition (WISC-III), age, MPH dose were included as co-variables. The occurrence of the COMT Val/Val genotype was significantly higher in children with ADHD (χ(2)(1)=7.13, p<0.01). However, there was no significant difference in the Val/Val genotype according to disorder, and WISC and ADHD rating scale scores, after correcting for the interaction between disorder and COMT genotype. Furthermore, no significant difference in MPH effect/adverse effects was observed in association with the COMT genotype in the ADHD group. These results showed a lack of association between the COMT Val/Val genotype and ADHD in Japan. Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  4. BDNF val66met polymorphism affects aging of multiple types of memory.

    PubMed

    Kennedy, Kristen M; Reese, Elizabeth D; Horn, Marci M; Sizemore, April N; Unni, Asha K; Meerbrey, Michael E; Kalich, Allan G; Rodrigue, Karen M

    2015-07-01

    The BDNF val66met polymorphism (rs6265) influences activity-dependent secretion of brain-derived neurotrophic factor in the synapse, which is crucial for learning and memory. Individuals homozygous or heterozygous for the met allele have lower BDNF secretion than val homozygotes and may be at risk for reduced declarative memory performance, but it remains unclear which types of declarative memory may be affected and how aging of memory across the lifespan is impacted by the BDNF val66met polymorphism. This cross-sectional study investigated the effects of BDNF polymorphism on multiple indices of memory (item, associative, prospective, subjective complaints) in a lifespan sample of 116 healthy adults aged 20-93 years. Advancing age showed a negative effect on item, associative and prospective memory, but not on subjective memory complaints. For item and prospective memory, there were significant age×BDNF group interactions, indicating the adverse effect of age on memory performance across the lifespan was much stronger in the BDNF met carriers than for the val homozygotes. BDNF met carriers also endorsed significantly greater subjective memory complaints, regardless of age, and showed a trend (p<.07) toward poorer associative memory performance compared to val homozygotes. These results suggest that genetic predisposition to the availability of brain-derived neurotrophic factor, by way of the BDNF val66met polymorphism, exerts an influence on multiple indices of episodic memory - in some cases in all individuals regardless of age (subjective memory and perhaps associative memory), in others as an exacerbation of age-related differences in memory across the lifespan (item and prospective memory). This article is part of a Special Issue entitled Memory & Aging. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Association of COMT (Val158Met) and BDNF (Val66Met) gene polymorphisms with anxiety, ADHD and tics in children with autism spectrum disorder.

    PubMed

    Gadow, Kenneth D; Roohi, Jasmin; DeVincent, Carla J; Kirsch, Sarah; Hatchwell, Eli

    2009-11-01

    The aim of the study is to examine rs4680 (COMT) and rs6265 (BDNF) as genetic markers of anxiety, ADHD, and tics. Parents and teachers completed a DSM-IV-referenced rating scale for a total sample of 67 children with autism spectrum disorder (ASD). Both COMT (p = 0.06) and BDNF (p = 0.07) genotypes were marginally significant for teacher ratings of social phobia (etap (2) = 0.06). Analyses also indicated associations of BDNF genotype with parent-rated ADHD (p = 0.01, etap (2) = 0.10) and teacher-rated tics (p = 0.04; etap (2) = 0.07). There was also evidence of a possible interaction (p = 0.02, etap (2) = 0.09) of BDNF genotype with DAT1 3' VNTR with tic severity. BDNF and COMT may be biomarkers for phenotypic variation in ASD, but these preliminary findings remain tentative pending replication with larger, independent samples.

  6. Physical and verbal aggressive behavior and COMT genotype: Sensitivity to the environment.

    PubMed

    Tuvblad, Catherine; Narusyte, Jurgita; Comasco, Erika; Andershed, Henrik; Andershed, Anna-Karin; Colins, Olivier F; Fanti, Kostas A; Nilsson, Kent W

    2016-07-01

    Catechol-O-methyltransferase (COMT) genotype has been implicated as a vulnerability factor for several psychiatric diseases as well as aggressive behavior, either directly, or in interaction with an adverse environment. The present study aimed at investigating the susceptibility properties of COMT genotype to adverse and favorable environment in relation to physical and verbal aggressive behavior. The COMT Val158Met polymorphism was genotyped in a Swedish population-based cohort including 1,783 individuals, ages 20-24 years (47% males). A significant three-way interaction was found, after correction for multiple testing, between COMT genotype, exposure to violence, and parent-child relationship in association with physical but not verbal aggressive behavior. Homozygous for the Val allele reported lower levels of physical aggressive behavior when they were exposed to violence and at the same time experienced a positive parent-child relationship compared to Met carriers. Thus, susceptibility properties of COMT genotype were observed in relation to physical aggressive behavior supporting the hypothesis that COMT genotypes are modifying the sensitivity to environment that confers either risk or protection for aggressive behavior. As these are novel findings, they warrant further investigation and replication in independent samples. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  7. Child exposure to serious life events, COMT, and aggression: Testing differential susceptibility theory.

    PubMed

    Hygen, Beate Wold; Belsky, Jay; Stenseng, Frode; Lydersen, Stian; Guzey, Ismail Cuneyt; Wichstrøm, Lars

    2015-08-01

    Both genetic and environmental factors contribute to individual differences in aggression. Catechol-O-methyltransferase Val158Met (COMT), a common, functional polymorphism, has been implicated in aggression and aggression traits, as have childhood experiences of adversity. It is unknown whether these effects are additive or interactional and, in the case of interaction, whether they conform to a diathesis-stress or differential susceptibility model. We examined Gene × Environment interactions between COMT and serious life events on measures of childhood aggression and contrasted these 2 models. The sample was composed of community children (N = 704); 355 were boys, and the mean age was 54.8 months (SD = 3.0). The children were genotyped for COMT rs4680 and assessed for serious life events and by teacher-rated aggression. Regression analysis showed no main effects of COMT and serious life events on aggression. However, a significant interactive effect of childhood serious life events and COMT genotype was observed: Children who had faced many serious life events and were Val homozygotes exhibited more aggression (p = .02) than did their Met-carrying counterparts. Notably, in the absence of serious life events, Val homozygotes displayed significantly lower aggression scores than did Met carriers (p = .03). When tested, this constellation of findings conformed to the differential susceptibility hypothesis: In this case, Val homozygotes are more malleable to the effect of serious life events on aggression and not simply more vulnerable to the negative effect of having experienced many serious life events. (c) 2015 APA, all rights reserved).

  8. Association of COMT (Val158Met) and BDNF (Val66Met) Gene Polymorphisms with Anxiety, ADHD and Tics in Children with Autism Spectrum Disorder

    PubMed Central

    Gadow, Kenneth D.; Roohi, Jasmin; DeVincent, Carla J.; Kirsch, Sarah; Hatchwell, Eli

    2015-01-01

    The aim of the study is to examine rs4680 (COMT) and rs6265 (BDNF) as genetic markers of anxiety, ADHD, and tics. Parents and teachers completed a DSM-IV-referenced rating scale for a total sample of 67 children with autism spectrum disorder (ASD). Both COMT (p = 0.06) and BDNF (p = 0.07) genotypes were marginally significant for teacher ratings of social phobia (ηp2 = 0.06). Analyses also indicated associations of BDNF genotype with parent-rated ADHD (p = 0.01, ηp2 = 0.10) and teacher-rated tics (p = 0.04; ηp2 = 0.07). There was also evidence of a possible interaction (p = 0.02, ηp2 = 0.09) of BDNF genotype with DAT1 3′ VNTR with tic severity. BDNF and COMT may be biomarkers for phenotypic variation in ASD, but these preliminary findings remain tentative pending replication with larger, independent samples. PMID:19582565

  9. Genetic Variation in COMT Activity Impacts Learning and Dopamine Release Capacity in the Striatum

    ERIC Educational Resources Information Center

    Simpson, Eleanor H.; Morud, Julia; Winiger, Vanessa; Biezonski, Dominik; Zhu, Judy P.; Bach, Mary Elizabeth; Malleret, Gael; Polan, H. Jonathan; Ng-Evans, Scott; Phillips, Paul E. M.; Kellendonk, Christoph; Krandel, Eric R.

    2014-01-01

    A common genetic polymorphism that results in increased activity of the dopamine regulating enzyme COMT (the "COMT Val" [superscript 158] allele) has been found to associate with poorer cognitive performance and increased susceptibility to develop psychiatric disorders. It is generally assumed that this increase in COMT activity…

  10. Influence of COMT genotype and affective distractors on the processing of self-generated thought.

    PubMed

    Kilford, Emma J; Dumontheil, Iroise; Wood, Nicholas W; Blakemore, Sarah-Jayne

    2015-06-01

    The catechol-O-methyltransferase (COMT) enzyme is a major determinant of prefrontal dopamine levels. The Val(158)Met polymorphism affects COMT enzymatic activity and has been associated with variation in executive function and affective processing. This study investigated the effect of COMT genotype on the flexible modulation of the balance between processing self-generated and processing stimulus-oriented information, in the presence or absence of affective distractors. Analyses included 124 healthy adult participants, who were also assessed on standard working memory (WM) tasks. Relative to Val carriers, Met homozygotes made fewer errors when selecting and manipulating self-generated thoughts. This effect was partly accounted for by an association between COMT genotype and visuospatial WM performance. We also observed a complex interaction between the influence of affective distractors, COMT genotype and sex on task accuracy: male, but not female, participants showed a sensitivity to the affective distractors that was dependent on COMT genotype. This was not accounted for by WM performance. This study provides novel evidence of the role of dopaminergic genetic variation on the ability to select and manipulate self-generated thoughts. The results also suggest sexually dimorphic effects of COMT genotype on the influence of affective distractors on executive function. © The Author (2014). Published by Oxford University Press.

  11. [The effect of the serotonin transporter 5-HTTLPR polymorphism on the recognition of facial emotions in schizophrenia].

    PubMed

    Alfimova, M V; Golimbet, V E; Korovaitseva, G I; Lezheiko, T V; Abramova, L I; Aksenova, E V; Bolgov, M I

    2014-01-01

    The 5-HTTLPR SLC6A4 and catechol-o-methyltransferase (COMT) Val158Met polymorphisms are reported to be associated with processing of facial expressions in general population. Impaired recognition of facial expressions that is characteristic of schizophrenia negatively impacts on the social adaptation of the patients. To search for molecular mechanisms of this deficit, we studied main and epistatic effects of 5-HTTLPR and Val158Met polymorphisms on the facial emotion recognition in patients with schizophrenia (n=299) and healthy controls (n=232). The 5-HTTLPR polymorphism was associated with the emotion recognition in patients. The ll-homozygotes recognized facial emotions significantly better compared to those with an s-allele (F=8.00; p=0.005). Although the recognition of facial emotions was correlated with negative symptoms, verbal learning and trait anxiety, these variables did not significantly modified the association. In both groups, no effect of the COMT on the recognition of facial emotions was found.

  12. Genetic polymorphisms in CYP1A1, CYP1B1 and COMT genes in Greenlandic Inuit and Europeans.

    PubMed

    Ghisari, Mandana; Long, Manhai; Bonefeld-Jørgensen, Eva C

    2013-01-01

    The Indigenous Arctic population is of Asian descent, and their genetic background is different from the Caucasian populations. Relatively little is known about the specific genetic polymorphisms in genes involved in the activation and detoxification mechanisms of environmental contaminants in Inuit and its relation to health risk. The Greenlandic Inuit are highly exposed to legacy persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs), and an elucidation of gene-environment interactions in relation to health risks is needed. The aim of this study was to determine and compare the genotype and allele frequencies of the cytochrome P450 CYP1A1 Ile462Val (rs1048943), CYP1B1 Leu432Val (rs1056836) and catechol-O-methyltransferase COMT Val158Met (rs4680) in Greenlandic Inuit (n=254) and Europeans (n=262) and explore the possible relation between the genotypes and serum levels of POPs. The genotype and allele frequency distributions of the three genetic polymorphisms differed significantly between the Inuit and Europeans. For Inuit, the genotype distribution was more similar to those reported for Asian populations. We observed a significant difference in serum polychlorinated biphenyl (CB-153) and the pesticide 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p'-DDE) levels between Inuit and Europeans, and for Inuit also associations between the POP levels and genotypes for CYP1A1, CYP1B1 and COMT. Our data provide new information on gene polymorphisms in Greenlandic Inuit that might support evaluation of susceptibility to environmental contaminants and warrant further studies.

  13. Association of BDNF Val66Met polymorphism with HPA and SAM axis reactivity to psychological and physical stress.

    PubMed

    Tsuru, Jusen; Tanaka, Yoshihiro; Ishitobi, Yoshinobu; Maruyama, Yoshihiro; Inoue, Ayako; Kawano, Aimi; Ikeda, Rie; Ando, Tomoko; Oshita, Harumi; Aizawa, Saeko; Masuda, Koji; Higuma, Haruka; Kanehisa, Masayuki; Ninomiya, Taiga; Akiyoshi, Jotaro

    2014-01-01

    Decreased expression of brain-derived neurotrophic factor (BDNF) is implicated in enhanced stress responses. The BDNF Val66Met polymorphism is associated with psychological changes; for example, carriers of the Met allele exhibit increased harm avoidance as well as a higher prevalence of depression and anxiety disorder. To analyze the effects of BDNF Val66Met on stress responses, we tested 226 university students (88 women and 138 men) using a social stress procedure (Trier Social Stress Test [TSST]) and an electrical stimulation stress test. Stress indices were derived from repeated measurements of salivary α-amylase, salivary cortisol, heart rate, and psychological testing during the stress tests. All subjects were genotyped for the Val66Met polymorphism (G196A). A significant three-way interaction (time [3 levels] × BDNF [Val/Val, Val/Met, Met/Met]; P<0.05) was demonstrated that revealed different salivary cortisol responses in the TSST but not in electrical stimulation. Met/Met women had stronger cortisol responses than Val/Met and Val/Val individuals in the TSST. Met/Met men exhibited stronger salivary cortisol responses than Val/Met and Val/Val individuals in the TSST. These results indicate that a common, functionally significant polymorphism in BDNF had different effects on hypothalamic-pituitary-adrenocortical axis reactivity but not on sympathetic adrenomedullary reactivity in TSST and electrical stimulation tests.

  14. Stress-related methylation of the catechol-O-methyltransferase Val 158 allele predicts human prefrontal cognition and activity.

    PubMed

    Ursini, Gianluca; Bollati, Valentina; Fazio, Leonardo; Porcelli, Annamaria; Iacovelli, Luisa; Catalani, Assia; Sinibaldi, Lorenzo; Gelao, Barbara; Romano, Raffaella; Rampino, Antonio; Taurisano, Paolo; Mancini, Marina; Di Giorgio, Annabella; Popolizio, Teresa; Baccarelli, Andrea; De Blasi, Antonio; Blasi, Giuseppe; Bertolino, Alessandro

    2011-05-04

    DNA methylation at CpG dinucleotides is associated with gene silencing, stress, and memory. The catechol-O-methyltransferase (COMT) Val(158) allele in rs4680 is associated with differential enzyme activity, stress responsivity, and prefrontal activity during working memory (WM), and it creates a CpG dinucleotide. We report that methylation of the Val(158) allele measured from peripheral blood mononuclear cells (PBMCs) of Val/Val humans is associated negatively with lifetime stress and positively with WM performance; it interacts with stress to modulate prefrontal activity during WM, such that greater stress and lower methylation are related to reduced cortical efficiency; and it is inversely related to mRNA expression and protein levels, potentially explaining the in vivo effects. Finally, methylation of COMT in prefrontal cortex and that in PBMCs of rats are correlated. The relationship of methylation of the COMT Val(158) allele with stress, gene expression, WM performance, and related brain activity suggests that stress-related methylation is associated with silencing of the gene, which partially compensates the physiological role of the high-activity Val allele in prefrontal cognition and activity. Moreover, these results demonstrate how stress-related DNA methylation of specific functional alleles impacts directly on human brain physiology beyond sequence variation.

  15. BDNF-Val66Met-Polymorphism Impact on Cortical Plasticity in Schizophrenia Patients: A Proof-of-Concept Study

    PubMed Central

    Nitsche, Michael A.; Wobrock, Thomas; Bunse, Tilmann; Rein, Bettina; Herrmann, Maximiliane; Schmitt, Andrea; Nieratschker, Vanessa; Witt, Stephanie H.; Rietschel, Marcella; Falkai, Peter; Hasan, Alkomiet

    2015-01-01

    Background: Brain-derived neurotrophic factor (BDNF) has been shown to be a moderator of neuroplasticity. A frequent BDNF-polymorphism (Val66Met) is associated with impairments of cortical plasticity. In patients with schizophrenia, reduced neuroplastic responses following non-invasive brain stimulation have been reported consistently. Various studies have indicated a relationship between the BDNF-Val66Met-polymorphism and motor-cortical plasticity in healthy individuals, but schizophrenia patients have yet to be investigated. The aim of this proof-of-concept study was, therefore, to test the impact of the BDNF-Val66Met-polymorphism on inhibitory and facilitatory cortical plasticity in schizophrenia patients. Methods: Cortical plasticity was investigated in 22 schizophrenia patients and 35 healthy controls using anodal and cathodal transcranial direct-current stimulation (tDCS) applied to the left primary motor cortex. Animal and human research indicates that excitability shifts following anodal and cathodal tDCS are related to molecular long-term potentiation and long-term depression. To test motor-cortical excitability before and after tDCS, well-established single- and paired-pulse transcranial magnetic stimulation protocols were applied. Results: Our analysis revealed increased glutamate-mediated intracortical facilitation in met-heterozygotes compared to val-homozygotes at baseline. Following cathodal tDCS, schizophrenia met-heterozygotes had reduced gamma-amino-butyric-acid-mediated short-interval intracortical inhibition, whereas healthy met-heterozygotes displayed the opposite effect. The BDNF-Val66Met-polymorphism did not influence single-pulse motor-evoked potential amplitudes after tDCS. Conclusions: These preliminary findings support the notion of an association of the BDNF-Val66Met-polymorphism with observable alterations in plasticity following cathodal tDCS in schizophrenia patients. This indicates a complex interaction between inhibitory

  16. Clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"): the influence of gender and genetics (CYP2D6, COMT, 5-HTT).

    PubMed

    Pardo-Lozano, Ricardo; Farré, Magí; Yubero-Lahoz, Samanta; O'Mathúna, Brian; Torrens, Marta; Mustata, Cristina; Pérez-Mañá, Clara; Langohr, Klaus; Cuyàs, Elisabet; Carbó, Marcel lí; de la Torre, Rafael

    2012-01-01

    The synthetic psychostimulant MDMA (± 3,4-methylenedioxymethamphetamine, ecstasy) acts as an indirect serotonin, dopamine, and norepinephrine agonist and as a mechanism-based inhibitor of the cytochrome P-450 2D6 (CYP2D6). It has been suggested that women are more sensitive to MDMA effects than men but no clinical experimental studies have satisfactorily evaluated the factors contributing to such observations. There are no studies evaluating the influence of genetic polymorphism on the pharmacokinetics (CYP2D6; catechol-O-methyltransferase, COMT) and pharmacological effects of MDMA (serotonin transporter, 5-HTT; COMT). This clinical study was designed to evaluate the pharmacokinetics and physiological and subjective effects of MDMA considering gender and the genetic polymorphisms of CYP2D6, COMT, and 5-HTT. A total of 27 (12 women) healthy, recreational users of ecstasy were included (all extensive metabolizers for CYP2D6). A single oral weight-adjusted dose of MDMA was administered (1.4 mg/kg, range 75-100 mg) which was similar to recreational doses. None of the women were taking oral contraceptives and the experimental session was performed during the early follicular phase of their menstrual cycle. Principal findings show that subjects reached similar MDMA plasma concentrations, and experienced similar positive effects, irrespective of gender or CYP2D6 (not taking into consideration poor or ultra-rapid metabolizers) or COMT genotypes. However, HMMA plasma concentrations were linked to CYP2D6 genotype (higher with two functional alleles). Female subjects displayed more intense physiological (heart rate, and oral temperature) and negative effects (dizziness, sedation, depression, and psychotic symptoms). Genotypes of COMT val158met or 5-HTTLPR with high functionality (val/val or l/*) determined greater cardiovascular effects, and with low functionality (met/* or s/s) negative subjective effects (dizziness, anxiety, sedation). In conclusion, the contribution of

  17. The BDNF Val66Met polymorphism affects HPA-axis reactivity to acute stress.

    PubMed

    Alexander, Nina; Osinsky, Roman; Schmitz, Anja; Mueller, Eva; Kuepper, Yvonne; Hennig, Juergen

    2010-07-01

    Growing evidence suggests that individual differences in HPA-axis reactivity to psychosocial stress are partly due to heritable influences. However, knowledge about the role of specific genetic variants remains very limited to date. Since brain-derived neurotrophic factor (BDNF) not only exhibits neurotrophic actions but is also involved in the regulation of hypothalamic neuropeptides, we investigated the role of a common functional polymorphism within the BDNF gene (BDNF Val66Met) in the context of endocrine and cardiovascular stress reactivity. Healthy male adults (N=100) were genotyped and exposed to a standardized laboratory stress task (Public Speaking). Saliva cortisol and self-reported mood levels were obtained at 6 time points prior to the stressor and during an extended recovery period. Furthermore, heart rate reactivity as an indicator of sympathetic activation was monitored continuously during the experimental procedure. We report a small, but significant effect of the BDNF Val66Met polymorphism on stress reactivity. More precisely, carriers of the met-allele showed a significantly attenuated HPA-axis and cardiovascular reactivity to the psychosocial stressor compared to subjects with the val/val genotype. Furthermore, the diminished physiological response in met-allele carriers was also attended by significantly lower self-reported ratings of perceived stress and nervousness. Our findings of a diminished endocrine and cardiovascular stress response in healthy male adults is consistent with a previously published study and adds further evidence for a crucial role of the BDNF Val66Met polymorphism in the modulation of stress reactivity. Copyright 2010. Published by Elsevier Ltd.

  18. Brain-derived neurotrophic factor Val66Met polymorphism and alcohol-related phenotypes.

    PubMed

    Nedic, Gordana; Perkovic, Matea Nikolac; Sviglin, Korona Nenadic; Muck-Seler, Dorotea; Borovecki, Fran; Pivac, Nela

    2013-01-10

    Alcoholism is a chronic psychiatric disorder affecting neural pathways that regulate motivation, stress, reward and arousal. Brain-derived neurotrophic factor (BDNF) regulates mood, response to stress and interacts with neurotransmitters and stress systems involved in reward pathways and addiction. Aim of the study was to evaluate the association between a single nucleotide polymorphism (BDNF Val66Met or rs6265) and alcohol related phenotypes in Caucasian patients. In ethnically homogenous Caucasian subjects of the Croatian origin, the BDNF Val66Met genotype distribution was determined in 549 male and 126 female patients with alcohol dependence and in 655 male and 259 female healthy non-alcoholic control subjects. Based on the structured clinical interview, additional detailed clinical interview, the Brown-Goodwin Scale, the Hamilton Rating Scale for Depression and the Clinical Global Impression scores, alcoholic patients were subdivided into those with or without comorbid depression, aggression, delirium tremens, withdrawal syndrome, early/late onset of alcohol abuse, prior suicidal attempt during lifetime, current suicidal behavior, and severity of alcohol dependence. The results showed no significant association between BDNF Val66Met variants and alcohol dependence and/or any of the alcohol related phenotypes in either Caucasian women, or men, with alcohol dependence. There are few limitations of the study. The overall study sample size was large (N=1589) but not well-powered to detect differences in BDNF Val66Met genotype distribution between studied groups. Healthy control women were older than female alcoholic patients. Only one BDNF polymorphism (rs6265) was studied. In conclusion, these data do not support the view that BDNF Val66Met polymorphism correlates with the specific alcohol related phenotypes in ethnically homogenous medication-free Caucasian subjects with alcohol dependence. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. Genetic polymorphisms in CYP1A1, CYP1B1 and COMT genes in Greenlandic Inuit and Europeans

    PubMed Central

    Ghisari, Mandana; Long, Manhai; Bonefeld-Jørgensen, Eva C.

    2013-01-01

    Background The Indigenous Arctic population is of Asian descent, and their genetic background is different from the Caucasian populations. Relatively little is known about the specific genetic polymorphisms in genes involved in the activation and detoxification mechanisms of environmental contaminants in Inuit and its relation to health risk. The Greenlandic Inuit are highly exposed to legacy persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs), and an elucidation of gene–environment interactions in relation to health risks is needed. Objectives The aim of this study was to determine and compare the genotype and allele frequencies of the cytochrome P450 CYP1A1 Ile462Val (rs1048943), CYP1B1 Leu432Val (rs1056836) and catechol-O-methyltransferase COMT Val158Met (rs4680) in Greenlandic Inuit (n=254) and Europeans (n=262) and explore the possible relation between the genotypes and serum levels of POPs. Results The genotype and allele frequency distributions of the three genetic polymorphisms differed significantly between the Inuit and Europeans. For Inuit, the genotype distribution was more similar to those reported for Asian populations. We observed a significant difference in serum polychlorinated biphenyl (CB-153) and the pesticide 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p′-DDE) levels between Inuit and Europeans, and for Inuit also associations between the POP levels and genotypes for CYP1A1, CYP1B1 and COMT. Conclusion Our data provide new information on gene polymorphisms in Greenlandic Inuit that might support evaluation of susceptibility to environmental contaminants and warrant further studies. PMID:23785672

  20. Clinical Pharmacology of 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”): The Influence of Gender and Genetics (CYP2D6, COMT, 5-HTT)

    PubMed Central

    O’Mathúna, Brian; Torrens, Marta; Mustata, Cristina; Pérez-Mañá, Clara; Langohr, Klaus; Cuyàs, Elisabet; Carbó, Marcel·lí; de la Torre, Rafael

    2012-01-01

    The synthetic psychostimulant MDMA (±3,4-methylenedioxymethamphetamine, ecstasy) acts as an indirect serotonin, dopamine, and norepinephrine agonist and as a mechanism-based inhibitor of the cytochrome P-450 2D6 (CYP2D6). It has been suggested that women are more sensitive to MDMA effects than men but no clinical experimental studies have satisfactorily evaluated the factors contributing to such observations. There are no studies evaluating the influence of genetic polymorphism on the pharmacokinetics (CYP2D6; catechol-O-methyltransferase, COMT) and pharmacological effects of MDMA (serotonin transporter, 5-HTT; COMT). This clinical study was designed to evaluate the pharmacokinetics and physiological and subjective effects of MDMA considering gender and the genetic polymorphisms of CYP2D6, COMT, and 5-HTT. A total of 27 (12 women) healthy, recreational users of ecstasy were included (all extensive metabolizers for CYP2D6). A single oral weight-adjusted dose of MDMA was administered (1.4 mg/kg, range 75–100 mg) which was similar to recreational doses. None of the women were taking oral contraceptives and the experimental session was performed during the early follicular phase of their menstrual cycle. Principal findings show that subjects reached similar MDMA plasma concentrations, and experienced similar positive effects, irrespective of gender or CYP2D6 (not taking into consideration poor or ultra-rapid metabolizers) or COMT genotypes. However, HMMA plasma concentrations were linked to CYP2D6 genotype (higher with two functional alleles). Female subjects displayed more intense physiological (heart rate, and oral temperature) and negative effects (dizziness, sedation, depression, and psychotic symptoms). Genotypes of COMT val158met or 5-HTTLPR with high functionality (val/val or l/*) determined greater cardiovascular effects, and with low functionality (met/* or s/s) negative subjective effects (dizziness, anxiety, sedation). In conclusion, the contribution of

  1. The BDNF Val66Met polymorphism impairs synaptic transmission and plasticity in the infralimbic medial prefrontal cortex

    PubMed Central

    Pattwell, Siobhan S.; Bath, Kevin G.; Perez-Castro, Rosalia; Lee, Francis S.; Chao, Moses V.; Ninan, Ipe

    2012-01-01

    The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is a common human single nucleotide polymorphism (SNP) that affects the regulated release of BDNF, and has been implicated in affective disorders and cognitive dysfunction. A decreased activation of the infralimbic medial prefrontal cortex (IL-mPFC), a brain region critical for the regulation of affective behaviors, has been described in BDNFMet carriers. However, it is unclear whether and how the Val66Met polymorphism affects the IL-mPFC synapses. Here we report that spike timing-dependent plasticity (STDP) was absent in the IL-mPFC pyramidal neurons from BDNFMet/Met mice, a mouse that recapitulates the specific phenotypic properties of the human BDNF Val66Met polymorphism. Also, we observed a decrease in N-methyl-D-aspartic acid (NMDA) and γ-aminobutyric acid (GABA) receptor-mediated synaptic transmission in the pyramidal neurons of BDNFMet/Met mice. While BDNF enhanced non-NMDA receptor transmission and depressed GABA receptor transmission in the wild-type mice, both effects were absent in BDNFMet/Met mice after BDNF treatment. Indeed, exogenous BDNF reversed the deficits in STDP and NMDA receptor transmission in BDNFMet/Met neurons. BDNF-mediated selective reversal of the deficit in plasticity and NMDA receptor transmission, but its lack of effect on GABA and non-NMDA receptor transmission in BDNFMet/Met mice, suggests separate mechanisms of Val66Met polymorphism upon synaptic transmission. The effect of the Val66Met polymorphism on synaptic transmission and plasticity in the IL-mPFC represents a mechanism to account for this SNP's impact on affective disorders and cognitive dysfunction. PMID:22396415

  2. Effects of the BDNF Val66Met Polymorphism on Anxiety-Like Behavior Following Nicotine Withdrawal in Mice

    PubMed Central

    Lee, Bridgin G.; Anastasia, Agustin; Hempstead, Barbara L.; Lee, Francis S.

    2015-01-01

    Introduction: Nicotine withdrawal is characterized by both affective and cognitive symptoms. Identifying genetic polymorphisms that could affect the symptoms associated with nicotine withdrawal are important in predicting withdrawal sensitivity and identifying personalized cessation therapies. In the current study we used a mouse model of a non-synonymous single nucleotide polymorphism in the translated region of the brain-derived neurotrophic factor (BDNF) gene that substitutes a valine (Val) for a methionine (Met) amino acid (Val66Met) to examine the relationship between the Val66Met single nucleotide polymorphism and nicotine dependence. Methods: This study measured proBDNF and the BDNF prodomain levels following nicotine and nicotine withdrawal and examined a mouse model of a common polymorphism in this protein (BDNFMet/Met) in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test. Results: Using the BDNF knock-in mouse containing the BDNF Val66Met polymorphism we found: (1) blunted anxiety-like behavior in BDNFMet/Met mice following withdrawal in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test; (2) the anxiolytic effects of chronic nicotine are absent in BDNFMet/Met mice; and (3) an increase in BDNF prodomain in BDNFMet/Met mice following nicotine withdrawal. Conclusions: Our study is the first to examine the effect of the BDNF Val66Met polymorphism on the affective symptoms of withdrawal from nicotine in mice. In these mice, a single-nucleotide polymorphism in the translated region of the BDNF gene can result in a blunted withdrawal, as measured by decreased anxiety-like behavior. The significant increase in the BDNF prodomain in BDNFMet/Met mice following nicotine cessation suggests a possible role of this ligand in the circuitry remodeling after withdrawal. PMID:25744957

  3. Association of codon 108/158 catechol-O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lachman, H.M.; Papolos, D.F.; Veit, S.

    Velo-cardio-facial-syndrome (VCFS) is a common congenital disorder associated with typical facial appearance, cleft palate, cardiac defects, and learning disabilities. The majority of patients have an interstitial deletion on chromosome 22q11. In addition to physical abnormalities, a variety of psychiatric illnesses have been reported in patients with VCFS, including schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder. The psychiatric manifestations of VCFS could be due to haploinsufficiency of a gene(s) within 22q11. One candidate that has been mapped to this region is catechol-O-methyltransferase (COMT). We recently identified a polymorphism in the COMT gene that leads to a valine{r_arrow}methionine substitution at aminomore » acid 158 of the membrane-bound form of the enzyme. Homozygosity for COMT158{sup met} leads to a 3- to 4-fold reduction in enzymatic activity, compared with homozygotes for COMT158{sup met}. We now report that in a population of patients with VCFS, there is an apparent association between the low-activity allele, COMT158{sup met}, and the development of bipolar spectrum disorder, and in particular, a rapid-cycling form. 33 refs., 3 tabs.« less

  4. Effects of the BDNF Val66Met Polymorphism on Anxiety-Like Behavior Following Nicotine Withdrawal in Mice.

    PubMed

    Lee, Bridgin G; Anastasia, Agustin; Hempstead, Barbara L; Lee, Francis S; Blendy, Julie A

    2015-12-01

    Nicotine withdrawal is characterized by both affective and cognitive symptoms. Identifying genetic polymorphisms that could affect the symptoms associated with nicotine withdrawal are important in predicting withdrawal sensitivity and identifying personalized cessation therapies. In the current study we used a mouse model of a non-synonymous single nucleotide polymorphism in the translated region of the brain-derived neurotrophic factor (BDNF) gene that substitutes a valine (Val) for a methionine (Met) amino acid (Val66Met) to examine the relationship between the Val66Met single nucleotide polymorphism and nicotine dependence. This study measured proBDNF and the BDNF prodomain levels following nicotine and nicotine withdrawal and examined a mouse model of a common polymorphism in this protein (BDNF(Met/Met)) in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test. Using the BDNF knock-in mouse containing the BDNF Val66Met polymorphism we found: (1) blunted anxiety-like behavior in BDNF(Met/Met) mice following withdrawal in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test; (2) the anxiolytic effects of chronic nicotine are absent in BDNF(Met/Met) mice; and (3) an increase in BDNF prodomain in BDNF(Met/Met) mice following nicotine withdrawal. Our study is the first to examine the effect of the BDNF Val66Met polymorphism on the affective symptoms of withdrawal from nicotine in mice. In these mice, a single-nucleotide polymorphism in the translated region of the BDNF gene can result in a blunted withdrawal, as measured by decreased anxiety-like behavior. The significant increase in the BDNF prodomain in BDNF(Met/Met) mice following nicotine cessation suggests a possible role of this ligand in the circuitry remodeling after withdrawal. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For

  5. Effects of COMT, DRD2, BDNF, and APOE Genotypic Variation on Treatment Efficacy and Cognitive Side Effects of Electroconvulsive Therapy.

    PubMed

    Bousman, Chad A; Katalinic, Natalie; Martin, Donel M; Smith, Deidre J; Ingram, Anna; Dowling, Nathan; Ng, Chee; Loo, Colleen K

    2015-06-01

    The aim of this study was to explore the main and interaction effects of the COMT Val158Met, DRD2 C957T, BDNF Val66Met, and APOE polymorphisms on treatment efficacy and cognitive side effects of electroconvulsive therapy (ECT). A total of 117 adult inpatients with a diagnosis of major depressive disorder recruited from 3 hospitals were administered the Montgomery-Äsberg Depression Rating Scale and a cognitive battery assessing global cognition, anterograde memory, executive function, speed and concentration, as well as retrograde memory at baseline and after ECT treatment. DRD2 C957T heterozygotes had 3.7 (95% confidence interval, 1.13-12.25; P = 0.032) greater odds of remission compared with CC homozygotes. Among the men, COMT Val/Val carriers had greater depressive symptom reduction compared with Met/Met carriers (Montgomery-Äsberg Depression Rating Scale percentage of reduction, 76% vs 35%; P = 0.020) but not among the women (P = 0.903) after ECT. For cognitive outcomes, an interaction effect on anterograde memory was observed between the DRD2 and BDNF polymorphisms (P = 0.016), in which carriers of the DRD2 TT and BDNF Val/Val genotypes had significantly less decline in anterograde performance than those that carried the TC and Met-allele (P = 0.001) or CC and Met-allele (P = 0.003) genotypes. However, no results withstood correction for multiple comparisons. These observations provide preliminary evidence supporting an association between common functional genotypic variation and ECT efficacy as well as anterograde memory side effects after ECT. Validation of these findings is required before firm conclusions can be made and clinical utility can be assessed.

  6. Brain-derived neurotrophic factor Val66Met polymorphism and dexamethasone/CRH test results in depressed patients.

    PubMed

    Schüle, Cornelius; Zill, Peter; Baghai, Thomas C; Eser, Daniela; Zwanzger, Peter; Wenig, Nadine; Rupprecht, Rainer; Bondy, Brigitta

    2006-09-01

    Data suggest that both neurotrophic and hypothalamic-pituitary-adrenocortical (HPA) systems are involved in the pathophysiology of depression. The aim of the present study was to investigate whether the non-conservative brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has an impact on HPA axis activity in depressed patients. At admission, the dexamethasone/CRH (DEX/CRH) test was performed in 187 drug-free in-patients suffering from major depression or depressed state of bipolar disorder (DSM-IV criteria). Moreover, genotyping of BDNF Val66Met polymorphism was carried out using the fluorescence resonance energy transfer method (FRET). Homozygous carriers of the Met/Met genotype showed a significantly higher HPA axis activity during the DEX/CRH test than patients carrying the Val/Val or Val/Met genotype (ACTH, cortisol). Our results further contribute to the hypothesized association between HPA axis dysregulation and reduced neuroplasticity in depression and are consistent with the assumption that BDNF is a stress-responsive intercellular messenger modifying HPA axis activity.

  7. BDNF Val66Met polymorphism modulates the effect of loneliness on white matter microstructure in young adults.

    PubMed

    Meng, Jie; Hao, Lei; Wei, Dongtao; Sun, Jiangzhou; Li, Yu; Qiu, Jiang

    2017-12-01

    Loneliness is a common experience. Susceptibility to loneliness is a stable trait and is heritable. Previous studies have suggested that loneliness may impact regional gray matter density and brain activation to social stimuli, but its relation to white matter structure and how it may interact with genetic factors remains unclear. In this study, we investigated whether and how a common polymorphism (Val66Met) in the brain-derived neurotrophic factor gene modulated the association between loneliness and white matter microstructure in 162 young adults. The tract-based spatial statistics analyses revealed that the relationships between loneliness and white matter microstructures were significantly different between Val/Met heterozygotes and Val/Val homozygotes. Specifically, loneliness was significantly correlated with reduced fractional anisotropy and increased radial diffusivity in widespread white matter fibers within Val/Met heterozygotes. It was also significantly correlated with increased radial diffusivity in Met/Met genotypes but showed no significant association with white matter measures in Val/Val genotypes. Furthermore, the associations between loneliness and fractional anisotropy (or radial diffusivity) in Val/Met heterozygotes turned out to be global effects. These results provide evidence that loneliness may interact with the BDNF Val66Met polymorphism to shape the microstructures of white matter, and the Val/Met heterozygotes may be more susceptible to social environment. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Suicide attempt, clinical correlates, and BDNF Val66Met polymorphism in chronic patients with schizophrenia.

    PubMed

    Xia, Haisen; Zhang, Guangya; Du, Xiangdong; Zhang, Yingyang; Yin, Guangzhong; Dai, Jing; He, Man-Xi; Soares, Jair C; Li, Xiaosi; Zhang, Xiang Yang

    2018-02-01

    Recent evidence suggests the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of suicidal behavior. Because schizophrenia patients usually have high suicide rates and numerous studies have suggested that BDNF may contribute to the psychopathology of schizophrenia, we hypothesized that the functional polymorphism of BDNF (Val66Met) was associated with suicide attempts in patients with schizophrenia in a Chinese Han population. This polymorphism was genotyped in 825 chronic schizophrenia patients with (n = 123) and without (n = 702) suicide attempts and 445 healthy controls without a history of suicide attempts using a case-control design. The schizophrenia symptoms were assessed by the Positive and Negative Syndrome Scale. There were no significant differences in BDNF Val66Met genotype and allele distributions between the patients and healthy controls. However, we found the Val allele (p = .023) and the Val/Val genotypes (p = .058) to be associated with a history of suicide attempts. Moreover, some clinical characteristics, including age and cigarettes smoked each day, interacted with the BDNF gene variant and appeared to play an important role in suicide attempts among schizophrenia patients. The BDNF Val66Met polymorphism itself and its interaction with some clinical variables may influence suicide attempts among schizophrenia patients. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

  9. Interaction between job stress and the BDNF Val66Met polymorphism affects depressive symptoms in Chinese healthcare workers.

    PubMed

    He, Shu-Chang; Wu, Shuang; Wang, Chao; Du, Xiang-Dong; Yin, Guangzhong; Jia, Qiufang; Zhang, Yingyang; Wang, Li; Soares, Jair C; Zhang, Xiang Yang

    2018-08-15

    Chronic exposure to job-related stress can lead to depression and BDNF polymorphism may play an important role in this process. The role of the stress × BDNF Val66Met interaction in depression has been studied widely using childhood stress, but few studies have utilized chronic stress in adulthood as a moderator. This study was to examine the chronic stress × BDNF Val66Met interaction in job-related depression in the healthcare workers in a Chinese Han population, which has not been reported yet. Using a cross-sectional design, 243 doctors and nurses were recruited from a general hospital in Beijing, and were assessed for depression with Self-rating Depression Scale (SDS), and the stress using the House and Rizzo's Work Stress Scale. The BDNF Val66Met polymorphism was genotyped. There was a significant positive association between job stress and depressive scores (p < 0.001). No significant main effect of the BDNF Val66Met genotype on depressive symptoms was observed (p > 0.05). A statistically significant interaction between BDNF Val66Met and job stress on depressive symptoms was found (p < 0.05); individuals with Val/Val genotype showed a higher SDS score than Met allele carriers only in the low-stress group, without significant differences in SDS score between the BDNF Val66Met subgroups in medium- or high-stress group. Limitations include cross-sectional study design, the small sample size only in healthcare workers and only one polymorphism in BDNF gene was analyzed. Our results suggest a close relationship between job-related stress and depression, and the interaction of the BDNF Val66Met polymorphism and chronic stress in adulthood may impact the depressive symptoms. Copyright © 2018. Published by Elsevier B.V.

  10. Effects of the BDNF Val66Met polymorphism on neural responses to facial emotion.

    PubMed

    Mukherjee, Prerona; Whalley, Heather C; McKirdy, James W; McIntosh, Andrew M; Johnstone, Eve C; Lawrie, Stephen M; Hall, Jeremy

    2011-03-31

    The brain derived neurotrophic factor (BDNF) Val66Met polymorphism has been associated with affective disorders, but its role in emotion processing has not been fully established. Due to the clinically heterogeneous nature of these disorders, studying the effect of genetic variation in the BDNF gene on a common attribute such as fear processing may elucidate how the BDNF Val66Met polymorphism impacts brain function. Here we use functional magnetic resonance imaging examine the effect of the BDNF Val66Met genotype on neural activity for fear processing. Forty healthy participants performed an implicit fear task during scanning, where subjects made gender judgments from facial images with neutral or fearful emotion. Subjects were tested for facial emotion recognition post-scan. Functional connectivity was investigated using psycho-physiological interactions. Subjects were genotyped for the BDNF Val66Met polymorphism and the measures compared between genotype groups. Met carriers showed overactivation in the anterior cingulate cortex (ACC), brainstem and insula bilaterally for fear processing, along with reduced functional connectivity from the ACC to the left hippocampus, and impaired fear recognition ability. The results show that during fear processing, Met allele carriers show an increased neural response in regions previously implicated in mediating autonomic arousal. Further, the Met carriers show decreased functional connectivity with the hippocampus, which may reflect differential retrieval of emotional associations. Together, these effects show significant differences in the neural substrate for fear processing with genetic variation in BDNF. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  11. Effects of BDNF Val66Met polymorphism on brain metabolism in Alzheimer's disease.

    PubMed

    Xu, Cunlu; Wang, Zhenhua; Fan, Ming; Liu, Bing; Song, Ming; Zhen, Xiantong; Jiang, Tianzi

    2010-08-23

    Earlier studies showed that the Val66Met polymorphisms of the brain-derived neurotrophic factor differentially affect gray matter volume and brain region activities. This study used resting positron emission tomography to investigate the relationship between the polymorphisms of Val66Met and the regional cerebral metabolic rate in the brain. We analyzed the positron emission tomography images of 215 patients from the Alzheimer's Disease Neuroimaging Initiative and found significant differences in the parahippocampal gyrus, superior temporal gyrus, prefrontal cortex, and inferior parietal lobule when comparing Met carriers with noncarriers among both the normal controls and those with mild cognitive impairment. For those with Alzheimer's disease, we also found additional differences in the bilateral insula between the carriers and noncarriers.

  12. Interaction between childhood adversity and functional polymorphisms in the dopamine pathway on first-episode psychosis.

    PubMed

    Trotta, Antonella; Iyegbe, Conrad; Yiend, Jenny; Dazzan, Paola; David, Anthony S; Pariante, Carmine; Mondelli, Valeria; Colizzi, Marco; Murray, Robin M; Di Forti, Marta; Fisher, Helen L

    2018-04-10

    There is consistent evidence of a cumulative relationship between childhood adversity and psychosis, with number of adversities experienced increasing the probability of psychosis onset. It is possible that genetic factors moderate the association between childhood adversity and psychosis, potentially by influencing how an individual reacts biologically and/or psychologically following exposure to adversity, in such a way as to set them off on the path to psychosis. However, identifying the specific genetic variants involved and how they interact with childhood adversity remains challenging. We examined whether the association between cumulative exposure to childhood adversity and development of psychotic disorder was moderated by the COMT Val 158 Met, AKT1 rs2494732 or DRD2 rs1076560 polymorphisms, known to affect dopamine levels. Participants were 285 first-presentation psychosis cases and 256 geographically-matched controls drawn from the Genetics and Psychosis (GAP) study. Childhood adversity was assessed using the Childhood Experience of Care and Abuse Questionnaire (CECA.Q) and blood- and cheek-derived genotype data were collected. Our findings revealed no main effect of COMT Val 158 Met, AKT1 rs2494732 and DRD2 rs1076560 polymorphisms on psychosis case status or reports of childhood adversity. Individuals reporting a history of multiple adversities were more likely to be psychosis patients than controls, regardless of their genetic risk. There was no evidence of candidate genotype by childhood adversity interactions in relation to psychosis onset. These findings did not provide evidence of a possible role of COMT Val 158 Met, AKT1 rs2494732 or DRD2 rs1076560 genotypes in modifying the association between childhood adversity and onset of psychosis. Copyright © 2018 Elsevier B.V. All rights reserved.

  13. The Role of the Catechol-O-Methyltransferase (COMT) Gene in Personality and Related Psychopathological Disorders

    PubMed Central

    Montag, Christian; Jurkiewicz, Magdalena; Reuter, Martin

    2015-01-01

    This review provides a short overview of the most significant biologically oriented theories of human personality. Personality concepts of Eysenck, Gray and McNaughton, Cloninger and Panksepp will be introduced and the focal evidence for the heritability of personality will be summarized. In this context, a synopsis of a large number of COMT genetic association studies (with a focus on the COMT Val158Met polymorphism) in the framework of the introduced biologically oriented personality theories will be given. In line with the theory of a continuum model between healthy anxious behavior and related psychopathological behavior, the role of the COMT gene in anxiety disorders will be discussed. A final outlook considers new research strategies such as genetic imaging and epigenetics for a better understanding of human personality. PMID:22483293

  14. Effects of the BDNF Val66Met polymorphism and met allele load on declarative memory related neural networks.

    PubMed

    Dodds, Chris M; Henson, Richard N; Suckling, John; Miskowiak, Kamilla W; Ooi, Cinly; Tait, Roger; Soltesz, Fruzsina; Lawrence, Phil; Bentley, Graham; Maltby, Kay; Skeggs, Andrew; Miller, Sam R; McHugh, Simon; Bullmore, Edward T; Nathan, Pradeep J

    2013-01-01

    It has been suggested that the BDNF Val66Met polymorphism modulates episodic memory performance via effects on hippocampal neural circuitry. However, fMRI studies have yielded inconsistent results in this respect. Moreover, very few studies have examined the effect of met allele load on activation of memory circuitry. In the present study, we carried out a comprehensive analysis of the effects of the BDNF polymorphism on brain responses during episodic memory encoding and retrieval, including an investigation of the effect of met allele load on memory related activation in the medial temporal lobe. In contrast to previous studies, we found no evidence for an effect of BDNF genotype or met load during episodic memory encoding. Met allele carriers showed increased activation during successful retrieval in right hippocampus but this was contrast-specific and unaffected by met allele load. These results suggest that the BDNF Val66Met polymorphism does not, as previously claimed, exert an observable effect on neural systems underlying encoding of new information into episodic memory but may exert a subtle effect on the efficiency with which such information can be retrieved.

  15. Is the Val66Met polymorphism of the brain-derived neurotrophic factor gene associated with panic disorder? A meta-analysis.

    PubMed

    Chen, Kaiyuan; Wang, Na; Zhang, Jie; Hong, Xiaohong; Xu, Haiyun; Zhao, Xiaofeng; Huang, Qingjun

    2017-06-01

    Although emerging evidence has suggested an association between the Val66Met (rs6265) polymorphisms in brain-derived neurotrophic factor (BDNF) gene and the panic disorder, the conclusion is inclusive given the mixed results. This meta-analysis reviewed and analyzed the recent studies addressing the potential association between the Val66Met polymorphisms and panic disorder susceptibility. Related case-control studies were retrieved by database searching and selected according to established inclusion criteria. Six articles were identified, which explored the association between the BDNF Val66Met polymorphism and panic disorder. Statistical analyses revealed no association for the allele contrast and the dominant model. However, the recessive model showed a significant association between the BDNF Val66Met polymorphism and panic disorder (odds ratio = 1.26, 95% confidence interval = 1.04-1.52, z = 2.39, P = 0.02). Despite of some limitations, this meta-analysis suggests that the Val66Met polymorphism of BDNF gene is a susceptibility factor for panic disorder. © 2015 Wiley Publishing Asia Pty Ltd.

  16. Val66Met Polymorphism of BDNF Alters Prodomain Structure to Induce Neuronal Growth Cone Retraction

    PubMed Central

    Anastasia, Agustin; Deinhardt, Katrin; Chao, Moses V.; Will, Nathan E.; Irmady, Krithi; Lee, Francis S.; Hempstead, Barbara L.; Bracken, Clay

    2013-01-01

    A common single-nucleotide polymorphism in the human brain-derived neurotrophic factor (BDNF) gene results in a Val66Met substitution in the BDNF prodomain region. This single-nucleotide polymorphism is associated with alterations in memory and with enhanced risk to develop depression and anxiety disorders in humans. Here we show that the isolated BDNF prodomain is detected in the hippocampus and that it can be secreted from neurons in an activity-dependent manner. Using nuclear magnetic resonance spectroscopy and circular dichroism we find that the prodomain is intrinsically disordered, and the Val66Met substitution induces structural changes. Surprisingly, application of Met66 (but not Val66) BDNF prodomain induces acute growth cone retraction and a decrease in Rac activity in hippocampal neurons. Expression of p75NTR and differential engagement of the Met66 prodomain to the SorCS2 receptor are required for this effect. These results identify the Met66 prodomain as a new active ligand which modulates neuronal morphology. PMID:24048383

  17. BDNF Val66Met polymorphism, life stress and depression: A meta-analysis of gene-environment interaction.

    PubMed

    Zhao, Mingzhe; Chen, Lu; Yang, Jiarun; Han, Dong; Fang, Deyu; Qiu, Xiaohui; Yang, Xiuxian; Qiao, Zhengxue; Ma, Jingsong; Wang, Lin; Jiang, Shixiang; Song, Xuejia; Zhou, Jiawei; Zhang, Jian; Chen, Mingqi; Qi, Dong; Yang, Yanjie; Pan, Hui

    2018-02-01

    Depression is thought to be multifactorial in etiology, including genetic and environmental components. While a number of gene-environment interaction studies have been carried out, meta-analyses are scarce. The present meta-analysis aimed to quantify evidence on the interaction between brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and stress in depression. Included were 31 peer-reviewed with a pooled total of 21060 participants published before October 2016 and literature searches were conducted using PubMed, Wolters Kluwer, Web of Science, EBSCO, Elsevier Science Direct and Baidu Scholar databases. The results indicated that the Met allele of BDNF Val66Met polymorphism significantly moderated the relationship between stress and depression (Z=2.666, p = 0.003). The results of subgroup analysis concluded that stressful life events and childhood adversity separately interacted with the Met allele of BDNF Val66Met polymorphism in depression (Z = 2.552, p = 0.005; Z = 1.775, p = 0.03). The results could be affected by errors or bias in primary studies which had small sample sizes with relatively lower statistic power. We could not estimate how strong the interaction effect between gene and environment was. We found evidence that supported the hypothesis that BDNF Val66Met polymorphism moderated the relationship between stress and depression, despite the fact that many included individual studies did not show this effect. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. [Association of Val66Met polymorphism of brain-derived neurotrophic factor gene with cognitive impairment and clinical symptoms in first episode schizophrenia].

    PubMed

    Zhang, Chengcheng; Gu, Xiaochu; Wang, Qiang; Li, Mingli; Deng, Wei; Guo, Wanjun; Zhao, Liansheng; Ma, Xiaohong; Li, Tao

    2017-08-10

    To assess the association of cognitive impairment and clinical symptoms in first-episode schizophrenia with the Val66Met (rs6265) polymorphism of brain-derived neurotrophic factor (BDNF) gene. For 87 patients with first-episode schizophrenia and 76 healthy controls, the Val66Met polymorphism was determined with a Taqman Assay-on-Demand method. Wechsler intelligence test was carried out for all participants. Correlation of cognitive impairment with clinical severity was also analyzed. The patients were significantly lower in total IQ, verbal IQ and performance IQ compared to the controls. The lower total IQ (F=4.59, P= 0.01) and verbal IQ (F=4.44, P=0.01) were influenced by genetic factors and diagnostic interaction. The vertal IQ of Val/Val patients was significantly lower than those of Val/Met and Met/Met carriers. For the control group, the verbal IQ of Met/Met carriers was lower than that of Val/Met carriers, and the total IQ of Met/Met carriers was lower than those of Val/Met and Val/Val carriers. For the patient group, the total IQ of Val/Val carriers was negatively correlated with positive symptoms (r=-0.65, P=0.03) and thought disorders (r=-0.61, P=0.02). Cognitive impairment in first-episode schizophrenic patients is associated with the Val66Met polymorphism of the BDNF gene, and has an important clinical relevance.

  19. BDNF val66met polymorphism is associated with age at onset and intensity of symptoms of paranoid schizophrenia in a Polish population.

    PubMed

    Suchanek, Renata; Owczarek, Aleksander; Paul-Samojedny, Monika; Kowalczyk, Małgorzata; Kucia, Krzysztof; Kowalski, Jan

    2013-01-01

    The brain-derived neurotrophic factor (BDNF) is one of the candidate genes for schizophrenia. There is evidence that val66met polymorphism may be involved in the pathophysiology of schizophrenia. The authors genotyped val66met (rs6265) polymorphism of the BDNF gene in 208 inpatients with paranoid schizophrenia and 254 control subjects in a Polish population. There was no association between val66met polymorphism and development of paranoid schizophrenia in either men or women. However, an association was found between this polymorphism and age at onset and psychopathology of paranoid schizophrenia. Men with the val/met genotype had an earlier age at onset, and the val/val genotype predisposed to more severe symptoms, particularly on the General Psychopathology Scale of the Positive and Negative Symptoms Scale (PANSS-G). The analysis of PANSS single items has shown that patients with the val/met genotype had higher scores on a hallucinatory behavior item than those with other genotypes.

  20. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism affects sympathetic tone in a gender-specific way.

    PubMed

    Chang, Chuan-Chia; Chang, Hsin-An; Chen, Tien-Yu; Fang, Wen-Hui; Huang, San-Yuan

    2014-09-01

    The Val/Val genotype of the brain-derived neurotrophic factor (BDNF) polymorphism (Val66Met) has been reported to affect human anxiety-related phenotypes. Substantial research has demonstrated that anxiety is associated with sympathetic activation, while sex steroid hormones have been shown to exert differential actions in regulating BDNF expression. Thus, we examined whether the BDNF variant modulates autonomic function in a gender-dependent manner. From 708 adults initially screened for medical and psychiatric illnesses, a final cohort of 583 drug-free healthy Han Chinese (355 males, 228 females; age 34.43±8.42 years) was recruited for BDNF genotyping (Val/Val: 136, 23.3%, Val/Met: 294, 50.4%, and Met/Met: 153, 26.2%). Time- and frequency-domain analyses of heart rate variability (HRV) were used to assess autonomic outflow to the heart. Significant genotype-by-gender interaction effects were found on HRV indices. Even after adjusting for possible confounders, male participants bearing the Val/Val genotype had significant increases in low frequency (LF), LF% and LF/high frequency (HF) ratio, indicating altered sympathovagal balance with increased sympathetic modulation, compared to male Met/Met homozygotes. Females, however, showed an opposite but non-significant pattern. These results suggest that the studied BDNF polymorphism is associated with sympathetic control in a gender-specific way. The findings here support the view that male subjects with the Val/Val genotype have increased risk of anxiety by association with sympathetic activation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Differential Genetic and Epigenetic Regulation of catechol-O-methyltransferase is Associated with Impaired Fear Inhibition in Posttraumatic Stress Disorder.

    PubMed

    Norrholm, Seth Davin; Jovanovic, Tanja; Smith, Alicia K; Binder, Elisabeth; Klengel, Torsten; Conneely, Karen; Mercer, Kristina B; Davis, Jennifer S; Kerley, Kimberly; Winkler, Jennifer; Gillespie, Charles F; Bradley, Bekh; Ressler, Kerry J

    2013-01-01

    The catechol-O-methyltransferase (COMT) enzyme is critical for the catabolic regulation of synaptic dopamine, resulting in altered cortical functioning. The COMT Val(158)Met polymorphism has been implicated in human mental illness, with Met/Met homozygotes associated with increased susceptibility to posttraumatic stress disorder (PTSD). Our primary objective was to examine the intermediate phenotype of fear inhibition in PTSD stratified by COMT genotype (Met/Met, Val/Met, and Val/Val) and differential gene regulation via methylation status at CpG sites in the COMT promoter region. More specifically, we examined the potential interaction of COMT genotype and PTSD diagnosis on fear-potentiated startle during fear conditioning and extinction and COMT DNA methylation levels (as determined using genomic DNA isolated from whole blood). Participants were recruited from medical and gynecological clinics of an urban hospital in Atlanta, GA, USA. We found that individuals with the Met/Met genotype demonstrated higher fear-potentiated startle to the CS- (safety signal) and during extinction of the CS+ (danger signal) compared to Val/Met and Val/Val genotypes. The PTSD+ Met/Met genotype group had the greatest impairment in fear inhibition to the CS- (p = 0.006), compared to Val carriers. In addition, the Met/Met genotype was associated with DNA methylation at four CpG sites, two of which were associated with impaired fear inhibition to the safety signal. These results suggest that multiple differential mechanisms for regulating COMT function - at the level of protein structure via the Val(158)Met genotype and at the level of gene regulation via differential methylation - are associated with impaired fear inhibition in PTSD.

  2. BDNF Val66Met polymorphism is associated with abnormal interhemispheric transfer of a newly acquired motor skill.

    PubMed

    Morin-Moncet, Olivier; Beaumont, Vincent; de Beaumont, Louis; Lepage, Jean-Francois; Théoret, Hugo

    2014-05-01

    Recent data suggest that the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene can alter cortical plasticity within the motor cortex of carriers, which exhibits abnormally low rates of cortical reorganization after repetitive motor tasks. To verify whether long-term retention of a motor skill is also modulated by the presence of the polymorphism, 20 participants (10 Val66Val, 10 Val66Met) were tested twice at a 1-wk interval. During each visit, excitability of the motor cortex was measured by transcranial magnetic stimulations (TMS) before and after performance of a procedural motor learning task (serial reaction time task) designed to study sequence-specific learning of the right hand and sequence-specific transfer from the right to the left hand. Behavioral results showed a motor learning effect that persisted for at least a week and task-related increases in corticospinal excitability identical for both sessions and without distinction for genetic group. Sequence-specific transfer of the motor skill from the right hand to the left hand was greater in session 2 than in session 1 only in the Val66Met genetic group. Further analysis revealed that the sequence-specific transfer occurred equally at both sessions in the Val66Val genotype group. In the Val66Met genotype group, sequence-specific transfer did not occur at session 1 but did at session 2. These data suggest a limited impact of Val66Met polymorphism on the learning and retention of a complex motor skill and its associated changes in corticospinal excitability over time, and a possible modulation of the interhemispheric transfer of procedural learning. Copyright © 2014 the American Physiological Society.

  3. The BDNF Val66Met polymorphism: relation to familiar risk of affective disorder, BDNF levels and salivary cortisol.

    PubMed

    Vinberg, Maj; Trajkovska, Viktorija; Bennike, Bente; Knorr, Ulla; Knudsen, Gitte M; Kessing, Lars V

    2009-10-01

    Brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis are considered to play an important role in the pathophysiology of affective disorders. The aim of the present study was to investigate whether the BDNF Val66Met polymorphism is associated with a familiar risk of affective disorder and whether these genotypes affect whole blood BDNF level and salivary cortisol. In a high-risk study, healthy monozygotic and dizygotic twins with and without a co-twin (high- and low-risk twins, respectively) history of affective disorder were identified through nationwide registers. Familiar predisposition to unipolar and bipolar disorder was not associated with any specific genotype pattern of the BDNF Val66Met polymorphism, not in this sample of 124 val/val, 58 val/met and 8 met/met individuals. However, the combination of having a high familiar risk of affective disorder and the met allele was associated with a higher whole blood BDNF (p=0.02) and a higher evening cortisol level (p=0.01), but not with awakening cortisol. Individuals at high risk of affective disorders and who are carriers of the met allele of the Val66Met polymorphism may present with an enhanced stress response. The presence of a specific genotype alone may not enhance the risk of developing an affective episode. Rather, the altered stress response may be expressed only in combination with other risk variants through interactions with the environment.

  4. Brain-Derived Neurotrophic Factor Val66Met Human Polymorphism Impairs the Beneficial Exercise-Induced Neurobiological Changes in Mice.

    PubMed

    Ieraci, Alessandro; Madaio, Alessandro I; Mallei, Alessandra; Lee, Francis S; Popoli, Maurizio

    2016-12-01

    Several studies have shown that exercise improves cognitive functions and emotional behaviors. Positive effects of exercise have been associated with enhanced brain plasticity, adult hippocampal neurogenesis, and increased levels of brain-derived neurotrophic factor (BDNF). However, a substantial variability of individual response to exercise has been described, which may be accounted for by individual genetic variants. Here, we have assessed whether and how the common human BDNF Val66Met polymorphism influences the neurobiological effects modulated by exercise in BDNF Val66Met knock-in male mice. Wild-type (BDNF Val/Val ) and homozygous BDNF Val66Met (BDNF Met/Met ) male mice were housed in cages equipped with or without running wheels for 4 weeks. Changes in behavioral phenotype, hippocampal adult neurogenesis, and gene expression were evaluated in exercised and sedentary control mice. We found that exercise reduced the latency to feed in the novelty suppressed feeding and the immobility time in the forced swimming test in BDNF Val/Val but not in BDNF Met/Met mice. Hippocampal neurogenesis was reduced in BDNF Met/Met mice compared with BDNF Val/Val mice. BDNF Met/Met mice had lower basal BDNF protein levels in the hippocampus, which was not recovered following exercise. Moreover, exercise-induced expression of total BDNF, BDNF splice variants 1, 2, 4, 6 and fibronectin type III domain-containing protein 5 (FNDC5) mRNA levels were absent or reduced in the dentate gyrus of BDNF Met/Met mice. Exercise failed to enhance PGC-1α and FNDC5 mRNA levels in the BDNF Met/Met muscle. Overall these results indicate that, in adult male mice, the BDNF Val66Met polymorphism impairs the beneficial behavioral and neuroplasticity effects induced by physical exercise.

  5. The BDNF Val66Met Polymorphism Influences Reading Ability and Patterns of Neural Activation in Children

    PubMed Central

    Jasińska, Kaja K.; Molfese, Peter J.; Kornilov, Sergey A.; Mencl, W. Einar; Frost, Stephen J.; Lee, Maria; Pugh, Kenneth R.; Grigorenko, Elena L.; Landi, Nicole

    2016-01-01

    Understanding how genes impact the brain’s functional activation for learning and cognition during development remains limited. We asked whether a common genetic variant in the BDNF gene (the Val66Met polymorphism) modulates neural activation in the young brain during a critical period for the emergence and maturation of the neural circuitry for reading. In animal models, the bdnf variation has been shown to be associated with the structure and function of the developing brain and in humans it has been associated with multiple aspects of cognition, particularly memory, which are relevant for the development of skilled reading. Yet, little is known about the impact of the Val66Met polymorphism on functional brain activation in development, either in animal models or in humans. Here, we examined whether the BDNF Val66Met polymorphism (dbSNP rs6265) is associated with children’s (age 6–10) neural activation patterns during a reading task (n = 81) using functional magnetic resonance imaging (fMRI), genotyping, and standardized behavioral assessments of cognitive and reading development. Children homozygous for the Val allele at the SNP rs6265 of the BDNF gene outperformed Met allele carriers on reading comprehension and phonological memory, tasks that have a strong memory component. Consistent with these behavioral findings, Met allele carriers showed greater activation in reading–related brain regions including the fusiform gyrus, the left inferior frontal gyrus and left superior temporal gyrus as well as greater activation in the hippocampus during a word and pseudoword reading task. Increased engagement of memory and spoken language regions for Met allele carriers relative to Val/Val homozygotes during reading suggests that Met carriers have to exert greater effort required to retrieve phonological codes. PMID:27551971

  6. The BDNF Val66Met Polymorphism Influences Reading Ability and Patterns of Neural Activation in Children.

    PubMed

    Jasińska, Kaja K; Molfese, Peter J; Kornilov, Sergey A; Mencl, W Einar; Frost, Stephen J; Lee, Maria; Pugh, Kenneth R; Grigorenko, Elena L; Landi, Nicole

    2016-01-01

    Understanding how genes impact the brain's functional activation for learning and cognition during development remains limited. We asked whether a common genetic variant in the BDNF gene (the Val66Met polymorphism) modulates neural activation in the young brain during a critical period for the emergence and maturation of the neural circuitry for reading. In animal models, the bdnf variation has been shown to be associated with the structure and function of the developing brain and in humans it has been associated with multiple aspects of cognition, particularly memory, which are relevant for the development of skilled reading. Yet, little is known about the impact of the Val66Met polymorphism on functional brain activation in development, either in animal models or in humans. Here, we examined whether the BDNF Val66Met polymorphism (dbSNP rs6265) is associated with children's (age 6-10) neural activation patterns during a reading task (n = 81) using functional magnetic resonance imaging (fMRI), genotyping, and standardized behavioral assessments of cognitive and reading development. Children homozygous for the Val allele at the SNP rs6265 of the BDNF gene outperformed Met allele carriers on reading comprehension and phonological memory, tasks that have a strong memory component. Consistent with these behavioral findings, Met allele carriers showed greater activation in reading-related brain regions including the fusiform gyrus, the left inferior frontal gyrus and left superior temporal gyrus as well as greater activation in the hippocampus during a word and pseudoword reading task. Increased engagement of memory and spoken language regions for Met allele carriers relative to Val/Val homozygotes during reading suggests that Met carriers have to exert greater effort required to retrieve phonological codes.

  7. BDNF Val66Met polymorphism moderates the link between child maltreatment and reappraisal ability.

    PubMed

    Miu, A C; Cărnuţă, M; Vulturar, R; Szekely-Copîndean, R D; Bîlc, M I; Chiş, A; Cioară, M; Fernandez, K C; Szentágotai-Tătar, A; Gross, J J

    2017-04-01

    Child maltreatment is associated with increased risk for virtually all common mental disorders, but it is not yet clear why. One possible mechanism is emotion regulation ability. The present study investigated for the first time the influence of a BDNF Val66Met genotype × child maltreatment interaction on emotion regulation, and compared differential susceptibility and diathesis-stress models. A sample of N = 254 healthy volunteers were genotyped for the BDNF Val66Met polymorphism and underwent an experimental assessment of reappraisal ability (i.e. the success of using reappraisal to downregulate negative affect). A self-report instrument previously validated against a clinical interview was used to investigate child maltreatment. There was a significant BDNF Val66Met genotype × child maltreatment interaction (B = -0.31, P < 0.015), with Met carriers showing both the lowest level of reappraisal ability in maltreated participants, and the highest level of reappraisal ability in non-maltreated participants. By assessing alternative models, we found that the best fitting model was in line with strong differential susceptibility. As expected, reappraisal ability was negatively correlated with depressive symptoms. Therefore, the BDNF Val66Met polymorphism moderates the link between child maltreatment and emotion regulation ability. Future studies could investigate whether improving reappraisal in maltreated BDNF Met carriers results in reduced risk for mental disorders. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  8. BDNF Val66Met polymorphism is associated with higher anticipatory cortisol stress response, anxiety, and alcohol consumption in healthy adults.

    PubMed

    Colzato, Lorenza S; Van der Does, A J Willem; Kouwenhoven, Coen; Elzinga, Bernet M; Hommel, Bernhard

    2011-11-01

    The brain-derived neurotrophic factor (BDNF) is a key protein in maintaining neuronal integrity. The BDNF gene is thought to play an important role in the pathophysiology of mood and anxiety disorders. The aim of this study was to investigate, for the first time in a single study, the association between BDNF Val(66)Met polymorphism, anxiety, alcohol consumption, and cortisol stress response. 98 healthy university students (54 females and 44 males), genotyped for the Val(66)Met polymorphism, participated in a physical-stress procedure (cold pressure test, CPT) after having been informed that they would undergo a painful experience. Indices of anxiety and of stress were collected from repeated measurement of salivary cortisol, blood pressure, and heart rate. BDNF Met carriers, were more anxious during the CPT (p<0.001), drank more alcohol per week, (p<0.05), and showed significantly higher anticipatory cortisol response (p<0.05), but not in response to the CPT, than Val/Val homozygotes. The association of BDNF Val(66)Met polymorphism with HPA axis reactivity to stress was not modulated by gender. These results suggest that Met carriers are particularly sensitive in anticipating stressful events, which extends previous findings on the moderating role of the BDNF Val(66)Met polymorphism in the face of stressful life events. Copyright © 2011 Elsevier Ltd. All rights reserved.

  9. Why Some People Discount More than Others: Baseline Activation in the Dorsal PFC Mediates the Link between COMT Genotype and Impatient Choice

    PubMed Central

    Gianotti, Lorena R. R.; Figner, Bernd; Ebstein, Richard P.; Knoch, Daria

    2012-01-01

    Individuals differ widely in how steeply they discount future rewards. The sources of these stable individual differences in delay discounting (DD) are largely unknown. One candidate is the COMT Val158Met polymorphism, known to modulate prefrontal dopamine levels and affect DD. To identify possible neural mechanisms by which this polymorphism may contribute to stable individual DD differences, we measured 73 participants’ neural baseline activation using resting electroencephalogram (EEG). Such neural baseline activation measures are highly heritable and stable over time, thus an ideal endophenotype candidate to explain how genes may influence behavior via individual differences in neural function. After EEG-recording, participants made a series of incentive-compatible intertemporal choices to determine the steepness of their DD. We found that COMT significantly affected DD and that this effect was mediated by baseline activation level in the left dorsal prefrontal cortex (DPFC): (i) COMT had a significant effect on DD such that the number of Val alleles was positively correlated with steeper DD (higher numbers of Val alleles means greater COMT activity and thus lower dopamine levels). (ii) A whole-brain search identified a cluster in left DPFC where baseline activation was correlated with DD; lower activation was associated with steeper DD. (iii) COMT had a significant effect on the baseline activation level in this left DPFC cluster such that a higher number of Val alleles was associated with lower baseline activation. (iv) The effect of COMT on DD was explained by the mediating effect of neural baseline activation in the left DPFC cluster. Our study thus establishes baseline activation level in left DPFC as salient neural signature in the form of an endophenotype that mediates the link between COMT and DD. PMID:22586360

  10. Paradoxical visuomotor adaptation to reversed visual input is predicted by BDNF Val66Met polymorphism

    PubMed Central

    Barton, Brian; Treister, Andrew; Humphrey, Melanie; Abedi, Garen; Cramer, Steven C.; Brewer, Alyssa A.

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the brain, influencing neural development, plasticity, and repair (Chen et al., 2004; Thoenen, 1995). The BDNF gene contains a single-nucleotide polymorphism (SNP) called Val66Met. The Met allele interferes with intracellular BDNF-trafficking, decreases activity-dependent BDNF secretion, and consequently is often associated with a shift from plasticity to stability in neural circuits (Egan et al., 2003). We investigated the behavioral consequences of the presence of the Met allele by comparing how 40 heterozygous subjects with the Val/Met genotype and 35 homozygous subjects with the Val/Val genotype performed on visuomotor tasks (reaching and navigation) under two conditions: normal vision and completely left-right reversed vision. As expected, subjects did not differ in their short-term ability to learn the tasks with normal vision (p = 0.58). Intuitively, it would be expected that homozygous Val/Val subjects with a propensity for greater BDNF-induced activity-dependent plasticity would learn new tasks more quickly than heterozygous Val/Met subjects with decreased BDNF secretion (Gilbert, Li, & Piech, 2009). However, we found the opposite here. When short-term mechanisms of visuomotor adaptation were engaged to compensate for the misalignment of visual and somatomotor information created by the left-right reversal of vision, heterozygous Val/Met subjects learned significantly more quickly than their homozygous Val/Val counterparts (p = 0.027). Our results demonstrate the paradoxical finding that the presence of the Met allele, which is thought to promote cortical stability, here improves immediate visuomotor adaptation to left–right-reversed visual input. PMID:25104829

  11. The BDNF Val66Met polymorphism and plasma brain-derived neurotrophic factor levels in Han Chinese heroin-dependent patients.

    PubMed

    Chen, Shiou-Lan; Lee, Sheng-Yu; Chang, Yun-Hsuan; Wang, Tzu-Yun; Chen, Shih-Heng; Chu, Chun-Hsien; Chen, Po See; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band

    2015-02-02

    BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and may become a key target in the physiopathology of long-term heroin use. Thus, we investigated the relationships between brain-derived neurotrophic factor (BDNF) plasma concentrations and the BDNF Val66Met nucleotide polymorphism (SNP) in heroin-dependent patients. The pretreatment expression levels of plasma BDNF and the BDNF Val66Met SNP in 172 heroin-dependent patients and 102 healthy controls were checked. BDNF levels were significantly lower in patients (F = 52.28, p < 0.0001), but the distribution of the SNP was not significantly different. Nor were plasma BDNF levels significantly different between Met/Met, Met/Val, and Val/Val carriers in each group, which indicated that the BDNF Val66Met SNP did not affect plasma BDNF levels in our participants. In heroin-dependent patients, plasma BDNF levels were negatively correlated with the length of heroin dependency. Long-term (>15 years) users had significantly lower plasma BDNF levels than did short-term (<5 years) users. We conclude that plasma BDNF concentration in habitual heroin users are not affected by BDNF Val66Met gene variants, but by the length of the heroin dependency.

  12. The BDNF Val66Met polymorphism and plasma brain-derived neurotrophic factor levels in Han Chinese heroin-dependent patients

    PubMed Central

    Chen, Shiou-Lan; Lee, Sheng-Yu; Chang, Yun-Hsuan; Wang, Tzu-Yun; Chen, Shih-Heng; Chu, Chun-Hsien; Chen, Po See; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band

    2015-01-01

    BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and may become a key target in the physiopathology of long-term heroin use. Thus, we investigated the relationships between brain-derived neurotrophic factor (BDNF) plasma concentrations and the BDNF Val66Met nucleotide polymorphism (SNP) in heroin-dependent patients. The pretreatment expression levels of plasma BDNF and the BDNF Val66Met SNP in 172 heroin-dependent patients and 102 healthy controls were checked. BDNF levels were significantly lower in patients (F = 52.28, p < 0.0001), but the distribution of the SNP was not significantly different. Nor were plasma BDNF levels significantly different between Met/Met, Met/Val, and Val/Val carriers in each group, which indicated that the BDNF Val66Met SNP did not affect plasma BDNF levels in our participants. In heroin-dependent patients, plasma BDNF levels were negatively correlated with the length of heroin dependency. Long-term (>15 years) users had significantly lower plasma BDNF levels than did short-term (<5 years) users. We conclude that plasma BDNF concentration in habitual heroin users are not affected by BDNF Val66Met gene variants, but by the length of the heroin dependency. PMID:25640280

  13. The brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism affects memory performance in older adults.

    PubMed

    Azeredo, Lucas A de; De Nardi, Tatiana; Levandowski, Mateus L; Tractenberg, Saulo G; Kommers-Molina, Julia; Wieck, Andrea; Irigaray, Tatiana Q; Silva, Irênio G da; Grassi-Oliveira, Rodrigo

    2017-01-01

    Memory impairment is an important contributor to the reduction in quality of life experienced by older adults, and genetic risk factors seem to contribute to variance in age-related cognitive decline. Brain-derived neurotrophic factor (BDNF) is an important nerve growth factor linked with development and neural plasticity. The Val66Met polymorphism in the BDNF gene has been associated with impaired episodic memory in adults, but whether this functional variant plays a role in cognitive aging remains unclear. The purpose of this study was to investigate the effects of the BDNF Val66Met polymorphism on memory performance in a sample of elderly adults. Eighty-seven subjects aged > 55 years were recruited using a community-based convenience sampling strategy in Porto Alegre, Brazil. The logical memory subset of the Wechsler Memory Scale-Revised was used to assess immediate verbal recall (IVR), delayed verbal recall (DVR), and memory retention rate. BDNF Met allele carriers had lower DVR scores (p = 0.004) and a decline in memory retention (p = 0.017) when compared to Val/Val homozygotes. However, we found no significant differences in IVR between the two groups (p = 0.088). These results support the hypothesis of the BDNF Val66Met polymorphism as a risk factor associated with cognitive impairment, corroborating previous findings in young and older adults.

  14. Effects of Mind-Body Training on Personality and Behavioral Activation and Inhibition System According to BDNF Val66Met Polymorphism.

    PubMed

    Jung, Ye-Ha; Lee, Ul Soon; Jang, Joon Hwan; Kang, Do-Hyung

    2016-05-01

    It has been known that mind-body training (MBT) can affect personality and behavior system as well as emotional well-being, but different effects of MBT on them has not been reported according to BDNF genetic polymorphism. Healthy subjects consisted of 64 subjects and the MBT group who practiced meditation regularly consisted of 72 practitioners. Participants completed neuroticism-extraversion-openness (NEO) Five-Factor Inventory and Behavioral Activation System/Behavioral Inhibition System (BAS/BIS) scales. All subjects were genotyped for the BDNF Val66Met polymorphism. In the same genotypes of the BDNF Val/Val+Val/Met group, MBT group showed the increased Extraversion (p=0.033) and the increased Openness to Experience (p=0.004) compared to the control group. Also, in the same Met/Met carriers, MBT group exhibited the increase of Extraversion (p=0.008), the reduction of Neuroticism (p=0.002), and the increase of Openness to Experience (p=0.008) compared to the control group. In the same genotypes of the BDNF Val/Val+Val/Met group, MBT group showed the decreased BAS-Reward Responsiveness (p=0.016) and the decrease of BIS (p=0.004) compared to the control group. In the BDNF Met/Met group, MBT group increased BAS-Fun Seeking (p=0.045) and decreased BIS (p=0.013) compared to the control group. MBT would differently contribute to NEO personality and BAS/BIS according to BDNF genetic polymorphism, compensating for different vulnerable traits based on each genotype.

  15. The BDNF-Val66Met polymorphism modulates parental rearing effects on adult psychiatric symptoms: a community twin-based study.

    PubMed

    Ibarra, P; Alemany, S; Fatjó-Vilas, M; Córdova-Palomera, A; Goldberg, X; Arias, B; González-Ortega, I; González-Pinto, A; Nenadic, I; Fañanás, L

    2014-06-01

    To test whether firstly, different parental rearing components were associated with different dimensions of psychiatric symptoms in adulthood, secondly BDNF-Val66Met polymorphism moderated this association and thirdly, this association was due to genetic confounding. Perceived parental rearing according to Parental Bonding Instrument (PBI), psychiatric symptoms evaluated with the Brief Symptom Inventory (BSI) and the BDNF-Val66Met polymorphism were analyzed in a sample of 232 adult twins from the general population. In the whole sample, paternal care was negatively associated with depression. Maternal overprotection was positively associated with paranoid ideation, obsession-compulsion and somatization. Gene-environment interaction effects were detected between the BDNF-Val66Met polymorphism and maternal care on phobic anxiety, paternal care on hostility, maternal overprotection on somatization and paternal overprotection also in somatization. In the subsample of MZ twins, intrapair differences in maternal care were associated with anxiety, paranoid ideation and somatization. Met carriers were, in general, more sensitive to the effects of parental rearing compared to Val/Val carriers in relation to anxiety and somatization. Contra-intuitively, our findings suggest that high rates of maternal care might be of risk for Met carriers regarding anxiety. Results from analyses controlling for genetic confounding were in line with this finding. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  16. The BDNF Val66Met polymorphism regulates glucocorticoid-induced corticohippocampal remodeling and behavioral despair

    PubMed Central

    Notaras, M; Du, X; Gogos, J; van den Buuse, M; Hill, R A

    2017-01-01

    The BDNF Val66Met polymorphism has been associated with sensitivity to stress and affective disorders. We therefore sought to model the inter-causality of these relationships under controlled laboratory conditions. We subjected humanized BDNF Val66Met (hBDNFVal66Met) transgenic mice to a history of stress, modeled by chronic late-adolescent corticosterone (CORT) exposure, before evaluating affective-related behavior using the forced-swim test (FST) in adulthood. While hBDNFMet/Met mice had a depression-like phenotype in the FST irrespective of CORT, hBDNFVal/Val wildtype mice had a resilient phenotype but developed an equally robust depressive-like phenotype following CORT. A range of stress-sensitive molecules were studied across the corticohippocampal axis, and where genotype differences occurred following CORT they tended to inversely coincide with the behavior of the hBDNFVal/Val group. Notably, tyrosine hydroxylase was markedly down-regulated in the mPFC of hBDNFVal/Val mice as a result of CORT treatment, which mimicked expression levels of hBDNFMet/Met mice and the FST behavior of both groups. The expression of calretinin, PSD-95, and truncated TrkB were also concomitantly reduced in the mPFC of hBDNFVal/Val mice by CORT. This work establishes BDNFVal66Met genotype as a regulator of behavioral despair, and identifies new biological targets of BDNF genetic variation relevant to stress-inducible disorders such as depression. PMID:28926000

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

    PubMed Central

    Hennig, Jürgen

    2016-01-01

    Abstract 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. PMID:28101524

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

    PubMed

    Billino, Jutta; Hennig, Jürgen; Gegenfurtner, Karl R

    2016-01-01

    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 Val 158 Met 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 Val 158 Met 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.

  19. Peripheral vascular reactivity and serum BDNF responses to aerobic training are impaired by the BDNF Val66Met polymorphism.

    PubMed

    Lemos, José R; Alves, Cleber R; de Souza, Sílvia B C; Marsiglia, Julia D C; Silva, Michelle S M; Pereira, Alexandre C; Teixeira, Antônio L; Vieira, Erica L M; Krieger, José E; Negrão, Carlos E; Alves, Guilherme B; de Oliveira, Edilamar M; Bolani, Wladimir; Dias, Rodrigo G; Trombetta, Ivani C

    2016-02-01

    Besides neuronal plasticity, the neurotrophin brain-derived neurotrophic factor (BDNF) is also important in vascular function. The BDNF has been associated with angiogenesis through its specific receptor tropomyosin-related kinase B (TrkB). Additionally, Val66Met polymorphism decreases activity-induced BDNF. Since BDNF and TrkB are expressed in vascular endothelial cells and aerobic exercise training can increase serum BDNF, this study aimed to test the hypotheses: 1) Serum BDNF levels modulate peripheral blood flow; 2) The Val66Met BDNF polymorphism impairs exercise training-induced vasodilation. We genotyped 304 healthy male volunteers (Val66Val, n = 221; Val66Met, n = 83) who underwent intense aerobic exercise training on a running track three times/wk for 4 mo. We evaluated pre- and post-exercise training serum BDNF and proBDNF concentration, heart rate (HR), mean blood pressure (MBP), forearm blood flow (FBF), and forearm vascular resistance (FVR). In the pre-exercise training, BDNF, proBDNF, BDNF/proBDNF ratio, FBF, and FVR were similar between genotypes. After exercise training, functional capacity (V̇o2 peak) increased and HR decreased similarly in both groups. Val66Val, but not Val66Met, increased BDNF (interaction, P = 0.04) and BDNF/proBDNF ratio (interaction, P < 0.001). Interestingly, FBF (interaction, P = 0.04) and the FVR (interaction, P = 0.01) responses during handgrip exercise (HG) improved in Val66Val compared with Val66Met, even with similar responses of HR and MBP. There were association between BDNF/proBDNF ratio and FBF (r = 0.64, P < 0.001) and FVR (r = -0.58, P < 0.001) during HG exercise. These results show that peripheral vascular reactivity and serum BDNF responses to exercise training are impaired by the BDNF Val66Met polymorphism and such responsiveness is associated with serum BDNF concentrations in healthy subjects. Copyright © 2016 the American Physiological Society.

  20. Epistasis Analysis for Estrogen Metabolic and Signaling Pathway Genes on Young Ischemic Stroke Patients

    PubMed Central

    Hsieh, Yi-Chen; Jeng, Jiann-Shing; Lin, Huey-Juan; Hu, Chaur-Jong; Yu, Chia-Chen; Lien, Li-Ming; Peng, Giia-Sheun; Chen, Chin-I; Tang, Sung-Chun; Chi, Nai-Fang; Tseng, Hung-Pin; Chern, Chang-Ming; Hsieh, Fang-I; Bai, Chyi-Huey; Chen, Yi-Rhu; Chiou, Hung-Yi; Jeng, Jiann-Shing; Tang, Sung-Chun; Yeh, Shin-Joe; Tsai, Li-Kai; Kong, Shin; Lien, Li-Ming; Chiu, Hou-Chang; Chen, Wei-Hung; Bai, Chyi-Huey; Huang, Tzu-Hsuan; Chi-Ieong, Lau; Wu, Ya-Ying; Yuan, Rey-Yue; Hu, Chaur-Jong; Sheu, Jau- Jiuan; Yu, Jia-Ming; Ho, Chun-Sum; Chen, Chin-I; Sung, Jia-Ying; Weng, Hsing-Yu; Han, Yu-Hsuan; Huang, Chun-Ping; Chung, Wen-Ting; Ke, Der-Shin; Lin, Huey-Juan; Chang, Chia-Yu; Yeh, Poh-Shiow; Lin, Kao-Chang; Cheng, Tain-Junn; Chou, Chih-Ho; Yang, Chun-Ming; Peng, Giia-Sheun; Lin, Jiann-Chyun; Hsu, Yaw-Don; Denq, Jong-Chyou; Lee, Jiunn-Tay; Hsu, Chang-Hung; Lin, Chun-Chieh; Yen, Che-Hung; Cheng, Chun-An; Sung, Yueh-Feng; Chen, Yuan-Liang; Lien, Ming-Tung; Chou, Chung-Hsing; Liu, Chia-Chen; Yang, Fu-Chi; Wu, Yi-Chung; Tso, An-Chen; Lai, Yu- Hua; Chiang, Chun-I; Tsai, Chia-Kuang; Liu, Meng-Ta; Lin, Ying-Che; Hsu, Yu-Chuan; Chen, Chih-Hung; Sung, Pi-Shan; Chern, Chang-Ming; Hu, Han-Hwa; Wong, Wen-Jang; Luk, Yun-On; Hsu, Li-Chi; Chung, Chih-Ping; Tseng, Hung-Pin; Liu, Chin-Hsiung; Lin, Chun-Liang; Lin, Hung-Chih; Hu, Chaur-Jong

    2012-01-01

    Background Endogenous estrogens play an important role in the overall cardiocirculatory system. However, there are no studies exploring the hormone metabolism and signaling pathway genes together on ischemic stroke, including sulfotransferase family 1E (SULT1E1), catechol-O-methyl-transferase (COMT), and estrogen receptor α (ESR1). Methods A case-control study was conducted on 305 young ischemic stroke subjects aged ≦ 50 years and 309 age-matched healthy controls. SULT1E1 -64G/A, COMT Val158Met, ESR1 c.454−397 T/C and c.454−351 A/G genes were genotyped and compared between cases and controls to identify single nucleotide polymorphisms associated with ischemic stroke susceptibility. Gene-gene interaction effects were analyzed using entropy-based multifactor dimensionality reduction (MDR), classification and regression tree (CART), and traditional multiple regression models. Results COMT Val158Met polymorphism showed a significant association with susceptibility of young ischemic stroke among females. There was a two-way interaction between SULT1E1 -64G/A and COMT Val158Met in both MDR and CART analysis. The logistic regression model also showed there was a significant interaction effect between SULT1E1 -64G/A and COMT Val158Met on ischemic stroke of the young (P for interaction = 0.0171). We further found that lower estradiol level could increase the risk of young ischemic stroke for those who carry either SULT1E1 or COMT risk genotypes, showing a significant interaction effect (P for interaction = 0.0174). Conclusions Our findings support that a significant epistasis effect exists among estrogen metabolic and signaling pathway genes and gene-environment interactions on young ischemic stroke subjects. PMID:23112845

  1. A brain-derived neurotrophic factor polymorphism Val66Met identifies fibromyalgia syndrome subgroup with higher body mass index and C-reactive protein.

    PubMed

    Xiao, Yangming; Russell, I Jon; Liu, Ya-Guang

    2012-08-01

    A common single nucleotide polymorphism (SNP) in the gene of brain-derived neurotrophic factor (BDNF) results from a substitution at position 66 from valine (Val) to methionine (Met) and may predispose to human neuropsychiatric disorders. We proposed to determine whether these BDNF gene SNPs were associated with fibromyalgia syndrome (FMS) and/or any of its typical phenotypes. Patients with FMS (N = 95) and healthy normal controls (HNC, N = 58) were studied. Serum high-sensitivity C-reactive protein (hsCRP) levels were measured using an enzyme-linked immunosorbent assay (ELISA). The BDNF SNPs were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).The BDNF SNP distribution was 65 (68%) Val/Val, 28 (30%) Val/Met, and 2 (2%) Met/Met for FMS and 40 (69%), 17(29%), and 1 (2%) for HNC, respectively. The serum high-sensitivity C-reactive protein (hsCRP)and body mass index (BMI) in FMS were higher than in HNC. The FMS with BDNF Val66Val had significantly higher mean BMI (P = 0.0001) and hsCRP (P = 0.02) than did FMS carrying the Val66Met genotype. This pattern was not found in HNC. Phenotypic measures of subjective pain, pain threshold, depression, or insomnia did not relate to either of the BDNF SNPs in FMS. The relative distribution BDNF SNPs did not differ between FMS and HNC. The BDNF Val66Met polymorphism is not selective for FMS. The BDNF Val66Val SNP identifies a subgroup of FMS with elevated hsCRP and higher BMI. This is the first study to associate a BDNF polymorphism with a FMS subgroup phenotype.

  2. COMT GENOTYPE INFLUENCES THE EFFECT OF ALCOHOL ON BLOOD PRESSURE: RESULTS FROM THE COMBINE STUDY

    PubMed Central

    Stewart, SH; Oroszi, G; Randall, PK; Anton, RF

    2009-01-01

    Background Heavy drinking can cause chronic hypertension, possibly due to effects on the autonomic nervous system. Catechol-O-methyltransferase (COMT) inactivates catecholamines, and a G to A substitution in codon 108 in the soluble COMT mRNA (or codon 158 in the membrane bound form) substitutes methionine for valine and alters enzyme activity. Methods We evaluated the association of COMT genotype at this locus with blood pressure in 839 alcohol dependent individuals before and during participation in an alcoholism treatment trial. Hierarchical linear models were used to account for within-subject correlation on repeated blood pressure measurements, and findings were adjusted for age, gender, ethnicity, alcohol use, body-mass index, current smoking, hypertension history, and study site. Results Relative to those with the val-val genotype, those with the met-met genotype had higher adjusted systolic (+4.9 mm Hg, p<0.01) and diastolic (+3.2 mm Hg, p<0.01) blood pressure at baseline. Those with the val-met genotype did not significantly differ from the val-val genotype. Changes in blood pressure between baseline and 4 weeks of alcohol treatment also differed by genotype. Relative to the val-val genotype, the met-met genotype had a greater reduction in adjusted systolic pressure (-3.9 mm Hg, p<0.01) and diastolic pressure (-2.8 mm Hg, p<0.01). Corresponding relative reductions for the val-met genotype were -2.2 mm Hg systolic (p=0.070) and -1.5 mm Hg diastolic (p<0.05). Conclusion Findings suggest that alcohol-induced blood pressure elevation may be related to the effects of catecholamines and their genetically determined inactivation. PMID:19023276

  3. Brain-Derived Neurotrophic Factor Val66Met Human Polymorphism Impairs the Beneficial Exercise-Induced Neurobiological Changes in Mice

    PubMed Central

    Ieraci, Alessandro; Madaio, Alessandro I; Mallei, Alessandra; Lee, Francis S; Popoli, Maurizio

    2016-01-01

    Several studies have shown that exercise improves cognitive functions and emotional behaviors. Positive effects of exercise have been associated with enhanced brain plasticity, adult hippocampal neurogenesis, and increased levels of brain-derived neurotrophic factor (BDNF). However, a substantial variability of individual response to exercise has been described, which may be accounted for by individual genetic variants. Here, we have assessed whether and how the common human BDNF Val66Met polymorphism influences the neurobiological effects modulated by exercise in BDNF Val66Met knock-in male mice. Wild-type (BDNFVal/Val) and homozygous BDNF Val66Met (BDNFMet/Met) male mice were housed in cages equipped with or without running wheels for 4 weeks. Changes in behavioral phenotype, hippocampal adult neurogenesis, and gene expression were evaluated in exercised and sedentary control mice. We found that exercise reduced the latency to feed in the novelty suppressed feeding and the immobility time in the forced swimming test in BDNFVal/Val but not in BDNFMet/Met mice. Hippocampal neurogenesis was reduced in BDNFMet/Met mice compared with BDNFVal/Val mice. BDNFMet/Met mice had lower basal BDNF protein levels in the hippocampus, which was not recovered following exercise. Moreover, exercise-induced expression of total BDNF, BDNF splice variants 1, 2, 4, 6 and fibronectin type III domain-containing protein 5 (FNDC5) mRNA levels were absent or reduced in the dentate gyrus of BDNFMet/Met mice. Exercise failed to enhance PGC-1α and FNDC5 mRNA levels in the BDNFMet/Met muscle. Overall these results indicate that, in adult male mice, the BDNF Val66Met polymorphism impairs the beneficial behavioral and neuroplasticity effects induced by physical exercise. PMID:27388329

  4. Monoamine Oxidase A (MAOA) and Catechol-O-Methyltransferase (COMT) Gene Polymorphisms Interact with Maternal Parenting in Association with Adolescent Reactive Aggression but not Proactive Aggression: Evidence of Differential Susceptibility.

    PubMed

    Zhang, Wenxin; Cao, Cong; Wang, Meiping; Ji, Linqin; Cao, Yanmiao

    2016-04-01

    To date, whether and how gene-environment (G × E) interactions operate differently across distinct subtypes of aggression remains untested. More recently, in contrast with the diathesis-stress hypothesis, an alternative hypothesis of differential susceptibility proposes that individuals could be differentially susceptible to environments depending on their genotypes in a "for better and for worse" manner. The current study examined interactions between monoamine oxidase A (MAOA) T941G and catechol-O-methyltransferase (COMT) Val158Met polymorphisms with maternal parenting on two types of aggression: reactive and proactive. Moreover, whether these potential G × E interactions would be consistent with the diathesis-stress versus the differential susceptibility hypothesis was tested. Within the sample of 1399 Chinese Han adolescents (47.2 % girls, M age = 12.32 years, SD = 0.50), MAOA and COMT genes both interacted with positive parenting in their associations with reactive but not proactive aggression. Adolescents with T alleles/TT homozygotes of MAOA gene or Met alleles of COMT gene exhibited more reactive aggression when exposed to low positive parenting, but less reactive aggression when exposed to high positive parenting. These findings provide the first evidence for distinct G × E interaction effects on reactive versus proactive aggression and lend further support for the differential susceptibility hypothesis.

  5. Meta-analysis of the brain-derived neurotrophic factor gene (BDNF) Val66Met polymorphism in anxiety disorders and anxiety-related personality traits.

    PubMed

    Frustaci, Alessandra; Pozzi, Gino; Gianfagna, Francesco; Manzoli, Lamberto; Boccia, Stefania

    2008-01-01

    Brain-derived neurotrophic factor (BDNF) is potentially involved in the pathogenesis of anxiety. We carried out meta-analyses to evaluate the relationship between the BDNF Val66Met (valine, methionine) polymorphism and anxiety disorders (AD) or anxiety-related personality traits (ARPT). Medline, Embase and PsycINFO were searched up to December 2007. We investigated 3 outcomes related to BDNF Val66Met polymorphisms: (1) clinically diagnosed cases of AD; (2) ARPT in subjects without psychiatric diagnoses, assessed either by the Neuroticism scale of NEO-Personality Inventory forms (NEO-PI, NEO-PI-R, NEO-FFI), or by (3) the Harm Avoidance (HA) scale of Tridimensional Personality Questionnaire (TPQ) or its extended version Temperament and Character Inventory (TCI). Seven case-control studies were selected for AD, including 1,092 cases and 8,394 controls, while 5 cross-sectional studies for Neuroticism (n = 1,633) and 4 for HA (n = 607). Both Met/Met and Val/Met individuals, as compared to Val/Val, showed a statistically significant lower Neuroticism score [SMD = -0.24 (95% CI: -0.44, -0.04), and -0.11 (95% CI: -0.22, -0.01), respectively]. No significant association was found between BDNF Val66Met polymorphism and AD [OR = 1.13 (95% CI: 0.85-1.52) for Met/Met versus Val/Val] or HA [SMD = 0.11 (95% CI: -0.19, 0.42) for Met/Met vs. Val/Val]. The low number of studies on this topic and their limited sample size, along with the inner limits in the definition of anxiety phenotypes, suggest caution in the interpretation of these results. Larger additional studies possibly investigating the interaction with other genes and environmental exposures are required to confirm these results. 2008 S. Karger AG, Basel.

  6. Interacting effect of BDNF Val66Met polymorphism and stressful life events on adolescent depression.

    PubMed

    Chen, J; Li, X; McGue, M

    2012-11-01

    There is a strong etiological link between brain-derived neurotrophic factor and depression, but the neurocellular mechanisms and gene-environment interactions remain obscure. This study investigated whether one functional polymorphism in the brain-derived neurotrophic factor gene (BDNF Val66Met) modulates the influence of stressful life events on adolescent depressive symptoms. A total of 780 pairs of ethnic Han Chinese adolescent twins, 11-17 years of age, were randomly assigned to one of two subgroups (twin1 and twin2). All subjects were genotyped as Val/Val, Val/Met or Met/Met, and assessed for depressive symptoms using the Children's Depression Inventory. The level of environmental stress was estimated by the frequency of stressful life events using the Life Events Checklist. The frequency of stressful life events was significantly correlated with depressive symptoms (twin1: β = 0.21, P = 0.01; twin2: β = 0.27, P < 0.01), but there was no significant main effect of the BDNF Val66Met genotype on depressive symptoms. In both subgroups, however, the interaction between the BDNF Val66Met genotype and stressful life event frequency was significant (twin1: β = 0.19, P = 0.01; twin2: β = 0.15, P = 0.04); individuals with one or two Val alleles demonstrated a greater susceptibility to both the detrimental effects of higher stress and the beneficial effects of lower stress compared to the Met/Met genotype. These findings support the 'differential-susceptibility' hypothesis, whereby the BDNF Val allele modulates the influence of environmental stress on depression by enhancing the neuroplastic response to all life events. © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

  7. Influence of Val108/158Met COMT Gene Polymorphism on the Efficacy of Modified Electroconvulsive Therapy in Patients with Treatment Resistant Depression.

    PubMed

    Lin, Zhaoyu; He, Hongbo; Zhang, Chunping; Wang, Zhijie; Jiang, Miaoling; Li, Qirong; Lan, Xiaochang; Zhang, Minling; Huang, Xiong

    2015-04-01

    Depression is a common emotional disorder associated with increased risk of suicide and rate of disability. In this double-blinded control study, we tested the efficacy of modified electroconvulsive therapy (MECT) in patients with treatment resistant depression (TRD) using the Hamilton Depression Rating Scale for Depression (HAMD). The total scores of HAMD were found to be significantly decreased after the treatment. The genotyping of catechol-O-methyltransferase (COMT) was carried out with polymerase chain reaction-based testing. Our results demonstrated that frequency of mutant COMT alleles in TRD patients was significantly higher than that of the controls indicating a correlation of the enzyme genotype to the occurrence of TRD. Moreover, the patients homozygous for wild-type COMT gene (G/G) were evidenced to be more sensitive to MECT treatment than those with an heterozygous mutant genotype (A/G).

  8. Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction.

    PubMed

    Anastasia, Agustin; Deinhardt, Katrin; Chao, Moses V; Will, Nathan E; Irmady, Krithi; Lee, Francis S; Hempstead, Barbara L; Bracken, Clay

    2013-01-01

    A common single-nucleotide polymorphism (SNP) in the human brain-derived neurotrophic factor (BDNF) gene results in a Val66Met substitution in the BDNF prodomain region. This SNP is associated with alterations in memory and with enhanced risk to develop depression and anxiety disorders in humans. Here we show that the isolated BDNF prodomain is detected in the hippocampus and that it can be secreted from neurons in an activity-dependent manner. Using nuclear magnetic resonance spectroscopy and circular dichroism, we find that the prodomain is intrinsically disordered, and the Val66Met substitution induces structural changes. Surprisingly, application of Met66 (but not Val66) BDNF prodomain induces acute growth cone retraction and a decrease in Rac activity in hippocampal neurons. Expression of p75(NTR) and differential engagement of the Met66 prodomain to the SorCS2 receptor are required for this effect. These results identify the Met66 prodomain as a new active ligand, which modulates neuronal morphology.

  9. Attention Deficit Hyperactivity Disorder comorbid oppositional defiant disorder and its predominately inattentive type: evidence for an association with COMT but not MAOA in a Chinese sample.

    PubMed

    Qian, Qiu-Jin; Liu, Jin; Wang, Yu-Feng; Yang, Li; Guan, Li-Li; Faraone, Stephen V

    2009-02-19

    There are three childhood disruptive behavior disorders (DBDs), attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD). The most common comorbid disorder in ADHD is ODD. DSM-IV describes three ADHD subtypes: predominantly inattentive type (ADHD-IA), predominantly hyperactive-impulsive type (ADHD-HI), and combined type (ADHD-C). Prior work suggests that specific candidate genes are associated with specific subtypes of ADHD in China. Our previous association studies between ADHD and functional polymorphisms of COMT and MAOA, consistently showed the low transcriptional activity alleles were preferentially transmitted to ADHD-IA boys. Thus, the goal of the present study is to test the hypothesis that COMT Val158Met and MAOA-uVNTR jointly contribute to the ODD phenotype among Chinese ADHD boys. 171 Chinese boys between 6 and 17.5 years old (mean = 10.3, SD = 2.6) with complete COMT val158met and MAOA-uVNTR genotyping information were studied. We used logistic regression with genotypes as independent variables and the binary phenotype as the dependent variable. We used p < 0.05 as the level of nominal statistical significance. Bonferroni correction procedures were used to adjust for multiple comparisons. Our results highlight the potential etiologic role of COMT in the ADHD with comorbid ODD and its predominately inattentive type in male Chinese subjects. ADHD with comorbid ODD was associated with homozygosity of the high-activity Val allele, while the predominantly inattentive ADHD subtype was associated with the low-activity Met allele. We found no evidence of association between the MAOA-uVNTR variant and ADHD with comorbid ODD or the ADHD-IA subtype. Our study of attention deficit hyperactivity disorder comorbid oppositional defiant disorder and its predominately inattentive type highlights the potential etiologic role of COMT for ADHD children in China. But we failed to observe an interaction between COMT and

  10. BDNF Val66Met polymorphism and stressful life events in melancholic childhood-onset depression.

    PubMed

    Rimay, Timea; Benak, Istvan; Kiss, Eniko; Baji, Ildiko; Feher, Agnes; Juhasz, Anna; Strauss, John; Kennedy, James; Barr, Cathy; Kovacs, Maria; Vetro, Agnes; Kapornai, Krisztina

    2015-12-01

    Brain-derived neurotrophic factor (BDNF) polymorphisms have been examined for their contribution toward depression with equivocal results. More homogeneous phenotypes might be used to improve our understanding of genetic liability to depression. The aim of our study was to (a) test for an association between the BDNF Val66Met polymorphism and childhood-onset melancholic depression and (b) to examine the interactive effects of stressful life events (SLE) and the Val66Met polymorphism on the risk of childhood-onset melancholic depression. A total of 583 depressed probands were involved in this study (162 of the melancholic subtype). Diagnoses were derived through the Interview Schedule for Children and Adolescents - Diagnostic Version and life event data were collected using an Intake General Information Sheet. Overall, 27.8% of the participants fulfilled the criteria for melancholy. In the melancholic group, the proportion of females was higher (53.1%), although there were more males in the overall depressed sample. We detected no significant differences in genotype or allele frequency between the melancholic and the nonmelancholic depressed group. The BDNF Val66Met polymorphism and SLE interaction was not significantly associated with the melancholy outcome. In our study, females were more prone to developing the early-onset melancholic phenotype. To our knowledge, this is the first study to investigate the differentiating effect of the genotype and the G×E interaction on the melancholic phenotype in a large sample of depressed young patients. We did not find an association between the melancholic subtype of major depression and the BDNF genotype and SLE interaction in this sample, which is representative of the Hungarian clinic-referred population of depressed youths.

  11. Positive symptoms in first-episode psychosis patients experiencing low maternal care and stressful life events: a pilot study to explore the role of the COMT gene.

    PubMed

    Ira, Elisa; De Santi, Katia; Lasalvia, Antonio; Bonetto, Chiara; Zanatta, Gioia; Cristofalo, Doriana; Bertani, Mariaelena; Bissoli, Sarah Saviana; Riolo, Rossana; Gardellin, Francesco; Morandin, Idana; Ramon, Luana; Tansella, Michele; Ruggeri, Mirella; Tosato, Sarah

    2014-09-01

    COMT Val(158)Met moderates the effect of stress on psychotic symptoms. Exposure to stress is also associated with mesolimbic dopamine release in individuals experiencing low maternal care. We therefore test the hypothesis that recent stressful life events are associated with more severe positive symptoms (associated with mesolimbic dopamine release) in first-episode psychosis (FEP) patients who experienced low maternal care during childhood. We hypothesized that COMT Val(158)Met moderates this association. A total of 149 FEP patients recruited within the Psychosis Incident Cohort Outcome Study (PICOS) participated in the present study. Maternal care was assessed by the Parental Bonding Instrument (PBI), stressful life events were collected by the List of Events Scale and positive symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS). We found that low maternal care and recent stressful life events were associated with higher level of positive symptoms at the onset (analysis of variance [ANOVA], p = 0.012), and that patients who were also homozygotes for the COMT Val(158) allele had the highest level of positive symptoms (ANOVA, p = 0.024). Low maternal care and severe stressful life events may contribute to a symptomatology characterized by more severe positive symptoms at the onset, possibly due to an increased mesolimbic dopamine release. Homozygosity for the COMT Val(158) allele seems to confer a biological predisposition to the stress-related hyperactivity of the mesolimbic dopaminergic system. The data imply that the mesolimbic dopaminergic system is involved in the mediation/modulation of the effect of stressful events on the vulnerability for psychosis.

  12. Psychosis-inducing effects of cannabis are related to both childhood abuse and COMT genotypes.

    PubMed

    Alemany, S; Arias, B; Fatjó-Vilas, M; Villa, H; Moya, J; Ibáñez, M I; Ortet, G; Gastó, C; Fañanás, L

    2014-01-01

    To test whether the association between childhood abuse, cannabis use and psychotic experiences (PEs) was moderated by the COMT (catechol-O-methyltransferase) gene. Psychotic experiences (PEs), childhood abuse, cannabis use and COMT Val158Met genotypes were assessed in 533 individuals from the general population. Data were analysed hierarchically by means of multiple linear regression models. Childhood abuse showed a significant main effect on both positive (β = 0.09; SE = 0.04; P = 0.047) and negative PEs (β = 0.11; SE = 0.05; P = 0.038). A significant three-way interaction effect was found among childhood abuse, cannabis use and the COMT gene on positive PEs (β = -0.30; SE = 0.11; P = 0.006). This result suggests that COMT genotypes and cannabis use only influenced PE scores among individuals exposed to childhood abuse. Furthermore, exposure to childhood abuse and cannabis use increased PE scores in Val carriers. However, in individuals exposed to childhood abuse but who did not use cannabis, PEs increased as a function of the Met allele copies of the COMT gene. Cannabis use after exposure to childhood abuse may have opposite effects on the risk of PEs, depending on the COMT genotypes providing evidence for a qualitative interaction. Val carriers exposed to childhood abuse are vulnerable to the psychosis-inducing effects of cannabis. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and post-stroke dementia: a hospital-based study from northern Iran.

    PubMed

    Rezaei, Sajjad; Asgari Mobarake, Karim; Saberi, Alia; Keshavarz, Parvaneh; Leili, Ehsan Kazemnejad

    2016-06-01

    Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with functional and cognitive outcomes of stroke and plays a key role in preventing neuronal death. This study aimed to answer the following question: does BDNF Val66Met polymorphism prognosticate survival status and risk of post-stroke dementia (PSD)? In a retrospective cohort study, 206 patients with ischemic stroke (IS) entered the study. They were consecutively being admitted to the neurology clinic in Poursina Hospital (northern Iran) from 2012 to 2014. The diagnosis of PSD was based on DSM-5 criteria. The current and the premorbid cognitive statuses of the patients were respectively assessed through the third edition of Addenbrooke's Cognitive Examination and the Informant Questionnaire on Cognitive Decline in the Elderly. BDNF Val66Met gene polymorphism was determined by PCR-RFLP. On average, 48 patients (23.3 %) developed PSD 6 months after IS. Log-rank test showed that the survival rate of at least one Val-allele carriers was significantly lower than that of Met/Met homozygotes (P = 0.0005), and the former developed PSD sooner than the latter (375, 492 days, respectively). Cox model showed that heterozygous carriers of Val/Met were at greater risk of PSD over time (HR 2.280, 95 % CI 1.566-4.106, P = 0.006). However, the risk ratio of patients with PSD among different BDNF genotypes decreased after adjusting demographic, clinical, and vascular risk factors, and was no longer statistically significant (AHR 2.434, 95 % CI 0.597-9.926, P = 0.215). Val-allele carriers or Val/Met genotypes were more quickly diagnosed as having dementia after IS. However, this genetic vulnerability became more destructive when it was added to demographic, clinical, and vascular risk factors.

  14. Social Support in Older Individuals: The Role of the BDNF Val66Met Polymorphism

    PubMed Central

    Taylor, Warren D.; Züchner, Stephan; McQuoid, Douglas R.; Steffens, David C.; Blazer, Dan G.; Krishnan, K. Ranga R.

    2008-01-01

    Although often viewed as a purely environmental construct, perception of social support may be influenced by genetic factors. This study examined the relationship between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and social support measures in older subjects. The sample consisted of 243 depressed and 115 nondepressed older subjects, age 60 years or older; 233 were Val66 allele homozygotes, while 125 were Met66 allele carriers. All subjects completed clinical assessments, including a self-report questionnaire assessing four social support domains, and provided blood for genotyping. Statistical models examined the relationship between scale scores of social support and BDNF Val66Met genotype, while controlling for presence or absence of major depressive disorder and other demographic factors significantly associated with social support. As social support measures were not normally distributed, log-transformed scores were examined. After controlling for diagnosis and education level, the Met66 allele was associated with lower levels of subjective social support (F1, 357 = 5.33, p = 0.0216) and a trend for fewer social interactions (F1, 357 = 3.66, p = 0.0567). To our knowledge, this is the first report associating a measure of social support with a genetic polymorphism. This supports previous work that genetic factors may influence social support perception. Further work is needed to determine the generalizability of this finding to the broader population, as well as its significance for clinical outcomes. PMID:18384075

  15. BDNF Binds Its Pro-Peptide with High Affinity and the Common Val66Met Polymorphism Attenuates the Interaction

    PubMed Central

    Uegaki, Koichi; Kumanogoh, Haruko; Mizui, Toshiyuki; Hirokawa, Takatsugu; Ishikawa, Yasuyuki; Kojima, Masami

    2017-01-01

    Most growth factors are initially synthesized as precursors then cleaved into bioactive mature domains and pro-domains, but the biological roles of pro-domains are poorly understood. In the present study, we investigated the pro-domain (or pro-peptide) of brain-derived neurotrophic factor (BDNF), which promotes neuronal survival, differentiation and synaptic plasticity. The BDNF pro-peptide is a post-processing product of the precursor BDNF. Using surface plasmon resonance and biochemical experiments, we first demonstrated that the BDNF pro-peptide binds to mature BDNF with high affinity, but not other neurotrophins. This interaction was more enhanced at acidic pH than at neutral pH, suggesting that the binding is significant in intracellular compartments such as trafficking vesicles rather than the extracellular space. The common Val66Met BDNF polymorphism results in a valine instead of a methionine in the pro-domain, which affects human brain functions and the activity-dependent secretion of BDNF. We investigated the influence of this variation on the interaction between BDNF and the pro-peptide. Interestingly, the Val66Met polymorphism stabilized the heterodimeric complex of BDNF and its pro-peptide. Furthermore, compared with the Val-containing pro-peptide, the complex with the Met-type pro-peptide was more stable at both acidic and neutral pH, suggesting that the Val66Met BDNF polymorphism forms a more stable complex. A computational modeling provided an interpretation to the role of the Val66Met mutation in the interaction of BDNF and its pro-peptide. Lastly, we performed electrophysiological experiments, which indicated that the BDNF pro-peptide, when pre-incubated with BDNF, attenuated the ability of BDNF to inhibit hippocampal long-term depression (LTD), suggesting a possibility that the BDNF pro-peptide may interact directly with BDNF and thereby inhibit its availability. It was previously reported that the BDNF pro-domain exerts a chaperone-like function

  16. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism interacts with gender to influence cortisol responses to mental stress.

    PubMed

    Jiang, Rong; Babyak, Michael A; Brummett, Beverly H; Siegler, Ilene C; Kuhn, Cynthia M; Williams, Redford B

    2017-05-01

    Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been associated with cortisol responses to stress with gender differences reported, although the findings are not entirely consistent. To evaluate the role of Val66Met genotype and gender on cortisol responses to stress, we conducted a 45-min mental stress protocol including four tasks and four rest periods. Blood cortisol was collected for assay immediately before and after each task and rest period. A significant two-way interaction of Val66Met genotype×gender (P=0.022) was observed on the total area under the curve (AUC), a total cortisol response over time, such that the Val/Val genotype was associated with a larger cortisol response to stress as compared to the Met group in women but not in men. Further contrast analyses between the Val/Val and Met group for each stress task showed a similar increased cortisol pattern among women Val/Val genotype but not among men. The present findings indicate the gender differences in the effect of Val66Met genotype on the cortisol responses to stress protocol, and extend the evidence for the importance of gender and the role of Val66Met in the modulation of stress reactivity and subsequent depression prevalence. Further studies and the underlying mechanism need to be investigated, which may provide an insight for prevention, intervention, and treatment strategies that target those at high risk. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Brain-Derived Neurotrophic Factor (BDNF) Val66Met Polymorphism Interacts with Gender to Influence Cortisol Responses to Mental Stress

    PubMed Central

    Jiang, Rong; Babyak, Michael A.; Brummett, Beverly H.; Siegler, Ilene C.; Kuhn, Cynthia M.; Williams, Redford B.

    2017-01-01

    Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been associated with cortisol responses to stress with gender differences reported, although the findings are not entirely consistent. To evaluate the role of Val66Met genotype and gender on cortisol responses to stress, we conducted a 45-min mental stress protocol including four tasks and four rest periods. Blood cortisol was collected for assay immediately before and after each task and rest period. A significant two-way interaction of Val66Met genotype × gender (P = 0.022) was observed on the total area under the curve (AUC), a total cortisol response over time, such that the Val/Val genotype was associated with a larger cortisol response to stress as compared to the Met group in women but not in men. Further contrast analyses between the Val/Val and Met group for each stress task showed a similar increased cortisol pattern among women Val/Val genotype but not among men. The present findings indicate the gender differences in the effect of Val66Met genotype on the cortisol responses to stress protocol, and extend the evidence for the importance of gender and the role of Val66Met in the modulation of stress reactivity and subsequent depression prevalence. Further studies and the underlying mechanism need to be investigated, which may provide an insight for prevention, intervention, and treatment strategies that target those at high risk. PMID:28249185

  18. Childhood Trauma and COMT Genotype Interact to Increase Hippocampal Activation in Resilient Individuals.

    PubMed

    van Rooij, Sanne J H; Stevens, Jennifer S; Ely, Timothy D; Fani, Negar; Smith, Alicia K; Kerley, Kimberly A; Lori, Adriana; Ressler, Kerry J; Jovanovic, Tanja

    2016-01-01

    Both childhood trauma and a functional catechol-O-methyltransferase (COMT) genetic polymorphism have been associated with posttraumatic stress disorder (PTSD) and depression; however, it is still unclear whether the two interact and how this interaction relates to long-term risk or resilience. Imaging and genotype data were collected on 73 highly traumatized women. DNA extracted from saliva was used to determine COMT genotype (Val/Val, n = 38, Met carriers, n = 35). Functional MRI data were collected during a Go/NoGo task to investigate the neurocircuitry underlying response inhibition. Self-report measures of adult and childhood trauma exposure, PTSD and depression symptom severity, and resilience were collected. Childhood trauma was found to interact with COMT genotype to impact inhibition-related hippocampal activation. In Met carriers, more childhood trauma was associated with decreased hippocampal activation, whereas in the Val/Val group childhood trauma was related to increased hippocampal activation. Second, hippocampal activation correlated negatively with PTSD and depression symptoms and positively with trait resilience. Moreover, hippocampal activation mediated the relationship between childhood trauma and psychiatric risk or resilience in the Val/Val, but not in the Met carrier group. These data reveal a potential mechanism by which childhood trauma and COMT genotype interact to increase risk for trauma-related psychopathology or resilience. Hippocampal recruitment during inhibition may improve the ability to use contextual information to guide behavior, thereby enhancing resilience in trauma-exposed individuals. This finding may contribute to early identification of individuals at risk and suggests a mechanism that can be targeted in future studies aiming to prevent or limit negative outcomes.

  19. The BDNF Val66Met Polymorphism Interacts with Maternal Parenting Influencing Adolescent Depressive Symptoms: Evidence of Differential Susceptibility Model.

    PubMed

    Zhang, Leilei; Li, Zhi; Chen, Jie; Li, Xinying; Zhang, Jianxin; Belsky, Jay

    2016-03-01

    Although depressive symptoms are common during adolescence, little research has examined gene-environment interaction on youth depression. This study chose the brain-derived neurotrophic factor (BDNF) gene, tested the interaction between a functional polymorphism resulting amino acid substitution of valine (Val) to methionine (Met) in the proBDNF protein at codon 66 (Val66Met), and maternal parenting on youth depressive symptoms in a sample of 780 community adolescents of Chinese Han ethnicity (aged 11-17, M = 13.6, 51.3 % females). Participants reported their depressive symptoms and perceived maternal parenting. Results indicated the BDNF Val66Met polymorphism significantly moderated the influence of maternal warmth-reasoning, but not harshness-hostility, on youth depressive symptoms. Confirmatory model evaluation indicated that the interaction effect involving warmth-reasoning conformed to the differential-susceptibility rather than diathesis-stress model of person-X-environment interaction. Thus, Val carriers experienced less depressive symptoms than Met homozygotes when mothering was more positive but more symptoms when mothering was less positive. The findings provided evidence in support of the differential susceptibility hypothesis of youth depressive symptoms and shed light on the importance of examining the gene-environment interaction from a developmental perspective.

  20. Evidence that COMT genotype and proline interact on negative-symptom outcomes in schizophrenia and bipolar disorder.

    PubMed

    Clelland, C L; Drouet, V; Rilett, K C; Smeed, J A; Nadrich, R H; Rajparia, A; Read, L L; Clelland, J D

    2016-09-13

    Elevated peripheral proline is associated with psychiatric disorders, and there is evidence that proline is a neuromodulator. The proline dehydrogenase (PRODH) gene, which encodes the enzyme that catalyzes proline catabolism, maps to human chromosome 22q11.2, a region conferring risk of schizophrenia. In the Prodh-null mouse, an interaction between elevated peripheral proline and another 22q11.2 gene, catechol-O-methyltransferase (COMT), on neurotransmission and behavior has been reported. We explored the relationship between fasting plasma proline levels and COMT Val(158)Met genotype on symptoms (positive, negative and total) in schizophrenia patients. In an exploratory study we also examined symptom change in patients with bipolar disorder. There was a significant interaction between peripheral proline and COMT on negative symptoms in schizophrenia (P<0.0001, n=95). In COMT Val/Val patients, high proline was associated with low Scale for the Assessment of Negative Symptom (SANS) scores. In contrast, high proline was associated with high SANS scores in patients carrying a Met allele. The relationship between proline and COMT also appears to modify negative symptoms across psychiatric illness. In bipolar disorder, a significant interaction was also observed on negative-symptom change (P=0.007, n=43). Negative symptoms are intractable and largely unaddressed by current medications. These data indicate a significant interaction between peripheral proline and COMT genotype, influencing negative symptoms in schizophrenia and bipolar disorder. That high proline has converse effects on symptoms by COMT genotype, may have implications for therapeutic decisions.

  1. BDNF Val66Met polymorphism is associated with HPA axis reactivity to psychological stress characterized by genotype and gender interactions.

    PubMed

    Shalev, Idan; Lerer, Elad; Israel, Salomon; Uzefovsky, Florina; Gritsenko, Inga; Mankuta, David; Ebstein, Richard P; Kaitz, Marsha

    2009-04-01

    A key protein in maintaining neuronal integrity throughout the life span is brain-derived neurotrophic factor (BDNF). The BDNF gene is characterized by a functional polymorphism, which has been associated with stress-related disorders such as anxiety-related syndromes and depression, prompting us to examine individual responses by Genotype and Sex to a standardized social stress paradigm. Gender differences in BDNFxstress responses were posited because estrogen induces synthesis of BDNF in several brain regions. 97 university students (51 females and 46 males) participated in a social stress procedure (Trier Social Stress Test, TSST). Indices of stress were derived from repeated measurement of cortisol, blood pressure, and heart rate during the TSST. All subjects were genotyped for the Val66Met polymorphism. Tests of within-subject effects showed a significant three-way interaction (SPSS GLM repeated measures: Time (eight levels)xBDNF (val/val, val/met)xSex: p=0.0002), which reflects gender differences in the pattern of cortisol rise and decline during the social challenge. In male subjects, val/val homozygotes showed a greater rise in salivary cortisol than val/met heterozygotes. In female subjects, there was a trend for the opposite response, which is significant when area under the curve increase (AUCi) was calculated for the val/val homozygotes to show the lowest rise. Overall, the same pattern of results was observed for blood pressure and heart rate. These results indicate that a common, functionally significant polymorphism in the BDNF gene modulates HPA axis reactivity and regulation during the TSST differently in men and women. Findings may be related to gender differences in reactivity and vulnerability to social stress.

  2. Role of BDNF val66met polymorphism on the association between physical activity and incident dementia.

    PubMed

    Kim, Jae-Min; Stewart, Robert; Bae, Kyung-Yeol; Kim, Sung-Wan; Yang, Su-Jin; Park, Kee-Hyung; Shin, Il-Seon; Yoon, Jin-Sang

    2011-03-01

    Increased physical activity may have beneficial effects on cognitive outcomes; a role of brain-derived neurotrophic factor (BDNF) has been suggested in animal models but not yet tested in humans. This study investigated modification by BDNF val66met polymorphism of the association between physical activity, incident dementia and other cognitive outcomes. Of 732 community elders, 107 had dementia at baseline, and 518 (83%) of the remainder were followed over 2.4 years. Cognitive impairment and decline were defined from Mini-Mental State Examination scores. Self-reported level of physical activity was recorded on a 4-point scale. BDNF val66met and apolipoprotein E genotypes were ascertained. Covariates included age, sex, education, depression, vascular risk factors, and instrumental activities of daily living. Baseline lower physical activity was significantly associated with incident dementia as well as with baseline dementia and cognitive impairment and incident cognitive decline. BDNF val66met polymorphism itself was not associated with any cognitive outcome. However, the strength of association between lower activity and all cognitive outcomes increased incrementally with the number of met alleles, and was strongest in those with the met/met genotype. BDNF×activity interaction terms were stronger for prospective outcomes (incident dementia, cognitive decline) compared to cross-sectional outcomes (prevalent dementia, cognitive impairment no dementia). This study supports a previously suggested neurobiological basis for the effects of physical activity on dementia involving the BDNF system since the met allele is recognised to be associated with lower activity-dependent secretion of BDNF. Copyright © 2010. Published by Elsevier Inc.

  3. The BDNF Val66Met polymorphism and plasma brain-derived neurotrophic factor levels in Han Chinese patients with bipolar disorder and schizophrenia.

    PubMed

    Chen, Shiou-Lan; Lee, Sheng-Yu; Chang, Yun-Hsuan; Chen, Shih-Heng; Chu, Chun-Hsien; Wang, Tzu-Yun; Chen, Po-See; Lee, I-Hui; Yang, Yen-Kuang; Hong, Jau-Shyong; Lu, Ru-Band

    2014-06-03

    Brain-derived neurotropic factor (BDNF) is widely distributed in the peripheral and central nervous systems. BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and may become a key target in the physiopathology of several mental illnesses. To elucidate the role of BDNF, we compared the plasma BDNF levels and the BDNF Val66Met gene variants effect in several mental disorders. We enrolled 644 participants: 177 patients with bipolar I disorder (BP-I), 190 with bipolar II disorder (BP-II), 151 with schizophrenia, and 126 healthy controls. Their plasma BDNF levels and BDNF Val66Met single nucleotide polymorphisms (SNP) were checked before pharmacological treatment. Plasma levels of BDNF were significantly lower in patients with schizophrenia than in healthy controls and patients with bipolar disorder (F = 37.667, p<0.001); the distribution of the BDNF Val66Met SNP was not different between groups (χ(2) = 5.289, p = 0.507). Nor were plasma BDNF levels significantly different between Met/Met, Met/Val, and Val/Val carriers in each group, which indicated that the BDNF Val66Met SNP did not influence plasma BDNF levels in our participants. Plasma BDNF levels were, however, significantly negatively correlated with depression scores in patients with bipolar disorder and with negative symptoms in patients with schizophrenia. We conclude that plasma BDNF profiles in different mental disorders are not affected by BDNF Val66Met gene variants, but by the process and progression of the illness itself. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. COMT-by-Sex Interaction Effect on Psychosis Proneness

    PubMed Central

    de Castro-Catala, Marta; Barrantes-Vidal, Neus; Sheinbaum, Tamara; Moreno-Fortuny, Artal; Kwapil, Thomas R.; Rosa, Araceli

    2015-01-01

    Schizotypy phenotypes in the general population share etiopathogenic mechanisms and risk factors with schizophrenia, supporting the notion of psychosis as a continuum ranging from nonclinical to clinical deviance. Catechol-O-methyltransferase (COMT) is a candidate susceptibility gene for schizophrenia that is involved in the regulation of dopamine in the prefrontal cortex. Several recent studies have reported a sex difference in the impact of COMT genotype on psychiatric and cognitive phenotypes and personality traits. The present study investigated the association of COMT Val158Met (rs4680) with psychometric positive and negative schizotypy and psychotic experiences in a sample of 808 nonclinical young adults. The main finding was that sex moderates the association of COMT genotype with the negative dimension of both schizotypy and psychotic experiences. Male subjects carrying the Val allele tended to score higher on the negative dimension of both trait and symptom-like measures. The results from the present study are consistent with recent work suggesting an association between negative schizotypy and diminished prefrontal dopamine availability. They support the idea that a biological differentiation underlies the positive and negative schizotypy dimensions. Additionally, these findings contribute to the growing literature on sex-specific effects of COMT on the predisposition to psychiatric disorders and personality traits. PMID:25722988

  5. Catechol-O-methyltransferase (COMT) genotype affects cognitive control during total sleep deprivation.

    PubMed

    Satterfield, Brieann C; Hinson, John M; Whitney, Paul; Schmidt, Michelle A; Wisor, Jonathan P; Van Dongen, Hans P A

    2018-02-01

    Adaptive decision making is profoundly impaired by total sleep deprivation (TSD). This suggests that TSD impacts fronto-striatal pathways involved in cognitive control, where dopamine is a key neuromodulator. In the prefrontal cortex (PFC), dopamine is catabolized by the enzyme catechol-O-methyltransferase (COMT). A functional polymorphism (Val158Met) influences COMT's enzymatic activity, resulting in markedly different levels of prefrontal dopamine. We investigated the effect of this polymorphism on adaptive decision making during TSD. Sixty-six healthy young adults participated in one of two in-laboratory studies. After a baseline day, subjects were randomized to either a TSD group (n = 32) with 38 h or 62 h of extended wakefulness or a well-rested control group (n = 34) with 10 h nighttime sleep opportunities. Subjects performed a go/no-go reversal learning (GNGr) task at well-rested baseline and again during TSD or equivalent control. During the task, subjects were required to learn stimulus-response relationships from accuracy feedback. The stimulus-response relationships were reversed halfway through the task, which required subjects to learn the new stimulus-response relationships from accuracy feedback. Performance on the GNGr task was quantified by discriminability (d') between go and no-go stimuli before and after the stimulus-response reversal. GNGr performance did not differ between COMT genotypes when subjects were well-rested. However, TSD exposed a significant vulnerability to adaptive decision making impairment in subjects with the Val allele. Our results indicate that sleep deprivation degrades cognitive control through a fronto-striatal, dopaminergic mechanism. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Influence of SLC6A3 and COMT Variation on Neural Activation During Response Inhibition

    PubMed Central

    Congdon, Eliza; Constable, R. Todd; Lesch, Klaus Peter; Canli, Turhan

    2009-01-01

    There is evidence concerning the neural and genetic correlates of inhibitory control, but there have been limited attempts to combine this information. This study tested the hypothesis that two dopaminergic polymorphisms, SLC6A3 and COMT, influence neural activation during response inhibition. Healthy adults were genotyped for these polymorphisms and performed a measure of response inhibition while undergoing functional magnetic resonance imaging (fMRI). Results support the role of key frontostriatal regions underlying response inhibition. Furthermore, results support a significant influence of SLC6A3 and COMT variants on neural activity during inhibition, with greater activation during inhibition in carriers of the SLC6A3 9-allele or the COMT met-allele as compared to carriers of the SLC6A3 10/10 genotype or the COMT val/val genotype. These 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. PMID:19482231

  7. BDNF Val66Met Polymorphism Interacts with Sleep Consolidation to Predict Ability to Create New Declarative Memories.

    PubMed

    Gosselin, Nadia; De Beaumont, Louis; Gagnon, Katia; Baril, Andrée-Ann; Mongrain, Valérie; Blais, Hélène; Montplaisir, Jacques; Gagnon, Jean-François; Pelleieux, Sandra; Poirier, Judes; Carrier, Julie

    2016-08-10

    It is hypothesized that a fundamental function of sleep is to restore an individual's day-to-day ability to learn and to constantly adapt to a changing environment through brain plasticity. Brain-derived neurotrophic factor (BDNF) is among the key regulators that shape brain plasticity. However, advancing age and carrying the BDNF Met allele were both identified as factors that potentially reduce BDNF secretion, brain plasticity, and memory. Here, we investigated the moderating role of BDNF polymorphism on sleep and next-morning learning ability in 107 nondemented individuals who were between 55 and 84 years of age. All subjects were tested with 1 night of in-laboratory polysomnography followed by a cognitive evaluation the next morning. We found that in subjects carrying the BDNF Val66Val polymorphism, consolidated sleep was associated with significantly better performance on hippocampus-dependent episodic memory tasks the next morning (β-values from 0.290 to 0.434, p ≤ 0.01). In subjects carrying at least one copy of the BDNF Met allele, a more consolidated sleep was not associated with better memory performance in most memory tests (β-values from -0.309 to -0.392, p values from 0.06 to 0.15). Strikingly, increased sleep consolidation was associated with poorer performance in learning a short story presented verbally in Met allele carriers (β = -0.585, p = 0.005). This study provides new evidence regarding the interacting roles of consolidated sleep and BDNF polymorphism in the ability to learn and stresses the importance of considering BDNF polymorphism when studying how sleep affects cognition. Individuals with the BDNF Val/Val (valine allele) polymorphism showed better memory performance after a night of consolidated sleep. However, we observed that middle-aged and older individuals who are carriers of the BDNF Met allele displayed no positive association between sleep quality and their ability to learn the next morning. This interaction between sleep and

  8. The role of brain-derived neurotrophic factor (BDNF) Val66Met genetic polymorphism in bipolar disorder: a case-control study, comorbidities, and meta-analysis of 16,786 subjects.

    PubMed

    González-Castro, Thelma Beatriz; Nicolini, Humberto; Lanzagorta, Nuria; López-Narváez, Lilia; Genis, Alma; Pool García, Sherezada; Tovilla-Zárate, Carlos Alfonso

    2015-02-01

    The aim of this study was to evaluate the association of Val66Met brain-derived neurotrophic factor (BDNF) polymorphism with bipolar disorder in (i) a meta-analysis and (ii) a case-control study in a Mexican population. We also investigated the possible association of this polymorphism with clinical features. We performed a keyword search of the PubMed and Web of Science databases. A total of 22 studies that have investigated the association of Val66Met (rs6265) with bipolar disorder were selected for inclusion and combined with random effects meta-analysis, using allelic, additive, dominant, and recessive models. Finally, the single nucleotide polymorphism (rs6265) Val66Met in the BDNF gene was genotyped and compared between 139 patients with bipolar disorder and 141 healthy volunteers in a Mexican population. The pooled results from the meta-analysis (9,349 cases and 7,437 controls) did not show a significant association in any of the models. The same results were obtained in our case-control study when analyzing the distribution of the genotypic frequencies of the Val66Met polymorphism in patients with bipolar disorder. However, when we analyzed the association between rs6265 and lifetime history of suicidal behavior, we found an association between genotype Val-Val and suicide attempt (p = 0.02). Although the present study has some limitations, the results indicate a lack of association between the Val66Met polymorphism and bipolar disorder. However, in our case-control study in a Mexican population, the Val66Met polymorphism was associated with suicidal behavior in patients with bipolar disorder. Nevertheless, it is important to consider potential interactions of the BDNF gene, the environment, and different inheritance patterns, when carrying out future genetic studies with larger samples. © 2014 The Authors. Bipolar Disorders Published by John Wiley & Sons Ltd.

  9. The BDNF Val66Met polymorphism does not moderate the effect of self-reported physical activity on depressive symptoms in midlife

    PubMed Central

    Gujral, Swathi; Manuck, Stephen B.; Ferrell, Robert E.; Flory, Janine D.; Erickson, Kirk I.

    2014-01-01

    Background The brain-derived neurotrophic factor (BDNF) Val66Met single nucleotide polymorphism may be associated with clinical and subsyndromal depression, but physical activity improves mood and increases BDNF expression. Aims To examine whether the BDNF polymorphism moderates an effect of physical activity on depressive symptoms. Methods BDNF genotype, physical activity measured by the Paffenbarger Questionnaire, and depressive symptoms using the Center for Epidemiology Depression Scale (CES-D) were collected on 1072 participants (Mean Age=44). Multiple linear regression was used to examine the association between BDNF genotype, physical activity, and depressive symptoms. Results After adjusting for family income, age, and education, depressive symptoms were higher in Met carriers compared to Val homozygotes (p=0.03), but this was only significant in men. Physical activity was associated with fewer depressive symptoms, but only in women (p=0.01). BDNF genotype did not moderate the effect of physical activity on depressive symptoms (p= 0.94). Conclusions In midlife, the BDNF Val66Met polymorphism neither attenuates nor magnifies the effect of physical activity on depressive symptoms. PMID:24745471

  10. Association of the brain-derived neurotrophic factor Val66Met polymorphism with negative symptoms severity, but not cognitive function, in first-episode schizophrenia spectrum disorders.

    PubMed

    Mezquida, G; Penadés, R; Cabrera, B; Savulich, G; Lobo, A; González-Pinto, A; Penzol, M J; Corripio, I; Fernandez-Egea, E; Gassó, P; Cuesta, M J; Bernardo, M

    2016-10-01

    A functional polymorphism of the brain-derived neurotrophic factor gene (BDNF) Val66Met has been associated with cognitive function and symptom severity in patients with schizophrenia. It has been suggested that the Val66Met polymorphism has a role as a modulator in a range of clinical features of the illness, including symptoms severity, therapeutic responsiveness, age of onset, brain morphology and cognitive function. However, little work has been done in first-episode schizophrenia (FES) spectrum disorders. The objective of this study is to investigate the association of the BDNF Val66Met polymorphism on cognitive function and clinical symptomatology in FES patients. Using a cross-sectional design in a cohort of 204 patients with FES or a schizophrenia spectrum disorder and 204 healthy matched controls, we performed BDNF Val66Met genotyping and tested its relationship with cognitive testing (attention, working memory, learning/verbal memory and reasoning/problem-solving) and assessment of clinical symptom severity. There was no significant influence of the BDNF allele frequency on cognitive factor scores in either patients or controls. An augmented severity of negative symptoms was found in FES patients that carried the Met allele. The results of this study suggest that in patients with a first-episode of schizophrenia or a schizophrenia spectrum disorder, the BDNF Val66Met polymorphism does not exert an influence on cognitive functioning, but is associated with negative symptoms severity. BDNF may serve as suitable marker of negative symptomatology severity in FES patients within the schizophrenia spectrum. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  11. Prediction of remission of depression with clinical variables, neuropsychological performance, and serotonergic/dopaminergic gene polymorphisms.

    PubMed

    Gudayol-Ferré, Esteve; Herrera-Guzmán, Ixchel; Camarena, Beatriz; Cortés-Penagos, Carlos; Herrera-Abarca, Jorge E; Martínez-Medina, Patricia; Asbun-Bojalil, Juan; Lira-Islas, Yuridia; Reyes-Ponce, Celia; Guàrdia-Olmos, Joan

    2012-11-01

    The aim of our work is to study the possible role of clinical variables, neuropsychological performance, and the 5HTTLPR, rs25531, and val108/58Met COMT polymorphisms on the prediction of depression remission after 12 weeks' treatment with fluoxetine. These variables have been studied as potential predictors of depression remission, but they present poor prognostic sensitivity and specificity by themselves. Seventy-two depressed patients were genotyped according to the aforementioned polymorphisms and were clinically and neuropsychologically assessed before a 12-week fluxetine treatment. Only the La allele of rs25531 polymorphism and the GG and AA forms of the val 108/158 Met polymorphism predict major depressive disorder remission after 12 weeks' treatment with fluoxetine. None of the clinical and neuropsychological variables studied predicted remission. Our results suggest that clinical and neuropsychological variables can initially predict early response to fluoxetine and mask the predictive role of genetic variables; but in remission, where clinical and neuropsychological symptoms associated with depression tend to disappear thanks to the treatment administered, the polymorphisms studied are the only variables in our model capable of predicting remission. However, placebo effects that are difficult to control require cautious interpretation of the results.

  12. Lack of an association of BDNF Val66Met polymorphism and plasma BDNF with hippocampal volume and memory

    PubMed Central

    Kim, Ana; Fagan, Anne M; Goate, Alison M; Benzinger, Tammie LS; Morris, John C; Head, Denise

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) has been shown to be important for neuronal survival and synaptic plasticity in the hippocampus in non-human animals. The Val66Met polymorphism in the BDNF gene, involving a valine (Val) to methionine (Met) substitution at codon 66, has been associated with lower BDNF secretion in vitro. However, there have been mixed results regarding associations between either circulating BDNF or the BDNF Val66Met polymorphism with hippocampal volume and memory in humans. The current study examined the association of BDNF genotype and plasma BDNF with hippocampal volume and memory in two large independent cohorts of middle-aged and older adults (both cognitively normal and early-stage dementia). Sample sizes ranged from 123 to 649. Measures of the BDNF genotype, plasma BDNF, MRI-based hippocampal volume and memory performance were obtained from the Knight Alzheimer Disease Research Center (ADRC) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). There were no significant differences between BDNF Met+ and Met- groups on either hippocampal volume or memory in either cohort. In addition, plasma BDNF was not significantly associated with either hippocampal volume or memory in either cohort. Neither age, cognitive status nor gender moderated any of the relationships. Overall, current findings suggest that BDNF genotype and plasma BDNF may not be robust predictors for variance in hippocampal volume and memory in middle age and older adult cohorts. PMID:25784293

  13. Val66Met BDNF polymorphism as a vulnerability factor for inflammation-associated depressive symptoms in women with breast cancer

    PubMed Central

    Dooley, Larissa N.; Ganz, Patricia A.; Cole, Steve W.; Crespi, Catherine M.; Bower, Julienne E.

    2016-01-01

    Background Inflammation contributes to the development of depression in a subset of individuals, but risk factors that render certain individuals vulnerable to inflammation-associated depression are undetermined. Drawing from animal studies showing that reduced neuroplasticity mediates effects of inflammation on depression, we hypothesized that individuals genetically predisposed to lower levels of neuroplasticity would be more susceptible to inflammation-associated depression. The current study examined whether the Met allele of the BDNF Val66met polymorphism, which predisposes individuals to reduced levels of brain-derived neurotrophic factor (BDNF), a protein vital for neuroplasticity, moderates the association between inflammation and depressive symptoms. Methods Our sample was 112 women with early-stage breast cancer who had recently completed cancer treatment, which can activate inflammation. Participants provided blood for genotyping and assessment of circulating inflammatory markers, and completed a questionnaire assessing depressive symptoms, including somatic, affective, and cognitive dimensions. Results There was a significant interaction between C-reactive protein (CRP) and the BDNF Val66met polymorphism in predicting cognitive depressive symptoms (p=.004), such that higher CRP was related to more cognitive depressive symptoms among Met allele carriers, but not among Val/Val homozygotes. Post-hoc longitudinal analyses suggested that, for Met carriers, higher CRP at baseline predicted higher cognitive depressive symptoms across a one-year follow-up period (p<.001). Conclusion The BDNF Met allele may be a risk factor for inflammation-associated cognitive depressive symptoms among breast cancer survivors. Women with breast cancer who carry this genotype may benefit from early identification and treatment. Limitation BDNF genotype is an indirect measure of BDNF protein levels. PMID:26967918

  14. Genetic predictor of working memory and prefrontal function in women with HIV.

    PubMed

    Sundermann, Erin E; Bishop, Jeffrey R; Rubin, Leah H; Little, Deborah M; Meyer, Vanessa J; Martin, Eileen; Weber, Kathleen; Cohen, Mardge; Maki, Pauline M

    2015-02-01

    The Val158Met (rs4680) single-nucleotide polymorphism (SNP) of the catechol-O-methyltransferase gene (COMT) influences executive function and prefrontal function through its effect on dopamine (DA) metabolism. Both HIV and the Val allele of the Val158Met SNP are associated with compromised executive function and inefficient prefrontal function. The present study used behavioral and neuroimaging techniques to determine independent and interactive associations between HIV serostatus and COMT genotype on working memory and prefrontal function in women. For the behavioral study, 54 HIV-infected and 33 HIV-uninfected women completed the 0-, 1-, and 2-back conditions of the verbal N-back, a working memory test. For the imaging study, 36 women (23 HIV-infected, 13 HIV-uninfected) underwent functional magnetic resonance imaging (fMRI) assessments while completing the N-back task. HIV-infected women demonstrated significantly worse N-back performance compared with HIV-uninfected women (p < 0.05). A significant serostatus by genotype interaction (p < 0.01) revealed that, among Val/Val, but not Met allele carriers, HIV-infected women performed significantly worse than HIV-uninfected controls across N-back conditions (p < 0.01). Analogous to behavioral findings, a serostatus by genotype interaction revealed that HIV-infected Val/Val carriers showed significantly greater prefrontal activation compared with HIV-uninfected Val/Val carriers (p < 0.01). Conversely, HIV-uninfected Met allele carriers demonstrated significantly greater prefrontal activation compared with HIV-infected Met allele carriers. Findings suggest that the combination of HIV infection and the Val/Val COMT genotype leads to working memory deficits and altered prefrontal function in HIV-infected individuals.

  15. The impact of brain-derived neurotrophic factor Val66Met polymorphism on cognition and functional brain networks in patients with intractable partial epilepsy.

    PubMed

    Sidhu, Meneka K; Thompson, Pamela J; Wandschneider, Britta; Foulkes, Alexandra; de Tisi, Jane; Stretton, Jason; Perona, Marina; Thom, Maria; Bonelli, Silvia B; Burdett, Jane; Williams, Elaine; Duncan, John S; Matarin, Mar

    2018-06-27

    Medial temporal lobe epilepsy (mTLE) is the most common refractory focal epilepsy in adults. Around 30%-40% of patients have prominent memory impairment and experience significant postoperative memory and language decline after surgical treatment. BDNF Val66Met polymorphism has also been associated with cognition and variability in structural and functional hippocampal indices in healthy controls and some patient groups. We examined whether BDNF Val66Met variation was associated with cognitive impairment in mTLE. In this study, we investigated the association of Val66Met polymorphism with cognitive performance (n = 276), postoperative cognitive change (n = 126) and fMRI activation patterns during memory encoding and language paradigms in 2 groups of patients with mTLE (n = 37 and 34). mTLE patients carrying the Met allele performed more poorly on memory tasks and showed reduced medial temporal lobe activation and reduced task-related deactivations within the default mode networks in both the fMRI memory and language tasks than Val/Val patients. Although cognitive impairment in epilepsy is the result of a complex interaction of factors, our results suggest a role of genetic factors on cognitive impairment in mTLE. © 2018 John Wiley & Sons Ltd.

  16. Effect of BDNF val(66)met polymorphism on declarative memory and its neural substrate: a meta-analysis.

    PubMed

    Kambeitz, Joseph P; Bhattacharyya, Sagnik; Kambeitz-Ilankovic, Lana M; Valli, Isabel; Collier, David A; McGuire, Philip

    2012-10-01

    Brain derived neurotrophic factor (BDNF) is a critical component of the molecular mechanism of memory formation. Variation in the BDNF gene, particularly the rs6265 (val(66)met) single nucleotide polymorphism (SNP), has been linked to variability in human memory performance and to both the structure and physiological response of the hippocampus, which plays a central role in memory processing. However, these effects have not been consistently reported, which may reflect the modest size of the samples studied to date. Employing a meta-analytic approach, we examined the effect of the BDNF val(66)met polymorphism on human memory (5922 subjects) and hippocampal structure (2985 subjects) and physiology (362 subjects). Our results suggest that variations in the rs6265 SNP of the BDNF gene have a significant effect on memory performance, and on both the structure and physiology of the hippocampus, with carriers of the met allele being adversely affected. These results underscore the role of BDNF in moderating variability between individuals in human memory performance and in mediating some of the neurocognitive impairments underlying neuropsychiatric disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. Brain-Derived Neurotrophic Factor Val66Met Polymorphism Affects the Relationship Between an Anxiety-Related Personality Trait and Resting Regional Cerebral Blood Flow.

    PubMed

    Wei, Shau-Ming; Eisenberg, Daniel P; Nabel, Katherine G; Kohn, Philip D; Kippenhan, J Shane; Dickinson, Dwight; Kolachana, Bhaskar; Berman, Karen F

    2017-03-01

    Brain-derived neurotrophic factor (BDNF) is an important modulator of constitutive stress responses mediated by limbic frontotemporal circuits, and its gene contains a functional polymorphism (Val66Met) that may influence trait stress sensitivity. Reports of an association of this polymorphism with anxiety-related personality traits have been controversial and without clear neurophysiological support. We, therefore, determined the relationship between resting regional cerebral blood flow (rCBF) and a well-validated measure of anxiety-related personality, the TPQ Harm Avoidance (HA) scale, as a function of BDNF Val66Met genotype. Sixty-four healthy participants of European ancestry underwent resting H215O positron emission tomography scans. For each genotype group separately, we first determined the relationship between participants' HA scores and their resting rCBF values in each voxel across the entire brain, and then directly compared these HA-rCBF relationships between Val66Met genotype groups. HA-rCBF relationships differed between Val homozygotes and Met carriers in several regions relevant to stress regulation: subgenual cingulate, orbital frontal cortex, and the hippocampal/parahippocampal region. In each of these areas, the relationship was positive in Val homozygotes and negative in Met carriers. These data demonstrate a coupling between trait anxiety and basal resting blood flow in frontolimbic neurocircuitry that may be determined in part by genetically mediated BDNF signaling. Published by Oxford University Press 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  18. COMT Val[superscript 108/158] Met Gene Variant, Birth Weight, and Conduct Disorder in Children with ADHD

    ERIC Educational Resources Information Center

    Sengupta, Sarojini M.; Grizenko, Natalie; Schmitz, Norbert; Schwartz, George; Amor, Leila Ben; Bellingham, Johanne; de Guzman, Rosherrie; Polotskaia, Anna; Stepanian, Marina Ter; Thakur, Geeta; Joober, Ridha

    2006-01-01

    Objective: In a recent study, Thapar and colleagues reported that COMT "gene variant and birth weight predict early-onset antisocial behavior in children" with attention-deficit/hyperactivity disorder. We have attempted to replicate these findings in a group of ADHD children using a similar research design. Method: Children (n = 191)…

  19. The Effects of BDNF Val66Met Gene Polymorphism on Serum BDNF and Cognitive Function in Methamphetamine-Dependent Patients and Normal Controls: A Case-Control Study.

    PubMed

    Su, Hang; Tao, Jingyan; Zhang, Jie; Xie, Ying; Wang, Yue; Zhang, Yu; Han, Bin; Lu, Yuling; Sun, Haiwei; Wei, Youdan; Zou, Shengzhen; Wu, Wenxiu; Zhang, Jiajia; Xu, Ke; Zhang, Xiangyang; He, Jincai

    2015-10-01

    Studies suggest that a functional polymorphism of the brain-derived neurotrophic factor gene (BDNF Val66Met) may contribute to methamphetamine dependence. We hypothesized that this polymorphism had a role in cognitive deficits in methamphetamine-dependent patients and in the relationship of serum BDNF with cognitive impairments. We conducted a case-control study by assessing 194 methamphetamine-dependent patients and 378 healthy volunteers without history of drug use on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the presence of the BDNF Val66Met polymorphism and serum BDNF levels. We showed no significant differences in genotype and allele distributions between the methamphetamine-dependent patients and controls. Some aspects of cognitive function significantly differed in the 2 groups. The serum BDNF levels in methamphetamine-dependent patients were significantly higher than those of the healthy controls. In the patients, partial correlation analysis showed a significant positive correlation between serum BDNF and the delayed memory index score. The RBANS scores showed statistically significant BDNF level × genotype interaction. Further regression analyses showed a significant positive association between BDNF levels and the RBANS total score, immediate memory or attention index among Val homozygote patients, whereas a significant negative association of BDNF levels with the RBANS total score, visuospatial/constructional, or language index was found among Met/Val heterozygous patients. We demonstrated significant impairment on some aspects of cognitive function and increased BDNF levels in methamphetamine-dependent patients as well as genotypic differences in the relationships between BDNF levels and RBANS scores on the BDNF Val66Met polymorphism only in these patients.

  20. BDNF Val66Met Polymorphism Interacts with Sleep Consolidation to Predict Ability to Create New Declarative Memories

    PubMed Central

    Gosselin, Nadia; De Beaumont, Louis; Gagnon, Katia; Baril, Andrée-Ann; Mongrain, Valérie; Blais, Hélène; Montplaisir, Jacques; Gagnon, Jean-François; Pelleieux, Sandra; Poirier, Judes; Carrier, Julie

    2016-01-01

    It is hypothesized that a fundamental function of sleep is to restore an individual’s day-to-day ability to learn and to constantly adapt to a changing environment through brain plasticity. Brain-derived neurotrophic factor (BDNF) is among the key regulators that shape brain plasticity. However, advancing age and carrying the BDNF Met allele were both identified as factors that potentially reduce BDNF secretion, brain plasticity, and memory. Here, we investigated the moderating role of BDNF polymorphism on sleep and next-morning learning ability in 107 nondemented individuals who were between 55 and 84 years of age. All subjects were tested with 1 night of in-laboratory polysomnography followed by a cognitive evaluation the next morning. We found that in subjects carrying the BDNF Val66Val polymorphism, consolidated sleep was associated with significantly better performance on hippocampus-dependent episodic memory tasks the next morning (β-values from 0.290 to 0.434, p ≤ 0.01). In subjects carrying at least one copy of the BDNF Met allele, a more consolidated sleep was not associated with better memory performance in most memory tests (β-values from −0.309 to −0.392, p values from 0.06 to 0.15). Strikingly, increased sleep consolidation was associated with poorer performance in learning a short story presented verbally in Met allele carriers (β = −0.585, p = 0.005). This study provides new evidence regarding the interacting roles of consolidated sleep and BDNF polymorphism in the ability to learn and stresses the importance of considering BDNF polymorphism when studying how sleep affects cognition. PMID:27511011

  1. Gray Matter Volume in Adolescent Anxiety: An Impact of the Brain-Derived Neurotrophic Factor Val[superscript 66]Met Polymorphism?

    ERIC Educational Resources Information Center

    Mueller, Sven C.; Aouidad, Aveline; Gorodetsky, Elena; Goldman, David; Pine, Daniel S.; Ernst, Monique

    2013-01-01

    Objective: Minimal research links anxiety disorders in adolescents to regional gray matter volume (GMV) abnormalities and their modulation by genetic factors. Prior research suggests that a brain-derived neurotrophic factor (BNDF) Val[superscript 66]Met polymorphism may modulate such brain morphometry profiles. Method: Using voxel-based…

  2. Interaction of motor training and intermittent theta burst stimulation in modulating motor cortical plasticity: influence of BDNF Val66Met polymorphism.

    PubMed

    Lee, Mina; Kim, Song E; Kim, Won Sup; Lee, Jungyeun; Yoo, Hye Kyung; Park, Kee-Duk; Choi, Kyoung-Gyu; Jeong, Seon-Yong; Kim, Byung Gon; Lee, Hyang Woon

    2013-01-01

    Cortical physiology in human motor cortex is influenced by behavioral motor training (MT) as well as repetitive transcranial magnetic stimulation protocol such as intermittent theta burst stimulation (iTBS). This study aimed to test whether MT and iTBS can interact with each other to produce additive changes in motor cortical physiology. We hypothesized that potential interaction between MT and iTBS would be dependent on BDNF Val66Met polymorphism, which is known to affect neuroplasticity in the human motor cortex. Eighty two healthy volunteers were genotyped for BDNF polymorphism. Thirty subjects were assigned for MT alone, 23 for iTBS alone, and 29 for MT + iTBS paradigms. TMS indices for cortical excitability and motor map areas were measured prior to and after each paradigm. MT alone significantly increased the motor cortical excitability and expanded the motor map areas. The iTBS alone paradigm also enhanced excitability and increased the motor map areas to a slightly greater extent than MT alone. A combination of MT and iTBS resulted in the largest increases in the cortical excitability, and the representational motor map expansion of MT + iTBS was significantly greater than MT or iTBS alone only in Val/Val genotype. As a result, the additive interaction between MT and iTBS was highly dependent on BDNF Val66Met polymorphism. Our results may have clinical relevance in designing rehabilitative strategies that combine therapeutic cortical stimulation and physical exercise for patients with motor disabilities.

  3. Genotype status of the dopamine-related catechol-O-methyltransferase (COMT) gene corresponds with desirability of “unhealthy” foods

    PubMed Central

    Wallace, Deanna L.; Aarts, Esther; Uquillas, Federico d’Oleire; Dang, Linh C.; Greer, Stephanie M.; Jagust, William J.; D’Esposito, Mark

    2015-01-01

    The role of dopamine is extensively documented in weight regulation and food intake in both animal models and humans. Yet the role of dopamine has not been well studied in individual differences for food desirability. Genotype status of the dopamine-related catechol-O-methyltransferase (COMT) gene has been shown to influence dopamine levels, with greater COMT enzymatic activity in val/val individuals corresponding to greater degradation of dopamine. Decreased dopamine has been associated with poorer cognitive control and diminished goal-directed behavior in various behavioral paradigms. Additionally, dopaminergic-rich regions such as the frontal cortex and dorsal striatum have been shown to be important for supporting food-related decision-making. However, the role of dopamine, as assessed by COMT genotype status, in food desirability has not been fully explored. Therefore, we utilized an individual’s COMT genotype status (n=61) and investigated food desirability based on self-rated “healthy” and “unhealthy” food perceptions. Here we found val/val individuals (n=19) have greater desirability for self-rated “unhealthy” food items, but not self-rated “healthy” food items, as compared to val/met (n=24) and met/met (n=18) individuals (p<0.005). Utilizing an objective health measure for the food items, we also found val/val and val/met individuals have greater desirability for objectively defined “unhealthy” food items, as compared to met/met individuals (p<0.01). This work further substantiates a role of dopamine in food-related behaviors and more specifically in relationship to food desirability for “unhealthy” food items. PMID:25963102

  4. Dopamine Inactivation Efficacy Related to Functional DAT1 and COMT Variants Influences Motor Response Evaluation

    PubMed Central

    Bender, Stephan; Rellum, Thomas; Freitag, Christine; Resch, Franz; Rietschel, Marcella; Treutlein, Jens; Jennen-Steinmetz, Christine; Brandeis, Daniel; Banaschewski, Tobias; Laucht, Manfred

    2012-01-01

    Background Dopamine plays an important role in orienting, response anticipation and movement evaluation. Thus, we examined the influence of functional variants related to dopamine inactivation in the dopamine transporter (DAT1) and catechol-O-methyltransferase genes (COMT) on the time-course of motor processing in a contingent negative variation (CNV) task. Methods 64-channel EEG recordings were obtained from 195 healthy adolescents of a community-based sample during a continuous performance task (A-X version). Early and late CNV as well as motor postimperative negative variation were assessed. Adolescents were genotyped for the COMT Val158Met and two DAT1 polymorphisms (variable number tandem repeats in the 3′-untranslated region and in intron 8). Results The results revealed a significant interaction between COMT and DAT1, indicating that COMT exerted stronger effects on lateralized motor post-processing (centro-parietal motor postimperative negative variation) in homozygous carriers of a DAT1 haplotype increasing DAT1 expression. Source analysis showed that the time interval 500–1000 ms after the motor response was specifically affected in contrast to preceding movement anticipation and programming stages, which were not altered. Conclusions Motor slow negative waves allow the genomic imaging of dopamine inactivation effects on cortical motor post-processing during response evaluation. This is the first report to point towards epistatic effects in the motor system during response evaluation, i.e. during the post-processing of an already executed movement rather than during movement programming. PMID:22649558

  5. Association of BDNF Val66Met Polymorphism and Brain BDNF Levels with Major Depression and Suicide.

    PubMed

    Youssef, Mariam M; Underwood, Mark D; Huang, Yung-Yu; Hsiung, Shu-Chi; Liu, Yan; Simpson, Norman R; Bakalian, Mihran J; Rosoklija, Gorazd B; Dwork, Andrew J; Arango, Victoria; Mann, J John

    2018-06-01

    Brain-derived neurotrophic factor is implicated in the pathophysiology of major depressive disorder and suicide. Both are partly caused by early life adversity, which reduces brain-derived neurotrophic factor protein levels. This study examines the association of brain-derived neurotrophic factor Val66Met polymorphism and brain brain-derived neurotrophic factor levels with depression and suicide. We hypothesized that both major depressive disorder and early life adversity would be associated with the Met allele and lower brain brain-derived neurotrophic factor levels. Such an association would be consistent with low brain-derived neurotrophic factor mediating the effect of early life adversity on adulthood suicide and major depressive disorder. Brain-derived neurotrophic factor Val66Met polymorphism was genotyped in postmortem brains of 37 suicide decedents and 53 nonsuicides. Additionally, brain-derived neurotrophic factor protein levels were determined by Western blot in dorsolateral prefrontal cortex (Brodmann area 9), anterior cingulate cortex (Brodmann area 24), caudal brainstem, and rostral brainstem. The relationships between these measures and major depressive disorder, death by suicide, and reported early life adversity were examined. Subjects with the Met allele had an increased risk for depression. Depressed patients also have lower brain-derived neurotrophic factor levels in anterior cingulate cortex and caudal brainstem compared with nondepressed subjects. No effect of history of suicide death or early life adversity was observed with genotype, but lower brain-derived neurotrophic factor levels in the anterior cingulate cortex were found in subjects who had been exposed to early life adversity and/or died by suicide compared with nonsuicide decedents and no reported early life adversity. This study provides further evidence implicating low brain brain-derived neurotrophic factor and the brain-derived neurotrophic factor Met allele in major depression

  6. Variant Brain-Derived Neurotrophic Factor Val66Met Polymorphism Alters Vulnerability to Stress and Response to Antidepressants

    PubMed Central

    Yu, Hui; Wang, Dong-Dong; Wang, Yue; Liu, Ting; Lee, Francis S.; Chen, Zhe-Yu

    2012-01-01

    Brain-derived neurotrophic factor (BDNF) plays important roles in cell survival, neural plasticity, learning, and stress regulation. However, whether the recently found human BDNF Val66Met (BDNFMet) polymorphism could alter stress vulnerability remains controversial. More importantly, the molecular and structural mechanisms underlying the interaction between the BDNFMet polymorphism and stress are unclear. We found that heterozygous BDNF+/Met mice displayed hypothalamic-pituitary-adrenal axis hyperreactivity, increased depressive-like and anxiety-like behaviors, and impaired working memory compared with WT mice after 7 d restraint stress. Moreover, BDNF+/Met miceexhibited more prominent changes in BDNF levels and apical dendritic spine density in the prefrontal cortex and amygdala after stress, which correlated with the impaired working memory and elevated anxiety-like behaviors. Finally, the depressive-like behaviors in BDNF+/Met mice could be selectively rescued by acute administration of desipramine but not fluoxetine. These data indicate selective behavioral, molecular, and structural deficits resulting from the interaction between stress and the human genetic BDNFMet polymorphism. Importantly, desipramine but not fluoxetine has antidepressant effects on BDNF+/Met mice, suggesting that specific classes of antidepressant may be a more effective treatment option for depressive symptoms in humans with this genetic variant BDNF. PMID:22442074

  7. Biological Effects of COMT Haplotypes and Psychosis Risk in 22q11.2 Deletion Syndrome

    PubMed Central

    Gothelf, Doron; Law, Amanda J.; Frisch, Amos; Chen, Jingshan; Zarchi, Omer; Michaelovsky, Elena; Ren-Patterson, Renee; Lipska, Barbara K.; Carmel, Miri; Kolachana, Bhaskar; Weizman, Abraham; Weinberger, Daniel R.

    2013-01-01

    Background 22q11.2 deletion syndrome (22q11.2DS) is the most common genetic syndrome associated with schizophrenia. The catechol-o-methyltransferase (COMT) gene is located in the obligatory deletion region, and possible associations between COMT variants and neuropsychiatric manifestations in 22q11.2DS have been reported. The purpose of the current study was to evaluate the effect of COMT hemizygosity and molecular haplotypes on gene expression and enzyme activity and its association with psychotic symptoms in 22q11.2DS. Methods Lymphoblast samples were drawn from 53 individuals with 22q11.2DS and 16 typically developing controls. We measured COMT mRNA and protein expression and enzyme activity using standard procedures. The presence of a psychotic disorder and cognitive deficits were also evaluated using structured testing. Results There was a ~50% reduction in COMT mRNA, protein and enzyme activity levels in 22q11.2DS samples. Haplotype analysis revealed clear phenotypic differences between various Val-containing haplotypes on COMT-3′UTR extended mRNA, S-COMT and MB proteins and enzyme activity. The G variant of rs165599, a 3′UTR SNP, was associated with low levels of COMT expression and with the presence of psychosis and lower performance IQ scores in our 22q11.2DS sample. Finally, we demonstrate that the COMT rs74745580 ‘T’ mutation is associated with absent S-COMT expression and very low COMT activity in two 22q11.2DS individuals. Conclusions Our findings confirm a robust effect of COMT hemizygosity on COMT activity and show complex interactions of variants within the COMT gene that influence COMT biology and confound conclusions based on associations with the Val158Met genotype alone. PMID:23992923

  8. Pilot study of association of catechol-O-methyl transferase rs4680 genotypes with acute kidney injury and tubular stress after open heart surgery.

    PubMed

    Albert, Christian; Kube, Johanna; Haase-Fielitz, Anja; Dittrich, Annemarie; Schanze, Denny; Zenker, Martin; Kuppe, Hermann; Hetzer, Roland; Bellomo, Rinaldo; Mertens, Peter R; Haase, Michael

    2014-01-01

    To assess the association of genetic variants of catecholamine-O-methyltransferase (COMT) genotypes with acute kidney injury (AKI) and tubular stress after open heart surgery. We genotyped 195 patients for the COMT-Val158Met polymorphism and measured creatinine, neutrophil gelatinase-associated lipocalin and midkine. We analyzed the association between such polymorphisms and these kidney-related variables. Nonsignificantly more COMT LL patients developed RIFLE-AKI compared with non-LL patients (p = 0.11). Compared with HL and HH patients, LL patients who developed AKI had lower increases in serum creatinine. COMT LL patients had less pronounced release of tubular stress biomarkers (neutrophil gelatinase-associated lipocalin: p = 0.045, midkine: p = 0.072). COMT genotype may associate with different patterns of renal functional changes and tubular stress biomarker release response after open heart surgery.

  9. Brain white matter structure and COMT gene are linked to second-language learning in adults

    PubMed Central

    Mamiya, Ping C.; Richards, Todd L.; Coe, Bradley P.; Eichler, Evan E.; Kuhl, Patricia K.

    2016-01-01

    Adult human brains retain the capacity to undergo tissue reorganization during second-language learning. Brain-imaging studies show a relationship between neuroanatomical properties and learning for adults exposed to a second language. However, the role of genetic factors in this relationship has not been investigated. The goal of the current study was twofold: (i) to characterize the relationship between brain white matter fiber-tract properties and second-language immersion using diffusion tensor imaging, and (ii) to determine whether polymorphisms in the catechol-O-methyltransferase (COMT) gene affect the relationship. We recruited incoming Chinese students enrolled in the University of Washington and scanned their brains one time. We measured the diffusion properties of the white matter fiber tracts and correlated them with the number of days each student had been in the immersion program at the time of the brain scan. We found that higher numbers of days in the English immersion program correlated with higher fractional anisotropy and lower radial diffusivity in the right superior longitudinal fasciculus. We show that fractional anisotropy declined once the subjects finished the immersion program. The relationship between brain white matter fiber-tract properties and immersion varied in subjects with different COMT genotypes. Subjects with the Methionine (Met)/Valine (Val) and Val/Val genotypes showed higher fractional anisotropy and lower radial diffusivity during immersion, which reversed immediately after immersion ended, whereas those with the Met/Met genotype did not show these relationships. Statistical modeling revealed that subjects’ grades in the language immersion program were best predicted by fractional anisotropy and COMT genotype. PMID:27298360

  10. Brain white matter structure and COMT gene are linked to second-language learning in adults.

    PubMed

    Mamiya, Ping C; Richards, Todd L; Coe, Bradley P; Eichler, Evan E; Kuhl, Patricia K

    2016-06-28

    Adult human brains retain the capacity to undergo tissue reorganization during second-language learning. Brain-imaging studies show a relationship between neuroanatomical properties and learning for adults exposed to a second language. However, the role of genetic factors in this relationship has not been investigated. The goal of the current study was twofold: (i) to characterize the relationship between brain white matter fiber-tract properties and second-language immersion using diffusion tensor imaging, and (ii) to determine whether polymorphisms in the catechol-O-methyltransferase (COMT) gene affect the relationship. We recruited incoming Chinese students enrolled in the University of Washington and scanned their brains one time. We measured the diffusion properties of the white matter fiber tracts and correlated them with the number of days each student had been in the immersion program at the time of the brain scan. We found that higher numbers of days in the English immersion program correlated with higher fractional anisotropy and lower radial diffusivity in the right superior longitudinal fasciculus. We show that fractional anisotropy declined once the subjects finished the immersion program. The relationship between brain white matter fiber-tract properties and immersion varied in subjects with different COMT genotypes. Subjects with the Methionine (Met)/Valine (Val) and Val/Val genotypes showed higher fractional anisotropy and lower radial diffusivity during immersion, which reversed immediately after immersion ended, whereas those with the Met/Met genotype did not show these relationships. Statistical modeling revealed that subjects' grades in the language immersion program were best predicted by fractional anisotropy and COMT genotype.

  11. Interaction of Motor Training and Intermittent Theta Burst Stimulation in Modulating Motor Cortical Plasticity: Influence of BDNF Val66Met Polymorphism

    PubMed Central

    Lee, Mina; Kim, Song E.; Kim, Won Sup; Lee, Jungyeun; Yoo, Hye Kyung; Park, Kee-Duk; Choi, Kyoung-Gyu; Jeong, Seon-Yong; Kim, Byung Gon; Lee, Hyang Woon

    2013-01-01

    Cortical physiology in human motor cortex is influenced by behavioral motor training (MT) as well as repetitive transcranial magnetic stimulation protocol such as intermittent theta burst stimulation (iTBS). This study aimed to test whether MT and iTBS can interact with each other to produce additive changes in motor cortical physiology. We hypothesized that potential interaction between MT and iTBS would be dependent on BDNF Val66Met polymorphism, which is known to affect neuroplasticity in the human motor cortex. Eighty two healthy volunteers were genotyped for BDNF polymorphism. Thirty subjects were assigned for MT alone, 23 for iTBS alone, and 29 for MT + iTBS paradigms. TMS indices for cortical excitability and motor map areas were measured prior to and after each paradigm. MT alone significantly increased the motor cortical excitability and expanded the motor map areas. The iTBS alone paradigm also enhanced excitability and increased the motor map areas to a slightly greater extent than MT alone. A combination of MT and iTBS resulted in the largest increases in the cortical excitability, and the representational motor map expansion of MT + iTBS was significantly greater than MT or iTBS alone only in Val/Val genotype. As a result, the additive interaction between MT and iTBS was highly dependent on BDNF Val66Met polymorphism. Our results may have clinical relevance in designing rehabilitative strategies that combine therapeutic cortical stimulation and physical exercise for patients with motor disabilities. PMID:23451258

  12. Polymorphisms in phase I and phase II genes and breast cancer risk and relations to persistent organic pollutant exposure: a case-control study in Inuit women.

    PubMed

    Ghisari, Mandana; Eiberg, Hans; Long, Manhai; Bonefeld-Jørgensen, Eva C

    2014-03-16

    We have previously reported that chemicals belonging to the persistent organic pollutants (POPs) such as perfluorinated compounds (PFAS) and polychlorinated biphenyls (PCBs) are risk factors in Breast Cancer (BC) development in Greenlandic Inuit women. The present case-control study aimed to investigate the main effect of polymorphisms in genes involved in xenobiotic metabolism and estrogen biosynthesis, CYP1A1, CYP1B1, COMT and CYP17, CYP19 and the BRCA1 founder mutation in relation to BC risk and to explore possible interactions between the gene polymorphisms and serum POP levels on BC risk in Greenlandic Inuit women. The study population consisted of 31 BC cases and 115 matched controls, with information on serum levels of POPs. Genotyping was conducted for CYP1A1 (Ile462Val; rs1048943), CYP1B1 (Leu432Val; rs1056836), COMT (Val158Met; rs4680), CYP17A1 (A1> A2; rs743572); CYP19A1 (C> T; rs10046) and CYP19A1 ((TTTA)n repeats) polymorphisms and BRCA1 founder mutation using TaqMan allelic discrimination method and polymerase chain reaction based restriction fragment length polymorphism. The χ2 -test was used to compare categorical variables between cases and controls and the odds ratios were estimated by unconditional logistic regression models. We found an independent association of CYP1A1 (Val) and CYP17 (A1) with BC risk.Furthermore, an increased BC risk was observed for women with high serum levels of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) and carriers of at least: one CYP1A1 variant Val allele; one variant COMT Met allele; or the common CYP17 A1 allele. No combined effects were seen between PFAS exposure and CYP1B1 and CYP19 polymorphisms. The risk of BC was not found significantly associated with exposure to PCBs and OCPs, regardless of genotype for all investigated SNPs. The frequency of the Greenlandic founder mutation in BRCA1 was as expected higher in cases than in controls. The BRCA1 founder mutation and polymorphisms in

  13. Biomarkers of Risk for Post-Traumatic Stress Disorder (PTSD)

    DTIC Science & Technology

    2011-04-01

    transporter (DAT), catechol-o- methyltransferase ( COMT Val66Met), brain-derived neurotrophic factor (BDNF), and polymorphisms in the gene for neuropeptide Y...study which has a larger number of participants and explores these effects more systematically), only one gene, again the COMT Val/Met polymorphism...relatively high or low exposure to combat on the Hoge scale (median split), there was an effect of COMT (B=4.8, p<.01), an effect of combat exposure

  14. Interaction Between 5-HTTLPR and BDNF Val66Met Polymorphisms on HPA Axis Reactivity in Preschoolers

    PubMed Central

    Dougherty, Lea R.; Klein, Daniel N.; Congdon, Eliza; Canli, Turhan; Hayden, Elizabeth P.

    2009-01-01

    This study examined whether the interaction between the serotonin transporter promoter region (5-HTTLPR) and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms was associated with hypothalamic-pituitary-adrenal (HPA) axis reactivity to stress. A community sample of 144 preschool-aged children was genotyped and exposed to stress-inducing laboratory tasks. Salivary cortisol was obtained at four time points during a standardized laboratory assessment before and after stressors involving separation from a parent and frustrating tasks. Children homozygous for the short-5-HTTLPR allele and carrying the Met-BDNF allele evidenced a significantly lower initial level of cortisol, followed by a positive increase in cortisol in response to the laboratory stressors. In contrast, children who were homozygous for the short-5-HTTLPR and the Val-BDNF alleles evidenced a greater decline in cortisol in response to the laboratory stressors. Findings indicated that the BDNF gene moderated the association between 5-HTTLPR and children’s biological stress responses, suggesting that epistatic effects play a role in individual differences in stress regulation, and possibly genetic vulnerability to stress-related disorders. PMID:19914329

  15. The role of the BDNF Val66Met polymorphism in individual differences in long-term memory capacity.

    PubMed

    Montag, Christian; Felten, Andrea; Markett, Sebastian; Fischer, Luise; Winkel, Katja; Cooper, Andrew; Reuter, Martin

    2014-12-01

    The protein brain-derived neurotrophic factor (BDNF) plays an important role in diverse memory processes and is strongly expressed in the hippocampus. The hippocampus itself is a key structure involved in the processing of information from short-term to long-term memory. Due to the putative role of BDNF in memory consolidation, a prominent single nucleotide polymorphism (SNP) on the BDNF gene (BDNF Val66Met) was investigated in the context of long-term memory performance. N=138 students were presented with 40 words from 10 categories, each consisting of eight words such as 'fruits' or 'vehicles' in a memory recognition task (specifically the Deese-Roediger-McDermott Paradigm). Recognition performance was analyzed 25 min after the initial presentation of the word list and subsequently 1 week after the initial presentation. Overall, individual long-term memory performance immediately after learning the word list (T1) and performance 1 week later (T2) did not differ on the basis of the BDNF SNP, but an interaction effect of BDNF Val66Met by time-of-recall was found: Carriers of the Met66+ variant showed the strongest decline in hit rate performance over time.

  16. Elevated Serum Brain-Derived Neurotrophic Factor (BDNF) but not BDNF Gene Val66Met Polymorphism Is Associated with Autism Spectrum Disorders.

    PubMed

    Meng, Wei-Dong; Sun, Shao-Jun; Yang, Jie; Chu, Rui-Xue; Tu, Wenjun; Liu, Qiang

    2017-03-01

    The aim of our study was to illuminate the potential role of brain-derived neurotrophic factor (BDNF) in autism spectrum disorder (ASD). We measured the circulating levels of BDNF in serum and BDNF gene (Val66Met) polymorphisms, in which two indicators were then compared between ASD and normal controls. A total of 82 drug-naïve ASD children and 82 age- and gender-matched normal controls were enrolled in the study. Their serum BDNF levels were detected by the ELISA. BDNF Val66Met polymorphism genotyping was conducted as according to the laboratory's standard protocol in laboratory. The ASD severity assessment was mainly determined by the score of the Childhood Autism Rating Scale (CARS). ELISA assay showed that the mean serum BDNF level of children with ASD was significantly (P < 0.0001) higher than that of the control cases (17.75 ± 5.43 vs. 11.49 ± 2.85 ng/ml; t = 9.236). Besides, the serum BDNF levels and CARS scores (P < 0.0001) were positively related. And, the BDNF genotyping results showed that there was no difference between the ASD cases and the control. Among the children with ASD, the mean serum BDNF level of Met/Met group was lower than other groups. According to the ROC curve generated from our clinical data, the optimal cutoff value of serum BDNF levels, an indicator for diagnosis of ASD, was projected to be 12.50 ng/ml. Thus, it yielded a corresponding sensitivity of 81.7 % and the specificity of 66.9 %. Accordingly, area value under the curve was 0.836 (95 % CI, 0.774-0.897); the positive predictive value (PPV) and the negative predictive value (NPV) were 70.1 and 79.1 %, respectively. These results suggested that rather than Val66Met polymorphism, BDNF was more possible to impact the pathogenesis of ASD.

  17. Interaction between 5-HTTLPR and BDNF Val66Met polymorphisms on HPA axis reactivity in preschoolers.

    PubMed

    Dougherty, Lea R; Klein, Daniel N; Congdon, Eliza; Canli, Turhan; Hayden, Elizabeth P

    2010-02-01

    This study examined whether the interaction between the serotonin transporter promoter region (5-HTTLPR) and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms was associated with hypothalamic-pituitary-adrenal (HPA) axis reactivity to stress. A community sample of 144 preschool-aged children was genotyped and exposed to stress-inducing laboratory tasks. Salivary cortisol was obtained at four time points during a standardized laboratory assessment before and after stressors involving separation from a parent and frustrating tasks. Children homozygous for the short-5-HTTLPR allele and carrying the Met-BDNF allele evidenced a significantly lower initial level of cortisol, followed by a positive increase in cortisol in response to the laboratory stressors. In contrast, children who were homozygous for the short-5-HTTLPR and the Val-BDNF alleles evidenced a greater decline in cortisol in response to the laboratory stressors. Findings indicated that the BDNF gene moderated the association between 5-HTTLPR and children's biological stress responses, suggesting that epistatic effects play a role in individual differences in stress regulation, and possibly genetic vulnerability to stress-related disorders. Copyright 2009 Elsevier B.V. All rights reserved.

  18. Genetic Modulation of Training and Transfer in Older Adults: BDNF Val66Met Polymorphism is Associated with Wider Useful Field of View

    PubMed Central

    Colzato, Lorenza S.; van Muijden, Jesse; Band, Guido P. H.; Hommel, Bernhard

    2011-01-01

    Western society has an increasing proportion of older adults. Increasing age is associated with a general decrease in the control over task-relevant mental processes. In the present study we investigated the possibility that successful transfer of game-based cognitive improvements to untrained tasks in elderly people is modulated by preexisting neuro-developmental factors as genetic variability related to levels of the brain-derived neurotrophic factor (BDNF), an important neuromodulator underlying cognitive processes. We trained participants, genotyped for the BDNF Val66Met polymorphism, on cognitive tasks developed to improve dynamic attention. Pre-training (baseline) and post-training measures of attentional processes (divided and selective attention) were acquired by means of the useful field of view task. As expected, Val/Val homozygous individuals showed larger beneficial transfer effects than Met/-carriers. Our findings support the idea that genetic predisposition modulates transfer effects. PMID:21909331

  19. The Brain-Derived Neurotrophic Factor Val66Met Polymorphism Moderates an Effect of Physical Activity on Working Memory Performance

    PubMed Central

    Erickson, Kirk I.; Banducci, Sarah E.; Weinstein, Andrea M.; MacDonald, Angus W.; Ferrell, Robert E.; Halder, Indrani; Flory, Janine D.; Manuck, Stephen B.

    2014-01-01

    Physical activity enhances cognitive performance, yet individual variability in its effectiveness limits its widespread therapeutic application. Genetic differences might be one source of this variation. For example, carriers of the methionine-specifying (Met) allele of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism have reduced secretion of BDNF and poorer memory, yet physical activity increases BDNF levels. To determine whether the BDNF polymorphism moderated an association of physical activity with cognitive functioning among 1,032 midlife volunteers (mean age = 44.59 years), we evaluated participants’ performance on a battery of tests assessing memory, learning, and executive processes, and evaluated their physical activity with the Paffenbarger Physical Activity Questionnaire. BDNF genotype interacted robustly with physical activity to affect working memory, but not other areas of cognitive functioning. In particular, greater levels of physical activity offset a deleterious effect of the Met allele on working memory performance. These findings suggest that physical activity can modulate domain-specific genetic (BDNF) effects on cognition. PMID:23907543

  20. The relation of serotonin-related gene and COMT gene polymorphisms with criminal behavior in schizophrenic disorder.

    PubMed

    Koh, Kyung Bong; Choi, Eun Hee; Lee, Young-joon; Han, Mooyoung; Choi, Sang-Sup; Kim, So Won; Lee, Min Goo

    2012-02-01

    It has been suggested that patients with schizophrenia might be involved in criminal behavior, such as homicidal and violent behavior. However, the relationship between criminal behavior and genes in patients with schizophrenia has not been clearly elucidated. The objective of this study was to examine the relation between criminal behavior and serotonin-related gene or catechol-O-methyltransferase (COMT) gene polymorphisms in patients with schizophrenia. Serotonin-related and COMT polymorphic markers were assessed by using single nucleotide polymorphism (SNP) genotyping. Ninety-nine crime-related inpatients with schizophrenia (57 homicidal and 42 nonhomicidal violent) and 133 healthy subjects were enrolled between October 2005 and May 2008. Diagnoses were made according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. The genotype frequencies of tryptophan hydroxylase-1 (TPH1) A218C and COMT V158M were compared between groups. The TPH1 CC genotype had 2.7-fold higher odds of crime-related schizophrenia compared with A-carrier genotype after the analysis was controlled for sex and age (OR, 2.69; 95% CI, 1.22 - 5.91; P = .01). In addition, the TPH1 CC genotype had 3.4-fold higher odds of homicidal schizophrenia compared with A-carrier genotype after the analysis was controlled for sex and age (OR, 3.38; 95% CI, 1.40 - 8.18; P = .007). However, no significant differences were found in the frequencies of genotype of COMT polymorphism between criminal schizophrenics and healthy subjects, nor were any significant differences found between nonhomicidal schizophrenics and healthy subjects. These results indicate that the TPH1 CC recessive genotype is likely to be a genetic risk factor for criminal behavior, especially homicidal behavior in patients with schizophrenia. However, COMT gene polymorphisms were not associated with criminal behavior in schizophrenic patients. © Copyright 2012 Physicians Postgraduate Press, Inc.

  1. Harsh parenting and serotonin transporter and BDNF Val66Met polymorphisms as predictors of adolescent depressive symptoms

    PubMed Central

    Koss, Kalsea J.; Cummings, E. Mark; Davies, Patrick T.; Hetzel, Susan; Cicchetti, Dante

    2016-01-01

    Objective Depressive symptoms are prevalent and rise during adolescence. The present study is a prospective investigation of environmental and genetic factors that contribute to the growth in depressive symptoms and the frequency of heightened symptoms during adolescence. Method Participants included 206 mother-father-adolescent triads (M age at T1 = 13.06 years, SD = .51, 52% female). Harsh parenting was observationally assessed during a family conflict paradigm. DNA was extracted from saliva samples and genotyped for the 5-HTTLPR and BDNF Val66Met polymorphisms. Adolescents provide self-reports of depressive symptoms annually across early adolescence. Results The results reveal gene-by-environment (GxE) interactions as predictors of adolescent depressive symptom trajectories in the context of harsh parenting as an environmental risk factor. A BDNF Val66Met x harsh parenting interaction predicted the rise in depressive symptoms across a three-year period while a 5-HTTLPR x harsh parenting interaction predicted greater frequency in elevated depressive symptoms. Conclusions The findings highlight the importance of unique genetic and environmental influences in the development and course of heightened depressive symptoms during adolescence. PMID:27736236

  2. BDNF Val66Met polymorphism and plasma levels in Chinese Han population with obsessive-compulsive disorder and generalized anxiety disorder.

    PubMed

    Wang, Yuan; Zhang, Haiyin; Li, Ying; Wang, Zhen; Fan, Qing; Yu, Shunying; Lin, Zhiguang; Xiao, Zeping

    2015-11-01

    Anxiety disorders are a category of mental disorders characterized by feelings of anxiety and fear, which include generalized anxiety disorder (GAD). Obsessive-Compulsive Disorder (OCD) used to be categorized as anxiety disorder in DSM-IV. However OCD was no longer included in anxiety disorders and came into its own category titled as Obsessive-Compulsive and Related Disorders (OCRD) in DSM-5. It will be interesting to explore is there any different biological characteristics between OCD and anxiety disorders. Brain-derived neurotrophic factor (BDNF) was a potential candidate gene in both OCD and GAD. The results of genetic association studies between BDNF and OCD have been inconsistent. BDNF plasma/serum levels in OCD have been found lower than those in healthy controls. However the heritable reason of the lowered BDNF levels was not well elucidated. The amount of studies about BDNF and GAD were relatively small. The aims of this study were to determine whether single nucleotide polymorphism Val66Met of BDNF was associated with OCD and GAD, to examine BDNF plasma levels in OCD and GAD, and to explore whether Val66Met variation influences BDNF plasma levels. We genotyped Val66Met variation in 148 OCD patients, 108 GAD patients and 99 healthy controls. Within the same sample, BDNF plasma levels were determined in 113 OCD patients, 102 GAD patients and 63 healthy controls. Val66Met variation was not associated with OCD or GAD. BDNF plasma levels in OCD and GAD patients were significant lower than those in healthy controls. Val66Met variation had no influence on BDNF plasma levels. No difference was found between OCD and GAD. Results do not change no matter taking OCD and GAD as one group or separated two. First, the sample size for genotyping was relatively small, which leaded to a low statistical power of the genetic part in this study. Second, we genotyped just one SNP in BDNF gene. Third, parts of the participants did not be assayed for BDNF plasma levels. Our

  3. Impact of DRD2/ANKK1 and COMT Polymorphisms on Attention and Cognitive Functions in Schizophrenia.

    PubMed

    Nkam, Irene; Ramoz, Nicolas; Breton, Florence; Mallet, Jasmina; Gorwood, Philip; Dubertret, Caroline

    2017-01-01

    Cognitive deficits such as poor selective attention and executive functions decline have been reported in patients with schizophrenia. Many studies have emphasized the role of dopamine in regulating cognitive functions in the general population as well as in schizophrenia. However, the relationship between cognitive processes, schizophrenia and dopaminergic candidate genes is an original approach given interesting results. The purpose of the current exploratory study was to examine the interaction of dopaminergic genes (coding for dopamine receptor D2, DRD2, and for Catecholamine-O-Methyl-Transferase, COMT) with the diagnostic of schizophrenia in (i) the executive control of attention, (ii) selective attention, and (iii) executive functions. We recruited 52 patients with schizophrenia and 53 healthy controls who performed the Stroop Color-Word Test, the Attention Network Test and the Wisconsin Card Sorting test. Four single nucleotide polymorphisms (SNPs) in the DRD2 gene (rs6275, rs6277, rs2242592 and rs1800497) and two SNPs in the COMT gene (rs4680 and rs165599) have been genotyped. Patients with schizophrenia performed significantly worse than controls in all cognitive performance, taking into account demographic variables. A significant gene by disease interaction was found for the Stroop interference (p = 0.002) for rs6275 of the DRD2 gene. The COMT Val/Val genotype and schizophrenia were associated with increased number of perseverative errors (p = 0.01). In our study, the DRD2 gene is involved in attention while the COMT gene is implicated in executive functions in patients with schizophrenia.

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

    PubMed

    Raz, Naftali; Daugherty, Ana M; Sethi, Sean K; Arshad, Muzamil; Haacke, E Mark

    2017-08-01

    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 18-74 years). Advanced age, elevated vascular risk, ACE Deletion, and COMT met alleles were linked to lower in- and outflow, with no effects of APOE 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.

  5. Lack of neural compensatory mechanisms of BDNF val66met met carriers and APOE E4 carriers in healthy aging, mild cognitive impairment, and Alzheimer's disease.

    PubMed

    Gomar, Jesus J; Conejero-Goldberg, Concepcion; Huey, Edward D; Davies, Peter; Goldberg, Terry E

    2016-03-01

    Compromises in compensatory neurobiologic mechanisms due to aging and/or genetic factors (i.e., APOE gene) may influence brain-derived neurotrophic factor (BDNF) val66met polymorphism effects on temporal lobe morphometry and memory performance. We studied 2 cohorts from Alzheimer's Disease Neuroimaging Initiative: 175 healthy subjects and 222 with prodromal and established Alzheimer's disease. Yearly structural magnetic resonance imaging and cognitive performance assessments were carried out over 3 years of follow-up. Both cohorts had similar BDNF Val/Val and Met allele carriers' (including both Val/Met and Met/Met individuals) distribution. In healthy subjects, a significant trend for thinner posterior cingulate and precuneus cortices was detected in Met carriers compared to Val homozygotes in APOE E4 carriers, with large and medium effect sizes, respectively. The mild cognitive impairment/Alzheimer's disease cohort showed a longitudinal decline in entorhinal thickness in BDNF Met carriers compared to Val/Val in APOE E4 carriers, with effect sizes ranging from medium to large. In addition, an effect of BDNF genotype was found in APOE E4 carriers for episodic memory (logical memory and ADAS-Cog) and semantic fluency measures, with Met carriers performing worse in all cases. These findings suggest a lack of compensatory mechanisms in BDNF Met carriers and APOE E4 carriers in healthy and pathological aging. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Depressive symptoms in schizophrenia and dopamine and serotonin gene polymorphisms.

    PubMed

    Peitl, Vjekoslav; Štefanović, Mario; Karlović, Dalibor

    2017-07-03

    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. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Enhanced extinction of cocaine seeking in brain-derived neurotrophic factor Val66Met knock-in mice.

    PubMed

    Briand, Lisa A; Lee, Francis S; Blendy, Julie A; Pierce, R Christopher

    2012-03-01

    The Val66Met polymorphism in the brain-derived neurotropic factor (BDNF) gene results in alterations in fear extinction behavior in both human populations and mouse models. However, it is not clear whether this polymorphism plays a similar role in extinction of appetitive behaviors. Therefore, we examined operant learning and extinction of both food and cocaine self-administration behavior in an inbred genetic knock-in mouse strain expressing the variant Bdnf. These mice provide a unique opportunity to relate alterations in aversive and appetitive extinction learning as well as provide insight into how human genetic variation can lead to differences in behavior. BDNF(Met/Met) mice exhibited a severe deficit in operant learning as demonstrated by an inability to learn the food self-administration task. Therefore, extinction experiments were performed comparing wildtype (BDNF(Val/Val) ) animals to mice heterozygous for the Met allele (BDNF(Val/Met) ), which did not differ in food or cocaine self-administration behavior. In contrast to the deficit in fear extinction previously demonstrated in these mice, we found that BDNF(Val/Met) mice exhibited more rapid extinction of cocaine responding compared to wildtype mice. No differences were found between the genotypes in the extinction of food self-administration behavior or the reinstatement of cocaine seeking, indicating that the effect is specific to extinction of cocaine responding. These results suggest that the molecular mechanisms underlying aversive and appetitive extinction are distinct from one another and BDNF may play opposing roles in the two phenomena. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  8. Variant BDNF (Val66Met) polymorphism contributes to developmental and estrous-stage-specific expression of anxiety-like behavior in female mice

    PubMed Central

    Bath, Kevin G.; Chuang, Jocelyn; Spencer-Segal, Joanna L.; Amso, Dima; Altemus, Margaret; McEwen, Bruce S.; Lee, Francis S.

    2012-01-01

    Background Most anxiety and depressive disorders are twice as common in women compared to men and the sex difference in prevalence typically emerges during adolescence. Hormonal changes across the menstrual cycle and during the postpartum and peri-menopausal periods are associated with increased risk for anxiety and depression symptoms. In humans and animals, reduced brain derived neurotrophic factor (BDNF) has been associated with increased expression of affective pathology. Recently, a single nucleotide polymorphism (SNP) in the BDNF gene (BDNF Val66Met), which reduces BDNF bioavailability, has been identified in humans and associated with a variety of neuropsychiatric disorders. Although BDNF expression can be directly influenced by estrogen and progesterone, the potential impact of the BDNF Val66Met SNP on sensitivity to reproductive hormone changes remains an open question. Approach As a predictive model, we used female mice in which the human SNP (BDNF Val66Met) was inserted into the mouse BDNF gene. Using standard behavioral paradigms, we tested the impact of this SNP on age and estrous-cycle specific expression of anxiety-like behaviors. Results Mice homozygous for the BDNF Val66Met SNP begin to exhibit increased anxiety-like behaviors over prepubertal and early adult development, show significant fluctuations in anxiety-like behaviors over the estrous cycle, and as adults differ from wild-type mice by showing significant fluctuations in anxiety-like behaviors over the estrous cycle, specifically more anxiety-like behaviors during the estrus phase. Conclusions These findings have implications regarding the potential role of this SNP in contributing to developmental and reproductive hormone-dependent changes in affective disorders in humans. PMID:22552045

  9. BDNF Val66Met in preclinical Alzheimer's disease is associated with short-term changes in episodic memory and hippocampal volume but not serum mBDNF.

    PubMed

    Lim, Yen Ying; Rainey-Smith, Stephanie; Lim, Yoon; Laws, Simon M; Gupta, Veer; Porter, Tenielle; Bourgeat, Pierrick; Ames, David; Fowler, Christopher; Salvado, Olivier; Villemagne, Victor L; Rowe, Christopher C; Masters, Colin L; Zhou, Xin Fu; Martins, Ralph N; Maruff, Paul

    2017-11-01

    The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism Met allele exacerbates amyloid (Aβ) related decline in episodic memory (EM) and hippocampal volume (HV) over 36-54 months in preclinical Alzheimer's disease (AD). However, the extent to which Aβ+ and BDNF Val66Met is related to circulating markers of BDNF (e.g. serum) is unknown. We aimed to determine the effect of Aβ and the BDNF Val66Met polymorphism on levels of serum mBDNF, EM, and HV at baseline and over 18-months. Non-demented older adults (n = 446) underwent Aβ neuroimaging and BDNF Val66Met genotyping. EM and HV were assessed at baseline and 18 months later. Fasted blood samples were obtained from each participant at baseline and at 18-month follow-up. Aβ PET neuroimaging was used to classify participants as Aβ- or Aβ+. At baseline, Aβ+ adults showed worse EM impairment and lower serum mBDNF levels relative to Aβ- adults. BDNF Val66Met polymorphism did not affect serum mBDNF, EM, or HV at baseline. When considered over 18-months, compared to Aβ- Val homozygotes, Aβ+ Val homozygotes showed significant decline in EM and HV but not serum mBDNF. Similarly, compared to Aβ+ Val homozygotes, Aβ+ Met carriers showed significant decline in EM and HV over 18-months but showed no change in serum mBDNF. While allelic variation in BDNF Val66Met may influence Aβ+ related neurodegeneration and memory loss over the short term, this is not related to serum mBDNF. Longer follow-up intervals may be required to further determine any relationships between serum mBDNF, EM, and HV in preclinical AD.

  10. Epistasis between dopamine regulating genes identifies a nonlinear response of the human hippocampus during memory tasks.

    PubMed

    Bertolino, Alessandro; Di Giorgio, Annabella; Blasi, Giuseppe; Sambataro, Fabio; Caforio, Grazia; Sinibaldi, Lorenzo; Latorre, Valeria; Rampino, Antonio; Taurisano, Paolo; Fazio, Leonardo; Romano, Raffaella; Douzgou, Sofia; Popolizio, Teresa; Kolachana, Bhaskar; Nardini, Marcello; Weinberger, Daniel R; Dallapiccola, Bruno

    2008-08-01

    Dopamine modulation of neuronal activity in prefrontal cortex maps to an inverted U-curve. Dopamine is also an important factor in regulation of hippocampal mediated memory processing. Here, we investigated the effect of genetic variation of dopamine inactivation via catechol-O-methyltransferase (COMT) and the dopamine transporter (DAT) on hippocampal activity in healthy humans during different memory conditions. Using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in 82 subjects matched for a series of demographic and genetic variables, we studied the effect of the COMT valine (Val)(158)methionine (Met) and the DAT 3' variable number tandem repeat (VNTR) polymorphisms on function of the hippocampus during encoding of recognition memory and during working memory. Our results consistently demonstrated a double dissociation so that DAT 9-repeat carrier alleles modulated activity in the hippocampus in the exact opposite direction of DAT 10/10-repeat alleles based on COMT Val(158)Met genotype during different memory conditions. Similar results were evident in ventrolateral and dorsolateral prefrontal cortex. These findings suggest that genetically determined dopamine signaling during memory processing maps to a nonlinear relationship also in the hippocampus. Our data also demonstrate in human brain epistasis of two genes implicated in dopamine signaling on brain activity during different memory conditions.

  11. Race moderates the association of Catechol-O-methyltransferase genotype and posttraumatic stress disorder in preschool children.

    PubMed

    Humphreys, Kathryn L; Scheeringa, Michael S; Drury, Stacy S

    2014-10-01

    The present study sought to replicate previous findings of an association between the Catechol-O-methyltransferase (COMT) val158met polymorphism with posttraumatic stress disorder (PTSD) and symptomatology in a novel age group, preschool children. COMT genotype was determined in a sample of 171 3-6-year-old trauma-exposed children. PTSD was assessed with a semistructured interview. Accounting for sex, trauma type, and age, genotype was examined in relation to categorical and continuous measures of PTSD both controlling for race and within the two largest racial categories (African American [AA] and European American [EA]). Race significantly moderated the association between genotype and PTSD. Specifically, the genotype associated with increased PTSD symptoms in one racial group had the opposite association in the other racial group. For AA children the met/met genotype was associated with more PTSD symptoms. However, for EA children, val allele carriers had more PTSD symptoms. Whereas every AA child with the met/met genotype met criteria for PTSD, none of the EA children with the met/met genotype did. This genetic association with COMT genotype, in both races but in opposite directions, was most associated with increased arousal symptoms. These findings replicate previous findings in participants of African descent, highlight the moderating effect of race on the association between COMT genotype and PTSD, and provide direct evidence that consideration of population stratification within gene-by-environment studies is valuable to prevent false negative findings.

  12. Race Moderates the Association of Catechol-O-methyltransferase Genotype and Posttraumatic Stress Disorder in Preschool Children

    PubMed Central

    Humphreys, Kathryn L.; Scheeringa, Michael S.

    2014-01-01

    Abstract Objective: The present study sought to replicate previous findings of an association between the Catechol-O-methyltransferase (COMT) val158met polymorphism with posttraumatic stress disorder (PTSD) and symptomatology in a novel age group, preschool children. Methods: COMT genotype was determined in a sample of 171 3–6-year-old trauma-exposed children. PTSD was assessed with a semistructured interview. Accounting for sex, trauma type, and age, genotype was examined in relation to categorical and continuous measures of PTSD both controlling for race and within the two largest racial categories (African American [AA] and European American [EA]). Results: Race significantly moderated the association between genotype and PTSD. Specifically, the genotype associated with increased PTSD symptoms in one racial group had the opposite association in the other racial group. For AA children the met/met genotype was associated with more PTSD symptoms. However, for EA children, val allele carriers had more PTSD symptoms. Whereas every AA child with the met/met genotype met criteria for PTSD, none of the EA children with the met/met genotype did. This genetic association with COMT genotype, in both races but in opposite directions, was most associated with increased arousal symptoms. Conclusions: These findings replicate previous findings in participants of African descent, highlight the moderating effect of race on the association between COMT genotype and PTSD, and provide direct evidence that consideration of population stratification within gene-by-environment studies is valuable to prevent false negative findings. PMID:25329975

  13. BDNF Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer's Prevention

    PubMed Central

    Boots, Elizabeth A.; Schultz, Stephanie A.; Clark, Lindsay R.; Racine, Annie M.; Darst, Burcu F.; Koscik, Rebecca L.; Carlsson, Cynthia M.; Gallagher, Catherine L.; Hogan, Kirk J.; Bendlin, Barbara B.; Asthana, Sanjay; Sager, Mark A.; Hermann, Bruce P.; Christian, Bradley T.; Dubal, Dena B.; Engelman, Corinne D.; Johnson, Sterling C.

    2017-01-01

    Objective: To examine the influence of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on longitudinal cognitive trajectories in a large, cognitively healthy cohort enriched for Alzheimer disease (AD) risk and to understand whether β-amyloid (Aβ) burden plays a moderating role in this relationship. Methods: One thousand twenty-three adults (baseline age 54.94 ± 6.41 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent BDNF genotyping and cognitive assessment at up to 5 time points (average follow-up 6.92 ± 3.22 years). A subset (n = 140) underwent 11C-Pittsburgh compound B (PiB) scanning. Covariate-adjusted mixed-effects regression models were used to elucidate the effect of BDNF on cognitive trajectories in 4 cognitive domains, including verbal learning and memory, speed and flexibility, working memory, and immediate memory. Secondary mixed-effects regression models were conducted to examine whether Aβ burden, indexed by composite PiB load, modified any observed BDNF-related cognitive trajectories. Results: Compared to BDNF Val/Val homozygotes, Met carriers showed steeper decline in verbal learning and memory (p = 0.002) and speed and flexibility (p = 0.017). In addition, Aβ burden moderated the relationship between BDNF and verbal learning and memory such that Met carriers with greater Aβ burden showed even steeper cognitive decline (p = 0.033). Conclusions: In a middle-aged cohort with AD risk, carriage of the BDNF Met allele was associated with steeper decline in episodic memory and executive function. This decline was exacerbated by greater Aβ burden. These results suggest that the BDNF Val66Met polymorphism may play an important role in cognitive decline and could be considered as a target for novel AD therapeutics. PMID:28468845

  14. BDNF Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer's Prevention.

    PubMed

    Boots, Elizabeth A; Schultz, Stephanie A; Clark, Lindsay R; Racine, Annie M; Darst, Burcu F; Koscik, Rebecca L; Carlsson, Cynthia M; Gallagher, Catherine L; Hogan, Kirk J; Bendlin, Barbara B; Asthana, Sanjay; Sager, Mark A; Hermann, Bruce P; Christian, Bradley T; Dubal, Dena B; Engelman, Corinne D; Johnson, Sterling C; Okonkwo, Ozioma C

    2017-05-30

    To examine the influence of the brain-derived neurotrophic factor ( BDNF ) Val66Met polymorphism on longitudinal cognitive trajectories in a large, cognitively healthy cohort enriched for Alzheimer disease (AD) risk and to understand whether β-amyloid (Aβ) burden plays a moderating role in this relationship. One thousand twenty-three adults (baseline age 54.94 ± 6.41 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent BDNF genotyping and cognitive assessment at up to 5 time points (average follow-up 6.92 ± 3.22 years). A subset (n = 140) underwent 11 C-Pittsburgh compound B (PiB) scanning. Covariate-adjusted mixed-effects regression models were used to elucidate the effect of BDNF on cognitive trajectories in 4 cognitive domains, including verbal learning and memory, speed and flexibility, working memory, and immediate memory. Secondary mixed-effects regression models were conducted to examine whether Aβ burden, indexed by composite PiB load, modified any observed BDNF -related cognitive trajectories. Compared to BDNF Val/Val homozygotes, Met carriers showed steeper decline in verbal learning and memory ( p = 0.002) and speed and flexibility ( p = 0.017). In addition, Aβ burden moderated the relationship between BDNF and verbal learning and memory such that Met carriers with greater Aβ burden showed even steeper cognitive decline ( p = 0.033). In a middle-aged cohort with AD risk, carriage of the BDNF Met allele was associated with steeper decline in episodic memory and executive function. This decline was exacerbated by greater Aβ burden. These results suggest that the BDNF Val66Met polymorphism may play an important role in cognitive decline and could be considered as a target for novel AD therapeutics. © 2017 American Academy of Neurology.

  15. Dopaminergic and Serotonergic Genotypes and the Subjective Experiences of Hypnosis.

    PubMed

    Katonai, E R; Szekely, Anna; Vereczkei, A; Sasvari-Szekely, Maria; Bányai, Éva I; Varga, Katalin

    2017-01-01

    Hypnotizability is related to the Val 158 Met polymorphism of the COMT gene. The authors' aim was to find associations between candidate genes and subjective dimensions of hypnosis; 136 subjects participated in hypnosis and noninvasive DNA sampling. The phenomenological dimensions were tapped by the Archaic Involvement Measure (AIM), the Phenomenology of Consciousness Inventory (PCI), and the Dyadic Interactional Harmony Questionnaire (DIH). The main results were that the "Need of dependence" subscale of AIM was associated with the COMT genotypes. The GG subgroup showed higher scores, whereas AA had below average scores on the majority of the subjective measures. An association between the 5-HTTLPR polymorphism and the intimacy scores on the DIH was also evident. The effects are discussed in the social-psychobiological model of hypnosis.

  16. Associations between glutathione S-transferase pi Ile105Val and glyoxylate aminotransferase Pro11Leu and Ile340Met polymorphisms and early-onset oxaliplatin-induced neuropathy.

    PubMed

    Kanai, Masashi; Yoshioka, Akira; Tanaka, Shiro; Nagayama, Satoshi; Matsumoto, Shigemi; Nishimura, Takafumi; Niimi, Miyuki; Teramukai, Satoshi; Takahashi, Ryo; Mori, Yukiko; Kitano, Toshiyuki; Ishiguro, Hiroshi; Yanagihara, Kazuhiro; Chiba, Tsutomu; Fukushima, Masanori; Matsuda, Fumihiko

    2010-04-01

    Although the risk of oxaliplatin-induced neuropathy depends on cumulative oxaliplatin dose, susceptibility to this adverse event differs greatly among patients. In this study, we investigated the associations between oxaliplatin-induced neuropathy and the following polymorphisms: glutathione S-transferase pi (GSTP1) Ile(105)Val, and glyoxylate aminotransferase (AGXT) Pro(11)Leu and AGXT Ile(340)Met. Eighty-two Japanese patients with histologically confirmed colorectal cancer who received at least six cycles of the modified FOLFOX6 (m-FOLFOX6) regimen were enrolled. To minimize differences in cumulative oxaliplatin dose between patients, oxaliplatin-induced neuropathy was evaluated using an oxaliplatin-specific scale during the 2-week period after completion of the sixth cycle of treatment. Forty-four patients developed grade 2/3 oxaliplatin-induced neuropathy. There were more patients carrying at least one GSTP1(105)Val allele among the group with grade 2/3 neuropathy (18/44, 41%) than among the group with grade 1 neuropathy (9/38, 24%), although the difference was not statistically significant (P=0.098). There were similar numbers of patients carrying at least one AGXT(105)Met allele in the grade 2/3 neuropathy (7/44, 16%) and grade 1 neuropathy groups (5/38, 13%; P=0.725). The AGXT(11)Leu allele was not found in any of our patients or controls. We found no significant association between oxaliplatin-induced neuropathy and the GSTP1 Ile(105)Val and AGXT Ile(340)Met polymorphisms. Given that no AGXT(11)Leu allele was found among our study population (n=177), evaluating this polymorphism in Japanese patients in future studies is likely to be uninformative.

  17. The BDNFval66met polymorphism and individual differences in temperament in 4-month-old infants: A pilot study.

    PubMed

    Giusti, Lorenzo; Provenzi, Livio; Tavian, Daniela; Missaglia, Sara; Butti, Niccolò; Montirosso, Rosario

    2017-05-01

    Individual differences in infants' temperament are under genetic control. We investigated the association between brain-derived-neurotrophic-factor (BDNF val66met ) polymorphism and temperament in 63 full-term infants. Met-carriers (N=25) had lower Regulatory capacities compared to val-homozygotes (N=38). These findings suggest that the BDNF polymorphism affects early temperament individual differences. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. The influence of high intensity exercise and the Val66Met polymorphism on circulating BDNF and locomotor learning.

    PubMed

    Helm, Erin E; Matt, Kathleen S; Kirschner, Kenneth F; Pohlig, Ryan T; Kohl, Dave; Reisman, Darcy S

    2017-10-01

    Brain-derived neurotrophic factor (BDNF) has been directly related to exercise-enhanced motor performance in the neurologically injured animal model; however literature concerning the role of BDNF in the enhancement of motor learning in the human population is limited. Previous studies in healthy subjects have examined the relationship between intensity of an acute bout of exercise, increases in peripheral BDNF and motor learning of a simple isometric upper extremity task. The current study examined the role of high intensity exercise on upregulation of peripheral BDNF levels as well as the role of high intensity exercise in mediation of motor learning and retention of a novel locomotor task in neurologically intact adults. In addition, the impact of a single nucleotide polymorphism in the BDNF gene (Val66Met) in moderating the relationship between exercise and motor learning was explored. It was hypothesized that participation in high intensity exercise prior to practicing a novel walking task (split-belt treadmill walking) would elicit increases in peripheral BDNF as well as promote an increased rate and magnitude of within session learning and retention on a second day of exposure to the walking task. Within session learning and retention would be moderated by the presence or absence of Val66Met polymorphism. Fifty-four neurologically intact participants participated in two sessions of split-belt treadmill walking. Step length and limb phase were measured to assess learning of spatial and temporal parameters of walking. Serum BDNF was collected prior to and immediately following either high intensity exercise or 5min of quiet rest. The results demonstrated that high intensity exercise provides limited additional benefit to learning of a novel locomotor pattern in neurologically intact adults, despite increases in circulating BDNF. In addition, presence of a single nucleotide polymorphism on the BDNF gene did not moderate the magnitude of serum BDNF increases

  19. No Association of BDNF, COMT, MAOA, SLC6A3, and SLC6A4 Genes and Depressive Symptoms in a Sample of Healthy Colombian Subjects.

    PubMed

    González-Giraldo, Yeimy; Camargo, Andrés; López-León, Sandra; Forero, Diego A

    2015-01-01

    Background. Major depressive disorder (MDD) is the second cause of years lived with disability around the world. A large number of studies have been carried out to identify genetic risk factors for MDD and related endophenotypes, mainly in populations of European and Asian descent, with conflicting results. The main aim of the current study was to analyze the possible association of five candidate genes and depressive symptoms in a Colombian sample of healthy subjects. Methods and Materials. The Spanish adaptation of the Hospital Anxiety and Depression Scale (HADS) was applied to one hundred eighty-eight healthy Colombian subjects. Five functional polymorphisms were genotyped using PCR-based assays: BDNF-Val66Met (rs6265), COMT-Val158Met (rs4680), SLC6A4-HTTLPR (rs4795541), MAOA-uVNTR, and SLC6A3-VNTR (rs28363170). Result. We did not find significant associations with scores of depressive symptoms, derived from the HADS, for any of the five candidate genes (nominal p values >0.05). In addition, we did not find evidence of significant gene-gene interactions. Conclusion. This work is one of the first studies of candidate genes for depressive symptoms in a Latin American sample. Study of additional genetic and epigenetic variants, taking into account other pathophysiological theories, will help to identify novel candidates for MDD in populations around the world.

  20. The Brain-Derived Neurotrophic Factor Val66Met Polymorphism, Delivery Method, Birth Weight, and Night Sleep Duration as Determinants of Obesity in Vietnamese Children of Primary School Age.

    PubMed

    Tuyet, Le Thi; Nhung, Bui Thi; Dao, Duong Thi Anh; Hanh, Nguyen Thi Hong; Tuyen, Le Danh; Binh, Tran Quang; Thuc, Vu Thi Minh

    2017-10-01

    Obesity is a complex disease that involves both environmental and genetic factors in its pathogenesis. Several studies have identified multiple obesity-associated loci in many populations. However, their contribution to obesity in the Vietnamese population is not fully described, especially in children. The study aimed to investigate the association of obesity with Val66Met polymorphism in brain-derived neurotrophic factor (BDNF) gene, delivery method, birth weight, and lifestyle factors in Vietnamese primary school children. A case-control study was conducted on 559 children aged 6-11 years (278 obese cases and 281 normal controls). The obesity of the children was classified using both criteria of International Obesity Task Force (IOTF, 2000) and World Health Organization (WHO, 2007). Lifestyle factors, birth delivery, and birth weight of the children were self-reported by parents. The BDNF genotype was analyzed using the polymerase chain reaction-restriction fragment length polymorphism method. Association was evaluated by multivariate logistic regression and cross-validated by the Bayesian model averaging method. The most significantly independent factors for obesity were delivery method (cesarean section vs. vaginal delivery, β = 0.56, p = 0.007), birth weight (>3500 to <4000 g vs. 2500-3500 g, β = 0.52, p = 0.035; ≥4000 g vs. 2500-3500 g, β = 1.06, p = 0.015), night sleep duration (<8 h/day vs. ≥8 h/day, β = 0.99, p < 0.0001), and BDNF Val66Met polymorphism (AA and GG vs. AG, β = 0.38, p = 0.039). The study suggested the significant association of delivery method, birth weight, night sleep duration, and BDNF Val66Met polymorphism, with obesity in Vietnamese primary school children.

  1. The BDNF polymorphism Val66Met may be predictive of swallowing improvement post pharyngeal electrical stimulation in dysphagic stroke patients.

    PubMed

    Essa, H; Vasant, D H; Raginis-Zborowska, A; Payton, A; Michou, E; Hamdy, S

    2017-08-01

    The aim of this study was to explore the effect of brain-derived neurotrophic factor (BDNF) polymorphism rs6265 (Val66Met) in both "natural" and treatment induced recovery of swallowing after dysphagic stroke. Sixteen dysphagic stroke patients that completed a single-blind randomized sham controlled trial of pharyngeal electrical stimulation (PES) within 6 weeks of their stroke (N=38), were genotyped for the BDNF SNP Val66Met (rs6265) from saliva samples. These patients received active or sham PES according to randomized allocation. PES was delivered at a set frequency (5 Hz), intensity (75% of maximal tolerated), and duration (10 minutes) once a day for three consecutive days. Clinical measurements were taken from patients at baseline, 2 weeks and 3 months post entering the study. Changes in swallowing ability based on the dysphagia severity rating scale (DSRS) were compared between active and sham groups and associated with BDNF SNP status. In the active stimulation group, patients with the Met BDNF allele demonstrated significantly greater improvements in DSRS at 3 months compared to patients homozygous for the Val allele (P=.009). By comparison, there were no significant associations at the 2 week stage in either the active or sham group, or at 3 month in the sham group. Functional scores including the Barthel Index and modified Rankin scale were also unaffected by BDNF status. Our findings suggest an association between BDNF and stimulation induced swallowing recovery. Further work will be required to validate these observations and demonstrate clinical utility in patients. © 2017 John Wiley & Sons Ltd.

  2. Is less really more: Does a prefrontal efficiency genotype actually confer better performance when working memory becomes difficult?

    PubMed

    Ihne, Jessica L; Gallagher, Natalie M; Sullivan, Marie; Callicott, Joseph H; Green, Adam E

    2016-01-01

    Perhaps the most widely studied effect to emerge from the combination of neuroimaging and human genetics is the association of the COMT-Val(108/158)Met polymorphism with prefrontal activity during working memory. COMT-Val is a putative risk factor in schizophrenia, which is characterized by disordered prefrontal function. Work in healthy populations has sought to characterize mechanisms by which the valine (Val) allele may lead to disadvantaged prefrontal cognition. Lower activity in methionine (Met) carriers has been interpreted as advantageous neural efficiency. Notably, however, studies reporting COMT effects on neural efficiency have generally not reported working memory performance effects. Those studies have employed relatively low/easy working memory loads. Higher loads are known to elicit individual differences in working memory performance that are not visible at lower loads. If COMT-Met confers greater neural efficiency when working memory is easy, a reasonable prediction is that Met carriers will be better able to cope with increasing demand for neural resources when working memory becomes difficult. To our knowledge, this prediction has thus far gone untested. Here, we tested performance on three working memory tasks. Performance on each task was measured at multiple levels of load/difficulty, including loads more demanding than those used in prior studies. We found no genotype-by-load interactions or main effects of COMT genotype on accuracy or reaction time. Indeed, even testing for performance differences at each load of each task failed to find a single significant effect of COMT genotype. Thus, even if COMT genotype has the effects on prefrontal efficiency that prior work has suggested, such effects may not directly impact high-load working memory ability. The present findings accord with previous evidence that behavioral effects of COMT are small or nonexistent and, more broadly, with a growing consensus that substantial effects on phenotype will

  3. Effects of sex and COMT genotype on environmentally modulated cognitive control in mice

    PubMed Central

    Papaleo, Francesco; Erickson, Lucy; Liu, Guangping; Chen, Jingshan; Weinberger, Daniel R.

    2012-01-01

    Cognitive functioning differs between males and females, likely in part related to genetic dimorphisms. An example of a common genetic variation reported to have sexually dimorphic effects on cognition and temperament in humans is the Val/Met polymorphism in catechol-O-methyltransferase (COMT). We tested male and female wild-type mice (+/+) and their COMT knockout littermates (+/− and −/−) in the five-choice serial reaction time task (5CSRTT) to investigate the effects of sex, COMT genotype, and their interactions with environmental manipulations of cognitive functions such as attention, impulsivity, compulsivity, motivation, and rule-reversal learning. No sex- or COMT-dependent differences were present in the basic acquisition of the five-choice serial reaction time task. In contrast, specific environmental manipulations revealed a variety of sex- and COMT-dependent effects. Following an experimental change to trigger impulsive responding, the sexes showed similar increases in impulsiveness, but males eventually habituated whereas females did not. Moreover, COMT knockout mice were more impulsive compared with wild-type littermates. Manipulations involving mild stress adversely affected cognitive performance in males, and particularly COMT knockout males, but not in females. In contrast, following amphetamine treatment, subtle sex by genotype and sex by treatment interactions emerged primarily limited to compulsive behavior. After repeated testing, female mice showed improved performance, working harder and eventually outperforming males. Finally, removing the food-restriction condition enhanced sex and COMT differences, revealing that overall, females outperform males and COMT knockout males outperform their wild-type littermates. These findings illuminate complex sex- and COMT-related effects and their interactions with environmental factors to influence specific executive cognitive domains. PMID:23169629

  4. BDNF Val66Met is Associated with Introversion and Interacts with 5-HTTLPR to Influence Neuroticism

    PubMed Central

    Terracciano, Antonio; Tanaka, Toshiko; Sutin, Angelina R; Deiana, Barbara; Balaci, Lenuta; Sanna, Serena; Olla, Nazario; Maschio, Andrea; Uda, Manuela; Ferrucci, Luigi; Schlessinger, David; Costa, Paul T

    2010-01-01

    Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurotransmission, and has been linked to neuroticism, a major risk factor for psychiatric disorders. A recent genome-wide association (GWA) scan, however, found the BDNF Val66Met polymorphism (rs6265) associated with extraversion but not with neuroticism. In this study, we examine the links between BDNF and personality traits, assessed using the Revised NEO Personality Inventory (NEO-PI-R), in a sample from SardiNIA (n=1560) and the Baltimore Longitudinal Study of Aging (BLSA; n=1131). Consistent with GWA results, we found that BDNF Met carriers were more introverted. By contrast, in both samples and in a meta-analysis inclusive of published data (n=15251), we found no evidence for a main effect of BDNF Val66Met on neuroticism. Finally, on the basis of recent reports of an epistatic effect between BDNF and the serotonin transporter, we explored a Val66Met × 5-HTTLPR interaction in a larger SardiNIA sample (n=2333). We found that 5-HTTLPR LL carriers scored lower on neuroticism in the presence of the BDNF Val variant, but scored higher on neuroticism in the presence of the BDNF Met variant. Our findings support the association between the BDNF Met variant and introversion and suggest that BDNF interacts with the serotonin transporter gene to influence neuroticism. PMID:20042999

  5. The brain-derived neurotrophic factor Val66Met polymorphism is associated with reduced functional magnetic resonance imaging activity in the hippocampus and increased use of caudate nucleus-dependent strategies in a human virtual navigation task

    PubMed Central

    Banner, Harrison; Bhat, Venkataramana; Etchamendy, Nicole; Joober, Ridha; Bohbot, Véronique D

    2011-01-01

    Multiple memory systems are involved in parallel processing of spatial information during navigation. A series of studies have distinguished between hippocampus-dependent ‘spatial’ navigation, which relies on knowledge of the relationship between landmarks in one’s environment to build a cognitive map, and habit-based ‘response’ learning, which requires the memorization of a series of actions and is mediated by the caudate nucleus. Studies have demonstrated that people spontaneously use one of these two alternative navigational strategies with almost equal frequency to solve a given navigation task, and that strategy correlates with functional magnetic resonance imaging (fMRI) activity and grey matter density. Although there is evidence for experience modulating grey matter in the hippocampus, genetic contributions may also play an important role in the hippocampus and caudate nucleus. Recently, the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene has emerged as a possible inhibitor of hippocampal function. We have investigated the role of the BDNF Val66Met polymorphism on virtual navigation behaviour and brain activation during an fMRI navigation task. Our results demonstrate a genetic contribution to spontaneous strategies, where ‘Met’ carriers use a response strategy more frequently than individuals homozygous for the ‘Val’ allele. Additionally, we found increased hippocampal activation in the Val group relative to the Met group during performance of a virtual navigation task. Our results support the idea that the BDNF gene with the Val66Met polymorphism is a novel candidate gene involved in determining spontaneous strategies during navigation behaviour. PMID:21255124

  6. Brain catechol-o-methyltransferase (COMT) inhibition by tolcapone counteracts recognition memory deficits in normal and chronic phencyclidine-treated rats and in COMT-Val transgenic mice

    PubMed Central

    Detrait, E.R.; Carr, G.V.; Ferraille, S.; Weinberger, D.R.; Lamberty, Y.

    2015-01-01

    The critical involvement of dopamine in cognitive processes has been well established, suggesting therapies targeting dopamine metabolism may alleviate cognitive dysfunction. COMT is a catecholamine-degrading enzyme, the substrates of which include dopamine, epinephrine, and norepinephrine. The present work illustrates the potential therapeutic efficacy of COMT inhibition for alleviating cognitive impairment. A brain penetrant COMT inhibitor, tolcapone, was tested in normal and phencyclidine (PCP)-treated rats and COMT–Val transgenic mice. In a Novel Object Recognition (NOR) procedure, tolcapone counteracted a 24h-dependent forgetting of a familiar object and counteracted PCP-induced recognition deficits in the rats at doses ranging from 7.5 to 30 mg/kg. In contrast, entacapone, a COMT inhibitor which does not readily cross the blood-brain barrier failed to show efficacy at doses up to 30mg/kg. Tolcapone at a dose of 30 mg/kg also improved NOR performance in the transgenic mice, which showed clear recognition deficits. Complementing earlier studies, our results indicate that central inhibition of COMT positively impacts recognition memory processes and might constitute an appealing treatment for cognitive dysfunction related to neuropsychiatric disorders. PMID:26919286

  7. Cerebellar transcranial direct current stimulation interacts with BDNF Val66Met in motor learning.

    PubMed

    van der Vliet, Rick; Jonker, Zeb D; Louwen, Suzanne C; Heuvelman, Marco; de Vreede, Linda; Ribbers, Gerard M; De Zeeuw, Chris I; Donchin, Opher; Selles, Ruud W; van der Geest, Jos N; Frens, Maarten A

    2018-04-11

    Cerebellar transcranial direct current stimulation has been reported to enhance motor associative learning and motor adaptation, holding promise for clinical application in patients with movement disorders. However, behavioral benefits from cerebellar tDCS have been inconsistent. Identifying determinants of treatment success is necessary. BDNF Val66Met is a candidate determinant, because the polymorphism is associated with motor skill learning and BDNF is thought to mediate tDCS effects. We undertook two cerebellar tDCS studies in subjects genotyped for BDNF Val66Met. Subjects performed an eyeblink conditioning task and received sham, anodal or cathodal tDCS (N = 117, between-subjects design) or a vestibulo-ocular reflex adaptation task and received sham and anodal tDCS (N = 51 subjects, within-subjects design). Performance was quantified as a learning parameter from 0 to 100%. We investigated (1) the distribution of the learning parameter with mixture modeling presented as the mean (M), standard deviation (S) and proportion (P) of the groups, and (2) the role of BDNF Val66Met and cerebellar tDCS using linear regression presented as the regression coefficients (B) and odds ratios (OR) with equally-tailed intervals (ETIs). For the eyeblink conditioning task, we found distinct groups of learners (M Learner  = 67.2%; S Learner  = 14.7%; P Learner  = 61.6%) and non-learners (M Non-learner  = 14.2%; S Non-learner  = 8.0%; P Non-learner  = 38.4%). Carriers of the BDNF Val66Met polymorphism were more likely to be learners (OR = 2.7 [1.2 6.2]). Within the group of learners, anodal tDCS supported eyeblink conditioning in BDNF Val66Met non-carriers (B = 11.9% 95%ETI = [0.8 23.0]%), but not in carriers (B = 1.0% 95%ETI = [-10.2 12.1]%). For the vestibulo-ocular reflex adaptation task, we found no effect of BDNF Val66Met (B = -2.0% 95%ETI = [-8.7 4.7]%) or anodal tDCS in either carriers (B = 3.4% 95%ETI = [-3

  8. Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF)

    PubMed Central

    Kailainathan, Sumangali; Piers, Thomas M.; Yi, Jee Hyun; Choi, Seongmin; Fahey, Mark S.; Borger, Eva; Gunn-Moore, Frank J.; O’Neill, Laurie; Lever, Michael; Whitcomb, Daniel J.; Cho, Kwangwook; Allen, Shelley J.

    2016-01-01

    This study describes a fundamental functional difference between the two main polymorphisms of the pro-form of brain-derived neurotrophic factor (proBDNF), providing an explanation as to why these forms have such different age-related neurological outcomes. Healthy young carriers of the Met66 form (present in ∼30% Caucasians) have reduced hippocampal volume and impaired hippocampal-dependent memory function, yet the same polymorphic population shows enhanced cognitive recovery after traumatic brain injury, delayed cognitive dysfunction during aging, and lower risk of late-onset Alzheimer’s disease (AD) compared to those with the more common Val66 polymorphism. To examine the differences between the protein polymorphisms in structure, kinetics of binding to proBDNF receptors and in vitro function, we generated purified cleavage-resistant human variants. Intriguingly, we found no statistical differences in those characteristics. As anticipated, exogenous application of proBDNF Val66 to rat hippocampal slices dysregulated synaptic plasticity, inhibiting long-term potentiation (LTP) and facilitating long-term depression (LTD). We subsequently observed that this occurred via the glycogen synthase kinase 3β (GSK3β) activation pathway. However, surprisingly, we found that Met66 had no such effects on either LTP or LTD. These novel findings suggest that, unlike Val66, the Met66 variant does not facilitate synapse weakening signaling, perhaps accounting for its protective effects with aging. PMID:26687096

  9. Pharmacogenetic analysis of opioid dependence treatment dose and dropout rate.

    PubMed

    Crist, Richard C; Li, James; Doyle, Glenn A; Gilbert, Alex; Dechairo, Bryan M; Berrettini, Wade H

    2018-01-01

    Currently, no pharmacogenetic tests for selecting an opioid-dependence pharmacotherapy have been approved by the US Food and Drug Administration. Determine the effects of variants in 11 genes on dropout rate and dose in patients receiving methadone or buprenorphine/naloxone (ClinicalTrials.gov Identifier: NCT00315341). Variants in six pharmacokinetic genes (CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4) and five pharmacodynamic genes (HTR2A, OPRM1, ADRA2A, COMT, SLC6A4) were genotyped in samples from a 24-week, randomized, open-label trial of methadone and buprenorphine/naloxone for the treatment of opioid dependence (n = 764; 68.7% male). Genotypes were then used to determine the metabolism phenotype for each pharmacokinetic gene. Phenotypes or genotypes for each gene were analyzed for association with dropout rate and mean dose. Genotype for 5-HTTLPR in the SLC6A4 gene was nominally associated with dropout rate when the methadone and buprenorphine/naloxone groups were combined. When the most significant variants associated with dropout rate were analyzed using pairwise analyses, SLC6A4 (5-HTTLPR) and COMT (Val158Met; rs4860) had nominally significant associations with dropout rate in methadone patients. None of the genes analyzed in the study was associated with mean dose of methadone or buprenorphine/naloxone. This study suggests that functional polymorphisms related to synaptic dopamine or serotonin levels may predict dropout rates during methadone treatment. Patients with the S/S genotype at 5-HTTLPR in SLC6A4 or the Val/Val genotype at Val158Met in COMT may require additional treatment to improve their chances of completing addiction treatment. Replication in other methadone patient populations will be necessary to ensure the validity of these findings.

  10. Brain-derived neurotrophic factor Val66met polymorphism and plasma levels in road traffic accident survivors.

    PubMed

    van den Heuvel, Leigh; Suliman, Sharain; Malan-Müller, Stefanie; Hemmings, Sian; Seedat, Soraya

    2016-11-01

    Alterations in brain-derived neurotrophic factor (BDNF) expression and release may play a role in the pathogenesis of post-traumatic stress disorder (PTSD). This study evaluated road traffic accident (RTA) survivors to determine whether PTSD and trauma-related factors were associated with plasma BDNF levels and BDNF Val66Met carrier status following RTA exposure. One hundred and twenty-three RTA survivors (mean age 33.2 years, SD = 10.6 years; 56.9% male) were assessed 10 (SD = 4.9) days after RTA exposure. Acute stress disorder (ASD), as assessed with the Acute Stress Disorder Scale, was present in 50 (42.0%) of the participants. Plasma BDNF levels were measured with enzyme-linked immunosorbent assay and BDNF Val66Met genotyping was performed. PTSD, as assessed with the Clinician-Administered PTSD Scale, was present in 10 (10.8%) participants at 6 months follow-up. Neither BDNF Val66Met genotype nor plasma BDNF was significantly associated with the presence or severity of ASD or PTSD. Plasma BDNF levels were, however, significantly correlated with the lifetime number of trauma exposures. In RTA survivors, plasma BDNF levels increased with increasing number of prior trauma exposures. Plasma BDNF may, therefore, be a marker of trauma load.

  11. Who gets afraid in the MRI-scanner? Neurogenetics of state-anxiety changes during an fMRI experiment.

    PubMed

    Mutschler, Isabella; Wieckhorst, Birgit; Meyer, Andrea H; Schweizer, Tina; Klarhöfer, Markus; Wilhelm, Frank H; Seifritz, Erich; Ball, Tonio

    2014-11-07

    Experiments using functional magnetic resonance imaging (fMRI) play a fundamental role in affective neuroscience. When placed in an MR scanner, some volunteers feel safe and relaxed in this situation, while others experience uneasiness and fear. Little is known about the basis and consequences of such inter-individually different responses to the general experimental fMRI setting. In this study emotional stimuli were presented during fMRI and subjects' state-anxiety was assessed at the onset and end of the experiment while they were within the scanner. We show that Val/Val but neither Met/Met nor Val/Met carriers of the catechol-O-methyltransferase (COMT) Val(158)Met polymorphism-a prime candidate for anxiety vulnerability-became significantly more anxious during the fMRI experiment (N=97 females: 24 Val/Val, 51 Val/Met, and 22 Met/Met). Met carriers demonstrated brain responses with increased stability over time in the right parietal cortex and significantly better cognitive performances likely mediated by lower levels of anxiety. Val/Val, Val/Met and Met/Met did not significantly differ in state-anxiety at the beginning of the experiment. The exposure of a control group (N=56 females) to the same experiment outside the scanner did not cause a significant increase in state-anxiety, suggesting that the increase we observe in the fMRI experiment may be specific to the fMRI setting. Our findings reveal that genetics may play an important role in shaping inter-individual different emotional, cognitive and neuronal responses during fMRI experiments. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  12. The Effects of a BDNF Val66Met Polymorphism on Posttraumatic Stress Disorder: A Meta-Analysis.

    PubMed

    Bountress, Kaitlin E; Bacanu, Silviu-Alin; Tomko, Rachel L; Korte, Kristina J; Hicks, Terrell; Sheerin, Christina; Lind, Mackenzie J; Marraccini, Marisa; Nugent, Nicole; Amstadter, Ananda B

    2018-06-06

    Given evidence that posttraumatic stress disorder (PTSD) is moderately heritable, a number of studies utilizing candidate gene approaches have attempted to examine the potential contributions of theoretically relevant genetic variation. Some of these studies have found sup port for a brain-derived neurotrophic factor (BDNF) variant, Val66Met, in the risk of developing PTSD, while others have failed to find this link. This study sought to reconcile these conflicting findings using a meta-analysis framework. Analyses were also used to determine whether there is significant heterogeneity in the link between this variant and PTSD. We conducted a systematic review of the literature on BDNF and PTSD from the PsycINFO and PubMed databases. A total of 11 studies were included in the analysis. Findings indicate a marginally significant effect of the BDNF Val66Met variant on PTSD (p < 0.1). However, of the 11 studies included, only 2 suggested an effect with a non-zero confidence interval, one of which showed a z score of 3.31. We did not find any evidence for heterogeneity. Findings from this meta-analytic investigation of the published literature provide little support for the Val66Met variant of BDNF as a predictor of PTSD. Future well-powered agnostic genome-wide association studies with more refined phenotyping are needed to clarify genetic influences on PTSD. © 2018 S. Karger AG, Basel.

  13. Preventing the Return of Fear Using Reconsolidation Update Mechanisms Depends on the Met-Allele of the Brain Derived Neurotrophic Factor Val66Met Polymorphism.

    PubMed

    Asthana, Manish Kumar; Brunhuber, Bettina; Mühlberger, Andreas; Reif, Andreas; Schneider, Simone; Herrmann, Martin J

    2016-06-01

    Memory reconsolidation is the direct effect of memory reactivation followed by stabilization of newly synthesized proteins. It has been well proven that neural encoding of both newly and reactivated memories requires synaptic plasticity. Brain derived neurotrophic factor (BDNF) has been extensively investigated regarding its role in the formation of synaptic plasticity and in the alteration of fear memories. However, its role in fear reconsolidation is still unclear; hence, the current study has been designed to investigate the role of the BDNF val66met polymorphism (rs6265) in fear memory reconsolidation in humans. An auditory fear-conditioning paradigm was conducted, which comprised of three stages (acquisition, reactivation, and spontaneous recovery). One day after fear acquisition, the experimental group underwent reactivation of fear memory followed by the extinction training (reminder group), whereas the control group (non-reminder group) underwent only extinction training. On day 3, both groups were subjected to spontaneous recovery of earlier learned fearful memories. The treat-elicited defensive response due to conditioned threat was measured by assessing the skin conductance response to the conditioned stimulus. All participants were genotyped for rs6265. The results indicate a diminishing effect of reminder on the persistence of fear memory only in the Met-allele carriers, suggesting a moderating effect of the BDNF polymorphism in fear memory reconsolidation. Our findings suggest a new role for BDNF gene variation in fear memory reconsolidation in humans. © The Author 2016. Published by Oxford University Press on behalf of CINP.

  14. Variation in the dopamine D2 receptor gene plays a key role in human pain and its modulation by transcranial magnetic stimulation.

    PubMed

    Jääskeläinen, Satu K; Lindholm, Pauliina; Valmunen, Tanja; Pesonen, Ullamari; Taiminen, Tero; Virtanen, Arja; Lamusuo, Salla; Forssell, Heli; Hagelberg, Nora; Hietala, Jarmo; Pertovaara, Antti

    2014-10-01

    We tested whether variation of the dopamine D2 receptor (DRD2) gene contributes to individual differences in thermal pain sensitivity and analgesic efficacy of repetitive transcranial magnetic stimulation (rTMS) in healthy subjects (n=29) or susceptibility to neuropathic pain in patients with neurophysiologically confirmed diagnosis (n=16). Thermal sensitivity of healthy subjects was assessed before and after navigated rTMS provided to the S1/M1 cortex. All subjects were genotyped for the DRD2 gene 957C>T and catechol-O-methyltransferase (COMT) protein Val158Met polymorphisms. In healthy subjects, 957C>T influenced both innocuous and noxious thermal detection thresholds that were lowest in 957TT homozygotes (P values from .0277 to .0462). rTMS to S1 cortex had analgesic effect only in 957TT homozygote genotype (P=.0086). In patients, prevalence of 957TT homozygote genotype was higher than in a healthy Finnish population (50% vs 27%; P=.0191). Patients with 957TT genotype reported more severe pain than patients with other genotypes (P=.0351). COMT Val158Met polymorphism was not independently associated with the studied variables. Genetic regulation of DRD2 function by 957C>T polymorphism thus seems to influence thermal and pain sensitivity, its modulation by rTMS, and susceptibility to neuropathic pain. This indicates a central role for the dopamine system and DRD2 in pain and analgesia. This may have clinical implications regarding individualized selection of patients for rTMS treatment and assessment of risks for neuropathic pain. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  15. Catechol-O-methyltransferase genotype modifies executive functioning and prefrontal functional connectivity in women with anorexia nervosa.

    PubMed

    Favaro, Angela; Clementi, Maurizio; Manara, Renzo; Bosello, Romina; Forzan, Monica; Bruson, Alice; Tenconi, Elena; Degortes, Daniela; Titton, Francesca; Di Salle, Francesco; Santonastaso, Paolo

    2013-07-01

    Anorexia nervosa is characterized by high levels of perseveration and inflexibility, which interfere with successful treatments. Dopamine (DA) signalling seems to play a key role in modulating the prefrontal cortex, since both DA deficiency and excess nega tively influence the efficiency of cognitive functions. The present study explores the effect of a functional polymorphism (Val158Met) in the catechol-O-methyltransferase (COMT) gene on the set-shifting abilities and prefrontal functional connectivity of patients with anorexia nervosa. All participants performed the Wisconsin Card Sorting Task, and a subsample underwent resting-state functional magnetic resonance imaging. We included 166 patients with DSM-IV lifetime anorexia nervosa and 140 healthy women in our study. Both underweight and weight-recovered patients with anorexia nervosa showed high levels of perseveration, but only in the underweight group did the Val158Met polymorphism affect cognitive performance, showing the U-shaped curve characteristic of increased DA signalling in the prefrontal cortex. Underweight patients with anorexia nervosa who are Met homozygotes had significantly higher levels of perseveration and increased prefrontal functional connectivity than underweight patients in the other genotype groups, indicating abnormal regional cortical processing. Although our data show that grey matter reduction in starving patients with anorexia nervosa did not explain our findings, the cross-sectional design of the present study did not allow us to distinguish between the effects of starvation and those of low estrogen levels. Starvation affects DA release in the prefrontal cortex of patients with anorexia nervosa with different effects on executive functioning and prefrontal functional connectivity according to the COMT genotype. This observation has several therapeutic implications that need to be addressed by future studies.

  16. The Interacting Effect of the BDNF Val66Met Polymorphism and Stressful Life Events on Adolescent Depression Is Not an Artifact of Gene-Environment Correlation: Evidence from a Longitudinal Twin Study

    ERIC Educational Resources Information Center

    Chen, Jie; Li, Xinying; McGue, Matt

    2013-01-01

    Background: Confounding introduced by gene-environment correlation (rGE) may prevent one from observing a true gene-environment interaction (G × E) effect on psychopathology. The present study investigated the interacting effect of the BDNF Val66Met polymorphism and stressful life events (SLEs) on adolescent depression while controlling for the…

  17. Right secondary somatosensory cortex-a promising novel target for the treatment of drug-resistant neuropathic orofacial pain with repetitive transcranial magnetic stimulation.

    PubMed

    Lindholm, Pauliina; Lamusuo, Salla; Taiminen, Tero; Pesonen, Ullamari; Lahti, Ari; Virtanen, Arja; Forssell, Heli; Hietala, Jarmo; Hagelberg, Nora; Pertovaara, Antti; Parkkola, Riitta; Jääskeläinen, Satu

    2015-07-01

    High-frequency repetitive transcranial magnetic stimulation (rTMS) of the motor cortex has analgesic effect; however, the efficacy of other cortical targets and the mode of action remain unclear. We examined the effects of rTMS in neuropathic orofacial pain, and compared 2 cortical targets against placebo. Furthermore, as dopaminergic mechanisms modulate pain responses, we assessed the influence of the functional DRD2 gene polymorphism (957C>T) and the catechol-O-methyltransferase (COMT) Val158Met polymorphism on the analgesic effect of rTMS. Sixteen patients with chronic drug-resistant neuropathic orofacial pain participated in this randomized, placebo-controlled, crossover study. Navigated high-frequency rTMS was given to the sensorimotor (S1/M1) and the right secondary somatosensory (S2) cortices. All subjects were genotyped for the DRD2 957C>T and COMT Val158Met polymorphisms. Pain, mood, and quality of life were monitored throughout the study. The numerical rating scale pain scores were significantly lower after the S2 stimulation than after the S1/M1 (P = 0.0071) or the sham (P = 0.0187) stimulations. The Brief Pain Inventory scores were also lower 3 to 5 days after the S2 stimulation than those at pretreatment baseline (P = 0.0127 for the intensity of pain and P = 0.0074 for the interference of pain) or after the S1/M1 (P = 0.001 and P = 0.0001) and sham (P = 0.0491 and P = 0.0359) stimulations. No correlations were found between the genetic polymorphisms and the analgesic effect in the present small clinical sample. The right S2 cortex is a promising new target for the treatment of neuropathic orofacial pain with high-frequency rTMS.

  18. Two single nucleotide polymorphisms in the CYP17 and COMT Genes--relation to bone mass and longitudinal bone changes in postmenopausal women with or without hormone replacement therapy. The Danish Osteoporosis Prevention Study.

    PubMed

    Tofteng, C L; Abrahamsen, B; Jensen, J E B; Petersen, S; Teilmann, J; Kindmark, A; Vestergaard, P; Gram, J; Langdahl, B L; Mosekilde, L

    2004-08-01

    Sex steroids are important physiologic regulators of bone mass, and genes regulating sex steroid production and metabolism are obvious as candidate genes for osteoporosis susceptibility. We present data from a study of 1795 recent postmenopausal women, assigned to either hormone replacement therapy (HRT) or no treatment and followed for 5 years. The association between bone mass measurements and two single nucleotide polymorphisms, a T (A1) to C (A2) transition in the 5'-UTR of the cytochrome P450c17alpha (CYP17) gene and a G (Val) to A (Met) transition in exon 4 of the catechol- O-methyltransferase (COMT) gene, was evaluated. Association with CYP17 genotype was modified by body mass index (BMI). In lean women, individuals homozygous for the CYP17 A2 allele were 1 cm shorter and had lower baseline BMD (bone mineral density), BMC, and CSA (cross sectional area) in the spine and femoral neck than did other women (BMD spine A2A2: 0.975 g/cm2 versus 1.011 g/cm2 in A1A1 + A1A2, P = 0.002). Conversely, an adverse association with A2A2 and bone loss over 5 years seemed present only in overweight women, but differences were small. Response to HRT was not dependent on CYP17 genotype. COMT genotype was not associated with bone mass at baseline, bone loss in untreated women, or response to HRT. In conclusion, the A2 allele of the CYP17 T(27)-C polymorphism is associated with reduced bone mass and bone size in lean perimenopausal women, whereas high BMI protects against this negative association. The COMT G(1947)-A polymorphism is not associated with bone parameters in this study.

  19. Plasma BDNF Concentration, Val66Met Genetic Variant, and Depression-Related Personality Traits

    PubMed Central

    Terracciano, Antonio; Martin, Bronwen; Ansari, David; Tanaka, Toshiko; Ferrucci, Luigi; Maudsley, Stuart; Mattson, Mark P.; Costa, Paul T.

    2010-01-01

    Brain derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurogenesis, and BDNF plasma and serum levels have been associated with depression, Alzheimer's disease, and other psychiatric and neurodegenerative disorders. In a relatively large community sample, drawn from the Baltimore Longitudinal Study of Aging (BLSA), we examine whether BDNF plasma concentration is associated with the Val66Met functional polymorphism of the BDNF gene (n = 335) and with depression-related personality traits assessed with the NEO-PI-R (n = 391). Plasma concentration of BDNF was not associated with the Val66Met variant in either men or women. However, in men, but not in women, BDNF plasma level was associated with personality traits linked to depression. Contrary to the notion that low BDNF is associated with negative outcomes, we found lower plasma levels in men who score lower on depression and vulnerability to stress (two facets of Neuroticism) and higher on Conscientiousness and Extraversion. These findings challenge the prevailing hypothesis that lower peripheral levels of BDNF are a marker of depression. PMID:20345896

  20. Genotypes do not confer risk for delinquency but rather alter susceptibility to positive and negative environmental factors: gene-environmentinteractions of BDNF Val66Met, 5-HTTLPR, and MAOA-uVNTR [corrected].

    PubMed

    Nilsson, Kent W; Comasco, Erika; Hodgins, Sheilagh; Oreland, Lars; Åslund, Cecilia

    2014-12-10

    Previous evidence of gene-by-environment interactions associated with emotional and behavioral disorders is contradictory. Differences in findings may result from variation in valence and dose of the environmental factor, and/or failure to take account of gene-by-gene interactions. The present study investigated interactions between the brain-derived neurotrophic factor gene (BDNF Val66Met), the serotonin transporter gene-linked polymorphic region (5-HTTLPR), the monoamine oxidase A (MAOA-uVNTR) polymorphisms, family conflict, sexual abuse, the quality of the child-parent relationship, and teenage delinquency. In 2006, as part of the Survey of Adolescent Life in Västmanland, Sweden, 1 337 high-school students, aged 17-18 years, anonymously completed questionnaires and provided saliva samples for DNA analyses. Teenage delinquency was associated with two-, three-, and four-way interactions of each of the genotypes and the three environmental factors. Significant four-way interactions were found for BDNF Val66Met × 5-HTTLPR×MAOA-uVNTR × family conflicts and for BDNF Val66Met × 5-HTTLPR×MAOA-uVNTR × sexual abuse. Further, the two genotype combinations that differed the most in expression levels (BDNF Val66Met Val, 5-HTTLPR LL, MAOA-uVNTR LL [girls] and L [boys] vs BDNF Val66Met Val/Met, 5-HTTLPR S/LS, MAOA-uVNTR S/SS/LS) in interaction with family conflict and sexual abuse were associated with the highest delinquency scores. The genetic variants previously shown to confer vulnerability for delinquency (BDNF Val66Met Val/Met × 5-HTTLPR S × MAOA-uVNTR S) were associated with the lowest delinquency scores in interaction with a positive child-parent relationship. Functional variants of the MAOA-uVNTR, 5-HTTLPR, and BDNF Val66Met, either alone or in interaction with each other, may be best conceptualized as modifying sensitivity to environmental factors that confer either risk or protection for teenage delinquency. © The Author 2015. Published by Oxford University

  1. Genotypes Do Not Confer Risk For Delinquency ut Rather Alter Susceptibility to Positive and Negative Environmental Factors: Gene-Environment Interactions of BDNF Val66Met, 5-HTTLPR, and MAOA-uVNTR

    PubMed Central

    Comasco, Erika; Hodgins, Sheilagh; Oreland, Lars; Åslund, Cecilia

    2015-01-01

    Background: Previous evidence of gene-by-environment interactions associated with emotional and behavioral disorders is contradictory. Differences in findings may result from variation in valence and dose of the environmental factor, and/or failure to take account of gene-by-gene interactions. The present study investigated interactions between the brain-derived neurotrophic factor gene (BDNF Val66Met), the serotonin transporter gene-linked polymorphic region (5-HTTLPR), the monoamine oxidase A (MAOA-uVNTR) polymorphisms, family conflict, sexual abuse, the quality of the child-parent relationship, and teenage delinquency. Methods: In 2006, as part of the Survey of Adolescent Life in Västmanland, Sweden, 1 337 high-school students, aged 17–18 years, anonymously completed questionnaires and provided saliva samples for DNA analyses. Results: Teenage delinquency was associated with two-, three-, and four-way interactions of each of the genotypes and the three environmental factors. Significant four-way interactions were found for BDNF Val66Met × 5-HTTLPR×MAOA-uVNTR × family conflicts and for BDNF Val66Met × 5-HTTLPR×MAOA-uVNTR × sexual abuse. Further, the two genotype combinations that differed the most in expression levels (BDNF Val66Met Val, 5-HTTLPR LL, MAOA-uVNTR LL [girls] and L [boys] vs BDNF Val66Met Val/Met, 5-HTTLPR S/LS, MAOA-uVNTR S/SS/LS) in interaction with family conflict and sexual abuse were associated with the highest delinquency scores. The genetic variants previously shown to confer vulnerability for delinquency (BDNF Val66Met Val/Met × 5-HTTLPR S × MAOA-uVNTR S) were associated with the lowest delinquency scores in interaction with a positive child-parent relationship. Conclusions: Functional variants of the MAOA-uVNTR, 5-HTTLPR, and BDNF Val66Met, either alone or in interaction with each other, may be best conceptualized as modifying sensitivity to environmental factors that confer either risk or protection for teenage delinquency. PMID

  2. BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer's disease.

    PubMed

    Lim, Yen Ying; Hassenstab, Jason; Cruchaga, Carlos; Goate, Alison; Fagan, Anne M; Benzinger, Tammie L S; Maruff, Paul; Snyder, Peter J; Masters, Colin L; Allegri, Ricardo; Chhatwal, Jasmeer; Farlow, Martin R; Graff-Radford, Neill R; Laske, Christoph; Levin, Johannes; McDade, Eric; Ringman, John M; Rossor, Martin; Salloway, Stephen; Schofield, Peter R; Holtzman, David M; Morris, John C; Bateman, Randall J

    2016-10-01

    SEE ROGAEVA AND SCHMITT-ULMS DOI101093/AWW201 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-β-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer's disease. However, the effect of BDNF in autosomal dominant Alzheimer's disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-β in preclinical autosomal dominant Alzheimer's disease. We explored effects of apolipoprotein E (APOE) ε4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation non-carriers and 143 preclinical autosomal dominant Alzheimer's disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val 66 homozygotes, 48 Met 66 carriers). Among preclinical mutation carriers, Met 66 carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val 66 homozygotes. Cortical amyloid-β and cerebrospinal fluid amyloid-β 42 levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val 66 homozygotes and Met 66 carriers. There was an effect of APOE on amyloid-β levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer's disease, the deleterious effects of amyloid-β on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer's disease mutation carriers are greater in Met 66 carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-β in autosomal dominant Alzheimer's disease. © The Author (2016

  3. COMT and MAO-A Polymorphisms and Obsessive-Compulsive Disorder: A Family-Based Association Study

    PubMed Central

    Sampaio, Aline Santos; Hounie, Ana Gabriela; Petribú, Kátia; Cappi, Carolina; Morais, Ivanil; Vallada, Homero; do Rosário, Maria Conceição; Stewart, S. Evelyn; Fargeness, Jesen; Mathews, Carol; Arnold, Paul; Hanna, Gregory L.; Richter, Margaret; Kennedy, James; Fontenelle, Leonardo; de Bragança Pereira, Carlos Alberto; Pauls, David L.; Miguel, Eurípedes Constantino

    2015-01-01

    Objective Obsessive-compulsive disorder (OCD) is a common and debilitating psychiatric illness. Although a genetic component contributes to its etiology, no single gene or mechanism has been identified to the OCD susceptibility. The catechol-O-methyltransferase (COMT) and monoamine oxidase A (MAO-A) genes have been investigated in previous OCD studies, but the results are still unclear. More recently, Taylor (2013) in a comprehensive meta-analysis of genetic association studies has identified COMT and MAO-A polymorphisms involved with OCD. In an effort to clarify the role of these two genes in OCD vulnerability, a family-based association investigation was performed as an alternative strategy to the classical case-control design. Methods Transmission disequilibrium analyses were performed after genotyping 13 single-nucleotide polymorphisms (eight in COMT and five in MAO-A) in 783 OCD trios (probands and their parents). Four different OCD phenotypes (from narrow to broad OCD definitions) and a SNP x SNP epistasis were also analyzed. Results OCD, broad and narrow phenotypes,were not associated with any of the investigated COMT and MAO-A polymorphisms. In addition, the analyses of gene-gene interaction did not show significant epistatic influences on phenotype between COMT and MAO-A. Conclusions The findings do not support an association between DSM-IV OCD and the variants of COMT or MAO-A. However, results from this study cannot exclude the contribution of these genes in the manifestation of OCD. The evaluation of broader spectrum phenotypes could help to understand the role of these and other genes in the pathophysiology of OCD and its spectrum disorders. PMID:25793616

  4. Genetic susceptibility to family environment: BDNF Val66met and 5-HTTLPR influence depressive symptoms.

    PubMed

    Dalton, Elizabeth D; Hammen, Constance L; Najman, Jake M; Brennan, Patricia A

    2014-12-01

    Functional genetic polymorphisms associated with Brain-Derived Neurotrophic Factor (BDNF) and serotonin (5-HTTLPR) have demonstrated associations with depression in interaction with environmental stressors. In light of evidence for biological connections between BDNF and serotonin, it is prudent to consider genetic epistasis between variants in these genes in the development of depressive symptoms. The current study examined the effects of val66met, 5-HTTLPR, and family environment quality on youth depressive symptoms in adolescence and young adulthood in a longitudinal sample oversampled for maternal depression history. A differential susceptibility model was tested, comparing the effects of family environment on depression scores across different levels of a cumulative plasticity genotype, defined as presence of both, either, or neither plasticity alleles (defined here as val66met Met and 5-HTTLPR 'S'). Cumulative plasticity genotype interacted with family environment quality to predict depression among males and females at age 15. After age 15, however, the interaction of cumulative plasticity genotype and early family environment quality was only predictive of depression among females. Results supported a differential susceptibility model at age 15, such that plasticity allele presence was associated with more or less depressive symptoms depending on valence of the family environment, and a diathesis-stress model of gene-environment interaction after age 15. These findings, although preliminary because of the small sample size, support prior results indicating interactive effects of 5-HTTLPR, val66met, and environmental stress, and suggest that family environment may have a stronger influence on genetically susceptible women than men.

  5. [Anxiety and polymorphism Val66Met of BDNF gene--predictors of depression severity in ischemic heart disease].

    PubMed

    Golimbet, V E; Volel', B A; Kopylov, F Iu; Dolzhikov, A V; Korovaitseva, G I; Kasparov, S V; Isaeva, M I

    2015-01-01

    In a framework of search for early predictors of depression in patients with ischemic heart disease (IHD) we studied effect of molecular-genetic factors (polymorphism of brain-derived neirotrophic factor--BDNF), personality traits (anxiety, neuroticism), IHD severity, and psychosocial stressors on manifestations of depression in men with verified diagnosis of IHD. Severity of depression was assessed by Hamilton Depression Rating Scale 21-item (HAMD 21), anxiety and neuroticism were evaluated by the Spielberger State-Trait Anxiety Inventory and "Big Five" questionnaire, respectively. It wa shown that personal anxiety and ValVal genotype of BDNF gene appeared to be predictors of moderate and severe depression.

  6. Catechol-O-methyltransferase genotype modifies executive functioning and prefrontal functional connectivity in women with anorexia nervosa

    PubMed Central

    Favaro, Angela; Clementi, Maurizio; Manara, Renzo; Bosello, Romina; Forzan, Monica; Bruson, Alice; Tenconi, Elena; Degortes, Daniela; Titton, Francesca; Di Salle, Francesco; Santonastaso, Paolo

    2013-01-01

    Background Anorexia nervosa is characterized by high levels of perseveration and inflexibility, which interfere with successful treatments. Dopamine (DA) signalling seems to play a key role in modulating the prefrontal cortex, since both DA deficiency and excess negatively influence the efficiency of cognitive functions. The present study explores the effect of a functional polymorphism (Val158Met) in the catechol-O-methyltransferase (COMT) gene on the set-shifting abilities and prefrontal functional connectivity of patients with anorexia nervosa. Methods All participants performed the Wisconsin Card Sorting Task, and a subsample underwent resting-state functional magnetic resonance imaging. Results We included 166 patients with DSM-IV lifetime anorexia nervosa and 140 healthy women in our study. Both underweight and weight-recovered patients with anorexia nervosa showed high levels of perseveration, but only in the underweight group did the Val158Met polymorphism affect cognitive performance, showing the U-shaped curve characteristic of increased DA signalling in the prefrontal cortex. Underweight patients with anorexia nervosa who are Met homozygotes had significantly higher levels of perseveration and increased prefrontal functional connectivity than underweight patients in the other genotype groups, indicating abnormal regional cortical processing. Limitations Although our data show that grey matter reduction in starving patients with anorexia nervosa did not explain our findings, the cross-sectional design of the present study did not allow us to distinguish between the effects of starvation and those of low estrogen levels. Conclusion Starvation affects DA release in the prefrontal cortex of patients with anorexia nervosa with different effects on executive functioning and prefrontal functional connectivity according to the COMT genotype. This observation has several therapeutic implications that need to be addressed by future studies. PMID:23046831

  7. Additive gene-environment effects on hippocampal structure in healthy humans.

    PubMed

    Rabl, Ulrich; Meyer, Bernhard M; Diers, Kersten; Bartova, Lucie; Berger, Andreas; Mandorfer, Dominik; Popovic, Ana; Scharinger, Christian; Huemer, Julia; Kalcher, Klaudius; Pail, Gerald; Haslacher, Helmuth; Perkmann, Thomas; Windischberger, Christian; Brocke, Burkhard; Sitte, Harald H; Pollak, Daniela D; Dreher, Jean-Claude; Kasper, Siegfried; Praschak-Rieder, Nicole; Moser, Ewald; Esterbauer, Harald; Pezawas, Lukas

    2014-07-23

    Hippocampal volume loss has been related to chronic stress as well as genetic factors. Although genetic and environmental variables affecting hippocampal volume have extensively been studied and related to mental illness, limited evidence is available with respect to G × E interactions on hippocampal volume. The present MRI study investigated interaction effects on hippocampal volume between three well-studied functional genetic variants (COMT Val158Met, BDNF Val66Met, 5-HTTLPR) associated with hippocampal volume and a measure of environmental adversity (life events questionnaire) in a large sample of healthy humans (n = 153). All three variants showed significant interactions with environmental adversity with respect to hippocampal volume. Observed effects were additive by nature and driven by both recent as well as early life events. A consecutive analysis of hippocampal subfields revealed a spatially distinct profile for each genetic variant suggesting a specific role of 5-HTTLPR for the subiculum, BDNF Val66Met for CA4/dentate gyrus, and COMT Val158Met for CA2/3 volume changes. The present study underscores the importance of G × E interactions as determinants of hippocampal volume, which is crucial for the neurobiological understanding of stress-related conditions, such as mood disorders or post-traumatic stress disorder (PTSD). Copyright © 2014 the authors 0270-6474/14/349917-10$15.00/0.

  8. A replicated molecular genetic basis for subtyping antisocial behavior in children with attention-deficit/hyperactivity disorder.

    PubMed

    Caspi, Avshalom; Langley, Kate; Milne, Barry; Moffitt, Terrie E; O'Donovan, Michael; Owen, Michael J; Polo Tomas, Monica; Poulton, Richie; Rutter, Michael; Taylor, Alan; Williams, Benjamin; Thapar, Anita

    2008-02-01

    Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder that in some cases is accompanied by antisocial behavior. To test if variations in the catechol O-methyltransferase gene (COMT) would prove useful in identifying the subset of children with ADHD who exhibit antisocial behavior. Three independent samples composed of 1 clinical sample of ADHD cases and 2 birth cohort studies. Participants in the clinical sample were drawn from child psychiatry and child health clinics in England and Wales. The 2 birth cohort studies included 1 sample of 2232 British children born in 1994-1995 and a second sample of 1037 New Zealander children born in 1972-1973. Diagnosis of ADHD and measures of antisocial behavior. We present replicated evidence that the COMT valine/methionine polymorphism at codon 158 (COMT Val158Met) was associated with phenotypic variation among children with ADHD. Across the 3 samples, valine/valine homozygotes had more symptoms of conduct disorder, were more aggressive, and were more likely to be convicted of criminal offenses compared with methionine carriers. The findings confirm the presence of genetic heterogeneity in ADHD and illustrate how genetic information may provide biological evidence pointing to clinical subtypes.

  9. The development of peripartum depressive symptoms is associated with gene polymorphisms of MAOA, 5-HTT and COMT.

    PubMed

    Doornbos, Bennard; Dijck-Brouwer, D A Janneke; Kema, Ido P; Tanke, Marit A C; van Goor, Saskia A; Muskiet, Frits A J; Korf, Jakob

    2009-10-01

    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. 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. 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 MAOA x COMT (p<0.001). Particularly, women carrying the combination of low activity variants of MAOA and COMT showed increased EPDS scores at week 36 of pregnancy and 6 weeks postpartum, but not during early pregnancy or 12 weeks postpartum. 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 GxE 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.

  10. Influence of variation in the catechol-O-methyltransferase gene on the clinical outcome after lumbar spine surgery for one-level symptomatic disc disease: a report on 176 cases.

    PubMed

    Rut, Marcin; Machoy-Mokrzyńska, Anna; Ręcławowicz, Daniel; Słoniewski, Paweł; Kurzawski, Mateusz; Droździk, Marek; Safranow, Krzysztof; Morawska, Michalina; Białecka, Monika

    2014-02-01

    This study was aimed at the evaluation of the relationship between genetic polymorphisms of catechol-O-methyltransferase (COMT) (rs4680:A > G-Val158Met, rs6269:A > G, rs4633:C > T, rs4818:C > G) and pain sensitivity after lumbar discectomy. All patients had one-level symptomatic disc herniation from L3 to S1. The primary data recorded included visual analogue pain scales assessing back and leg pain, Oswestry Disability Questionnaire assessing quality of life and pain intensity, received/filled pre- and postoperatively. Each subject was genotyped for single-nucleotide polymorphism in the COMT gene. Clinical outcome was measured by difference between pre- and postoperative values and those results were analyzed with genetics findings. Pain intensity was associated with the COMT polymorphism. Carriers of rs6269 AA, rs4633 TT, rs4818 CC, and rs4680 AA genotypes were characterized by the lowest preoperative scores related to pain intensity and lower pain intensity at 1 year after the surgery. The rs4633 CC, rs4680 GG genotypes demonstrated significant clinical improvement in VASBACK score at 1 year after the surgery. Patients with COMT haplotype associated with low metabolic activity of enzyme (A_C_C_G) showed better clinical outcome measured by ODI score and VASBACK score 1 year after surgery. We did not observe any significant correlation between leg pain and single-nucleotide polymorphisms in the COMT gene. The results of our study indicate that polymorphism in the COMT gene may play an important role in the mechanism of pain perception, which may have a potential implication for clinical decision-making in the future.

  11. Joint Effects of Smoking and Gene Variants Involved in Sex Steroid Metabolism on Hot Flashes in Late Reproductive-Age Women

    PubMed Central

    Freeman, Ellen W.; Sammel, Mary D.; Queen, Kaila; Lin, Hui; Rebbeck, Timothy R.

    2012-01-01

    Background: Although smoking has a known association with hot flashes, the factors distinguishing smokers at greatest risk for menopausal symptoms have not been well delineated. Recent evidence supports a relationship between menopausal symptoms and variants in several genes encoding enzymes that metabolize substrates such as sex steriods, xenobiotics, and catechols. It is currently not known whether the impact of smoking on hot flashes is modified by the presence of such variants. Objective: The objective of the study was to investigate the relationship between smoking and hot flash occurrence as a function of genetic variation in sex steroid-metabolizing enzymes. Methods: A cross-sectional analysis of data from the Penn Ovarian Aging study, an ongoing population-based cohort of late reproductive-aged women, was performed. Smoking behavior was characterized. Single-nucleotide polymorphisms in five genes were investigated: COMT Val158Met (rs4680), CYP1A2*1F (rs762551), CYP1B1*4 (Asn452Ser, rs1800440), CYP1B1*3 (Leu432Val, rs1056836), and CYP3A4*1B (rs2740574). Results: Compared with nonsmokers, European-American COMT Val158Met double-variant carriers who smoked had increased odds of hot flashes [adjusted odds ratio (AOR) 6.15, 95% confidence interval (CI) 1.32–28.78)]; European-American COMT Val158Met double-variant carriers who smoked heavily had more frequent moderate or severe hot flashes than nonsmokers (AOR 13.7, 95% CI 1.2–154.9). European-American CYP 1B1*3 double-variant carriers who smoked described more frequent moderate or severe hot flashes than nonsmoking (AOR 20.6, 95% CI 1.64–257.93) and never-smoking (AOR 20.59, 95% CI 1.39–304.68) carriers, respectively. African-American single-variant CYP 1A2 carriers who smoked were more likely to report hot flashes than the nonsmoking carriers (AOR 6.16, 95% CI 1.11–33.91). Conclusion: This is the first report demonstrating the effects of smoking within the strata of gene variants involved in sex

  12. Joint effects of smoking and gene variants involved in sex steroid metabolism on hot flashes in late reproductive-age women.

    PubMed

    Butts, Samantha F; Freeman, Ellen W; Sammel, Mary D; Queen, Kaila; Lin, Hui; Rebbeck, Timothy R

    2012-06-01

    Although smoking has a known association with hot flashes, the factors distinguishing smokers at greatest risk for menopausal symptoms have not been well delineated. Recent evidence supports a relationship between menopausal symptoms and variants in several genes encoding enzymes that metabolize substrates such as sex steriods, xenobiotics, and catechols. It is currently not known whether the impact of smoking on hot flashes is modified by the presence of such variants. The objective of the study was to investigate the relationship between smoking and hot flash occurrence as a function of genetic variation in sex steroid-metabolizing enzymes. A cross-sectional analysis of data from the Penn Ovarian Aging study, an ongoing population-based cohort of late reproductive-aged women, was performed. Smoking behavior was characterized. Single-nucleotide polymorphisms in five genes were investigated: COMT Val158Met (rs4680), CYP1A2*1F (rs762551), CYP1B1*4 (Asn452Ser, rs1800440), CYP1B1*3 (Leu432Val, rs1056836), and CYP3A4*1B (rs2740574). Compared with nonsmokers, European-American COMT Val158Met double-variant carriers who smoked had increased odds of hot flashes [adjusted odds ratio (AOR) 6.15, 95% confidence interval (CI) 1.32-28.78)]; European-American COMT Val158Met double-variant carriers who smoked heavily had more frequent moderate or severe hot flashes than nonsmokers (AOR 13.7, 95% CI 1.2-154.9). European-American CYP 1B1*3 double-variant carriers who smoked described more frequent moderate or severe hot flashes than nonsmoking (AOR 20.6, 95% CI 1.64-257.93) and never-smoking (AOR 20.59, 95% CI 1.39-304.68) carriers, respectively. African-American single-variant CYP 1A2 carriers who smoked were more likely to report hot flashes than the nonsmoking carriers (AOR 6.16, 95% CI 1.11-33.91). This is the first report demonstrating the effects of smoking within the strata of gene variants involved in sex steroid metabolism on hot flashes in late reproductive-age women

  13. Translational Advances in Pain and Anesthesia for Cancer Patients

    DTIC Science & Technology

    2012-01-01

    Surgical Research, Fort Sam Houston, TX. Fax: þ210 271 0830. E mail: christopher.maani@us.army.mil Received 10 August 2010; Accepted 18 November 2010 DOI...and response to anesthetics and analgesics have been identified, including COMT (catechol O methyltransferase), MCR1R (melocortin 1 receptor), and...and persistence. Nat Med 2006;12:1269 1277. 42. Zubieta JK, Heitzeg MM, Smith YR, et al.: COMT val158met genotype affects mu opioid neurotransmitter

  14. Preservation of General Intelligence following Traumatic Brain Injury: Contributions of the Met66 Brain-Derived Neurotrophic Factor

    PubMed Central

    Barbey, Aron K.; Colom, Roberto; Paul, Erick; Forbes, Chad; Krueger, Frank; Goldman, David; Grafman, Jordan

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) promotes survival and synaptic plasticity in the human brain. The Val66Met polymorphism of the BDNF gene interferes with intracellular trafficking, packaging, and regulated secretion of this neurotrophin. The human prefrontal cortex (PFC) shows lifelong neuroplastic adaption implicating the Val66Met BDNF polymorphism in the recovery of higher-order executive functions after traumatic brain injury (TBI). In this study, we examined the effect of this BDNF polymorphism on the preservation of general intelligence following TBI. We genotyped a sample of male Vietnam combat veterans (n = 156) consisting of a frontal lobe lesion group with focal penetrating head injuries for the Val66Met BDNF polymorphism. Val/Met did not differ from Val/Val genotypes in general cognitive ability before TBI. However, we found substantial average differences between these groups in general intelligence (≈ half a standard deviation or 8 IQ points), verbal comprehension (6 IQ points), perceptual organization (6 IQ points), working memory (8 IQ points), and processing speed (8 IQ points) after TBI. These results support the conclusion that Val/Met genotypes preserve general cognitive functioning, whereas Val/Val genotypes are largely susceptible to TBI. PMID:24586380

  15. Modification of the association between early adversity and obsessive-compulsive disorder by polymorphisms in the MAOA, MAOB and COMT genes.

    PubMed

    McGregor, N W; Hemmings, S M J; Erdman, L; Calmarza-Font, I; Stein, D J; Lochner, C

    2016-12-30

    The monoamine oxidases (MAOA/B) and catechol-O-methyltransferase (COMT) enzymes break down regulatory components within serotonin and dopamine pathways, and polymorphisms within these genes are candidates for OCD susceptibility. Childhood trauma has been linked OCD psychopathology, but little attention has been paid to the interactions between genes and environment in OCD aetiology. This pilot study investigated gene-by-environment interactions between childhood trauma and polymorphisms in the MAOA, MAOB and COMT genes in OCD. Ten polymorphisms (MAOA: 3 variants, MAOB: 4 variants, COMT: 3 variants) were genotyped in a cohort of OCD patients and controls. Early-life trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Gene-by-gene (GxG) and gene-by-environment interactions (GxE) of the variants and childhood trauma were assessed using logistic regression models. Significant GxG interactions were found between rs362204 (COMT) and two independent polymorphisms in the MAOB gene (rs1799836 and rs6651806). Haplotype associations for OCD susceptibility were found for MAOB. Investigation of GxE interactions indicated that the sexual abuse sub-category was significantly associated with all three genes in haplotype x environment interaction analyses. Preliminary findings indicate that polymorphisms within the MAOB and COMT genes interact resulting in risk for OCD. Childhood trauma interacts with haplotypes in COMT, MAOA and MAOB, increasing risk for OCD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  16. Effect of BDNF Val66Met on Memory Decline and Hippocampal Atrophy in Prodromal Alzheimer’s Disease: A Preliminary Study

    PubMed Central

    Lim, Yen Ying; Villemagne, Victor L.; Laws, Simon M.; Ames, David; Pietrzak, Robert H.; Ellis, Kathryn A.; Harrington, Karra; Bourgeat, Pierrick; Bush, Ashley I.; Martins, Ralph N.; Masters, Colin L.; Rowe, Christopher C.; Maruff, Paul

    2014-01-01

    Objective Cross-sectional genetic association studies have reported equivocal results on the relationship between the brain-derived neurotrophic factor (BDNF) Val66Met and risk of Alzheimer’s disease (AD). As AD is a neurodegenerative disease, genetic influences may become clearer from prospective study. We aimed to determine whether BDNF Val66Met polymorphism influences changes in memory performance, hippocampal volume, and Aβ accumulation in adults with amnestic mild cognitive impairment (aMCI) and high Aβ. Methods Thirty-four adults with aMCI were recruited from the Australian, Imaging, Biomarkers and Lifestyle (AIBL) Study. Participants underwent PiB-PET and structural MRI neuroimaging, neuropsychological assessments and BDNF genotyping at baseline, 18 month, and 36 month assessments. Results In individuals with aMCI and high Aβ, Met carriers showed significant and large decline in episodic memory (d = 0.90, p = .020) and hippocampal volume (d = 0.98, p = .035). BDNF Val66Met was unrelated to the rate of Aβ accumulation (d = −0.35, p = .401). Conclusions Although preliminary due to the small sample size, results of this study suggest that high Aβ levels and Met carriage may be useful prognostic markers of accelerated decline in episodic memory, and reductions in hippocampal volume in individuals in the prodromal or MCI stage of AD. PMID:24475133

  17. Sleep and COMT Polymorphism in ADHD Children: Preliminary Actigraphic Data

    ERIC Educational Resources Information Center

    Gruber, Reut; Grizenko, Natalie; Schwartz, George; Amor, Leila Ben; Gauthier, Julie; de Guzman, Rosherrie; Joober, Ridha

    2006-01-01

    Objective: To examine whether COMT (catechol-O-methyltransferase) polymorphism modulates aspects of sleep in children diagnosed with attention-deficit/hyperactivity disorder (ADHD). Method: Nightly sleep actigraphic recordings during a double-blind, placebo-controlled, crossover clinical study (1 week of 0.5 mg/kg MPH; 1 week of placebo) were…

  18. Cytochrome P450 1B1 and catechol-O-methyltransferase genetic polymorphisms and breast cancer risk in Chinese women: results from the shanghai breast cancer study and a meta-analysis.

    PubMed

    Wen, Wanqing; Cai, Qiuyin; Shu, Xiao-Ou; Cheng, Jia-Rong; Parl, Fritz; Pierce, Larry; Gao, Yu-Tang; Zheng, Wei

    2005-02-01

    Cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) are important estrogen-metabolizing enzymes and, thus, genetic polymorphisms of these enzymes may affect breast cancer risk. A population-based case-control study was conducted to assess the association of breast cancer risk with CYP1B1 and COMT polymorphisms. A meta-analysis was done to summarize the findings from this and previous studies. Included in this study were 1,135 incident breast cancer cases diagnosed from August 1996 through March 1998 among female residents of Shanghai and 1,235 randomly selected, age frequency-matched controls from the same general population. The common alleles of the CYP1B1 gene were Arg (79.97%) in codon 48, Ala (80.53%) in codon 119, and Leu (86.57%) in codon 432. The Val allele accounted for 72.46% of the total alleles identified in codon 108/158 of the COMT gene. No overall associations of breast cancer risk were found with any of the single nucleotide polymorphisms described above. This finding was supported by a meta-analysis of all previous published studies. No gene-gene interactions were observed between CYP1B1 and COMT genotypes. The associations of breast cancer risk with factors related to endogenous estrogen exposure, such as years of menstruation and body mass index, were not significantly modified by the CYP1B1 and COMT genotypes. We observed, however, that women who carried one copy of the variant allele in CYP1B1 codons 48 or 119 were less likely to have estrogen receptor-positive breast cancer than those who carried two copies of the corresponding wild-type alleles. The results from this study were consistent with those from most previous studies, indicating no major associations of breast cancer risk with CYP1B1 and COMT polymorphisms.

  19. The role of COMT and plasma proline in the variable penetrance of autistic spectrum symptoms in 22q11.2 deletion syndrome.

    PubMed

    Hidding, E; Swaab, H; de Sonneville, L M J; van Engeland, H; Vorstman, J A S

    2016-11-01

    This paper examines how COMT 158 genotypes and plasma proline levels are associated with variable penetrance of social behavioural and social cognitive problems in 22q11.2 deletion syndrome (22q11DS). Severity of autistic spectrum symptoms of 45 participants with 22q11DS was assessed using the Autism Diagnostic Interview Revised. Face and facial emotion recognition was evaluated using standardized computer-based test-paradigms. Associations with COMT 158 genotypes and proline levels were examined. High proline levels and poor face recognition in individuals with the COMT MET allele, and poor facial emotion recognition, explained almost 50% of the variance in severity of autism symptomatology in individuals with 22q11DS. High proline levels and a decreased capacity to break down dopamine as a result of the COMT MET variant are both relevant in the expression of the social phenotype in patients. This epistatic interaction effect between the COMT 158 genotype and proline on the expression of social deficits in 22q11DS shows how factors other than the direct effects of the deletion itself can modulate the penetrance of associated cognitive and behavioural outcomes. These findings are not only relevant to our insight into 22q11DS, but also provide a model to better understand the phenomenon of variable penetrance in other pathogenic genetic variants. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. EEG alpha power as an intermediate measure between brain-derived neurotrophic factor Val66Met and depression severity in patients with major depressive disorder.

    PubMed

    Zoon, Harriët F A; Veth, C P M; Arns, Martijn; Drinkenburg, W H I M; Talloen, Willem; Peeters, Pieter J; Kenemans, J L

    2013-06-01

    Major depressive disorder has a large impact on patients and society and is projected to be the second greatest global burden of disease by 2020. The brain-derived neurotrophic factor (BDNF) gene is considered to be one of the important factors in the etiology of major depressive disorder. In a recent study, alpha power was found to mediate between BDNF Met and subclinical depressed mood. The current study looked at a population of patients with major depressive disorder (N = 107) to examine the association between the BDNF Val66Met polymorphism, resting state EEG alpha power, and depression severity. For this purpose, repeated-measures analysis of variance, partial correlation, and multiple linear models were used. Results indicated a negative association between parietal-occipital alpha power in the eyes open resting state and depression severity. In addition, Met/Met patients showed lower global absolute alpha power in the eyes closed condition compared with Val-carriers. These findings are in accordance with the previously uncovered pathway between BDNF Val66Met, resting state EEG alpha power, and depression severity. Additional research is needed for the clarification of this tentative pathway and its implication in personalized treatment of major depressive disorder.

  1. Acute effects of cocaine and cannabis on reversal learning as a function of COMT and DRD2 genotype.

    PubMed

    Spronk, Desirée B; Van der Schaaf, Marieke E; Cools, Roshan; De Bruijn, Ellen R A; Franke, Barbara; van Wel, Janelle H P; Ramaekers, Johannes G; Verkes, Robbert J

    2016-01-01

    Long-term cannabis and cocaine use has been associated with impairments in reversal learning. However, how acute cannabis and cocaine administration affect reversal learning in humans is not known. In this study, we aimed to establish the acute effects of administration of cannabis and cocaine on valence-dependent reversal learning as a function of DRD2 Taq1A (rs1800497) and COMT Val108/158Met (rs4680) genotype. A double-blind placebo-controlled randomized 3-way crossover design was used. Sixty-one regular poly-drug users completed a deterministic reversal learning task under the influence of cocaine, cannabis, and placebo that enabled assessment of both reward- and punishment-based reversal learning. Proportion correct on the reversal learning task was increased by cocaine, but decreased by cannabis. Effects of cocaine depended on the DRD2 genotype, as increases in proportion correct were seen only in the A1 carriers, and not in the A2/A2 homozygotes. COMT genotype did not modulate drug-induced effects on reversal learning. These data indicate that acute administration of cannabis and cocaine has opposite effects on reversal learning. The effects of cocaine, but not cannabis, depend on interindividual genetic differences in the dopamine D2 receptor gene.

  2. A protective effect of the BDNF Met/Met genotype in obesity in healthy Caucasian subjects but not in patients with coronary heart disease.

    PubMed

    Sustar, A; Nikolac Perkovic, M; Nedic Erjavec, G; Svob Strac, D; Pivac, N

    2016-08-01

    Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor with an important role in the regulation of body weight, body mass index (BMI) and obesity. Increased BMI that leads to obesity is a substantial risk factor for coronary heart disease (CHD). The functional BDNF Val66Met polymorphism (rs6265) has been associated with CHD, obesity and BMI. The aim of the study was to determine the association between BDNF rs6265 polymorphism and CHD and/or BMI in patients with CHD and healthy control subjects. The study included 704 Caucasian subjects: 206 subjects with CHD and 498 healthy control subjects. The BDNF rs6265 genotype frequency was similar in male and female subjects, and there were no differences in the frequency of the BDNF rs6265 genotypes in 206 patients with CHD and in 498 healthy subjects. When study participants were subdivided according to the BMI categories into normal weight, overweight and obese subjects, significantly different BDNF rs6265 genotype frequency was found within healthy subjects, but not within patients with CHD. Healthy subjects, but not patients with CHD, subdivided into carriers of the Met/Met, Met/Val and Val/Val genotype, had different BMI scores. The BDNF rs6265 genotype frequency was similar in male and female subjects, and there were no differences in the frequency of the BDNF rs6265 genotypes in 206 patients with CHD and in 498 healthy subjects. When study participants were subdivided according to the BMI categories into normal weight, overweight and obese subjects, significantly different BDNF rs6265 genotype frequency was found within healthy subjects, but not within patients with CHD. Healthy subjects, but not patients with CHD, subdivided into carriers of the Met/Met, Met/Val and Val/Val genotype, had different BMI scores. BDNF rs6265 polymorphism was not associated with a diagnosis of CHD or with BMI categories among patients with CHD. In contrast, healthy Caucasians, carriers of the BDNF Met/Met genotype, had more

  3. Impact of brain-derived neurotrophic factor genetic polymorphism on cognition: A systematic review.

    PubMed

    Toh, Yi Long; Ng, Terence; Tan, Megan; Tan, Azrina; Chan, Alexandre

    2018-06-01

    Brain-derived neurotrophic factor (BDNF) has an important role in the neurogenesis and neuroplasticity of the brain. This systematic review was designed to examine the association between BDNF Val66Met (rs6265) polymorphism and four cognitive domains-attention and concentration, executive function, verbal fluency, and memory, respectively. Primary literature search was performed using search engines such as PubMed and Scopus. Observational studies that evaluated the neurocognitive performances in relation to BDNF polymorphism within human subjects were included in this review, while animal studies, overlapping studies, and meta-analysis were excluded. Forty of 82 reviewed studies (48.8%) reported an association between Val66Met polymorphism and neurocognitive domains. The proportion of the studies showing positive findings in cognitive performances between Val/Val homozygotes and Met carriers was comparable, at 30.5% and 18.3%, respectively. The highest percentage of positive association between Val66Met polymorphism and neurocognition was reported under the memory domain, with 26 of 63 studies (41.3%), followed by 18 of 47 studies (38.3%) under the executive function domain and four of 23 studies (17.4%) under the attention and concentration domain. There were no studies showing an association between Val66Met polymorphism and verbal fluency. In particular, Val/Val homozygotes performed better in tasks related to the memory domain, while Met carriers performed better in terms of executive function, in both healthy individuals and clinical populations. While numerous studies report an association between Val66Met polymorphism and neurocognitive changes in executive function and memory domains, the effect of Met allele has not been clearly established. © 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.

  4. Catechol-O-methyltransferase (COMT) polymorphisms modulate working memory in individuals with schizophrenia and healthy controls.

    PubMed

    Matsuzaka, Camila T; Christofolini, Denise; Ota, Vanessa K; Gadelha, Ary; Berberian, Arthur A; Noto, Cristiano; Mazzotti, Diego R; Spindola, Leticia M; Moretti, Patricia N; Smith, Marilia A C; Melaragno, Maria I; Belangero, Sintia I; Bressan, Rodrigo A

    2017-01-01

    Cognitive impairment is a core feature of schizophrenia, related to dopaminergic dysfunction in the prefrontal cortex (PFC). It is hypothesized that functional single nucleotide polymorphism (SNP) rs4680 of the catechol-O-methyltransferase (COMT) gene could mediate the relationship between cognition and dopamine activity in the PFC. Other COMT SNPs could also play a role. We evaluated the role of three COMT SNPs (rs737865, rs165599, and rs4680) in schizophrenia and their impact on three working memory tasks. For genetic association analyses, 212 individuals with schizophrenia and 257 healthy controls (HCs) were selected. The Visual Working Memory (VWM) Task, Keep Track Task, and Letter Memory Task were administered to 133 schizophrenics and 93 HCs. We found a significant association of rs737865, with the GG genotype exerting a protective effect and the GA haplotype (rs4680/rs165599) exerting a risk effect for schizophrenia. COMT rs4680 AA carriers and rs737865 AA carriers scored lowest on the Keep Track Task. When the genotype*group interaction effect was evaluated, rs165599 exerted opposite effects for VWM and Keep Track task performance in patients and controls, with AA carriers scoring lowest on both tests among controls, but highest among patients. These data support the hypothesis that COMT polymorphisms may be associated with schizophrenia and modulate cognition in patients and controls.

  5. Placebo analgesia and reward processing: integrating genetics, personality, and intrinsic brain activity.

    PubMed

    Yu, Rongjun; Gollub, Randy L; Vangel, Mark; Kaptchuk, Ted; Smoller, Jordan W; Kong, Jian

    2014-09-01

    Our expectations about an event can strongly shape our subjective evaluation and actual experience of events. This ability, applied to the modulation of pain, has the potential to affect therapeutic analgesia substantially and constitutes a foundation for non-pharmacological pain relief. A typical example of such modulation is the placebo effect. Studies indicate that placebo may be regarded as a reward, and brain activity in the reward system is involved in this modulation process. In the present study, we combined resting-state functional magnetic resonance imaging (rs-fMRI) measures, genotype at a functional COMT polymorphism (Val158Met), and personality measures in a model to predict the magnitude of placebo conditioning effect indicated by subjective pain rating reduction to calibrated noxious stimuli. We found that the regional homogeneity (ReHo), an index of local neural coherence, in the ventral striatum, was significantly associated with conditioning effects on pain rating changes. We also found that the number of Met alleles at the COMT polymorphism was linearly correlated to the suppression of pain. In a fitted regression model, we found the ReHo in the ventral striatum, COMT genotype, and Openness scores accounted for 59% of the variance in the change in pain ratings. The model was further tested using a separate data set from the same study. Our findings demonstrate the potential of combining resting-state connectivity, genetic information, and personality to predict placebo effect. Copyright © 2014 Wiley Periodicals, Inc.

  6. The interaction of BDNF Val66Met, PTSD, and child abuse on psychophysiological reactivity and HPA axis function in a sample of Gulf War Veterans.

    PubMed

    Young, Dmitri A; Neylan, Thomas C; O'Donovan, Aoife; Metzler, Thomas; Richards, Anne; Ross, Jessica A; Inslicht, Sabra S

    2018-08-01

    While the BDNF Val66Met polymorphism has been linked to various psychological disorders, limited focus has been on its relationship to posttraumatic stress disorder (PTSD) and early traumas such as child abuse. Therefore, we assessed whether Val66Met was associated with fear potentiated psychophysiological response and HPA axis dysfunction and whether PTSD status or child abuse history moderated these outcomes in a sample of Veterans. 226 and 173 participants engaged in a fear potentiated acoustic startle paradigm and a dexamethasone suppression test (DST) respectively. Fear conditions included no, ambiguous, and high threat conditions. Psychophysiological response measures included electromyogram (EMG), skin conductance response (SCR), and heart rate. The Clinician Administered PTSD Scale (CAPS) and the Trauma History Questionnaire (THQ) were used to assess PTSD status and child abuse history respectively. Met allele carriers exhibited greater SCR magnitudes in the no and ambiguous threat conditions (p < 0.01 and p < 0.05 respectively). Met carriers with PTSD exhibited greater physiological response magnitudes in the ambiguous (SCR, p < 0.001) and high threat conditions (SCR and heart rate, both p ≤ 0.005). Met carrier survivors of child abuse exhibited blunted heart rate magnitudes in the high threat condition (p < 0.01). Met allele carries with PTSD also exhibited greater percent cortisol suppression (p < 0.005). Limitations included small sample size and the cross-sectional nature of the data. The Val66met may impact PTSD susceptibility differentially via enhanced threat sensitivity and HPA axis dysregulation. Child abuse may moderate Val66Met's impact on threat reactivity. Future research should explore how neuronal mechanisms might mediate this risk. Published by Elsevier B.V.

  7. Sequential processing deficits in schizophrenia: relationship to neuropsychology and genetics.

    PubMed

    Hill, S Kristian; Bjorkquist, Olivia; Carrathers, Tarra; Roseberry, Jarett E; Hochberger, William C; Bishop, Jeffrey R

    2013-12-01

    Utilizing a combination of neuropsychological and cognitive neuroscience approaches may be essential for characterizing cognitive deficits in schizophrenia and eventually assessing cognitive outcomes. This study was designed to compare the stability of select exemplars for these approaches and their correlations in schizophrenia patients with stable treatment and clinical profiles. Reliability estimates for serial order processing were comparable to neuropsychological measures and indicate that experimental serial order processing measures may be less susceptible to practice effects than traditional neuropsychological measures. Correlations were moderate and consistent with a global cognitive factor. Exploratory analyses indicated a potentially critical role of the Met allele of the Catechol-O-methyltransferase (COMT) Val158Met polymorphism in externally paced sequential recall. Experimental measures of serial order processing may reflect frontostriatal dysfunction and be a useful supplement to large neuropsychological batteries. © 2013.

  8. Sequential Processing Deficits in Schizophrenia: Relationship to Neuropsychology and Genetics

    PubMed Central

    Hill, S. Kristian; Bjorkquist, Olivia; Carrathers, Tarra; Roseberry, Jarett E.; Hochberger, William C.; Bishop, Jeffrey R.

    2014-01-01

    Utilizing a combination of neuropsychological and cognitive neuroscience approaches may be essential for characterizing cognitive deficits in schizophrenia and eventually assessing cognitive outcomes. This study was designed to compare the stability of select exemplars for these approaches and their correlations in schizophrenia patients with stable treatment and clinical profiles. Reliability estimates for serial order processing were comparable to neuropsychological measures and indicate that experimental serial order processing measures may be less susceptible to practice effects than traditional neuropsychological measures. Correlations were moderate and consistent with a global cognitive factor. Exploratory analyses indicated a potentially critical role of the Met allele of the Catechol-O-methyltransferase (COMT) Val158Met polymorphism in externally paced sequential recall. Experimental measures of serial order processing may reflect frontostriatal dysfunction and be a useful supplement to large neuropsychological batteries. PMID:24119464

  9. Spontaneous abortion and functional polymorphism (Val16Ala) in the manganese SOD gene.

    PubMed

    Eskafi Sabet, E; Salehi, Z; Khodayari, S; Sabouhi Zarafshan, S; Zahiri, Z

    2015-02-01

    Spontaneous abortion is the most common complication of early pregnancy. Genetic factors have been hypothesised to play a role in spontaneous abortion. Since it is possible that the balance of oxidants and antioxidants can be affected by different genetic variants, gene polymorphisms have been proposed as a susceptibility factor that increases the chance of miscarriage. Manganese superoxide dismutase is an important antioxidant enzyme encoded by manganese superoxide dismutase (MnSOD) gene. The aim of this experiment was to assess whether Val16Ala polymorphism of MnSOD gene is associated with miscarriage in northern Iran. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for genotyping. Statistical analyses were conducted using the χ(2)-test. The genetic distributions did not differ significantly between cases and controls, however slightly more Val/Val genotypes were found among the patients compared with control subjects (p = 0.059). No correlation was observed between susceptibility to abortion and MnSOD Val16Ala polymorphism. Larger population-based studies are needed for clarifying the relationship between abortion and MnSOD genotypes.

  10. COMT and DRD2/ANKK-1 gene-gene interaction account for resetting of gamma neural oscillations to auditory stimulus-driven attention.

    PubMed

    Garcia-Garcia, Manuel; Via, Marc; Zarnowiec, Katarzyna; SanMiguel, Iria; Escera, Carles; Clemente, Immaculada C

    2017-01-01

    Attention capture by potentially relevant environmental stimuli is critical for human survival, yet it varies considerably among individuals. A large series of studies has suggested that attention capture may depend on the cognitive balance between maintenance and manipulation of mental representations and the flexible switch between goal-directed representations and potentially relevant stimuli outside the focus of attention; a balance that seems modulated by a prefrontostriatal dopamine pathway. Here, we examined inter-individual differences in the cognitive control of attention through studying the effects of two single nucleotide polymorphisms regulating dopamine at the prefrontal cortex and the striatum (i.e., COMTMet108/158Val and ANKK1/DRD2TaqIA) on stimulus-driven attention capture. Healthy adult participants (N = 40) were assigned to different groups according to the combination of the polymorphisms COMTMet108/158Val and ANKK1/DRD2TaqIA, and were instructed to perform on a well-established distraction protocol. Performance in individuals with a balance between prefrontal dopamine display and striatal receptor density was slowed down by the occurrence of unexpected distracting events, while those with a rather unbalanced dopamine activity were able maintain task performance with no time delay, yet at the expense of a slightly lower accuracy. This advantage, associated to their distinct genetic profiles, was paralleled by an electrophysiological mechanism of phase-resetting of gamma neural oscillation to the novel, distracting events. Taken together, the current results suggest that the epistatic interaction between COMTVal108/158Met and ANKK1/DRD2 TaqIa genetic polymorphisms lies at the basis of stimulus-driven attention capture.

  11. Imaging oxytocin × dopamine interactions: an epistasis effect of CD38 and COMT gene variants influences the impact of oxytocin on amygdala activation to social stimuli

    PubMed Central

    Sauer, Carina; Montag, Christian; Reuter, Martin; Kirsch, Peter

    2013-01-01

    Although oxytocin (OT) has become a major target for the investigation of positive social processes, it can be assumed that it exerts its effects in concert with other neurotransmitters. One candidate for such an interaction is dopamine (DA). For both systems, genetic variants have been identified that influence the availability of the particular substance. A variant of the gene coding for the transmembrane protein CD38 (rs3796863), which is engaged in OT secretion, has been associated with OT plasma level. The common catechol-O-methyltransferase (COMT) val158met polymorphism is known to influence COMT activity and therefore the degradation of DA. The present study aimed to investigate OT × DA interactions in the context of an OT challenge study. Hence, we tested the influence of the above mentioned genetic variants and their interaction on the activation of different brain regions (amygdala, VTA, ventral striatum and fusiform gyrus) during the presentation of social stimuli. In a pharmacological cross-over design 55 participants were investigated under OT and placebo (PLA) by means of fMRI. Brain imaging results revealed no significant effects for VTA or ventral striatum. Regarding the fusiform gyrus, we could not find any effects apart from those already described in Sauer et al. (2012). Analyses of amygdala activation resulted in no gene main effect, no gene × substance interaction but a significant gene × gene × substance interaction. While under PLA the effect of CD38 on bilateral amygdala activation to social stimuli was modulated by the COMT genotype, no such epistasis effect was found under OT. Our results provide evidence for an OT × DA interaction during responses to social stimuli. We postulate that the effect of central OT secretion on amygdala response is modulated by the availability of DA. Therefore, for an understanding of the effect of social hormones on social behavior, interactions of OT with other transmitter systems have to be taken into

  12. A Val85Met Mutation in Melanocortin-1 Receptor Is Associated with Reductions in Eumelanic Pigmentation and Cell Surface Expression in Domestic Rock Pigeons (Columba livia)

    PubMed Central

    Guernsey, Michael W.; Ritscher, Lars; Miller, Matthew A.; Smith, Daniel A.; Schöneberg, Torsten; Shapiro, Michael D.

    2013-01-01

    Variation in the melanocortin-1 receptor (Mc1r) is associated with pigmentation diversity in wild and domesticated populations of vertebrates, including several species of birds. Among domestic bird species, pigmentation variation in the rock pigeon ( Columba livia ) is particularly diverse. To determine the potential contribution of Mc1r variants to pigment diversity in pigeons, we sequenced Mc1r in a wide range of pigeon breeds and identified several single nucleotide polymorphisms, including a variant that codes for an amino acid substitution (Val85Met). In contrast to the association between Val85Met and eumelanism in other avian species, this change was associated with pheomelanism in pigeons. In vitro cAMP accumulation and protein expression assays revealed that Val85Met leads to decreased receptor function and reduced cell surface expression of the mutant protein. The reduced in vitro function is consistent with the observed association with reduced eumelanic pigmentation. Comparative genetic and cellular studies provide important insights about the range of mechanisms underlying diversity among vertebrates, including different phenotypic associations with similar mutations in different species. PMID:23977400

  13. The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with increased body mass index and insulin resistance measures in bipolar disorder and schizophrenia.

    PubMed

    Bonaccorso, Stefania; Sodhi, Monsheel; Li, Jiang; Bobo, William V; Chen, Yuejin; Tumuklu, Mevhibe; Theleritis, Christos; Jayathilake, Karuna; Meltzer, Herbert Y

    2015-08-01

    We tested the hypothesis that a common functional variant in brain-derived neurotrophic factor (BDNF), Val66Met, which has been shown to be associated with increased body mass index (BMI) in schizophrenia (SCZ) and schizoaffective disorder (SAD), is also associated with antipsychotic-induced weight gain in bipolar disorder (BPD). Association of Val66Met with other metabolic measures, including high- and low-density cholesterol, triglycerides, total cholesterol, fasting blood glucose, and hemoglobin A1c, was also tested. This was a 12-month, prospective, randomized trial of two atypical antipsychotic drugs (APDs) with moderate (risperidone) or high (olanzapine) risk to cause weight gain. Subjects were diagnosed as having BPD (n = 90) and SCZ or SAD (n = 76). BMI was significantly greater in all diagnoses for Met66 allele carriers at six months (p = 0.01). Met66 carriers with BPD showed a greater increase in the triglycerides/high-density (HDL) cholesterol ratio (p = 0.01), a key marker for metabolic syndrome related to insulin resistance, and log-triglycerides (p = 0.04), after three or six months of treatment. Met66 carriers had the greatest increase in log-triglycerides (p = 0.03) and triglycerides/HDL cholesterol ratio after three months of treatment with risperidone (p = 0.003), and the highest BMI at six months (p = 0.01). The positive association of BNDF Val66Met with high BMI values replicates previous findings in patients with SCZ and indicates the BDNF Val66Met genotype as a potential risk factor for obesity and insulin resistance measures in patients with BPD receiving antipsychotics as well. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Conscientiousness is modified by genetic variation in catechol-O-methyltransferase to reduce symptom complaints in IBS patients.

    PubMed

    Hall, Kathryn T; Tolkin, Benjamin R; Chinn, Garrett M; Kirsch, Irving; Kelley, John M; Lembo, Anthony J; Kaptchuk, Ted J; Kokkotou, Efi; Davis, Roger B; Conboy, Lisa A

    2015-01-01

    Attention to and perception of physical sensations and somatic states can significantly influence reporting of complaints and symptoms in the context of clinical care and randomized trials. Although anxiety and high neuroticism are known to increase the frequency and severity of complaints, it is not known if other personality dimensions or genes associated with cognitive function or sympathetic tone can influence complaints. Genetic variation in catechol-O-methyltransferase (COMT) is associated with anxiety, personality, pain, and response to placebo treatment. We hypothesized that the association of complaint reporting with personality might be modified by variation in the COMT val158met genotype. We administered a standard 25-item complaint survey weekly over 3-weeks to a convenience sample of 187 irritable bowel syndrome patients enrolled in a placebo intervention trial and conducted a repeated measures analysis. We found that complaint severity rating, our primary outcome, was negatively associated with the personality measures of conscientiousness (β = -0.31 SE 0.11, P = 0.003) and agreeableness (β = -0.38 SE 0.12, P = 0.002) and was positively associated with neuroticism (β = 0.24 SE 0.09, P = 0.005) and anxiety (β = 0.48 SE 0.09, P < 0.0001). We also found a significant interaction effect of COMT met alleles (β = -32.5 SE 14.1, P = 0.021). in patients genotyped for COMT val158met (N  = 87) specifically COMT × conscientiousness (β = 0.73 SE 0.26, P = 0.0042) and COMT × anxiety (β = -0.42 SE 0.16, P = 0.0078) interaction effects. These findings potentially broaden our understanding of the factors underlying clinical complaints to include the personality dimension of conscientiousness and its modification by COMT.

  15. Brain-derived neurotrophic factor Val66Met genotype modulates amygdala habituation.

    PubMed

    Perez-Rodriguez, M Mercedes; New, Antonia S; Goldstein, Kim E; Rosell, Daniel; Yuan, Qiaoping; Zhou, Zhifeng; Hodgkinson, Colin; Goldman, David; Siever, Larry J; Hazlett, Erin A

    2017-05-30

    A deficit in amygdala habituation to repeated emotional stimuli may be an endophenotype of disorders characterized by emotion dysregulation, such as borderline personality disorder (BPD). Amygdala reactivity to emotional stimuli is genetically modulated by brain-derived neurotrophic factor (BDNF) variants. Whether amygdala habituation itself is also modulated by BDNF genotypes remains unknown. We used imaging-genetics to examine the effect of BDNF Val66Met genotypes on amygdala habituation to repeated emotional stimuli. We used functional magnetic resonance imaging (fMRI) in 57 subjects (19 BPD patients, 18 patients with schizotypal personality disorder [SPD] and 20 healthy controls [HC]) during a task involving viewing of unpleasant, neutral, and pleasant pictures, each presented twice to measure habituation. Amygdala responses across genotypes (Val66Met SNP Met allele-carriers vs. Non-Met carriers) and diagnoses (HC, BPD, SPD) were examined with ANOVA. The BDNF 66Met allele was significantly associated with a deficit in amygdala habituation, particularly for emotional pictures. The association of the 66Met allele with a deficit in habituation to unpleasant emotional pictures remained significant in the subsample of BPD patients. Using imaging-genetics, we found preliminary evidence that deficient amygdala habituation may be modulated by BDNF genotype. Copyright © 2017. Published by Elsevier B.V.

  16. Effect of Early-Life Fluoxetine on Anxiety-Like Behaviors in BDNF Val66Met Mice.

    PubMed

    Dincheva, Iva; Yang, Jianmin; Li, Anfei; Marinic, Tina; Freilingsdorf, Helena; Huang, Chienchun; Casey, B J; Hempstead, Barbara; Glatt, Charles E; Lee, Francis S; Bath, Kevin G; Jing, Deqiang

    2017-12-01

    Adolescence is a developmental stage in which the incidence of psychiatric disorders, such as anxiety disorders, peaks. Selective serotonin reuptake inhibitors (SSRIs) are the main class of agents used to treat anxiety disorders. However, the impact of SSRIs on the developing brain during adolescence remains unknown. The authors assessed the impact of developmentally timed SSRI administration in a genetic mouse model displaying elevated anxiety-like behaviors. Knock-in mice containing a common human single-nucleotide polymorphism (Val66Met; rs6265) in brain-derived neurotrophic factor (BDNF), a growth factor implicated in the mechanism of action of SSRIs, were studied based on their established phenotype of increased anxiety-like behavior. Timed administration of fluoxetine was delivered during one of three developmental periods (postnatal days 21-42, 40-61, or 60-81), spanning the transition from childhood to adulthood. Neurochemical and anxiety-like behavioral analyses were performed. We identified a "sensitive period" during periadolescence (postnatal days 21-42) in which developmentally timed fluoxetine administration rescued anxiety-like phenotypes in BDNF Val66Met mice in adulthood. Compared with littermate controls, BDNF Met/Met mice exhibited diminished maturation of serotonergic fibers projecting particularly to the prefrontal cortex, as well as decreased expression of the serotonergic trophic factor S100B in the dorsal raphe. Interestingly, deficient serotonergic innervation, as well as S100B levels, were rescued with fluoxetine administration during periadolescence. These findings suggest that SSRI administration during a "sensitive period" during periadolescence leads to long-lasting anxiolytic effects in a genetic mouse model of elevated anxiety-like behaviors. These persistent effects highlight the role of BDNF in the maturation of the serotonin system and the capacity to enhance its development through a pharmacological intervention.

  17. Association of glutathione S-transferase pi (GSTP1) Ile105Val polymorphism with the risk of skin cancer: a meta-analysis.

    PubMed

    Zhou, Cheng-Fan; Ma, Tai; Zhou, Deng-Chuan; Shen, Tong; Zhu, Qi-Xing

    2015-08-01

    Numerous epidemiological studies have evaluated the association of Glutathione S-transferase P1 (GSTP1) Ile105Val polymorphism with the risk of skin cancer. However, the results remain inconclusive. To derive a more precise estimation of the association between the GSTP1 Ile105Val polymorphism and skin cancer risk, a meta-analysis was performed. A comprehensive search was conducted to identify the eligible studies. We used odds ratios (ORs) with 95 % confidence intervals (CIs) to assess the association of GSTP1 Ile105Val polymorphism with skin cancer risk. Thirteen case-control studies in nine articles, which included a total of 1504 cases and 2243 controls. Overall, we found that GSTP1 Ile105Val polymorphism was not associated with skin cancer risk. Furthermore, subgroup analysis by histological types showed that GSTP1 Ile105Val polymorphism was associated with risks of malignant melanoma under the dominant model (Val/Val + Val/Ile vs. Ile/Ile: OR 1.230, 95 % CI 1.017-1.488, P = 0.033). However, lack of association between GSTP1 Ile105Val polymorphism and BCC and SCC risk in all genetic models. Our meta-analysis suggested that the GSTP1 Ile105Val polymorphism might be associated with increased risk of malignant melanoma in Caucasian population.

  18. Genetic influences on insight problem solving: the role of catechol-O-methyltransferase (COMT) gene polymorphisms

    PubMed Central

    Jiang, Weili; Shang, Siyuan; Su, Yanjie

    2015-01-01

    People may experience an “aha” moment, when suddenly realizing a solution of a puzzling problem. This experience is called insight problem solving. Several findings suggest that catecholamine-related genes may contribute to insight problem solving, among which the catechol-O-methyltransferase (COMT) gene is the most promising candidate. The current study examined 753 healthy individuals to determine the associations between 7 candidate single nucleotide polymorphisms on the COMT gene and insight problem-solving performance, while considering gender differences. The results showed that individuals carrying A allele of rs4680 or T allele of rs4633 scored significantly higher on insight problem-solving tasks, and the COMT gene rs5993883 combined with gender interacted with correct solutions of insight problems, specifically showing that this gene only influenced insight problem-solving performance in males. This study presents the first investigation of the genetic impact on insight problem solving and provides evidence that highlights the role that the COMT gene plays in insight problem solving. PMID:26528222

  19. Genetic influences on insight problem solving: the role of catechol-O-methyltransferase (COMT) gene polymorphisms.

    PubMed

    Jiang, Weili; Shang, Siyuan; Su, Yanjie

    2015-01-01

    People may experience an "aha" moment, when suddenly realizing a solution of a puzzling problem. This experience is called insight problem solving. Several findings suggest that catecholamine-related genes may contribute to insight problem solving, among which the catechol-O-methyltransferase (COMT) gene is the most promising candidate. The current study examined 753 healthy individuals to determine the associations between 7 candidate single nucleotide polymorphisms on the COMT gene and insight problem-solving performance, while considering gender differences. The results showed that individuals carrying A allele of rs4680 or T allele of rs4633 scored significantly higher on insight problem-solving tasks, and the COMT gene rs5993883 combined with gender interacted with correct solutions of insight problems, specifically showing that this gene only influenced insight problem-solving performance in males. This study presents the first investigation of the genetic impact on insight problem solving and provides evidence that highlights the role that the COMT gene plays in insight problem solving.

  20. The activity of catechol-O-methyltransferase (COMT) is not impaired by high doses of epigallocatechin-3-gallate (EGCG) in vivo.

    PubMed

    Lorenz, Mario; Paul, Friedemann; Moobed, Minoo; Baumann, Gert; Zimmermann, Benno F; Stangl, Karl; Stangl, Verena

    2014-10-05

    Catechol-O-methyltransferase (COMT) inactivates many endogenous and exogenous compounds by O-methylation. Therefore, it represents a major enzyme of the metabolic pathway with important biological functions in hormonal and drug metabolism. The tea catechin epigallocatechin-3-gallate (EGCG) is known to inhibit COMT enzymatic activity in vitro. Based on beneficial in vitro results, EGCG is extensively used in human intervention studies in a variety of human diseases. Owing to its low bioavailability, rather high doses of EGCG are frequently applied that may impair COMT activity in vivo. Enzymatic activities of four functional COMT single-nucleotide polymorphisms (SNPs) were determined in red blood cells (RBCs) in 24 healthy human volunteers (14 women, 10 men). The subjects were supplemented with 750 mg of EGCG and EGCG plasma levels and COMT enzyme activities in erythrocytes were measured before and 2 h after intervention. The homozygous Val→Met substitution in the SNP rs4680 resulted in significantly decreased COMT activity. Enzymatic COMT activities in RBCs were also affected by the other three COMT polymorphisms. EGCG plasma levels significantly increased after intervention. They were not influenced by any of the COMT SNPs and different enzyme activities. Ingestion of 750 mg EGCG did not result in impairment of COMT activity. However, COMT activity was significantly increased by 24% after EGCG consumption. These results indicate that supplementation with a high dose of EGCG does not impair the activity of COMT. Consequently, it may not interfere with COMT-mediated metabolism and elimination of exogenous and endogenous COMT substrates. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. The association of 5-HTR2A-1438A/G, COMTVal158Met, MAOA-LPR, DATVNTR and 5-HTTVNTR gene polymorphisms and antisocial personality disorder in male heroin-dependent Chinese subjects.

    PubMed

    Yang, Mei; Kavi, Vasish; Wang, Wenfu; Wu, Zhimei; Hao, Wei

    2012-03-30

    To explore the association between the 5-HTR2A-1438A/G, COMTVal158Met, MAOA-LPR, DATVNTR and 5-HTTVNTR polymorphisms with comorbidity of antisocial personality disorder in male heroin-dependent patients. In case control study, we compared the polymorphic distributions of 5-HTR2A-1438A/G, COMTVal158Met, MAOA-LPR, DATVNTR and 5-HTTVNTR in 588 male heroin-dependent patients (including 311 patients with antisocial personality disorder and 277 patients without antisocial personality disorder) and 194 normal males by genotypes, alleles, and interaction between genes. Between male heroin-dependent patients with antisocial personality disorder and normal males, and between male heroin-dependent patients with and without antisocial personality disorder, the distributions of 5-HTTVNTR polymorphic genotypes and alleles were in statistical significance. Individuals carrying 10R allele were in higher risk of the comorbidity of antisocial personality disorder and heroin dependence. By MDR analyses, the interaction between 5-HTTVNTR and DATVNTR was close to statistical significance in predicting the risk of antisocial personality disorder in male heroin dependent patients. In male heroin dependent patients, individuals carrying 5-HTTVNTR 10R allele or/and DATVNTR 9R allele were in higher risks of co-occurring antisocial personality disorder, while individuals with 5-HTTVNTR 12R/12R and DATVNTR 10R/10R genotypes together were in lower risks of antisocial personality disorder. 5-HTTVNTR, and the interaction between 5-HTTVNTR and DATVNTR may be associated with the comorbidity of antisocial personality disorder in male heroin-dependent patients. Copyright © 2011 Elsevier Inc. All rights reserved.

  2. BDNF val66met modulates the association between childhood trauma, cognitive and brain abnormalities in psychoses.

    PubMed

    Aas, Monica; Haukvik, Unn K; Djurovic, Srdjan; Bergmann, Ørjan; Athanasiu, Lavinia; Tesli, Martin S; Hellvin, Tone; Steen, Nils Eiel; Agartz, Ingrid; Lorentzen, Steinar; Sundet, Kjetil; Andreassen, Ole A; Melle, Ingrid

    2013-10-01

    Brain derived neurotrophic factor (BDNF) is important for brain development and plasticity, and here we tested if the functional BDNF val66met variant modulates the association between high levels of childhood abuse, cognitive function, and brain abnormalities in psychoses. 249 patients with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder were consecutively recruited to the TOP research study (mean±age: 30.7±10.9; gender: 49% males). History of childhood trauma was obtained using the Childhood Trauma Questionnaire. Cognitive function was assessed through a standardized neuropsychological test battery. BDNF val66met was genotyped using standardized procedures. A sub-sample of n=106 Caucasians with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder (mean±age: 32.67±10.85; 49% males) had data on sMRI. Carriers of the Methionine (met) allele exposed to high level of childhood abuse demonstrated significantly poorer cognitive functioning compared to homozygotic Valine (val/val) carriers. Taking in consideration multiple testing, using a more conservative p value, this was still shown for physical abuse and emotional abuse, as well as a trend level for sexual abuse. Further, met carriers exposed to high level of childhood sexual abuse showed reduced right hippocampal volume (r(2)=0.43; p=0.008), and larger right and left lateral ventricles (r(2)=0.37; p=0.002, and r(2)=0.27; p=0.009, respectively). Our findings were independent of age, gender, diagnosis and intracranial volume. Our data demonstrate that in patients with psychoses, met carriers of the BDNF val66met with high level of childhood abuse have more cognitive and brain abnormalities than all other groups. © 2013.

  3. [The polymorphism of catechol-O-methyltransferase (COMT) and hemochromatosis (HFE) genes in the radiocontaminated regions residents with different chromosome aberration frequency].

    PubMed

    Ivanova, T I; Kondrashova, T V; Krikunova, L I; Smirnova, I A; Shentereva, N I; Sychenkova, N I; Rykova, E V; Zharikova, I A; Khorokhorina, V A; Riabchenko, N I; Zamulaeva, I A

    2010-01-01

    The association between polymorphisms in genes COMT, HFE that takes part in oxidative stress regulation, and chromosome aberration frequency in lymphocytes was assessed in 278 female residents of radiation polluted regions of Central Russia: Bryansk (322 kBk/m2) and Tula Districts (137Cs - 171 kBk/m2). The C187G, G845A genotyping of HFE and G1947A (H/L) of COMT was done by means of polymerase chain reaction-restriction fragment length polymorphism. Studied population was divided into 3 subgroups by level of chromosome aberrations per cell (0-2, 3-4, >5). There was shown statistically significant difference in distribution of COMTand HFE genotypes between the groups. The high frequency of chromosome aberrations (> or = 5%) was associated with homozygotes of the high activity COMT G/G and HFE CC. Heterozygotes for G1947A COMT and C187G HFE reveal negative association with the high frequency of chromosome aberrations and correspond to "resistance factors".

  4. Analysis of CYP1A1 and COMT polymorphisms in women with cervical cancer.

    PubMed

    Kleine, J P; Camargo-Kosugi, C M; Carvalho, C V; Silva, F C; Silva, I D C G

    2015-12-29

    The aim of this case-control study was to obtain a comprehensive panel of genetic polymorphisms present only in genes (cytochrome P-450 1A1--CYP1A1 and catechol-O-methyl transferase--COMT) within the metabolic pathway of sex steroids and determine their possible associations with the presence or absence of cervical cancer. Genotypes of 222 women were analyzed: a) 81 with cancer of the cervix treated at the Cancer Hospital Alfredo Abram, between June 2012 and May 2013, with diagnosis confirmed surgically and/or through histomorphological examination; and b) 141 healthy women who assisted at the Endocrine Gynecology and Climacteric Ambulatory, Department of Gynecology, UNIFESP-EPM. These polymorphisms were detected by polymerase chain reaction amplification-restriction fragment length polymorphism analysis and visualized on 3% agarose gels stained with ethidium bromide. We found a significant association between the frequency of the CYP1A1 polymorphism and the development of cervical cancer. A statistical difference was observed between patient and control groups for CYP1A1 polymorphism genotype distributions (P < 0.05). However, no significant differences were found in the COMT gene polymorphism genotype distributions between the patient and control groups (P > 0.05) or between other risk variables analyzed. The CYP1A1 gene involved in the metabolic pathway of sex steroids might influence the emergence of pathological conditions such as cervical cancer in women who carry a mutated allele, and result in 1.80 and 13.46 times increased risk for women with heterozygous or homozygous mutated genotypes, respectively.

  5. HER2 Ile655Val polymorphism contributes to breast cancer risk: evidence from 27 case-control studies.

    PubMed

    Lu, Su; Wang, Zhanwei; Liu, Hong; Hao, Xishan

    2010-12-01

    Proto-oncogene HER2 (also known as erbB-2 or neu) plays an important role in the carcinogenesis and the prognosis of breast cancer. Many epidemiological studies have been conducted to explore the association between the HER2 Ile655Val polymorphism and breast cancer risk. However, inconsistency existed in the results. Therefore, we performed a meta-analysis of 27 published case-control studies including 11,504 cases and 12,538 controls. We assessed the strength of the association by crude odds ratios (ORs) with 95% confidence intervals (CIs) and reached a result that HER2 Ile655Val polymorphism was associated with an increased breast cancer risk in overall populations (for Ile/Val vs. Ile/Ile: OR = 1.05, 95% CI = 1.00-1.12, P = 0.07 for heterogeneity; for the dominant model Ile/Val + Val/Val vs. Ile/Ile: OR = 1.10, 95% CI = 1.01-1.20, P = 0.01 for heterogeneity). In subgroup analysis by ethnicity, we found a significant association among Africans (for Val/Val vs. Ile/Ile: OR = .78, 95% CI = 1.94-39.72, P = 0.35 for heterogeneity; for the recessive model Val/Val vs. Ile/Val +Ile/Ile: OR = 8.60, 95% CI = 1.92-38.48, P = 0.31 for heterogeneity) and Asians (for Ile/Val vs. Ile/Ile: OR = 1.18, 95% CI = 1.01-1.39, P = 0.41 for heterogeneity; for the dominant model Val/Val + Ile/Val vs. Ile/Ile: OR = 1.18, 95% CI = 1.01-1.38, P = 0.27 for heterogeneity). In conclusion, our meta-analysis suggests that HER2 Ile 655Val polymorphism may contribute to breast cancer risk.

  6. Association of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism with early-onset bipolar disorder.

    PubMed

    Nassan, Malik; Croarkin, Paul E; Luby, Joan L; Veldic, Marin; Joshi, Paramjit T; McElroy, Susan L; Post, Robert M; Walkup, John T; Cercy, Kelly; Geske, Jennifer R; Wagner, Karen D; Cuellar-Barboza, Alfredo B; Casuto, Leah; Lavebratt, Catharina; Schalling, Martin; Jensen, Peter S; Biernacka, Joanna M; Frye, Mark A

    2015-09-01

    Brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) functional polymorphism has been implicated in early-onset bipolar disorder. However, results of studies are inconsistent. We aimed to further explore this association. DNA samples from the Treatment of Early Age Mania (TEAM) and Mayo Clinic Bipolar Disorder Biobank were investigated for association of rs6265 with early-onset bipolar disorder. Bipolar cases were classified as early onset if the first manic or depressive episode occurred at age ≤19 years (versus adult-onset cases at age >19 years). After quality control, 69 TEAM early-onset bipolar disorder cases, 725 Mayo Clinic bipolar disorder cases (including 189 early-onset cases), and 764 controls were included in the analysis of association, assessed with logistic regression assuming log-additive allele effects. Comparison of TEAM cases with controls suggested association of early-onset bipolar disorder with the rs6265 minor allele [odds ratio (OR) = 1.55, p = 0.04]. Although comparison of early-onset adult bipolar disorder cases from the Mayo Clinic versus controls was not statistically significant, the OR estimate indicated the same direction of effect (OR = 1.21, p = 0.19). When the early-onset TEAM and Mayo Clinic early-onset adult groups were combined and compared with the control group, the association of the minor allele rs6265 was statistically significant (OR = 1.30, p = 0.04). These preliminary analyses of a relatively small sample with early-onset bipolar disorder are suggestive that functional variation in BDNF is implicated in bipolar disorder risk and may have a more significant role in early-onset expression of the disorder. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Effects of BDNF polymorphism and physical activity on episodic memory in the elderly: a cross sectional study.

    PubMed

    Canivet, Anne; Albinet, Cédric T; André, Nathalie; Pylouster, Jean; Rodríguez-Ballesteros, Montserrat; Kitzis, Alain; Audiffren, Michel

    2015-01-01

    The brain-derived neurotrophic factor (BDNF) concentration is highest in the hippocampus compared with that in other brain structures and affects episodic memory, a cognitive function that is impaired in older adults. According to the neurotrophic hypothesis, BDNF released during physical activity enhances brain plasticity and consequently brain health. However, even if the physical activity level is involved in the secretion of neurotrophin, this protein is also under the control of a specific gene. The aim of the present study was to examine the effect of the interaction between physical activity and BDNF Val66Met (rs6265), a genetic polymorphism, on episodic memory. Two hundred and five volunteers aged 55 and older with a Mini Mental State Examination score ≥ 24 participated in this study. Four groups of participants were established according to their physical activity level and polymorphism BDNF profile (Active Val homozygous, Inactive Val homozygous, Active Met carriers, Inactive Met carriers). Episodic memory was evaluated based on the delayed recall of the Logical Memory test of the MEM III battery. As expected, the physical activity level interacted with BDNF polymorphism to affect episodic memory performance (p < .05). The active Val homozygous participants significantly outperformed the active Met carriers and inactive Val homozygous participants. This study clearly demonstrates an interaction between physical activity and BDNF Val66Met polymorphism that affects episodic memory in the elderly and confirms that physical activity contributes to the neurotrophic mechanism implicated in cognitive health. The interaction shows that only participants with Val/Val polymorphism benefited from physical activity.

  8. LRP5 gene polymorphism and cortical bone.

    PubMed

    Lauretani, Fulvio; Cepollaro, Chiara; Bandinelli, Stefania; Cherubini, Antonio; Gozzini, Alessia; Masi, Laura; Falchetti, Alberto; Del Monte, Francesca; Carbonell-Sala, Silvia; Marini, Francesca; Tanini, Annalisa; Corsi, Anna Maria; Ceda, Gian Paolo; Brandi, Maria Luisa; Ferrucci, Luigi

    2010-08-01

    There is evidence that distinct genetic polymorphisms of LRP5 are associated with low Bone Mineral Density (BMD) and the risk of fracture. However, relationships between LRP5 polymorphisms and micro- and macro architectural bone characteristics assessed by pQCT have not been studied. The aim of the present study was to investigate the association of Ala1330Val and Val667Met polymorphisms in LRP5 gene with volumetric BMD (vBMD) and macro-architectural bone parameters in a population-based sample of men and women. We studied 959 participants of the InCHIANTI study (451 men and 508 women, age range: 21-94 yrs). Trabecular vBMD (vBMDt, mg/cm3), cortical vBMD (vBMDc, mg/cm3), cortical bone area (CBA, mm2) and cortical thickness (Ct.Th, mm) at the level of the tibia were assessed by peripheral quantitative computed tomography (pQCT). Ala1330Val and Val667Met genotypes were determined on genomic DNA by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In age-adjusted analyses both LRP 1330-valine and LRP 667-metionin variants were associated with lower vBMDt in men (p<0.05), and lower vBMDt (p<0.05), Ct.Th (p<0.05) and CBA (p<0.05) in women. After adjusting for multiple confounders, only the association of LRP5 1330-valine and 667-metionin with CBA remained statistically significant (p=0.04 and p=0.01, respectively) in women. These findings suggest that both Ala1330Val and Val667Met LRP5 polymorphisms may affect the determination of geometric bone parameters in women.

  9. Contributions of COMT Val[superscript 158]Met to Cognitive Stability and Flexibility in Infancy

    ERIC Educational Resources Information Center

    Markant, Julie; Cicchetti, Dante; Hetzel, Susan; Thomas, Kathleen M.

    2014-01-01

    Adaptive behavior requires focusing on relevant tasks while remaining sensitive to novel information. In adult studies of cognitive control, cognitive stability involves maintaining robust cognitive representations while cognitive flexibility involves updating of representations in response to novel information. Previous adult research has shown…

  10. Sweet Taste Receptor TAS1R2 Polymorphism (Val191Val) Is Associated with a Higher Carbohydrate Intake and Hypertriglyceridemia among the Population of West Mexico

    PubMed Central

    Ramos-Lopez, Omar; Panduro, Arturo; Martinez-Lopez, Erika; Roman, Sonia

    2016-01-01

    Some high-carbohydrate diets may lead to obesity and multiple metabolic disorders, including hypertriglyceridemia (HTG). This lipid abnormality is considered an important risk factor for cardiovascular disease and type 2 diabetes. The sweet taste receptor TAS1R2 polymorphism (Ile191Val) has been reported to be associated with carbohydrate intake. The aim of this study was to analyze the association of the TAS1R2 gene polymorphism with carbohydrate intake and HTG among the population of West Mexico. In a cross-sectional study, 441 unrelated subjects were analyzed for TAS1R2 genotypes (Ile/Ile, Ile/Val and Val/Val) by an allelic discrimination assay. Biochemical tests and a three-day food record were assessed. The Val/Val genotype carriers had a higher intake of total carbohydrates, fiber and servings of cereals and vegetables than the other genotype carriers. The Val/Val genotype conferred a higher risk for HTG than the Ile/Val and Ile/Ile genotypes (OR = 3.26, 95%CI 1.35–7.86, p = 0.006 and OR = 2.61, 95%CI 1.12–6.07, p = 0.02, respectively). Furthermore, the Val/Val genotype was associated with approximately 30% higher triglycerides compared with Ile/Val and Ile/Ile genotypes (β = 44.09, 95%CI 9.94–78.25, p = 0.01 and β = 45.7, 95%CI 10.85–80.54, p = 0.01, respectively). In conclusion, the Val/Val genotype of TAS1R2 was associated with a higher carbohydrate intake and HTG. PMID:26907331

  11. The association between COMT rs4680 and 5-HTTLPR genotypes and concussion history in South African rugby union players.

    PubMed

    Mc Fie, Sarah; Abrahams, Shameemah; Patricios, Jon; Suter, Jason; Posthumus, Michael; September, Alison V

    2018-04-01

    The objective was to investigate the relationship between Catechol-O-methyltransferase (COMT) rs4680 and serotonin-transporter-linked polymorphic region (5-HTTLPR) genotypes with concussion history and personality traits. Rugby players ("all levels": n = 303), from high schools ("junior", n = 137), senior amateur, and professional teams ("senior", n = 166), completed a self-reported concussion history questionnaire, Cloninger's Tridimensional Personality Questionnaire, and donated a DNA sample. Participants were allocated into control (non-concussed, n = 140), case (all) (previous suspected or diagnosed concussions, n = 163), or case (diagnosed only) (previous diagnosed concussion, n = 140) groups. COMT rs4680 Val/Val genotypes were over-represented in controls in all levels (P = 0.013, OR:2.00, 95% CI:1.15-3.57) and in juniors (P = 0.003, OR:3.57, 95% CI:1.45-9.09). Junior Val/Val participants displayed increased "anticipatory worry" (P = 0.023). The 5-HTTLPR low expressing group was under-represented in controls when all levels were considered (P = 0.032; OR:2.02, 95% CI:1.05-3.90) and in juniors (P = 0.021; OR:3.36, 95% CI:1.16-9.72). Junior 5-HTTLPR low and intermediate expressing groups displayed decreased "harm avoidance" (P = 0.009), "anticipatory worry" (P = 0.041), and "fear of uncertainty" (P < 0.001). This study provides preliminary indications that personality associated genetic variants can influence concussion in rugby.

  12. Variant BDNF-Val66Met Polymorphism is Associated with Layer-Specific Alterations in GABAergic Innervation of Pyramidal Neurons, Elevated Anxiety and Reduced Vulnerability of Adolescent Male Mice to Activity-Based Anorexia.

    PubMed

    Chen, Yi-Wen; Surgent, Olivia; Rana, Barkha S; Lee, Francis; Aoki, Chiye

    2017-08-01

    Previously, we determined that rodents' vulnerability to food restriction (FR)-evoked wheel running during adolescence (activity-based anorexia, ABA) is associated with failures to increase GABAergic innervation of hippocampal and medial prefrontal pyramidal neurons. Since brain-derived neurotrophic factor (BDNF) promotes GABAergic synaptogenesis, we hypothesized that individual differences in this vulnerability may arise from differences in the link between BDNF bioavailability and FR-evoked wheel running. We tested this hypothesis in male BDNF-Val66Met knock-in mice (BDNFMet/Met), known for reduction in the activity-dependent BDNF secretion and elevated anxiety-like behaviors. We found that 1) in the absence of FR or a wheel (i.e., control), BDNFMet/Met mice are more anxious than wild-type (WT) littermates, 2) electron microscopically verified GABAergic innervations of pyramidal neurons of BDNFMet/Met mice are reduced at distal dendrites in hippocampal CA1 and medial prefrontal cortex, 3) following ABA, WT mice exhibit anxiety equal to those of the BDNFMet/Met mice and have lost GABAergic innervation along distal dendrites, 4) BDNFMet/Met mice show blunted ABA vulnerability, and 5) unexpectedly, GABAergic innervation is higher at somata of BDNFMet/Met mice than of WT. We conclude that lamina-specific GABAergic inhibition is important for regulating anxiety, whether arising from environmental stress, such as food deprivation, or genetically, such as BDNFMet/Met single nucleotide polymorphism. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  13. LRP5 gene polymorphism and cortical bone

    PubMed Central

    Lauretani, Fulvio; Cepollaro, Chiara; Bandinelli, Stefania; Cherubini, Antonio; Gozzini, Alessia; Masi, Laura; Falchetti, Alberto; Del Monte, Francesca; Carbonell-Sala, Silvia; Marini, Francesca; Tanini, Annalisa; Corsi, Anna Maria; Ceda, Gian Paolo; Brandi, Maria Luisa; Ferrucci, Luigi

    2016-01-01

    Background and aims There is evidence that distinct genetic polymorphisms of LRP5 are associated with low Bone Mineral Density (BMD) and the risk of fracture. However, relationships between LRP5 polymorphisms and micro- and macro-architectural bone characteristics assessed by pQCT have not been studied. The aim of the present study was to investigate the association of Ala1330Val and Val667Met polymorphisms in LRP5 gene with volumetric BMD (vBMD) and macro-architectural bone parameters in a population-based sample of men and women. Methods We studied 959 participants of the InCHIANTI study (451 men and 508 women, age range: 21–94 yrs). Trabecular vBMD (vBMDt, mg/cm3), cortical vBMD (vBMDc, mg/cm3), cortical bone area (CBA, mm2) and cortical thickness (Ct.Th, mm) at the level of the tibia were assessed by peripheral quantitative computed tomography (pQCT). Ala1330Val and Val667Met genotypes were determined on genomic DNA by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results In age-adjusted analyses both LRP 1330-valine and LRP 667-metionin variants were associated with lower vBMDt in men (p<0.05), and lower vBMDt (p<0.05), Ct.Th (p<0.05) and CBA (p<0.05) in women. After adjusting for multiple confounders, only the association of LRP5 1330-valine and 667-metionin with CBA remained statistically significant (p=0.04 and p=0.01, respectively) in women. Conclusion These findings suggest that both Ala1330Val and Val667Met LRP5 polymorphisms may affect the determination of geometric bone parameters in women. PMID:21116122

  14. Analysis of Oxidative Stress Status, Catalase and Catechol-O-Methyltransferase Polymorphisms in Egyptian Vitiligo Patients

    PubMed Central

    Mehaney, Dina A.; Darwish, Hebatallah A.; Hegazy, Rehab A.; Nooh, Mohammed M.; Tawdy, Amira M.; Gawdat, Heba I.; El-Sawalhi, Maha M.

    2014-01-01

    Vitiligo is the most common depigmentation disorder of the skin. Oxidative stress is implicated as one of the probable events involved in vitiligo pathogenesis possibly contributing to melanocyte destruction. Evidence indicates that certain genes including those involved in oxidative stress and melanin synthesis are crucial for development of vitiligo. This study evaluates the oxidative stress status, the role of catalase (CAT) and catechol-O-Methyltransferase (COMT) gene polymorphisms in the etiology of generalized vitiligo in Egyptians. Total antioxidant capacity (TAC) and malondialdehyde (MDA) levels as well as CAT exon 9 T/C and COMT 158 G/A polymorphisms were determined in 89 patients and 90 age and sex-matched controls. Our results showed significantly lower TAC along with higher MDA levels in vitiligo patients compared with controls. Meanwhile, genotype and allele distributions of CAT and COMT polymorphisms in cases were not significantly different from those of controls. Moreover, we found no association between both polymorphisms and vitiligo susceptibility. In conclusion, the enhanced oxidative stress with the lack of association between CAT and COMT polymorphisms and susceptibility to vitiligo in our patients suggest that mutations in other genes related to the oxidative pathway might contribute to the etiology of generalized vitiligo in Egyptian population. PMID:24915010

  15. Investigating the genetic basis of theory of mind (ToM): the role of catechol-O-methyltransferase (COMT) gene polymorphisms.

    PubMed

    Xia, Haiwei; Wu, Nan; Su, Yanjie

    2012-01-01

    The ability to deduce other persons' mental states and emotions which has been termed 'theory of mind (ToM)' is highly heritable. First molecular genetic studies focused on some dopamine-related genes, while the genetic basis underlying different components of ToM (affective ToM and cognitive ToM) remain unknown. The current study tested 7 candidate polymorphisms (rs4680, rs4633, rs2020917, rs2239393, rs737865, rs174699 and rs59938883) on the catechol-O-methyltransferase (COMT) gene. We investigated how these polymorphisms relate to different components of ToM. 101 adults participated in our study; all were genetically unrelated, non-clinical and healthy Chinese subjects. Different ToM tasks were applied to detect their theory of mind ability. The results showed that the COMT gene rs2020917 and rs737865 SNPs were associated with cognitive ToM performance, while the COMT gene rs5993883 SNP was related to affective ToM, in which a significant gender-genotype interaction was found (p = 0.039). Our results highlighted the contribution of DA-related COMT gene on ToM performance. Moreover, we found out that the different SNP at the same gene relates to the discriminative aspect of ToM. Our research provides some preliminary evidence to the genetic basis of theory of mind which still awaits further studies.

  16. Lack of association between alpha2-macroglobulin polymorphisms and Alzheimer's disease.

    PubMed

    Wang, X; Luedecking, E K; Minster, R L; Ganguli, M; DeKosky, S T; Kamboh, M I

    2001-02-01

    This study was undertaken to investigate the role of two alpha2-macroglobulin (A2M) polymorphisms, an intronic 5-bp deletion and Ile1000Val, in the development of Alzheimer's disease (AD) and to evaluate the interaction between the apolipoprotein E (APOE) and A2M polymorphisms. The A2M polymorphisms were screened by using polymerase-chain-reaction-based assays in 555 white late-onset AD cases and 446 controls. The gentoype distributions of the 5-bp deletion and Ile1000Val polymorphisms were comparable between cases and controls (P = 0.158 and P = 0.148, respectively). Likewise, there was no significant difference in allele frequencies of each polymorphism among cases and controls (P = 0.361 and P = 0.062, respectively). The stratification of data by APOE*4 status also did not yield any significant association. In conclusion, we observed no association between either the intronic deletion polymorphism or the Ile1000Val polymorphism of A2M and AD in our case-control cohort.

  17. The psychology of psychiatric genetics: evidence that positive emotions in females moderate genetic sensitivity to social stress associated with the BDNF Val-sup-6-sup-6Met polymorphism.

    PubMed

    Wichers, Marieke; Kenis, Gunter; Jacobs, Nele; Myin-Germeys, Inez; Schruers, Koen; Mengelers, Ron; Delespaul, Philippe; Derom, Catherine; Vlietinck, Robert; van Os, Jim

    2008-08-01

    Previous work indicated protective effects of positive emotions on genetically influenced stress sensitivity. Given the fact that expression of brain-derived-neurotrophic-factor (BDNF) is associated with stress-induced behavioral changes, it was hypothesized that the BDNF Val-sup-6-sup-6Met genotype may mediate genetic effects on stress sensitivity, conditional on the level of concurrent positive emotions. Subjects (n=446) participated in a momentary assessment study, collecting appraisals of stress and affect in the flow of daily life. Multilevel regression analyses examined moderation of daily life stress-induced negative affect (NA) by BDNF genotype, and to what degree this was conditional on concurrent positive emotions. Results showed that heterozygous BDNF "Met" carriers exhibited an increased NA response to social stress compared with "Val/Val" subjects. Positive emotions at the time of the stressor decreased BDNF genetic moderation of the NA response to social stress in a dose-response fashion. This effect was most pronounced in BDNF Met carriers. Thus, the impact of BDNF genotype on stress sensitivity is conditional on the experience of positive emotions. Interdisciplinary research in psychology and psychiatric genetics may lead to the improvement of treatment choices in stress-related disorders. Copyright (c) 2008 APA, all rights reserved.

  18. The MAOA, COMT, MTHFR and ESR1 gene polymorphisms are associated with the risk of depression in menopausal women.

    PubMed

    Różycka, Agata; Słopień, Radosław; Słopień, Agnieszka; Dorszewska, Jolanta; Seremak-Mrozikiewicz, Agnieszka; Lianeri, Margarita; Maciukiewicz, Małgorzata; Warenik-Szymankiewicz, Alina; Grzelak, Teresa; Kurzawińska, Grażyna; Drews, Krzysztof; Klejewski, Andrzej; Jagodziński, Paweł P

    2016-02-01

    The aim of the study was assessment of a possible relationship between the polymorphisms of the candidate genes participating in the etiology of some neurological and psychiatric disorders and the risk of depression in perimenopausal and postmenopausal women. A total of 167 (54 perimenopausal and 113 postmenopausal) Caucasian women from western Poland, aged 42-67, were recruited as the patient group in the study because of depressive symptoms, and another 321 healthy women (102 perimenopausal and 219 postmenopausal) served as the controls. All study participants were evaluated for climacteric and depressive disorders according to the Kupperman index and Hamilton rating scale for depression (HRSD), respectively. The following candidate genes were selected for the study: 5HTR2A, 5HTR1B, 5HTR2C, TPH1, TPH2, MAOA, COMT, NET, GABRB1, ESR1, MTHFR, MTR and MTHFD1. In each group the frequencies of the polymorphisms were determined using PCR-RFLP analysis. After correcting for Bonferroni multiple tests, we found associations between the MAOA c.1460C>T (SNP 1137070), COMT c.472G>A (SNP 4680), MTHFR c.677C>T (SNP 1801133) and ESR1 454(-351) A>G (SNP 9340799) polymorphisms to mild and moderate depressive symptoms in menopausal women. In the perimenopausal and postmenopausal women, genotype association of the MAOA c.1460 CT and c.1460 CT+TT (OR=1.83; pcorr=0.009 and OR=1.85; pcorr=0.003, resp.), and of the MTHFR c.677 TT and c.677 CT+TT (OR=3.52; pcorr=0.00009 and OR=2.06; pcorr=0.0006, resp.), as well as of the COMT c.472 GA and COMT c.472 GA+AA genotypes (OR=2.23; pcorr=0.03 and OR=2.17; pcorr=0.027, resp.) in the postmenopausal women revealed significantly higher frequencies of these variants in depressed female patients than in controls, whereas the ESR1 454(-351) AG and 454(-351) AG+GG genotypes were associated with lower risk of depression in postmenopausal women (OR=0.48; pcorr=0.012, and OR=0.52; pcorr=0.015, resp.). Our study substantiates the involvement of the MAOA

  19. Association of the F13A1 Val34Leu polymorphism and recurrent pregnancy loss: A meta-analysis.

    PubMed

    Jung, Jae Hyun; Kim, Jae-Hoon; Song, Gwan Gyu; Choi, Sung Jae

    2017-08-01

    Factor XIII (FXIII) plays role in stabilizing the linkage between fibrins during blood clotting and has been implicated in recurrent pregnancy loss (RPL). The relationship between the Val34Leu polymorphism in F13A1, which encodes the enzymatic subunit of FXIII, and RPL is unclear. The aim of this meta-analysis was to evaluate the association betweenF13A1 Val34Leu and the risk of RPL. We performed a meta-analysis of 11 studies involving 1092 cases and 678 controls using published literature from PubMed and Embase. We detected an association in recessive (Val/Val vs. Val/Leu+Leu/Leu; OR=0.71, 95% CI=0.51-0.99, P=0.04), and one of the two co-dominant (Val/Val vs. Val/Leu; OR=0.71, 95% CI=0.52-0.98, P=0.03) models of in heritance. Subgroup analysis revealed that the F13A1 Val34Leu polymorphism was associated with RPL in Asians (Val vs. Leu; OR=0.53, CI=0.33-0.85, P=0.01). However, there was no association between F13A1 Val34Leu and RPL in Europeans and South Americans. Our meta-analysis supports an association between F13A1 Val34Leu and RPL. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Protective Effect of Val129-PrP against Bovine Spongiform Encephalopathy but not Variant Creutzfeldt-Jakob Disease

    PubMed Central

    Fernández-Borges, Natalia; Espinosa, Juan Carlos; Marín-Moreno, Alba; Aguilar-Calvo, Patricia; Asante, Emmanuel A.; Kitamoto, Tetsuyuki; Mohri, Shirou; Andréoletti, Olivier

    2017-01-01

    Bovine spongiform encephalopathy (BSE) is the only known zoonotic prion that causes variant Creutzfeldt-Jakob disease (vCJD) in humans. The major risk determinant for this disease is the polymorphic codon 129 of the human prion protein (Hu-PrP), where either methionine (Met129) or valine (Val129) can be encoded. To date, all clinical and neuropathologically confirmed vCJD cases have been Met129 homozygous, with the exception of 1 recently reported Met/Val heterozygous case. Here, we found that transgenic mice homozygous for Val129 Hu-PrP show severely restricted propagation of the BSE prion strain, but this constraint can be partially overcome by adaptation of the BSE agent to the Met129 Hu-PrP. In addition, the transmission of vCJD to transgenic mice homozygous for Val129 Hu-PrP resulted in a prion with distinct strain features. These observations may indicate increased risk for vCJD secondary transmission in Val129 Hu-PrP–positive humans with the emergence of new strain features. PMID:28820136

  1. Factor XIII Val34Leu polymorphism and the risk of myocardial infarction under the age of 36 years.

    PubMed

    Rallidis, Loukianos S; Politou, Marianna; Komporozos, Christoforos; Panagiotakos, Demosthenes B; Belessi, Chrisoula I; Travlou, Anthi; Lekakis, John; Kremastinos, Dimitrios T

    2008-06-01

    There are limited and controversial data regarding the impact of factor XIII (FXIII) Val34Leu polymorphism in the pathogenesis of premature myocardial infarction (MI). We examined whether FXIII Val34Leu polymorphism is associated with the development of early MI. We recruited 159 consecutive patients who had survived their first acute MI under the age of 36 years (mean age = 32.1 +/- 3.6 years, 138 were men). The control group consisted of 121 healthy individuals matched with cases for age and sex, without a family history of premature coronary heart disease (CHD). FXIII Val34Leu polymorphism was tested with polymerase chain reaction and reverse hybridization. There was a lower prevalence of carriers of the Leu34 allele in patients than in controls (30.2 vs. 47.1%, p = 0.006). FXIII Val34Leu polymorphism was associated with lower risk for acute MI after adjusting for major cardiovascular risk factors (odds ratio [OR] = 0.51, 95% confidence interval [CI] 0.27-0.95, p = 0.03). Subgroup analysis according to angiographic findings ("normal" coronary arteries [n = 29] or significant CHD [n = 130]) showed that only patients with MI and significant CHD had lower prevalence of carriers of the Leu34 allele compared to controls after adjusting for major cardiovascular risk factors (OR = 0.42, 95% CI 0.22-0.83, p = 0.01). Our data indicate that FXIII Val34Leu polymorphism has a protective effect against the development of MI under the age of 36 years, particularly in the setting of significant CHD.

  2. The association of 5-HTR2A-1438A/G, COMTVal158Met, MAOA-LPR, DATVNTR and 5-HTTVNTR gene polymorphisms and borderline personality disorder in female heroin-dependent Chinese subjects.

    PubMed

    Yang, Mei; Mamy, Jules; Wang, Qiang; Liao, Yan-Hui; Seewoobudul, Vasish; Xiao, Shui-Yuan; Hao, Wei

    2014-04-03

    To explore the association between the 5-HTR2A-1438A/G, COMTVal158Met, MAOA-LPR, DATVNTR and 5-HTTVNTR polymorphisms with co-morbid borderline personality disorder (BPD) in female heroin-dependent patients. In a case control study, we compared the polymorphic distributions of 5-HTR2A-1438A/G, COMTVal158Met, MAOA-LPR, DATVNTR and 5-HTTVNTR in 296 female heroin-dependent patients (including 61 patients with BPD and 235 without BPD) and 101 normal females by genotypes, alleles, and interaction between genes. Female heroin-dependent subjects with BPD have lower frequency of the high activity allele (L: 4 repeats (4R)) of MAOA-LPR than those female heroin-dependent subjects without BPD, and have higher 5-HTTVNTR 10R/10R genotype frequency than normal female controls, with adjusted P-value<0.05 (after adjusted for multiple testing by 1000-fold permutation tests) respectively. By MDR (Multifactor Dimensionality Reduction) analyses, the interactive effects between MAOA-LPR and 5-HTTVNTR, and among MAOA-LPR, 5-HTTVNTR and rs6311 were close to the significance level (P=0.05) in predicting the risk of co-morbidity of BPD and heroin dependence relative to normal female controls, with 1000-fold permutation testing P-value<0.06 however >0.05 respectively. 5-HTTVNTR and MAOA-LPR may have independent predictive effects on co-morbid BPD in female heroin-dependent patients; the gene-gene interactions between MAOA-LPR and 5-HTTVNTR, and among MAOA-LPR, 5-HTTVNTR and rs6311 might also be involved in the etiology of this co-morbidity. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. The role of clinical variables, neuropsychological performance and SLC6A4 and COMT gene polymorphisms on the prediction of early response to fluoxetine in major depressive disorder.

    PubMed

    Gudayol-Ferré, Esteve; Herrera-Guzmán, Ixchel; Camarena, Beatriz; Cortés-Penagos, Carlos; Herrera-Abarca, Jorge E; Martínez-Medina, Patricia; Cruz, David; Hernández, Sandra; Genis, Alma; Carrillo-Guerrero, Mariana Y; Avilés Reyes, Rubén; Guàrdia-Olmos, Joan

    2010-12-01

    Major depressive disorder (MDD) is treated with antidepressants, but only between 50% and 70% of the patients respond to the initial treatment. Several authors suggested different factors that could predict antidepressant response, including clinical, psychophysiological, neuropsychological, neuroimaging, and genetic variables. However, these different predictors present poor prognostic sensitivity and specificity by themselves. The aim of our work is to study the possible role of clinical variables, neuropsychological performance, and the 5HTTLPR, rs25531, and val108/58Met COMT polymorphisms in the prediction of the response to fluoxetine after 4weeks of treatment in a sample of patient with MDD. 64 patients with MDD were genotyped according to the above-mentioned polymorphisms, and were clinically and neuropsychologically assessed before a 4-week fluoxetine treatment. Fluoxetine response was assessed by using the Hamilton Depression Rating Scale. We carried out a binary logistic regression model for the potential predictive variables. Out of the clinical variables studied, only the number of anxiety disorders comorbid with MDD have predicted a poor response to the treatment. A combination of a good performance in variables of attention and low performance in planning could predict a good response to fluoxetine in patients with MDD. None of the genetic variables studied had predictive value in our model. The possible placebo effect has not been controlled. Our study is focused on response prediction but not in remission prediction. Our work suggests that the combination of the number of comorbid anxiety disorders, an attentional variable, and two planning variables makes it possible to correctly classify 82% of the depressed patients who responded to the treatment with fluoxetine, and 74% of the patients who did not respond to that treatment. Copyright © 2010 Elsevier B.V. All rights reserved.

  4. Altered declarative memory in introverted middle-aged adults carrying the BDNF val66met allele.

    PubMed

    De Beaumont, Louis; Fiocco, Alexandra J; Quesnel, Geneviève; Lupien, Sonia; Poirier, Judes

    2013-09-15

    The val66met polymorphism of the brain-derived neurotrophic factor gene (BDNFMet) is associated with impaired learning/memory function, affective dysregulation and maladaptive personality traits. Here, we examine the potential relationship between the BDNFMet allele, introversion and declarative memory in middle-age adults. A total of 132 middle-aged healthy adults took part in this study that included taking a blood sample for genetic profiling, a short battery of neuropsychological tests and the NEO-Five Factor Inventory (NEO-FFI), widely used to assess the Big Five personality. Controlling for age, level of education and sex, a multiple analysis of covariance (MANCOVA) computing the effect of BDNF polymorphism on extraversion and declarative memory revealed a significant association (D1,128=4.79; p=0.03; ηp(2)=0.053). Using the Sobel Goodman Mediation Test, it was found that 25.61% of the relationship between genotype and declarative memory performance was mediated by introversion. Subsequent correlational analyses yielded a strong and significant correlation (β=0.53; p<0.001) between introversion and declarative memory specific to BDNFMet individuals. this study highlights the pertinence of further investigating gene×personality×environment interactions to account for the significant variability that is observed in cognitive function in late life. Copyright © 2013 Elsevier B.V. All rights reserved.

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

    PubMed

    Baetu, Irina; Burns, Nicholas R; Urry, Kristi; Barbante, Girolamo Giovanni; Pitcher, Julia B

    2015-11-01

    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

  6. Preproghrelin Leu72Met polymorphism in obese Korean children.

    PubMed

    Jo, Dae-Sun; Kim, Se-Lim; Kim, Sun-Young; Hwang, Pyoung Han; Lee, Kee-Hyoung; Lee, Dae-Yeol

    2005-11-01

    Ghrelin is a novel gut-brain peptide that has somatotropic, orexigenic, and adipogenic effects. We examined the preproghrelin Leu72Met polymorphism in 222 obese Korean children to determine whether it is associated with obesity. The frequencies of the Leu72Met polymorphism were 29.3% in obese, 32.3% in overweight, and 32.5% in lean Korean children. No significant difference was found between Met72 carrier and non-carrier obese children with respect to BMI, total body fat, serum triglycerides, total cholesterol, or LDL-cholesterol levels. Our data suggest that the preproghrelin Leu72Met polymorphism is not associated with obesity in children.

  7. The catechol-O-methyltransferase gene (COMT) and cognitive function from childhood through adolescence

    PubMed Central

    Gaysina, Darya; Xu, Man K.; Barnett, Jennifer H.; Croudace, Tim J.; Wong, Andrew; Richards, Marcus; Jones, Peter B.

    2013-01-01

    Genetic variation in the catechol-O-methyltransferase gene (COMT) can influence cognitive function, and this effect may depend on developmental stage. Using a large representative British birth cohort, we investigated the effect of COMT on cognitive function (verbal and non-verbal) at ages 8 and 15 years taking into account the possible modifying effect of pubertal stage. Five functional COMT polymorphisms, rs6269, rs4818, rs4680, rs737865 and rs165599 were analysed. Associations between COMT polymorphisms and cognition were tested using regression and latent variable structural equation modelling (SEM). Before correction for multiple testing, COMT rs737865 showed association with reading comprehension, verbal ability and global cognition at age 15 years in pubescent boys only. Although there was some evidence for age- and sex-specific effects of the COMT rs737865 none remained significant after correction for multiple testing. Further studies are necessary in order to make firmer conclusions. PMID:23178897

  8. Impact of BDNF Val66Met and 5-HTTLPR polymorphism variants on neural substrates related to sadness and executive function.

    PubMed

    Wang, L; Ashley-Koch, A; Steffens, D C; Krishnan, K R R; Taylor, W D

    2012-04-01

    The brain-derived neurotrophic factor (BDNF) Val(66) Met allelic variation is linked to both the occurrence of mood disorders and antidepressant response. These findings are not universally observed, and the mechanism by which this variation results in increased risk for mood disorders is unclear. One possible explanation is an epistatic relationship with other neurotransmitter genes associated with depression risk, such as the serotonin-transporter-linked promotor region (5-HTTLPR). Further, it is unclear how the coexistence of the BDNF Met and 5-HTTLPR S variants affects the function of the affective and cognitive control systems. To address this question, we conducted a functional magnetic resonance imaging (fMRI) study in 38 older adults (20 healthy and 18 remitted from major depressive disorder). Subjects performed an emotional oddball task during the fMRI scan and provided blood samples for genotyping. Our analyses examined the relationship between genotypes and brain activation to sad distractors and attentional targets. We found that 5-HTTLPR S allele carriers exhibited stronger activation in the amygdala in response to sad distractors, whereas BDNF Met carriers exhibited increased activation to sad stimuli but decreased activation to attentional targets in the dorsolateral prefrontal and dorsomedial prefrontal cortices. In addition, subjects with both the S allele and Met allele genes exhibited increased activation to sad stimuli in the subgenual cingulate and posterior cingulate. Our results indicate that the Met allele alone or in combination with 5-HTTLPR S allele may increase reactivity to sad stimuli, which might represent a neural mechanism underlying increased depression vulnerability. © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

  9. Monoamine oxidase A gene polymorphisms and enzyme activity associated with risk of gout in Taiwan aborigines.

    PubMed

    Tu, Hung-Pin; Ko, Albert Min-Shan; Wang, Shu-Jung; Lee, Chien-Hung; Lea, Rod A; Chiang, Shang-Lun; Chiang, Hung-Che; Wang, Tsu-Nai; Huang, Meng-Chuan; Ou, Tsan-Teng; Lin, Gau-Tyan; Ko, Ying-Chin

    2010-02-01

    Taiwanese aborigines have a high prevalence of hyperuricemia and gout. Uric acid levels and urate excretion have correlated with dopamine-induced glomerular filtration response. MAOs represent one of the major renal dopamine metabolic pathways. We aimed to identify the monoamine oxidase A (MAOA, Xp11.3) gene variants and MAO-A enzyme activity associated with gout risk. This study was to investigate the association between gout and the MAOA single-nucleotide polymorphisms (SNPs) rs5953210, rs2283725, and rs1137070 as well as between gout and the COMT SNPs rs4680 Val158Met for 374 gout cases and 604 controls. MAO-A activity was also measured. All three MAOA SNPs were significantly associated with gout. A synonymous MAOA SNP, rs1137070 Asp470Asp, located in exon 14, was associated with the risk of having gout (P = 4.0 x 10(-5), adjusted odds ratio 1.46, 95% confidence intervals [CI]: 1.11-1.91). We also showed that, when compared to individuals with the MAOA GAT haplotype, carriers of the AGC haplotype had a 1.67-fold (95% CI: 1.28-2.17) higher risk of gout. Moreover, we found that MAOA enzyme activity correlated positively with hyperuricemia and gout (P for trend = 2.00 x 10(-3) vs. normal control). We also found that MAOA enzyme activity by rs1137070 allele was associated with hyperuricemia and gout (P for trend = 1.53 x 10(-6) vs. wild-type allele). Thus, our results show that some MAOA alleles, which have a higher enzyme activity, predispose to the development of gout.

  10. Effects of BDNF polymorphisms on antidepressant action.

    PubMed

    Tsai, Shih-Jen; Hong, Chen-Jee; Liou, Ying-Jay

    2010-12-01

    Evidence suggests that the down-regulation of the signaling pathway involving brain-derived neurotrophic factor (BDNF), a molecular element known to regulate neuronal plasticity and survival, plays an important role in the pathogenesis of major depression. The restoration of BDNF activity induced by antidepressant treatment has been implicated in the antidepressant therapeutic mechanism. Because there is variability among patients with major depressive disorder in terms of response to antidepressant treatment and since genetic factors may contribute to this inter-individual variability in antidepressant response, pharmacogenetic studies have tested the associations between genetic polymorphisms in candidate genes related to antidepressant therapeutic action. In human BDNF gene, there is a common functional polymorphism (Val66Met) in the pro-region of BDNF, which affects the intracellular trafficking of proBDNF. Because of the potentially important role of BDNF in the antidepressant mechanism, many pharmacogenetic studies have tested the association between this polymorphism and the antidepressant therapeutic response, but they have produced inconsistent results. A recent meta-analysis of eight studies, which included data from 1,115 subjects, suggested that the Val/Met carriers have increased antidepressant response in comparison to Val/Val homozygotes, particularly in the Asian population. The positive molecular heterosis effect (subjects heterozygous for a specific genetic polymorphism show a significantly greater effect) is compatible with animal studies showing that, although BDNF exerts an antidepressant effect, too much BDNF may have a detrimental effect on mood. Several recommendations are proposed for future antidepressant pharmacogenetic studies of BDNF, including the consideration of multiple polymorphisms and a haplotype approach, gene-gene interaction, a single antidepressant regimen, controlling for age and gender interactions, and pharmacogenetic

  11. Cigarettes, genetic background, and menopausal timing: the presence of single nucleotide polymorphisms in cytochrome P450 genes is associated with increased risk of natural menopause in European-American smokers.

    PubMed

    Butts, Samantha F; Sammel, Mary D; Greer, Christine; Rebbeck, Timothy R; Boorman, David W; Freeman, Ellen W

    2014-07-01

    This study aims to evaluate associations between variations in genes involved in the metabolism of environmental chemicals and steroid hormones and risk of menopause in smokers. Survival analysis was performed on 410 eligible participants from the Penn Ovarian Aging study (ongoing for 14 years), a cohort study of late-reproductive-age women. Single nucleotide polymorphisms at the following loci were studied: COMT Val158Met, CYP1B1*4 Asn452Ser, CYP1B1*3 Leu432Val, and CYP3A4*1B. Significant interactions between smoking and single nucleotide polymorphisms were observed in European-American carriers of CYP3A4*1B and CYP1B1*3, supporting a greater risk of menopause entry compared with those not carrying these alleles. Among CYP1B1*3 carriers, smokers had a greater risk of menopause entry than nonsmokers (adjusted hazard ratio [HR], 2.26; 95% CI, 1.4-3.67; median time to menopause, 10.42 and 11.07 y, respectively). No association between smoking and menopause was identified in CYP1B1 wild types. Among CYP3A4*1B carriers, smokers were at greater risk for menopause entry than nonsmokers (adjusted HR, 15.1; 95% CI, 3.31-69.2; median time to menopause, 11.36 and 13.91 y, respectively). Risk of menopause entry in CYP3A4 wild types who smoked was far lower (adjusted HR, 1.59; 95% CI, 1.03-2.44). Heavily smoking CYP1B1*3 carriers (adjusted HR, 3.0; 95% CI, 1.54-5.84; median time to menopause, 10.41 y) and heavily smoking CYP3A4*1B carriers (adjusted HR, 17.79; 95% CI, 3.21-98.65; median time to menopause, 5.09 y) had the greatest risk of menopause entry. Our finding that the risk of menopause entry in European-American smokers varies depending on genetic background represents a novel gene-environment interaction in reproductive aging.

  12. Interaction between BDNF Polymorphism and Physical Activity on Inhibitory Performance in the Elderly without Cognitive Impairment.

    PubMed

    Canivet, Anne; Albinet, Cédric T; Rodríguez-Ballesteros, Montserrat; Chicherio, Christian; Fagot, Delphine; André, Nathalie; Audiffren, Michel

    2017-01-01

    Background: In the elderly, physical activity (PA) enhances cognitive performances, increases brain plasticity and improves brain health. The neurotrophic hypothesis is that the release of brain-derived neurotrophic factor (BDNF), which is implicated in brain plasticity and cognition, is triggered by PA because motoneurons secrete BDNF into the bloodstream during exercise. Individual differences in cognitive performance may be explained by individual differences in genetic predisposition. A single nucleotide polymorphism on the BDNF gene, BDNF Val66Met, affects activity-dependent BDNF secretion. This study investigated the influence of the BDNFVal66Met polymorphism on the relationship between PA and controlled inhibition performance in older adults. Methods: A total of 114 healthy elderly volunteers (mean age = 71.53 years old) were evaluated. Participants were genotyped for the BDNFVal66Met polymorphism. We evaluated inhibitory performance using choice reaction times (RT) and error rates from a Simon-like task and estimated their PA using two self-reported questionnaires. We established four groups according to PA level (active vs. inactive) and BDNFVal66Met genotype (Met carriers vs. Val-homozygous). The results were analyzed using ANOVA and ANCOVA, including age, gender and body mass index as covariates. Results: The BDNFVal66Met polymorphism interacted with PA on controlled inhibition performance. More specifically, inactive Val-homozygous participants exhibited a lower inhibition performance than active Val homozygotes and inactive Met carriers; the former had a higher error rate without differences in RT. Conclusion: Differences between individuals on inhibitory performance may be partially understood by the interaction between genetic influence in BDNF secretion and PA level. The results of this study clearly support the neurotrophic hypothesis that BDNF synthesis is an important mechanism underlying the influence of physical activity on brain structure and

  13. Genetic sensitivity to the caregiving context: The influence of 5httlpr and BDNF val66met on indiscriminate social behavior

    PubMed Central

    Drury, Stacy S; Gleason, Mary Margaret; Theall, Katherine; Smyke, Anna T; Nelson, Charles A; Fox, Nathan A; Zeanah, Charles H

    2014-01-01

    Evidence that gene x environment interactions can reflect differential sensitivity to the environmental context, rather than risk or resilience, is increasing. To test this model, we examined the genetic contribution to indiscriminate social behavior, in the setting of a randomized controlled trial of foster care compared to institutional rearing. Children enrolled in the Bucharest Early Intervention Project (BEIP) were assessed comprehensively before the age of 30 months and subsequently randomized to either care as usual (CAUG) or high quality foster care (FCG). Indiscriminate social behavior was assessed at four time points, baseline, 30 months, 42 months and 54 months of age, using caregiver report with the Disturbances of Attachment Interview (DAI). General linear mixed-effects models were used to examine the effect of the interaction between group status and functional polymorphisms in Brain Derived Neurotrophic Factor (BDNF) and the Serotonin Transporter (5htt) on levels of indiscriminate behavior over time. Differential susceptibility, relative to levels of indiscriminate behavior, was demonstrated in children with either the s/s 5httlpr genotype or met 66 BDNF allele carriers. Specifically children with either the s/s 5httlpr genotype or met66 carriers in BDNF demonstrated the lowest levels of indiscriminate behavior in the FCG and the highest levels in the CAUG. Children with either the long allele of the 5httlpr or val/val genotype of BDNF demonstrated little difference in levels of indiscriminate behaviors over time and no group x genotype interaction. Children with both plasticity genotypes had the most signs of indiscriminate behavior at 54 months if they were randomized to the CAUG in the institution, while those with both plasticity genotypes randomized to the FCG intervention had the fewest signs at 54 months. Strikingly children with no plasticity alleles demonstrated no intervention effect on levels of indiscriminate behavior at 54 months. These

  14. Is SOD2 Ala16Val Polymorphism Associated with Migraine with Aura Phenotype?

    PubMed Central

    Barbanti, Piero; De Marchis, Maria Laura; Egeo, Gabriella; Aurilia, Cinzia; Fofi, Luisa; Ialongo, Cristiano; Valente, Maria Giovanna; Ferroni, Patrizia; Della-Morte, David; Guadagni, Fiorella

    2015-01-01

    Abstract Several studies suggest a role of oxidative stress in the physiopathology of migraine, particularly in the form with aura. In a case-control study, we investigated the association between migraine and superoxide dismutase 1 (SOD1) and superoxide dismutase 2 (SOD2) genes in a cohort of 490 consecutive unrelated Caucasian migraineurs (migraine with aura [MwA], n=107; migraine without aura [MwoA], n=246; chronic migraine [CM], n=137) and 246 healthy controls recruited at our Headache and Pain Unit and stored in the Interinstitutional Multidisciplinary BioBank (BioBIM). Migraine phenotype was carefully detailed using face-to-face interviews. We examined polymorphisms of SOD1 gene (A/C substitution—rs2234694) and SOD2 gene (C/T transition—rs4880—Ala16Val). The rs4880 TT (Val/Val) genotype was associated (p=0.042) with the presence of unilateral cranial autonomic symptoms (UAs) in MwA patients. We also found a mild correlation between SOD2 rs4880 genotype and the type of acute migraine treatment (p=0.048) in MwA patients. Our findings suggest that SOD2 is a disease-modifier gene influencing oxidative mechanisms in MwA. These observations lead to the hypothesis that SOD2 polymorphism may cause a defective control of the oxidative phenomena linked to cortical spreading depression, the neurophysiological hallmark of migraine aura, causing an overstimulation of trigeminal neurons and UAs triggering. Antioxid. Redox Signal. 22, 275–279. PMID:25295643

  15. Preproghrelin Leu72Met polymorphism is not associated with type 2 diabetes mellitus.

    PubMed

    Kim, Sun-Young; Jo, Dae-Sun; Hwang, Pyoung Han; Park, Ji Hyun; Park, Sung Kwang; Yi, Ho Keun; Lee, Dae-Yeol

    2006-03-01

    Ghrelin is a novel gut-brain peptide, which exerts somatotropic, orexigenic, and adipogenic effects. Genetic variants of ghrelin have been associated with both obesity and insulin metabolism. In this study, we determined a role of preproghrelin Leu72Met polymorphism on type 2 diabetes mellitus and its relationship to variables studied. Genotypes were assessed by polymerase chain reaction. Frequencies of the Leu72Met polymorphism were found to be 35.4% in the type 2 diabetic patients and 32.5% in the normal controls. The Leu72Met polymorphism was not associated with hypertension, macroangiopathy, retinopathy, serum cholesterol, triglyceride, blood urea nitrogen, HbA(1c), lipoprotein (a), fasting insulin, or 24-hour urinary protein levels in the type 2 diabetic group. However, the Leu72Met polymorphism was clearly associated with serum creatinine levels in the diabetic group, as the Met72 carriers exhibited lower serum creatinine levels than the Met72 noncarriers. Our data indicate that the preproghrelin Leu72Met polymorphism is not associated with type 2 diabetes mellitus. However, the Leu72Met polymorphism is associated with serum creatinine levels. These data suggest that Met72 carrier status may be a predictable marker for diabetic nephropathy or renal impairment in type 2 diabetes mellitus.

  16. Effect of GSTM1, GSTT1, and GSTP1 IIe105Val polymorphisms on susceptiblity to gestational diabetes mellitus.

    PubMed

    Qiu, Y H; Xu, Y L; Zhang, W H

    2016-06-03

    We investigate the role of the GSTM1, GSTT1, and GSTP1 IIe105Val genetic polymorphisms in the susceptibility to gestational diabetes mellitus. A total of 223 pregnant women with gestational diabetes mellitus and 265 healthy pregnant women were examined at The Second Affiliated Hospital of Shaanxi University of Chinese Medicine from May 2013 to November 2013. Genotyping for detection of GSTM1, GSTT1, and GSTP1 IIe105Val polymorphisms was conducted using the restriction fragment length polymorphism-polymerase chain reaction. There were statistically significant differences between patients with gestational diabetes mellitus and control subjects in terms of age (χ(2) = 6.68, P = 0.01) and BMI (t = 7.56, P < 0.001) levels of HDL-C (t = 2.62, P = 0.005) and LDL-C (t = 3.98, P < 0.001). By the chi-square test, we found significant differences between the present and null genotype distributions of GSTM1 (χ(2) = 10.95, P = 0.0009). Null genotype of GSTM1 could influence the susceptibility to gestational diabetes mellitus compared to the present genotype [adjusted OR (95%CI) = 1.85 (1.26-2.72)]. However, the unconditional logistic analysis revealed that GSTT1 and GSTP1 IIe105Val polymorphisms could not influence the risk of gestational diabetes mellitus in a Chinese population. In summary, we suggest that the GSTM1 gene polymorphism could influence the susceptibility to gestational diabetes mellitus in a Chinese population.

  17. Lack of association between uncoupling protein-2 Ala55Val polymorphism and incident diabetes in the atherosclerosis risk in communities study.

    PubMed

    Bielinski, Suzette J; Pankow, James S; Boerwinkle, Eric; Bray, Molly S; Kao, W H Linda; Folsom, Aaron R

    2008-09-01

    Type 2 diabetes mellitus (T2DM) is characterized by impaired insulin secretion, peripheral insulin resistance, and increased hepatic glucose production. Genes that contribute to genetic susceptibility to T2DM function in numerous biochemical pathways. Uncoupling protein-2 (UCP2) functions as a negative regulator of insulin secretion. Animal studies show induction of UCP2 plays a pathogenic role in the progression of obesity-induced T2DM and some human studies have shown an association between a common UCP2 polymorphism, Ala55Val (rs660339), and T2DM, obesity, and resting metabolic rate with the Val/Val genotype conferring increased risk. We investigated the relationship between the Ala55Val variant and incidence of T2DM among 12,056 participants in the Atherosclerosis Risk in Communities (ARIC) Study aged 45-64 years at baseline. Incident T2DM (n = 1,406) cases were identified over 9 years of follow-up. The Val55 allele frequency was 44% in blacks and 41% in whites. The rate of T2DM per 1,000 person was 15.0, 15.6, and 15.6 yearsfor Ala/Ala, Ala/Val, and Val/Val genotypes, respectively. We found no significant association between UCP2 genotypes and incident T2DM in the whole cohort, in race-gender subgroups, or in categories of body mass index (normal, overweight and obese). The Ala55Val polymorphism of UCP2 was not associated with incident T2DM in the ARIC cohort.

  18. Genotype distribution of estrogen receptor-alpha, catechol-O-methyltransferase, and cytochrome P450 17 gene polymorphisms in Caucasian women with uterine leiomyomas.

    PubMed

    Denschlag, Dominik; Bentz, Eva-Katrin; Hefler, Lukas; Pietrowski, Detlef; Zeillinger, Robert; Tempfer, Clemens; Tong, Dan

    2006-02-01

    To evaluate the association between the presence of uterine leiomyomas and three functional single nucleotide polymorphisms (SNPs) of the estrogen receptor alpha (ESR1), catechol-O-methyltransferase (COMT), and cytochrom P450 17 (CYP17A) genes, which have been described to modify the estrogen metabolism. Prospective case control study. Academic research institution. One hundred thirty women with clinically and surgically diagnosed uterine leiomyomas and 139 population controls. Peripheral venous puncture. Polymerase chain reaction and pyrosequencing were performed to genotype women with respect to the ESR1 IVS1-397 T/C (PvuII), COMT G158A, and the CYP17A 34T-->C SNPs. Comparing women with uterine leiomyomas and controls, no statistically significant differences with respect to allele frequency and genotype distribution were ascertained for ESR1 IVS 1-397 T/C (PvuII) (P=0.9 and P=0.6, respectively), COMT G158A (P=0.3 and P=0.6, respectively), and CYP17A 34T-->C (P=0.1 and P=0.5, respectively). When all two-way interactions of investigated SNPs were ascertained, no significant interactions were observed. In a multivariate model, no SNP was significantly associated with leiomyomas. Carriage of the ESR1 IVS1-397 T/C (PvuII), COMT G158A, and the CYP17A 34T-->C SNPs is not associated with the susceptibility to uterine leiomyoma in a Caucasian population.

  19. APOE, MAPT, and COMT and Parkinson's Disease Susceptibility and Cognitive Symptom Progression.

    PubMed

    Paul, Kimberly C; Rausch, Rebecca; Creek, Michelle M; Sinsheimer, Janet S; Bronstein, Jeff M; Bordelon, Yvette; Ritz, Beate

    2016-04-02

    Cognitive decline is well recognized in Parkinson's disease (PD) and a major concern for patients and caregivers. Apolipoprotein E (APOE), catechol-O-methyl transferase (COMT), and microtubule-associated protein tau (MAPT) are of interest related to their contributions to cognitive decline or dementia in PD. Here, we investigate whether APOE, COMT, or MAPT influence the rate of cognitive decline in PD patients. We relied on 634 PD patients and 879 controls to examine gene-PD susceptibility associations, and nested longitudinal cohort of 246 patients from the case-control study, which followed patients on average 5 years and 7.5 years into disease. We repeatedly assessed cognitive symptom progression with the MMSE and conducted a full neuropsychological battery on a subset of 183 cognitively normal patients. We used repeated-measures regression analyses to assess longitudinal associations between genotypes and cognitive progression scores. The MAPT H1 haplotype was associated with PD susceptibility. APOE 4 carriers (ɛ4+) (p = 0.03) and possibly COMT Met/Met (p = 0.06) carriers exhibited faster annual decline on the MMSE. Additionally, APOEɛ4+ carriers showed faster decline in many of the neuropsychological test scores. No such differences in neuropsychological outcomes were seen for the COMT genotypes. This work supports a growing set of research identifying overlapping etiology and pathology between synucleinopathies, such as PD, Alzheimer's disease, and tauopathies, especially in the context of cognitive dysfunction in PD. We provide support for the argument that APOE ɛ4+ and COMT Met/Met genotypes can be used as predictors of faster cognitive decline in PD.

  20. Linking unfounded beliefs to genetic dopamine availability

    PubMed Central

    Schmack, Katharina; Rössler, Hannes; Sekutowicz, Maria; Brandl, Eva J.; Müller, Daniel J.; Petrovic, Predrag; Sterzer, Philipp

    2015-01-01

    Unfounded convictions involving beliefs in the paranormal, grandiosity ideas or suspicious thoughts are endorsed at varying degrees among the general population. Here, we investigated the neurobiopsychological basis of the observed inter-individual variability in the propensity toward unfounded beliefs. One hundred two healthy individuals were genotyped for four polymorphisms in the COMT gene (rs6269, rs4633, rs4818, and rs4680, also known as val158met) that define common functional haplotypes with substantial impact on synaptic dopamine degradation, completed a questionnaire measuring unfounded beliefs, and took part in a behavioral experiment assessing perceptual inference. We found that greater dopamine availability was associated with a stronger propensity toward unfounded beliefs, and that this effect was statistically mediated by an enhanced influence of expectations on perceptual inference. Our results indicate that genetic differences in dopaminergic neurotransmission account for inter-individual differences in perceptual inference linked to the formation and maintenance of unfounded beliefs. Thus, dopamine might be critically involved in the processes underlying one's interpretation of the relationship between the self and the world. PMID:26483654

  1. Association of single Nucleotide Missence Polymorphism Val109Asp of Omentin-1 gene and coronary artery disease in Pakistani population: Multicenter study

    PubMed Central

    Nazar, Shazia; Zehra, Sitwat; Azhar, Abid

    2017-01-01

    Background & Objective: Coronary artery disease (CAD) is a most important cause of morbidity and mortality worldwide as well as in Pakistan. Recent studies have shown that the combination of obesity, insulin resistance and fluctuation in circulating adipocytokines levels is associated with the pathogenesis of coronary artery disease. Omentin-1 is recently found adipocytokine that is highly expressed in visceral adipose tissue. It has anti- inflammatory properties and is negatively correlated with ischemic heart disease. Therefore, this study was designed to investigate the relationship between omentin-1 Val109Asp polymorphism and CAD in Pakistani population. Methods: A total of 350 subjects were included in the study. Two hundred fifty were diagnosed with coronary artery disease while 100 served as healthy controls. PCR-RFLP was performed at Dr. A Q. Khan Institute of Biotechnology (KIBGE) to analyze Val109Asp polymorphism. In this, case control study SPSS software version 16 (Chicago, IL, USA) was used for data analysis. Continuous variables and categorical variables were presented as mean±SD or in percentage. Independent sample test and chi-square test was performed to compare the differences in means between cases and controls. Genotype distribution was analyzed by chi-square test and results were presented as percentage and frequency. Multivarible regression analysis indicated that Val109Asp SNP might be an independent risk factor for CAD susceptibility after adjustment for some well- known CAD risk factors including age, gender, body mass index, smoking, hypertension, diabetes mellitus and lipid abnormalities. There was estimation of odd ratios (OR) and 95% confidence intervals (CIs) to determine the correlation between genotypes and the risk of CAD. (p> 0.05). Genotype frequencies were compared by Chi-square test. Results: There was prevalence of Omentin-1 Val109Asp polymorphism in both case and control groups. However, Val/Asp (heterozygous mutant) genotype

  2. Catechol-O-Methyltransferase moderates effect of stress mindset on affect and cognition

    PubMed Central

    Akinola, Modupe; Turnwald, Bradley P.; Kaptchuk, Ted J.; Hall, Kathryn T.

    2018-01-01

    There is evidence that altering stress mindset—the belief that stress is enhancing vs. debilitating—can change cognitive, affective and physiological responses to stress. However individual differences in responsiveness to stress mindset manipulations have not been explored. Given the previously established role of catecholamines in both placebo effects and stress, we hypothesized that genetic variation in catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, would moderate responses to an intervention intended to alter participants’ mindsets about stress. Participants (N = 107) were exposed to a stress mindset manipulation (videos highlighting either the enhancing or debilitating effects of stress) prior to engaging in a Trier Social Stress task and subsequent cognitive tasks. The associations of the COMT rs4680 polymorphism with the effect of stress mindset video manipulations on cognitive and affective responses were examined. Genetic variation at rs4680 modified the effects of stress mindset on affective and cognitive responses to stress. Individuals homozygous for rs4680 low-activity allele (met/met) were responsive to the stress-is-enhancing mindset manipulation as indicated by greater increases in positive affect, improved cognitive functioning, and happiness bias in response to stress. Conversely, individuals homozygous for the high-activity allele (val/val) were not as responsive to the stress mindset manipulation. These results suggest that responses to stress mindset intervention may vary with COMT genotype. These findings contribute to the understanding of gene by environment interactions for mindset interventions and stress reactivity and therefore warrant further investigations. PMID:29677196

  3. Variability in Estrogen-Metabolizing Genes and Their Association with Genomic Instability in Untreated Breast Cancer Patients and Healthy Women

    PubMed Central

    Alves dos Santos, Raquel; Teixeira, Ana Cláudia; Mayorano, Mônica Beatriz; Carrara, Hélio Humberto Angotti; Moreira de Andrade, Jurandyr; Takahashi, Catarina Satie

    2011-01-01

    In the present study, we investigated the relationship between polymorphisms in the estrogen-metabolizing genes CYP17, CYP1B1, CYP1A1, and COMT and genomic instability in the peripheral blood lymphocytes of 62 BC patients and 62 controls considering that increased or prolonged exposure to estrogen can damage the DNA molecule and increase the genomic instability process in breast tissue. Our data demonstrated increased genomic instability in BC patients and that individuals with higher frequencies of MN exhibited higher risk to BC when belonging Val/Met genotype of the COMT gene. We also observed that CYP17 and CYP1A1 polymorphisms can modify the risk to BC depending on the menopause status. We can conclude that the genetic background in estrogen metabolism pathway can modulate chromosome damage in healthy controls and patients and thereby influence the risk to BC. These findings suggest the importance to ally biomarkers of susceptibility and effects to estimate risk groups. PMID:21716904

  4. A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS.

    PubMed

    Cheeran, Binith; Talelli, Penelope; Mori, Francesco; Koch, Giacomo; Suppa, Antonio; Edwards, Mark; Houlden, Henry; Bhatia, Kailash; Greenwood, Richard; Rothwell, John C

    2008-12-01

    The brain-derived neurotrophic factor gene (BDNF) is one of many genes thought to influence synaptic plasticity in the adult brain and shows a common single nucleotide polymorphism (BDNF Val66Met) in the normal population that is associated with differences in hippocampal volume and episodic memory. It is also thought to influence possible synaptic changes in motor cortex following a simple motor learning task. Here we extend these studies by using new non-invasive transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS) techniques that directly test the excitability and plasticity of neuronal circuits in human motor cortex in subjects at rest. We investigated whether the susceptibility to TMS probes of plasticity is significantly influenced by the BDNF polymorphism. Val66Met carriers were matched with Val66Val individuals and tested on the following protocols: continuous and intermittent theta burst TMS; median nerve paired associative stimulation; and homeostatic plasticity in the TDCS/1 Hz rTMS model. The response of Met allele carriers differed significantly in all protocols compared with the response of Val66Val individuals. We suggest that this is due to the effect of BNDF on the susceptibility of synapses to undergo LTP/LTD. The circuits tested here are implicated in the pathophysiology of movement disorders such as dystonia and are being assessed as potential new targets in the treatment of stroke. Thus the polymorphism may be one factor that influences the natural response of the brain to injury and disease.

  5. Effects of the Brain-Derived Neurotrophic Factor Val66Met polymorphism and resting brain functional connectivity on individual differences in tactile cognitive performance in healthy young adults.

    PubMed

    Yang, Xuejuan; Xu, Ziliang; Liu, Lin; Liu, Peng; Sun, Jinbo; Jin, Lingmin; Zhu, Yuanqiang; Fei, Ningbo; Qin, Wei

    2017-07-28

    Cognitive processes involve input from multiple sensory modalities and obvious differences in the level of cognitive function can be observed between individuals. Evidence to date understanding the biological basis of tactile cognitive variability, however, is limited compared with other forms of sensory cognition. Data from auditory and visual cognition research suggest that variations in both genetics and intrinsic brain function might contribute to individual differences in tactile cognitive performance. In the present study, by using the tactual performance test (TPT), a widely used neuropsychological assessment tool, we investigated the effects of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and resting-state brain functional connectivity (FC) on interindividual variability in TPT performance in healthy, young Chinese adults. Our results showed that the BDNF genotypes and resting-state FC had significant effects on the variability in TPT performance, together accounting for 32.5% and 19.1% of the variance on TPT total score and Memory subitem score respectively. Having fewer Met alleles, stronger anticorrelations between left posterior superior temporal gyrus and somatosensory areas (right postcentral gyrus and right parietal operculum cortex), and greater positive correlation between left parietal operculum cortex and left central opercular cortex, all correspond with better performance of TPT task. And FC between left parietal operculum cortex and left central opercular cortex might be a mediator of the relationship between BDNF genotypes and Memory subitem score. These data demonstrate a novel contribution of intrinsic brain function to tactile cognitive capacity, and further confirm the genetic basis of tactile cognition. Our findings might also explain the interindividual differences in cognitive ability observed in those who are blind and/or deaf from a new perspective. Copyright © 2017. Published by Elsevier Ltd.

  6. Her2 Ile655Val polymorphism and its association with breast cancer risk: an updated meta-analysis of case-control studies.

    PubMed

    Krishna, B Madhu; Chaudhary, Sanjib; Panda, Aditya K; Mishra, Dipti Ranjan; Mishra, Sandip K

    2018-05-09

    Breast cancer (BC) is one of the most common types of cancer in women worldwide. Several factors including genetic and environmental have been linked with susceptibility to development of BC. Her2 is a transmembrane protein with tyrosine kinase activity, overexpressed in several cancers including BC. Various studies in different populations have shown association of Her2 variants with susceptibility to BC, however these results were inconsistent, inconclusive and controversial. To obtain a common conclusive finding, we performed meta-analysis of 35 case-control studies reported earlier including 19, 220 cases and 22, 306 controls. We observed significant association of Her2 Ile 655 Val polymorphism with susceptibility to development of breast cancer (Overall allele Val vs Ile: OR = 1.130, 95% CI = 1.051-1.216, p = 0.001; Ile-Val vs Ile-Ile: OR = 1.100, 95% CI = 1.016-1.192, p = 0.019; Val-Val+Ile-Val vs Ile-Ile: OR = 1.127, 95% CI = 1.038-1.223, p = 0.004). Subgroup analysis indicated a significant association with susceptibility to breast cancer in African and Asian populations. However, such association was not observed in other ethnic groups. Our findings suggested that Her2 Ile 655 Val polymorphism is associated with breast cancer risk in overall, Asian and African populations, and can be used as diagnostic marker for BC.

  7. Preproghrelin Leu72Met polymorphism in patients with type 2 diabetes mellitus.

    PubMed

    Ukkola, O; Kesäniemi, Y A

    2003-10-01

    The association between the Leu72Met polymorphism of the preproghrelin gene and diabetic complications was examined in patients with type 2 diabetes mellitus. A total of 258 patients with type 2 diabetes mellitus and 522 control subjects were screened. Genotypes were determined by polymerase chain reaction technique. The diagnosis of coronary heart disease was based on clinical and ECG criteria. Laboratory analyses were carried out in the hospital laboratory. No differences in the genotype distributions and allele frequencies of the preproghrelin Leu72Met polymorphism were found between type 2 diabetes mellitus patients and controls. The polymorphism was not associated with macro- or micro-angiopathy or hypertension. However, Leu72Met polymorphism was associated with serum creatinine (P = 0.006) and lipoprotein(a) [Lp(a)] levels (P = 0.006) with Leu72Leu subjects showing the highest values. This association was observed only amongst diabetic group. The Leu72Met polymorphism of the preproghrelin gene was not related to cardiovascular disease in type 2 diabetes mellitus patients. Leu72Met polymorphism was, however, associated with serum creatinine and Lp(a) levels in diabetic patients. The mechanism might be associated with a possible change in ghrelin product and its somatotropic effect.

  8. The Influence of DAT1, COMT, and BDNF Genetic Polymorphisms on Total and Subregional Hippocampal Volumes in Early Onset Heavy Cannabis Users.

    PubMed

    Batalla, Albert; Lorenzetti, Valentina; Chye, Yann; Yücel, Murat; Soriano-Mas, Carles; Bhattacharyya, Sagnik; Torrens, Marta; Crippa, José A S; Martín-Santos, Rocío

    2018-01-01

    Introduction: Hippocampal neuroanatomy is affected by genetic variations in dopaminergic candidate genes and environmental insults, such as early onset of chronic cannabis exposure. Here, we examine how hippocampal total and subregional volumes are affected by cannabis use and functional polymorphisms of dopamine-relevant genes, including the catechol-O-methyltransferase (COMT), dopamine transporter (DAT1), and the brain-derived neurotrophic factor (BDNF) genes. Material and Methods: We manually traced total hippocampal volumes and automatically segmented hippocampal subregions using high-resolution MRI images, and performed COMT, DAT1, and BDNF genotyping in 59 male Caucasian young adults aged 18-30 years. These included 30 chronic cannabis users with early-onset (regular use at <16 years) and 29 age-, education-, and intelligence-matched controls. Results: Cannabis use and dopaminergic gene polymorphism had both distinct and interactive effects on the hippocampus. We found emerging alterations of hippocampal total and specific subregional volumes in cannabis users relative to controls (i.e., CA1, CA2/3, and CA4), and associations between cannabis use levels and total and specific subregional volumes. Furthermore, total hippocampal volume and the fissure subregion were affected by cannabis×DAT1 polymorphism (i.e., 9/9R and in 10/10R alleles), reflecting high and low levels of dopamine availability. Conclusion: These findings suggest that cannabis exposure alters the normal relationship between DAT1 polymorphism and the anatomy of total and subregional hippocampal volumes, and that specific hippocampal subregions may be particularly affected.

  9. Interaction between BDNF Polymorphism and Physical Activity on Inhibitory Performance in the Elderly without Cognitive Impairment

    PubMed Central

    Canivet, Anne; Albinet, Cédric T.; Rodríguez-Ballesteros, Montserrat; Chicherio, Christian; Fagot, Delphine; André, Nathalie; Audiffren, Michel

    2017-01-01

    Background: In the elderly, physical activity (PA) enhances cognitive performances, increases brain plasticity and improves brain health. The neurotrophic hypothesis is that the release of brain-derived neurotrophic factor (BDNF), which is implicated in brain plasticity and cognition, is triggered by PA because motoneurons secrete BDNF into the bloodstream during exercise. Individual differences in cognitive performance may be explained by individual differences in genetic predisposition. A single nucleotide polymorphism on the BDNF gene, BDNFVal66Met, affects activity-dependent BDNF secretion. This study investigated the influence of the BDNFVal66Met polymorphism on the relationship between PA and controlled inhibition performance in older adults. Methods: A total of 114 healthy elderly volunteers (mean age = 71.53 years old) were evaluated. Participants were genotyped for the BDNFVal66Met polymorphism. We evaluated inhibitory performance using choice reaction times (RT) and error rates from a Simon-like task and estimated their PA using two self-reported questionnaires. We established four groups according to PA level (active vs. inactive) and BDNFVal66Met genotype (Met carriers vs. Val-homozygous). The results were analyzed using ANOVA and ANCOVA, including age, gender and body mass index as covariates. Results: The BDNFVal66Met polymorphism interacted with PA on controlled inhibition performance. More specifically, inactive Val-homozygous participants exhibited a lower inhibition performance than active Val homozygotes and inactive Met carriers; the former had a higher error rate without differences in RT. Conclusion: Differences between individuals on inhibitory performance may be partially understood by the interaction between genetic influence in BDNF secretion and PA level. The results of this study clearly support the neurotrophic hypothesis that BDNF synthesis is an important mechanism underlying the influence of physical activity on brain structure and

  10. Association of GSTM1, GSTT1, GSTP1-ILE105VAL and ACE I/D polymorphisms with ankylosing spondylitis.

    PubMed

    İnal, Esra Erkol; Görükmez, Orhan; Eroğlu, Selma; Görükmez, Özlem; Solak, Özlem; Topak, Ali; Yakut, Tahsin

    2016-01-01

    Ankylosing spondylitis (AS) is a chronic inflammatory disease of unknown origin. The aim of this study is to clarify the relationships between susceptibility and severity of AS and GST-mu1 (GSTM1), GST-theta1 (GSTT1), GST-pi1 (GSTP1)-Ile105Val and angiotensin-converting enzyme (ACE) I/D polymorphisms in AS patients. One hundred thirty-eight AS patients and seventy-one healthy controls were enrolled in this study. Erythrocyte sedimentation rate and C-reactive protein (CRP) levels of the AS patients were recorded. The scores of the numeric rating scale (NRS) pain, the Bath Ankylosing Spondylitis Activity Index, the Bath Ankylosing Spondylitis Metrology Index and the Bath Ankylosing Spondylitis Functional Index were calculated. The genotypes distributions and allele frequencies of GSTM1, GSTT1, GSTP1-Ile105Val and ACE I/D polymorphisms were compared between patients and healthy controls. The Multiplex polymerase chain reaction (PCR) and the PCR-restriction fragment length polymorphism methods were used to detect the polymorphisms of ACE I/D, the GSTT1 and GSTM1 genes and the GSTP1-Ile105Val polymorphism, respectively. There were significantly higher levels of the GSTT1 null and the ACE II genotypes in AS patients compared to those in healthy controls (p = 0.002 and 0.005, respectively). We found significantly higher levels of CRP and the NRS pain scores in the patients with ACE ID or DD genotypes compared to those in the patients with ACE II genotypes (p = 0.005 and 0.035, respectively). The present results showed that genes involved in protection from oxidative stress and ACE gene may influence disease development and course in AS.

  11. Brain-derived neurotrophic factor genetic polymorphism (rs6265) is protective against chemotherapy-associated cognitive impairment in patients with early-stage breast cancer.

    PubMed

    Ng, Terence; Teo, Shu Mei; Yeo, Hui Ling; Shwe, Maung; Gan, Yan Xiang; Cheung, Yin Ting; Foo, Koon Mian; Cham, Mooi Tai; Lee, Jung Ah; Tan, Yee Pin; Fan, Gilbert; Yong, Wei Sean; Preetha, Madhukumar; Loh, Wei-Jen Kiley; Koo, Si-Lin; Jain, Amit; Lee, Guek Eng; Wong, Mabel; Dent, Rebecca; Yap, Yoon Sim; Ng, Raymond; Khor, Chiea Chuen; Ho, Han Kiat; Chan, Alexandre

    2016-02-01

    Brain-derived neurotrophic factor (BDNF), a neurotrophin that regulates neuronal function and development, is implicated in several neurodegenerative conditions. Preliminary data suggest that a reduction of BDNF concentrations may lead to postchemotherapy cognitive impairment. We hypothesized that a single nucleotide polymorphism (rs6265) of the BDNF gene may predispose patients to cognitive impairment. This study aimed to evaluate the effect of BDNF gene polymorphism on chemotherapy-associated cognitive impairment. Overall, 145 patients receiving chemotherapy for early-stage breast cancer (mean age: 50.8 ± 8.8 y; 82.1% Chinese) were recruited. Patients' cognitive functions were assessed longitudinally using the validated Functional Assessment of Cancer Therapy-Cognitive Function (v.3) and an objective computerized tool, Headminder. Genotyping was performed using Sanger sequencing. Logistic regression was used to evaluate the association between BDNF Val66Met polymorphism and cognition after adjusting for ethnicity and clinically important covariates. Of the 145 patients, 54 (37%) reported cognitive impairment postchemotherapy. The Met/Met genotype was associated with statistically significant lower odds of developing cognitive impairment (odds ratio [OR] = 0.26; 95% CI: 0.08-0.92; P = .036). The Met carriers were less likely to experience impairment in the domains of verbal fluency (OR = 0.34; 95% CI: 0.12-0.90; P = .031) and multitasking ability (OR = 0.37; 95% CI: 0.15-0.91; P = .030) compared with the Val/Val homozygote. No associations were observed between Headminder and the BDNF Val66Met polymorphism. This is the first study to provide evidence that carriers of the BDNF Met allele are protected against chemotherapy-associated cognitive impairment. Further studies are required to validate the findings. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

  12. Investigating the role of the brain-derived neurotrophic factor (BDNF) val66met variant in obsessive-compulsive disorder (OCD).

    PubMed

    Hemmings, Sîan M J; Kinnear, Craig J; Van der Merwe, Lize; Lochner, Christine; Corfield, Valerie A; Moolman-Smook, Johanna C; Stein, Dan J

    2008-01-01

    Although evidence from family studies suggest that genetic factors play an important role in mediating obsessive-compulsive disorder (OCD), results from genetic case-control association analyses have been inconsistent. Discrepant findings may be attributed to the lack of phenotypic resolution, and population stratification. The aim of the present study was to investigate the role that the val66met variant within the gene encoding brain-derived neurotrophic factor (BDNF) may play in mediating the development of selected OCD subtypes accounting for the aforementioned confounding factors. One hundred and twelve OCD subjects and 140 controls were selected from the South African Afrikaner population. A significant association was observed in the male subgroup, with the met66 allele implicated as the risk allele in the development of OCD. This allele was also found to be associated with an earlier age at onset of OCD in males. On the other hand, the val66val genotype was associated with more severe OCD in the female population. No evidence of population stratification was observed in Afrikaner control subjects. These preliminary results point towards genetically distinct characteristics of OCD mediated by dysfunctions in BDNF. The present investigation forms part of ongoing research to elucidate the genetic components involved in the aetiology of OCD and OCD-related characteristics.

  13. Association of brain-derived neurotrophic factor valine to methionine polymorphism with sexual dysfunction following selective serotonin reuptake inhibitor treatment in female patients with major depressive disorder.

    PubMed

    Nazree, Nur Elia; Mohamed, Zahurin; Reynolds, Gavin P; Mohd Zain, Shamsul; Masiran, Ruziana; Sidi, Hatta; Chong, Lu Ann; Hway, Anne Yee; Adlan, Aida Syarinaz; Zainal, Nor Zuraida

    2016-12-01

    The occurrence of female sexual dysfunction (FSD) in patients with major depressive disorder (MDD) receiving selective serotonin reuptake inhibitors (SSRIs) treatment gives negative impacts on patients' quality of life and causes treatment discontinuation. We aimed to investigate whether genetic polymorphism of identified candidate gene is associated with FSD in our study population. This is a cross-sectional study. A total of 95 female patients with MDD who met the criteria of the study were recruited and were specifically assessed on the sexual function by trained psychiatrists. Patients' DNA was genotyped for BDNF Val66Met polymorphism using real-time polymerase chain reaction. The prevalence of FSD in this study is 31.6%. In the FSD group, patients with problematic marriage were significantly more frequent compared with patients who did not have problematic marriage (P = 0.009). Significant association was detected in the lubrication domain with BDNF Val66Met polymorphism (P = 0.030) using additive genetic model, with even stronger association when using the recessive model (P = 0.013). This study suggested that there was no significant association between BDNF Val66Met with FSD. However, this polymorphism is significantly associated with lubrication disorder in patients treated with SSRIs. © 2015 Wiley Publishing Asia Pty Ltd.

  14. Glutathione S-transferase P1 Ile105Val Polymorphism and Male Infertility Risk: An Updated Meta-analysis

    PubMed Central

    Huang, Xue-Kun; Huang, Yong-Han; Huang, Juan-Hua; Liang, Jing-Yao

    2017-01-01

    Background: Several studies concerning the association between glutathione S-transferase P1 (GSTP1) Ile105Val polymorphism and male infertility risk have reported controversial findings. The present study was aimed to explore this association using a meta-analysis. Methods: The PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), and Wanfang databases were searched. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the association. Results: A total of 3282 cases and 3268 controls in nine case-control studies were included. There was no significant association between GSTP1 Ile105Val polymorphism and male infertility in the overall population, but significant associations were found under the dominant (OR = 1.23, 95% CI = 1.04–1.46, I2 = 32.2%) and heterozygote (OR = 1.29, 95% CI = 1.08–1.53, I2 = 26.8%) models after excluding studies for which the data did not satisfy Hardy-Weinberg equilibrium (HWE). Similarly, subgroup analyses revealed no significant association in Asians or Chinese population although a significant association was apparent among Chinese population in studies with HWE under the heterozygote model (OR = 1.25, 95% CI = 1.03–1.52, I2 = 44.1%). Significant heterogeneity could be observed in some genetic models, but this heterogeneity was not significant when stratified by HWE. No evidence for publication bias was found. Conclusions: The GSTP1 Ile105Val polymorphism might not be associated with male infertility risk, and thus additional well-designed studies with larger sample size are warranted. PMID:28397729

  15. The Influence of DAT1, COMT, and BDNF Genetic Polymorphisms on Total and Subregional Hippocampal Volumes in Early Onset Heavy Cannabis Users

    PubMed Central

    Batalla, Albert; Lorenzetti, Valentina; Chye, Yann; Yücel, Murat; Soriano-Mas, Carles; Bhattacharyya, Sagnik; Torrens, Marta; Crippa, José A.S.; Martín-Santos, Rocío

    2018-01-01

    Abstract Introduction: Hippocampal neuroanatomy is affected by genetic variations in dopaminergic candidate genes and environmental insults, such as early onset of chronic cannabis exposure. Here, we examine how hippocampal total and subregional volumes are affected by cannabis use and functional polymorphisms of dopamine-relevant genes, including the catechol-O-methyltransferase (COMT), dopamine transporter (DAT1), and the brain-derived neurotrophic factor (BDNF) genes. Material and Methods: We manually traced total hippocampal volumes and automatically segmented hippocampal subregions using high-resolution MRI images, and performed COMT, DAT1, and BDNF genotyping in 59 male Caucasian young adults aged 18–30 years. These included 30 chronic cannabis users with early-onset (regular use at <16 years) and 29 age-, education-, and intelligence-matched controls. Results: Cannabis use and dopaminergic gene polymorphism had both distinct and interactive effects on the hippocampus. We found emerging alterations of hippocampal total and specific subregional volumes in cannabis users relative to controls (i.e., CA1, CA2/3, and CA4), and associations between cannabis use levels and total and specific subregional volumes. Furthermore, total hippocampal volume and the fissure subregion were affected by cannabis×DAT1 polymorphism (i.e., 9/9R and in 10/10R alleles), reflecting high and low levels of dopamine availability. Conclusion: These findings suggest that cannabis exposure alters the normal relationship between DAT1 polymorphism and the anatomy of total and subregional hippocampal volumes, and that specific hippocampal subregions may be particularly affected. PMID:29404409

  16. Glucocorticoid Receptors, Brain-Derived Neurotrophic Factor, Serotonin and Dopamine Neurotransmission are Associated with Interferon-Induced Depression

    PubMed Central

    Udina, M; Navinés, R; Egmond, E; Oriolo, G; Langohr, K; Gimenez, D; Valdés, M; Gómez-Gil, E; Grande, I; Gratacós, M; Kapczinski, F; Artigas, F; Vieta, E; Solà, R

    2016-01-01

    .14), disorderliness (p = 0.0339, HR = 1.11), and low scores on extravagance (p = 0.0040, HR = 0.85). An interaction between HTR1A and COMT genes was found. Patients carrying the G allele of HTR1A plus the Met substitution of the COMT polymorphism had a greater risk for depression during antiviral treatment (HR = 3.83) than patients with the CC (HTR1A) and Met allele (COMT) genotypes. Patients carrying the HTR1A CC genotype and the COMT Val/Val genotype (HR = 3.25) had a higher risk of depression than patients with the G allele (HTR1A) and the Val/Val genotype. Moreover, functional variants of the GCR1 (GG genotype: p = 0.0436, HR = 1.88) and BDNF genes (Val/Val genotype: p = 0.0453, HR = 0.55) were associated with depression. Conclusions: The results of the study support the theory that IFN-induced depression is associated with a complex pathophysiological background, including serotonergic and dopaminergic neurotransmission as well as glucocorticoid and neurotrophic factors. These findings may help to improve the management of patients on antiviral treatment and broaden our understanding of the pathogenesis of mood disorders. PMID:26721949

  17. Cigarettes, genetic background, and menopausal timing: the presence of single nucleotide polymorphisms in cytochrome P450 genes is associated with increased risk of natural menopause in European-American smokers

    PubMed Central

    Butts, Samantha F.; Sammel, Mary D.; Greer, Christine; Rebbeck, Timothy R.; Boorman, David W.; Freeman, Ellen W.

    2016-01-01

    Objective This study aims to evaluate associations between variations in genes involved in the metabolism of environmental chemicals and steroid hormones and risk of menopause in smokers. Methods Survival analysis was performed on 410 eligible participants from the Penn Ovarian Aging study (ongoing for 14 years), a cohort study of late-reproductive-age women. Single nucleotide polymorphisms at the following loci were studied: COMT Val158Met, CYP1B1*4 Asn452Ser, CYP1B1*3 Leu432Val, and CYP3A4*1B. Results Significant interactions between smoking and single nucleotide polymorphisms were observed in European-American carriers of CYP3A4*1B and CYP1B1*3, supporting a greater risk of menopause entry compared with those not carrying these alleles. Among CYP1B1*3 carriers, smokers had a greater risk of menopause entry than nonsmokers (adjusted hazard ratio [HR], 2.26; 95% CI, 1.4–3.67; median time to menopause, 10.42 and 11.07 y, respectively). No association between smoking and menopause was identified in CYP1B1 wild types. Among CYP3A4*1B carriers, smokers were at greater risk for menopause entry than nonsmokers (adjusted HR, 15.1; 95% CI, 3.31–69.2; median time to menopause, 11.36 and 13.91 y, respectively). Risk of menopause entry in CYP3A4 wild types who smoked was far lower (adjusted HR, 1.59; 95% CI, 1.03–2.44). Heavily smoking CYP1B1*3 carriers (adjusted HR, 3.0; 95% CI, 1.54–5.84; median time to menopause, 10.41 y) and heavily smoking CYP3A4*1B carriers (adjusted HR, 17.79; 95% CI, 3.21–98.65; median time to menopause, 5.09 y) had the greatest risk of menopause entry. Conclusions Our finding that the risk of menopause entry in European-American smokers varies depending on genetic background represents a novel gene-environment interaction in reproductive aging. PMID:24448104

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

    PubMed Central

    Belfer, Inna; Segall, Samantha K.; Lariviere, William R.; Smith, Shad B.; Dai, Feng; Slade, Gary G.; Rashid, Naim U.; Mogil, Jeffrey S.; Campbell, Claudia; Edwards, Robert; Liu, Qian; Bair, Eric; Maixner, William; Diatchenko, Luda

    2013-01-01

    The enzyme catechol-O-methyltransferase (COMT) metabolizes catecholamine neurotransmitters involved in a number of physiological functions including pain perception. Both human and mouse COMT genes possess functional polymorphisms contributing to inter-individual variability in pain phenotypes such as sensitivity to noxious stimuli, severity of clinical pain and response to pain treatment. In this study, we found that the effects of Comt functional variation in mice are modality-specific. Spontaneous inflammatory nociception and thermal nociception behaviors were correlated the most with the presence of the B2 SINE transposon insertion residing in the 3’UTR mRNA region. Similarly, in humans, COMT functional haplotypes were associated with thermal pain perception and with capsaicin-induced pain. Furthermore, COMT genetic variations contributed to pain behaviors in mice and pain ratings in humans in a sex-specific manner. The ancestral Comt variant, without a B2 SINE insertion, was more strongly associated with sensitivity to capsaicin in female versus male mice. In humans, the haplotype coding for low COMT activity increased capsaicin-induced pain perception in women, but not men. These findings reemphasize the fundamental contribution of COMT to pain processes, and provide a fine-grained resolution of this contribution at the genetic level that can be used to guide future studies in the area of pain genetics. PMID:23701723

  19. [The Val606Met mutation of human beta myosin heavy chain in a Chinese familial hypertrophic cardiomyopathy family].

    PubMed

    Yuan, Jian-song; Qiao, Shu-bin; Wang, Shu-xia; Teng, Si-yong; You, Shi-jie; Yang, Wei-xian; Gao, Run-lin; Chen, Ji-lin; Yang, Yue-jin

    2008-04-01

    To explore the disease-causing gene mutation in Chinese families with hypertrophic cardiomyopathy (HCM) and to analyze the correlation between the genotype and phenotype. Samples of peripheral blood were collected from three Chinese families with HCM (at least two HCM patients existed/family). The exons in the functional regions of the beta myosin heavy chain gene (MYH7) were amplified with PCR and the products were sequenced. A Val606Met missen mutation was identified in the exon 16 of MYH7 gene in a Chinese family and this mutation was identified in all HCM patients (n = 4) and there was also a 15-years-old young mutation carrier who was not HCM patient now (penetrance of 80%). This mutation was not identified in other healthy family members in this family, in other 2 Chinese familiar HCM families and in 120 non-HCM control patients. The Val606Met missen mutation is closely associated with familiar HCM in a Chinese family which is associated with clinical phenotype with a penetrance of 80%.

  20. Role of Superoxide Dismutase 2 Gene Ala16Val Polymorphism and Total Antioxidant Capacity in Diabetes and its Complications

    PubMed Central

    Pourvali, Katayoun; Abbasi, Mehrnaz; Mottaghi, Azadeh

    2016-01-01

    Diabetes Mellitus (DM) is a chronic heterogeneous disorder and oxidative stress is a key participant in the development and progression of it and its complications. Anti-oxidant status can affect vulnerability to oxidative damage, onset and progression of diabetes and diabetes complications. Superoxide dismutase 2 (SOD2) is one of the major antioxidant defense systems against free radicals. SOD2 is encoded by the nuclear SOD2 gene located on the human chromosome 6q25 and the Ala16Val polymorphism has been identified in exon 2 of the human SOD2 gene. Ala16Val (rs4880) is the most commonly studied SOD2 single nucleotide polymorphism (SNP) in SOD2 gene. This SNP changes the amino acid at position 16 from valine (Val) to alanine (Ala), which has been shown to cause a conformational change in the target sequence of manganese superoxide dismutase (MnSOD) and also affects MnSOD activity in mitochondria. Ala16Val SNP and changes in the activity of the SOD2 antioxidant enzyme have been associated with altered progression and risk of different diseases. Association of this SNP with diabetes and some of its complications have been studied in numerous studies. This review evaluated how rs4880, oxidative stress and antioxidant status are associated with diabetes and its complications although some aspects of this line still remain unclear. PMID:27141263

  1. Preproghrelin Leu72Met polymorphism in Chinese subjects with coronary artery disease and controls.

    PubMed

    Tang, Na-Ping; Wang, Lian-Sheng; Yang, Li; Gu, Hai-Juan; Zhu, Huai-Jun; Zhou, Bo; Sun, Qing-Min; Cong, Ri-Hong; Wang, Bin

    2008-01-01

    Ghrelin, a novel endogenous ligand for the growth hormone secretagogue receptor, is considered to exert a protective effect against atherosclerosis. The Leu72Met (+408C>A) polymorphic variant of the preproghrelin, the gene for the ghrelin precursor, has been linked to obesity, diabetes and metabolic syndrome. However, it is unclear whether this polymorphism is associated with coronary artery disease (CAD). We conducted a case-control study with 317 CAD patients and 323 controls to investigate the potential association of the Leu72Met polymorphism with the occurrence of CAD and CAD-related phenotypes in Chinese population. No significant difference in the Leu72Met genotype frequency was observed between CAD patients and controls (P=NS). The Leu72Met polymorphism was not associated with hypertension, diabetes, dyslipidemia, the number of diseased vessels, plasma total cholesterol, triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol or fasting glucose levels in CAD patients. However, among CAD patients, those with variant genotypes (Leu72Met and Met72Met) had lower BMI (24.4+/-0.3 kg/m(2)) than Leu72Leu carriers (25.4+/-0.2 kg/m(2), adjusted P=0.033). Our data indicate that the preproghrelin Leu72Met polymorphism is not associated with CAD in Chinese population. However, the Leu72Met variant is associated with BMI among CAD patients.

  2. BDNF Val 66 Met and 5-HTTLPR genotype moderate the impact of early psychosocial adversity on plasma brain-derived neurotrophic factor and depressive symptoms: a prospective study.

    PubMed

    Buchmann, Arlette F; Hellweg, Rainer; Rietschel, Marcella; Treutlein, Jens; Witt, Stephanie H; Zimmermann, Ulrich S; Schmidt, Martin H; Esser, Günter; Banaschewski, Tobias; Laucht, Manfred; Deuschle, Michael

    2013-08-01

    Recent studies have emphasized an important role for neurotrophins, such as brain-derived neurotrophic factor (BDNF), in regulating the plasticity of neural circuits involved in the pathophysiology of stress-related diseases. The aim of the present study was to examine the interplay of the BDNF Val⁶⁶Met and the serotonin transporter promoter (5-HTTLPR) polymorphisms in moderating the impact of early-life adversity on BDNF plasma concentration and depressive symptoms. Participants were taken from an epidemiological cohort study following the long-term outcome of early risk factors from birth into young adulthood. In 259 individuals (119 males, 140 females), genotyped for the BDNF Val⁶⁶Met and the 5-HTTLPR polymorphisms, plasma BDNF was assessed at the age of 19 years. In addition, participants completed the Beck Depression Inventory (BDI). Early adversity was determined according to a family adversity index assessed at 3 months of age. Results indicated that individuals homozygous for both the BDNF Val and the 5-HTTLPR L allele showed significantly reduced BDNF levels following exposure to high adversity. In contrast, BDNF levels appeared to be unaffected by early psychosocial adversity in carriers of the BDNF Met or the 5-HTTLPR S allele. While the former group appeared to be most susceptible to depressive symptoms, the impact of early adversity was less pronounced in the latter group. This is the first preliminary evidence indicating that early-life adverse experiences may have lasting sequelae for plasma BDNF levels in humans, highlighting that the susceptibility to this effect is moderated by BDNF Val⁶⁶Met and 5-HTTLPR genotype. Copyright © 2013. Published by Elsevier B.V.

  3. Convergent genetic modulation of the endocrine stress response involves polymorphic variations of 5-HTT, COMT and MAOA.

    PubMed

    Jabbi, M; Korf, J; Kema, I P; Hartman, C; van der Pompe, G; Minderaa, R B; Ormel, J; den Boer, J A

    2007-05-01

    Highly prevalent stress-related disorders such as major depression (MD) are characterised by a dysregulation of the neuroendocrine system. Although heritability for these disorders is high, the role of genes in the underlying pathophysiology is poorly understood. Here, we show that polymorphic variations in genes coding for serotonin transporter (5-HTT), catechol-O-methyl transferase (COMT) and monoamine oxidase A (MAOA) as well as sex differences influence the regulation of hypothalamic-pituitary-adrenal (HPA)-axis response to acute psychological and endocrine challenges. In our sample, the effects of COMT on the release of adrenocorticotrophin hormone (ACTH) depend on the presence of the low-expression MAOA variant in the same individual. By including individuals varying in their degree of susceptibility to MD, we showed evidence of interactions between 5-HTT and MD susceptibility in baseline cortisol, and between MAOA and MD susceptibility in baseline ACTH measures, indicating a role for these genotypes in stable-state endocrine regulation. Collectively, these results indicate that the simultaneous investigation of multiple monoaminergic genes in interaction with gender have to be measured to understand the endocrine regulation of stress. These findings point towards a genetic susceptibility to stress-related disorders.

  4. No evidence for a role of Ile587Val polymorphism of EIF2B5 gene in multiple sclerosis in Kashmir Valley of India.

    PubMed

    Zahoor, Insha; Asimi, Ravouf; Haq, Ehtishamul

    2015-12-15

    Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the nervous system with a profound genetic element. It is already known that alterations in Eukaryotic Translation Initiation Factor 2B (EIF2B) gene encoding the five subunits of eIF2B complex cause Vanishing White Matter (VWM) disease of the brain and emerging evidences have advocated certain resemblances between MS and VWM in terms of clinical and epidemiological characteristics, thus validating the association study between EIF2B and MS. Moreover, a recent study has implicated EIF2B5 Ile587Val (rs843358) polymorphism as a susceptibility factor for MS. In order to investigate the association of EIF2B5 Ile587Val polymorphism with MS susceptibility in Kashmir region in India, we screened EIF2B5 Exon 13 in 30 MS patients and 65 controls (a total of 95 participants). During the present course of study, we could not find statistically significant difference in the frequency of Ile587Val between MS patients and controls, thus indicating that such alteration does not appear to influence MS development in Kashmiri population. Our results provide evidence against a major role for Ile587Val polymorphism in MS susceptibility. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. BDNF Val66Met but not transcranial direct current stimulation affects motor learning after stroke.

    PubMed

    van der Vliet, Rick; Ribbers, Gerard M; Vandermeeren, Yves; Frens, Maarten A; Selles, Ruud W

    tDCS is a non-invasive neuromodulation technique that has been reported to improve motor skill learning after stroke. However, the contribution of tDCS to motor skill learning has only been investigated in a small number of studies. In addition, it is unclear if tDCS effects are mediated by activity-dependent BDNF release and dependent on timing of tDCS relative to training. Investigate the role of activity-dependent BDNF release and timing of tDCS relative to training in motor skill learning. Double-blind, between-subjects randomized controlled trial of circuit tracing task improvement (ΔMotor skill) in 80 chronic stroke patients who underwent tDCS and were genotyped for BDNF Val66Met. Patients received either short-lasting tDCS (20 min) during training (short-lasting online group), long-lasting tDCS (10 min-25 min break - 10 min) one day before training (long-lasting offline group), short-lasting tDCS one day before training (short-lasting offline group), or sham tDCS. ΔMotor skill was defined as the skill difference on the circuit tracing task between day one and day nine of the study. Having at least one BDNF Met allele was found to diminish ΔMotor skill (β BDNF,Met  = -0.217 95%HDI = [-0.431 -0.0116]), indicating activity-dependent BDNF release is important for motor skill learning after stroke. However, none of the tDCS protocols affected ΔMotor skill (β Short-lasting,online  = 0.0908 95%HDI = [-0.227 0.403]; β Long-lasting,offline  = 0.0242 95%HDI = [-0.292 0.349]; β Short-lasting,offline  = -0.108 95%HDI = [-0.433 0.210]). BDNF Val66Met is a determinant of motor skill learning after stroke and could be important for prognostic models. tDCS does not modulate motor skill learning in our study and might be less effective than previously assumed. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. A frontal dopamine system for reflective exploratory behavior.

    PubMed

    Blanco, Nathaniel J; Love, Bradley C; Cooper, Jessica A; McGeary, John E; Knopik, Valerie S; Maddox, W Todd

    2015-09-01

    The COMT gene modulates dopamine levels in prefrontal cortex with Met allele carriers having lower COMT enzyme activity and, therefore, higher dopamine levels compared to Val/Val homozygotes. Concordantly, Val/Val homozygotes tend to perform worse and display increased (interpreted as inefficient) frontal activation in certain cognitive tasks. In a sample of 209 participants, we test the hypothesis that Met carriers will be advantaged in a decision-making task that demands sequencing exploratory and exploitive choices to minimize uncertainty about the reward structure in the environment. Previous work suggests that optimal performance depends on limited cognitive resources supported by prefrontal systems. If so, Met carriers should outperform Val/Val homozygotes, particularly under dual-task conditions that tax limited cognitive resources. In accord with these a priori predictions, Met carriers were more resilient in the face of cognitive load, continuing to explore in a sophisticated manner. We fit computational models that embody sophisticated reflective and simple reflexive strategies to further evaluate participants' exploration behavior. The Ideal Actor model reflectively updates beliefs and plans ahead, taking into account the information gained by each choice and making choices that maximize long-term payoffs. In contrast, the Naïve Reinforcement Learning (RL) model instantiates the reflexive account of choice, in which the values of actions are based only on the rewards experienced so far. Its beliefs are updated reflexively in response to observed changes in rewards. Converging with standard analyses, Met carriers were best characterized by the Ideal Actor model, whereas Val/Val homozygotes were best characterized by the Naive RL model, particularly under dual-task conditions. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. A Frontal Dopamine System for Reflective Exploratory Behavior

    PubMed Central

    Blanco, Nathaniel J.; Love, Bradley C.; Cooper, Jessica A.; McGeary, John E.; Knopik, Valerie S.; Maddox, W. Todd

    2015-01-01

    The COMT gene modulates dopamine levels in prefrontal cortex with Met allele carriers having lower COMT enzyme activity and, therefore, higher dopamine levels compared to Val/Val homozygotes. Concordantly, Val/Val homozygotes tend to perform worse and display increased (interpreted as inefficient) frontal activation in certain cognitive tasks. In a sample of 209 participants, we test the hypothesis that Met carriers will be advantaged in a decision-making task that demands sequencing exploratory and exploitive choices to minimize uncertainty about the reward structure in the environment. Previous work suggests that optimal performance depends on limited cognitive resources supported by prefrontal systems. If so, Met carriers should outperform Val/Val homozygotes, particularly under dual-task conditions that tax limited cognitive resources. In accord with these a priori predictions, Met carriers were more resilient in the face of cognitive load, continuing to explore in a sophisticated manner. We fit computational models that embody sophisticated reflective and simple reflexive strategies to further evaluate participants' exploration behavior. The Ideal Actor model reflectively updates beliefs and plans ahead, taking into account the information gained by each choice and making choices that maximize long-term payoffs. In contrast, the Naïve Reinforcement Learning (RL) model instantiates the reflexive account of choice, in which the values of actions are based only on the rewards experienced so far. Its beliefs are updated reflexively in response to observed changes in rewards. Converging with standard analyses, Met carriers were best characterized by the Ideal Actor model, whereas Val/Val homozygotes were best characterized by the Naive RL model, particularly under dual-task conditions. PMID:26004676

  8. Association between glutathione S-transferase P1 Ile (105) Val gene polymorphism and chronic obstructive pulmonary disease: A meta-analysis based on seventeen case-control studies.

    PubMed

    Yang, Lingjing; Li, Xixia; Tong, Xiang; Fan, Hong

    2015-12-01

    Previous studies have shown that glutathione S-transferase P1 (GSTP1) was associated with chronic obstructive pulmonary disease (COPD). However, the association between GSTP1 Ile (105) Val gene polymorphism and COPD remains controversial. To drive a more precise estimation, we performed a meta-analysis based on published case-control studies. An electronic search of PubMed, EMBASE, Cochrane library, Web of Science and China Knowledge Resource Integrated (CNKI) Database for papers on GSTP1 Ile (105) Val gene polymorphism and COPD risk was performed. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the homozygote model, heterozygote model, dominant model, recessive model and an additive mode. Statistical heterogeneity, test of publication bias and sensitivity analysis was performed. The software STATA (Version 13.0) was used data analysis. Overall, seventeen studies with 1892 cases and 2012 controls were included in this meta-analysis. The GSTP1 Ile (105) Val polymorphism showed pooled odds ratios for the homozygote comparison (OR = 1.501, 95%CI [0.862, 2.614]), heterozygote comparison (OR = 0.924, 95%CI [0.733, 1.165]), dominant model (OR = 1.003, 95%CI [0.756, 1.331]), recessive model (OR = 1.510, 95%CI [0.934, 2.439]), and an additive model (OR = 1.072, 95%CI [0.822, 1.398]). In conclusion, the current meta-analysis, based on the most updated information, showed no significant association between GSTP1 Ile (105) Val gene polymorphism and COPD risk in any genetic models. The results of subgroup analysis also showed no significant association between GSTP1 Ile (105) Val gene polymorphism and COPD risk in Asian population and Caucasian population. Further studies involving large populations and careful control with age, sex, ethnicity, and cigarette smoking are greatly needed.

  9. Association between glutathione S-transferase P1 Ile (105) Val gene polymorphism and chronic obstructive pulmonary disease: A meta-analysis based on seventeen case–control studies

    PubMed Central

    Yang, Lingjing; Li, Xixia; Tong, Xiang; Fan, Hong

    2015-01-01

    Introduction Previous studies have shown that glutathione S-transferase P1 (GSTP1) was associated with chronic obstructive pulmonary disease (COPD). However, the association between GSTP1 Ile (105) Val gene polymorphism and COPD remains controversial. To drive a more precise estimation, we performed a meta-analysis based on published case–control studies. Methods An electronic search of PubMed, EMBASE, Cochrane library, Web of Science and China Knowledge Resource Integrated (CNKI) Database for papers on GSTP1 Ile (105) Val gene polymorphism and COPD risk was performed. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the homozygote model, heterozygote model, dominant model, recessive model and an additive mode. Statistical heterogeneity, test of publication bias and sensitivity analysis was performed. The software STATA (Version 13.0) was used data analysis. Results Overall, seventeen studies with 1892 cases and 2012 controls were included in this meta-analysis. The GSTP1 Ile (105) Val polymorphism showed pooled odds ratios for the homozygote comparison (OR = 1.501, 95%CI [0.862, 2.614]), heterozygote comparison (OR = 0.924, 95%CI [0.733, 1.165]), dominant model (OR = 1.003, 95%CI [0.756, 1.331]), recessive model (OR = 1.510, 95%CI [0.934, 2.439]), and an additive model (OR = 1.072, 95%CI [0.822, 1.398]). Conclusions In conclusion, the current meta-analysis, based on the most updated information, showed no significant association between GSTP1 Ile (105) Val gene polymorphism and COPD risk in any genetic models. The results of subgroup analysis also showed no significant association between GSTP1 Ile (105) Val gene polymorphism and COPD risk in Asian population and Caucasian population. Further studies involving large populations and careful control with age, sex, ethnicity, and cigarette smoking are greatly needed. PMID:26504746

  10. Modification of COMT-dependent pain sensitivity by psychological stress and sex.

    PubMed

    Meloto, Carolina B; Bortsov, Andrey V; Bair, Eric; Helgeson, Erika; Ostrom, Cara; Smith, Shad B; Dubner, Ronald; Slade, Gary D; Fillingim, Roger B; Greenspan, Joel D; Ohrbach, Richard; Maixner, William; McLean, Samuel A; Diatchenko, Luda

    2016-04-01

    Catecholamine-O-methyltransferase (COMT) is a polymorphic gene whose variants affect enzymatic activity and pain sensitivity via adrenergic pathways. Although COMT represents one of the most studied genes in human pain genetics, findings regarding its association with pain phenotypes are not always replicated. Here, we investigated if interactions among functional COMT haplotypes, stress, and sex can modify the effect of COMT genetic variants on pain sensitivity. We tested these interactions in a cross-sectional study, including 2 cohorts, one of 2972 subjects tested for thermal pain sensitivity (Orofacial Pain: Prospective Evaluation and Risk Assessment) and one of 948 subjects with clinical acute pain after motor vehicle collision (post-motor vehicle collision). In both cohorts, the COMT high-pain sensitivity (HPS) haplotype showed robust interaction with stress and number of copies of the HPS haplotype was positively associated with pain sensitivity in nonstressed individuals, but not in stressed individuals. In the post-motor vehicle collision cohort, there was additional modification by sex: the HPS-stress interaction was apparent in males, but not in females. In summary, our findings indicate that stress and sex should be evaluated in association studies aiming to investigate the effect of COMT genetic variants on pain sensitivity.

  11. BDNF and TNF-α polymorphisms in memory.

    PubMed

    Yogeetha, B S; Haupt, L M; McKenzie, K; Sutherland, H G; Okolicsyani, R K; Lea, R A; Maher, B H; Chan, R C K; Shum, D H K; Griffiths, L R

    2013-09-01

    Here, we investigate the genetic basis of human memory in healthy individuals and the potential role of two polymorphisms, previously implicated in memory function. We have explored aspects of retrospective and prospective memory including semantic, short term, working and long-term memory in conjunction with brain derived neurotrophic factor (BDNF) and tumor necrosis factor-alpha (TNF-α). The memory scores for healthy individuals in the population were obtained for each memory type and the population was genotyped via restriction fragment length polymorphism for the BDNF rs6265 (Val66Met) SNP and via pyrosequencing for the TNF-α rs113325588 SNP. Using univariate ANOVA, a significant association of the BDNF polymorphism with visual and spatial memory retention and a significant association of the TNF-α polymorphism was observed with spatial memory retention. In addition, a significant interactive effect between BDNF and TNF-α polymorphisms was observed in spatial memory retention. In practice visual memory involves spatial information and the two memory systems work together, however our data demonstrate that individuals with the Val/Val BDNF genotype have poorer visual memory but higher spatial memory retention, indicating a level of interaction between TNF-α and BDNF in spatial memory retention. This is the first study to use genetic analysis to determine the interaction between BDNF and TNF-α in relation to memory in normal adults and provides important information regarding the effect of genetic determinants and gene interactions on human memory.

  12. Association of Functional Polymorphisms from Brain-Derived Neurotrophic Factor and Serotonin-Related Genes with Depressive Symptoms after a Medical Stressor in Older Adults

    PubMed Central

    Rawson, Kerri S.; Dixon, David; Nowotny, Petra; Ricci, William M.; Binder, Ellen F.; Rodebaugh, Thomas L.; Wendleton, Leah; Doré, Peter; Lenze, Eric J.

    2015-01-01

    Depressive symptoms are common in older adults after a disabling medical event and interfere with rehabilitation and recovery from the disability. This prospective study examined the role of genetic polymorphisms implicated in synaptic integrity and stress-associated depression as predictors of depressive symptoms after hip fracture. We recruited healthy comparisons from the community and participants with hip fracture after surgical fixation from Saint Louis, Missouri hospitals. We examined the valine (Val) to methionine (Met) polymorphism in brain-derived neurotrophic factor (BDNF), serotonin 1A receptor (5HT1a-rs6295) polymorphism, and the serotonin transporter-linked polymorphic region (5HTTLPR) interaction with the rs25531 A to G single nucleotide polymorphism (5HTTLPR-rs25531) as predictors of depressive symptoms. We also examined whether depressive symptoms mediate the influence of BDNF genotype on functional recovery. Among 429 participants with hip fracture, BDNF Met/Met carriers developed significantly more depressive symptoms than Val/Val carriers during a four-week period after the fracture (p=.012). BDNF genotype also predicted functional recovery over the ensuing year, mediated by its effects on depressive symptoms (CI: 0.07-3.37). Unlike prior studies of stressful life events, the S′ 5HTTLPR-rs25531 variant did not predict higher levels of depressive symptoms; instead, we report an exploratory finding of an epistatic effect between BDNF and 5HTTLPR-rs25531 whereby the compounded effects of two LA alleles and BDNF Met/Met genotype elevate risk of depressive symptoms after hip fracture (p=.006). No differences between 5HT1a genotypes were found. Our findings suggest plasticity-related genetic factors contribute to the neural mechanisms of mental and functional well-being after a disabling medical stressor. PMID:25781924

  13. Pulp Sensitivity: Influence of Sex, Psychosocial Variables, COMT Gene, and Chronic Facial Pain.

    PubMed

    Mladenovic, Irena; Krunic, Jelena; Supic, Gordana; Kozomara, Ruzica; Bokonjic, Dejan; Stojanovic, Nikola; Magic, Zvonko

    2018-05-01

    The purpose of this study was to evaluate the associations of variability in pulp sensitivity with sex, psychosocial variables, the gene that encodes for the enzyme catechol-O-methyltransferase (COMT), and chronic painful conditions (temporomandibular disorders [TMDs]). The study was composed of 97 subjects (68 women and 29 men aged 20-44 years). The electric (electric pulp tester) and cold (refrigerant spray) stimuli were performed on mandibular lateral incisors. The results were expressed as pain threshold values for electric pulp stimulation (0-80 units) and as pain intensity scores (visual numeric scale from 0-10) for cold stimulation. The Research Diagnostic Criteria for TMD were used to assess TMD, depression, and somatization. DNA extracted from peripheral blood was genotyped for 3 COMT polymorphisms (rs4680, rs6269, and rs165774) using the real-time TaqMan method. Multivariate linear regression was used to investigate the joint effect of the predictor variables (clinical and genetic) on pulp sensitivity (dependent variables). Threshold responses to electric stimuli were related to female sex (P < .01) and the homozygous GG genotype for the rs165774 polymorphism (P < .05). Pain intensity to cold stimuli was higher in TMD patients (P < .01) and tended to be higher in women. Multivariate linear regression identified sex and the rs165774 COMT polymorphism as the determinants of electric pain sensitivity, whereas TMD accounts for the variability in the cold response. Our findings indicate that sex/a COMT gene variant and TMD as a chronic painful condition may contribute to individual variation in electric and cold pulp sensitivity, respectively. Copyright © 2018 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  14. BDNF Met66 modulates the cumulative effect of psychosocial childhood adversities on major depression in adolescents.

    PubMed

    Cruz-Fuentes, Carlos S; Benjet, Corina; Martínez-Levy, Gabriela A; Pérez-Molina, Amado; Briones-Velasco, Magdalena; Suárez-González, Jesús

    2014-03-01

    The interplay among lifetime adversities and the genetic background has been previously examined on a variety of measures of depression; however, only few studies have focused on major depression disorder (MDD) in adolescence. Using clinical data and DNA samples from mouthwash gathered from an epidemiological study on the prevalence of mental disorders in youths between 12 and 17 years old, we tested the statistical interaction between a set of psychosocial adversities experienced during childhood (CAs) with two common polymorphisms in the brain-derived neurotrophic factor (BDNF) (Val66Met) and SLC6A4 (L/S) genes on the probability of suffering MDD in adolescence. Genotype or allele frequencies for both polymorphisms were similar between groups of comparison (MDD N = 246; controls N = 270). The CAs factors: Abuse, neglect, and family dysfunctions; parental maladjustment, parental death, and to have experienced a life-threatening physical illness were predictors of clinical depression in adolescents. Remarkably, the cumulative number of psychosocial adversities was distinctly associated with an increase in the prevalence of depression but only in those Val/Val BDNF individuals; while the possession of at least a copy of the BDNF Met allele (i.e., Met +) was statistically linked with a "refractory" or resilient phenotype to the noticeable influence of CAs. Liability or resilience to develop MDD in adolescence is dependent of a complex interplay between particular environmental exposures and a set of plasticity genes including BDNF. A better understanding of these factors is important for developing better prevention and early intervention measures.

  15. Association of GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms with clinical response to imatinib mesylate treatment among Malaysian chronic myeloid leukaemia patients.

    PubMed

    Makhtar, Siti Maziras; Husin, Azlan; Baba, Abdul Aziz; Ankathil, Ravindran

    2017-09-01

    The detoxifying activity of glutathione S-transferases (GST) enzymes not only protect cells from the adverse effects of xenobiotics, but also alters the effectiveness of drugs in cancer cells, resulting in toxicity or drug resistance. In this study, we aimed to evaluate the association of GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms with treatment response among Malaysian chronic myeloid leukaemia (CML) patients who everyday undergo 400 mg of imatinib mesylate (IM) therapy. Multiplex polymerase chain reaction (multiplex-PCR) was performed to detect GSTM1 and GSTT1 polymorphisms simultaneously and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was conducted to detect the GSTP1 Ile195Val polymorphism. On evaluating the association of the variant genotype with treatment outcome, heterozygous variant (AG) and homozygous variant (GG) of GSTP1 Ile105Val showed significantly a higher risk for the development of resistance to IM with OR: 1.951 (95% CI: 1.186-3.209, P = 0.009) and OR: 3.540 (95% CI: 1.305-9.606, P = 0.013), respectively. Likewise, GSTT1 null genotype was also associated with a significantly higher risk for the development of resistance to IM with OR = 1.664 (95% CI: 1.011-2.739, P = 0.045). Our results indicate the potential usefulness of GST polymorphism genotyping in predicting the IM treatment response among CML patients.

  16. No association between catechol-O-methyltransferase polymorphisms and neurotic disorders among mainland Chinese university students.

    PubMed

    Kou, Changgui; Meng, Xiangfei; Xie, Bing; Shi, Jieping; Yu, Qiong; Yu, Yaqin; D'Arcy, Carl

    2012-07-30

    This study investigates the genetic association between catechol-O-methyltransferase (COMT) gene polymorphisms and neurotic disorders. Data were derived from a case-control association study of 255 undergraduates affected by neurotic disorders and 269 matched healthy undergraduate controls. The polymorphisms of eight tag single nucleotide polymorphisms (SNPs) on the COMT gene were tested using polymerase chain reaction (PCR)-based Ligase Detection Reaction (PCR-LDR). The eight tag SNPs on the COMT gene assessed were not associated with neurotic disorders. Our finding suggests that the COMT gene may not be a susceptibility gene for neurotic disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. BDNF polymorphism predicts the rate of decline in skilled task performance and hippocampal volume in healthy individuals

    PubMed Central

    Sanchez, M Millan; Das, D; Taylor, J L; Noda, A; Yesavage, J A; Salehi, A

    2011-01-01

    Numerous studies have indicated a link between the presence of polymorphism in brain-derived neurotrophic factor (BDNF) and cognitive and affective disorders. However, only a few have studied these effects longitudinally along with structural changes in the brain. This study was carried out to investigate whether valine-to-methionine substitution at position 66 (val66met) of pro-BDNF could be linked to alterations in the rate of decline in skilled task performance and structural changes in hippocampal volume. Participants consisted of 144 healthy Caucasian pilots (aged 40–69 years) who completed a minimum of 3 consecutive annual visits. Standardized flight simulator score (SFSS) was measured as a reliable and quantifiable indicator for skilled task performance. In addition, a subset of these individuals was assessed for hippocampal volume alterations using magnetic resonance imaging. We found that val66met substitution in BDNF correlated longitudinally with the rate of decline in SFSS. Structurally, age-dependent hippocampal volume changes were also significantly altered by this substitution. Our study suggests that val66met polymorphism in BDNF can be linked to the rate of decline in skilled task performance. Furthermore, this polymorphism could be used as a predictor of the effects of age on the structure of the hippocampus in healthy individuals. Such results have implications for understanding possible disabilities in older adults performing skilled tasks who are at a higher risk for cognitive and affective disorders. PMID:22833197

  18. Preproghrelin Leu72Met polymorphism predicts a lower rate of developing renal dysfunction in type 2 diabetic nephropathy.

    PubMed

    Lee, Dae-Yeol; Kim, Sun-Young; Jo, Dae-Sun; Hwang, Pyoung Han; Kang, Kyung Pyo; Lee, Sik; Kim, Won; Park, Sung Kwang

    2006-07-01

    Ghrelin is a novel peptide hormone, which exerts somatotropic, orexigenic and adipogenic effects. Recent studies have shown that the preproghrelin Leu72Met polymorphism is associated with serum creatinine (Scr) concentration in type 2 diabetes; 72Met carriers exhibited lower Scr levels as compared with the 72Met non-carriers. We hypothesized that the preproghrelin Leu72Met polymorphism is associated with a lower rate of developing renal dysfunction in patients with type 2 diabetic nephropathy. The preproghrelin Leu72Met polymorphism was investigated using PCR techniques in 138 patients with diabetic nephropathy divided into two groups, one with normal renal function and the other with renal dysfunction. Determination of the frequency of the preproghrelin Leu72Met polymorphism was the main outcome measure. The frequency of the Leu72Met polymorphism in diabetic nephropathy was significantly lower in patients with renal dysfunction (15.9%, P < 0.01) than in patients with normal renal function (42.0%) or in the diabetes control group (40.6%). The Leu72Met polymorphism was also associated with serum total cholesterol levels in diabetic nephropathy patients with renal dysfunction; the 72Met carriers had lower total cholesterol levels than the 72Met non-carriers (P < 0.05). These data suggest that 72Met carrier status may be used as a marker predicting a lower chance of developing renal dysfunction in diabetic nephropathy.

  19. Predictive value of GSTP1 Ile105Val polymorphism in clinical outcomes of chemotherapy in gastric and colorectal cancers: a systematic review and meta-analysis.

    PubMed

    Shen, Xiaobing; Wang, Jia; Yan, Xiaoluan; Ren, Xiaofeng; Wang, Fan; Chen, Xiaowei; Xu, Yuchao

    2016-06-01

    Gastric and colorectal cancers remain the major causes of cancer-related death with a bad prognosis. Up to now, platinum combined with fluoropyrimidines has been most commonly used in chemotherapy regimens of gastric and colorectal cancers. Recently, a series of studies have been conducted to investigate the associations of biomarkers, such as GSTP1 Ile105Val polymorphism, with the chemotherapy efficacy in gastric and colorectal cancers; however, the results were not consistent and inconclusive. Here, we performed a systematic review and meta-analysis to summarize the associations of GSTP1 Ile105Val polymorphism with the chemotherapy efficacy in gastric and colorectal cancers. A systematic review was conducted to search relevant studies in English databases (PubMed, ISI Web of Science, and EMBASE) up to November 30, 2015. The pooling ORs or HRs were used to assess the strength of the associations of GSTP1 Ile105Val polymorphism with clinical outcomes such as tumor response, toxicity, progression-free survival (PFS), and overall survival (OS). Forty-one papers containing 8169 cases were finally included in the present meta-analysis study. Of which, 28 articles were performed in colorectal cancers, one in gastrointestinal carcinoma (gastric and colon cancer), 11 in gastric cancers, and one in colorectal and gastroesophageal cancers. After pooling all the eligible studies, we identified significant associations of GSTP1 Ile105Val polymorphism with chemotherapy-related tumor response (G vs. A: OR 1.697, 95 % CI 1.191-2.418; GG vs. AA: OR 2.804, 95 % CI 1.414-5.560; AG vs. AA: OR 1.540, 95 % CI 1.011-2.347; GG vs. AAAG: OR 2.139, 95 % CI 1.256-3.641), PFS (GG vs. AA, HR 0.640, 95 % CI 0.455-0.900; AGGG vs. AA: HR 0.718, 95 % CI 0.562-0.919), and OS (AG vs. AA: HR 0.857, 95 % CI 0.746-0.986; GG vs. AA: HR 0.679, 95 % CI 0.523-0.882; AGGG vs. AA: HR 0.663, 95 % CI 0.542-0.812) in gastric and colorectal cancers and no significant association was found

  20. The role of histamine degradation gene polymorphisms in moderating the effects of food additives on children's ADHD symptoms.

    PubMed

    Stevenson, Jim; Sonuga-Barke, Edmund; McCann, Donna; Grimshaw, Kate; Parker, Karen M; Rose-Zerilli, Matthew J; Holloway, John W; Warner, John O

    2010-09-01

    Food additives can exacerbate ADHD symptoms and cause non-immunoglobulin E-dependent histamine release from circulating basophils. However, children vary in the extent to which their ADHD symptoms are exacerbated by the ingestion of food additives. The authors hypothesized that genetic polymorphisms affecting histamine degradation would explain the diversity of responses to additives. In a double-blind, placebo-controlled crossover trial, challenges involving two food color additive and sodium benzoate (preservative) mixtures in a fruit drink were administered to a general community sample of 3-year-old children (N = 153) and 8/9-year-old children (N = 144). An aggregate ADHD symptom measure (based on teacher and parent blind ratings of behavior, blind direct observation of behavior in the classroom, and--for 8/9-year-old children only--a computerized measure of attention) was the main outcome variable. The adverse effect of food additives on ADHD symptoms was moderated by histamine degradation gene polymorphisms HNMT T939C and HNMT Thr105Ile in 3- and 8/9-year-old children and by a DAT1 polymorphism (short versus long) in 8/9-year-old children only. There was no evidence that polymorphisms in catecholamine genes COMT Val108Met, ADRA2A C1291G, and DRD4-rs7403703 moderated the effect on ADHD symptoms. Histamine may mediate the effects of food additives on ADHD symptoms, and variations in genes influencing the action of histamine may explain the inconsistency between previous studies. Genes influencing a range of neurotransmitter systems and their interplay with environmental factors, such as diet, need to be examined to understand genetic influences on ADHD symptoms.

  1. Racial Differences in Prediction of Time to Prostate Cancer Diagnosis in a Prospective Screening Cohort of High-Risk Men: Effect of TMPRSS2 Met160Val

    PubMed Central

    Giri, Veda N.; Ruth, Karen; Hughes, Lucinda; Uzzo, Robert G.; Chen, David Y.T.; Boorjian, Stephen A.; Viterbo, Rosalia; Rebbeck, Timothy R.

    2011-01-01

    Introduction The TMPRSS2-ERG gene fusion occurs in >50% of prostate tumors and has been associated with poor outcomes. The T-allele (Valine) of the Met160Val (rs12329760) in TMPRSS2 has been associated with this fusion. We evaluated this polymorphism with respect to self-identified race or ethnicity (SIRE), time to prostate cancer (PCA) diagnosis, and screening parameters in the Prostate Cancer Risk Assessment Program, a prospective screening program for high-risk men. Patients and Methods 631 men ages 35-69 years were studied. “High-risk” was defined as ≥ one first degree or two second degree relatives with PCA, any African American (AA) man regardless of familial PCA, and men with BRCA1/2 mutations. Men with elevated PSA or other indications for PCA underwent biopsy. Men were followed from time of study entry to PCA diagnosis. Cox models were used to evaluate time to PCA diagnosis by genotype. Results Genotype distribution differed significantly by SIRE (CT/TT vs. CC, p<0.0001). Among 183 Caucasian men with at least one follow-up visit, PCA was more than doubled in men carrying CT/TT vs CC genotypes (HR= 2.55, 95% CI=1.14-5.70) after controlling for age and PSA. No association was seen among AA men by TMPRSS2 genotype. Conclusions The T-allele of the Met160Val variant in TMPRSS2, which has been associated with the TMPRSS2-ERG fusion, may be informative of time to PCA diagnosis for a subset of high-risk Caucasian men who are undergoing regular PCA screening. This variant along with other genetic markers warrant further study for personalizing PCA screening. PMID:20735386

  2. The Val30Met familial amyloid polyneuropathy specific Rasch-built overall disability scale (FAP-RODS(©) ).

    PubMed

    Pruppers, Mariëlle H J; Merkies, Ingemar S J; Faber, Catharina G; Da Silva, Ana M; Costa, Vanessa; Coelho, Teresa

    2015-09-01

    Familial amyloid polyneuropathy (FAP) is a chronic debilitating multi-organic disorder, mainly assessed using ordinal-based impairment measures. To date, no outcome measure at the activity and participation level has been constructed in FAP. The current study aimed to design an interval activity/participation scale for FAP through Rasch methodology. A preliminary FAP Rasch-built overall disability scale (pre-FAP-RODS) containing 146 activity/participation items was assessed twice (interval: 2-4 week; test-retest reliability) in 248 patients with Val30Met FAP examined in Porto, Portugal, of which 65.7% have received liver transplantation. An ordinal-based 24-item FAP-symptoms inventory questionnaire (FAP-SIQ) was also assessed (validity purposes). The pre-FAP-RODS and FAP-SIQ data were subjected to Rasch analyses. The pre-FAP-RODS did not meet model's expectations. On the basis of requirements such as misfit statistics, differential item functioning, and local dependency, items were systematically removed until a final 34-item FAP-RODS(©) was constructed fulfilling all Rasch requirements. Acceptable reliability/validity scores were demonstrated. In conclusion, the 34-item FAP-RODS(©) is a disease-specific interval measure suitable for detecting activity and participation restrictions in patients with FAP. The use of the FAP-RODS(©) is recommended for future international clinical trials in patients with Val30Met FAP determining its responsiveness and its cross-cultural validation. Its expansion to other forms of FAP should also be focus of future clinical studies. © 2015 Peripheral Nerve Society.

  3. Association study between BDNF C-281A polymorphism and paranoid schizophrenia in Polish population.

    PubMed

    Suchanek, Renata; Owczarek, Aleksander; Kowalski, Jan

    2012-01-01

    Brain-derived neurotrophic factor (BDNF) is one of the candidate genes for schizophrenia. Polymorphism C-281A (rs28383487) in BDNF gene leads to the reduction of promoter activity in the hippocampal neurons in vitro. To our knowledge, this is the first study to examine the influence of alleles and genotypes of BDNF C-281A polymorphism on development, as well as the clinical course (age of onset, suicidal behaviour and psychopathology) of paranoid schizophrenia. The psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) as subscale scores and also single-item scores. We have also performed the haplotype analysis with val66met BDNF polymorphism, which is known to be involved in the pathogenesis of schizophrenia. We have not found significant differences in the distribution of genotypes and alleles between schizophrenic patients and controls in both the overall analysis, as well as sex stratified. Also, we have not shown statistically significant differences between genotype groups and PANSS scale. However, an association between C-281A polymorphism and time of the first episode of paranoid schizophrenia was revealed. Genotype C/A had been connected with later age of onset of paranoid schizophrenia in men but not in women (p < 0.01). The C-281A and val66met polymorphisms have been in a strong linkage disequilibrium (D' = 0.9875; p < 0.05). The haplotype analysis has shown a tendency to a significantly lower frequency of the Met-C haplotype in the schizophrenia group compared to the controls.

  4. Prion Protein M129V Polymorphism Affects Retrieval-Related Brain Activity

    ERIC Educational Resources Information Center

    Buchmann, Andreas; Mondadori, Christian R. A.; Hanggi, Jurgen; Aerni, Amanda; Vrticka, Pascal; Luechinger, Roger; Boesiger, Peter; Hock, Christoph; Nitsch, Roger M.; de Quervain, Dominique J.-F.; Papassotiropoulos, Andreas; Henke, Katharina

    2008-01-01

    The prion protein Met129Val polymorphism has recently been related to human long-term memory with carriers of either the 129[superscript MM] or the 129[superscript MV] genotype recalling 17% more words than 129[superscript VV] carriers at 24 h following learning. Here, we sampled genotype differences in retrieval-related brain activity at 30 min…

  5. Influence of DAT1 and COMT variants on neural activation during response inhibition in adolescents with attention-deficit/hyperactivity disorder and healthy controls.

    PubMed

    van Rooij, D; Hoekstra, P J; Bralten, J; Hakobjan, M; Oosterlaan, J; Franke, B; Rommelse, N; Buitelaar, J K; Hartman, C A

    2015-11-01

    Impairment of response inhibition has been implicated in attention-deficit/hyperactivity disorder (ADHD). Dopamine neurotransmission has been linked to the behavioural and neural correlates of response inhibition. The current study aimed to investigate the relationship of polymorphisms in two dopamine-related genes, the catechol-O-methyltransferase gene (COMT) and the dopamine transporter gene (SLC6A3 or DAT1), with the neural and behavioural correlates of response inhibition. Behavioural and neural measures of response inhibition were obtained in 185 adolescents with ADHD, 111 of their unaffected siblings and 124 healthy controls (mean age 16.9 years). We investigated the association of DAT1 and COMT variants on task performance and whole-brain neural activation during response inhibition in a hypothesis-free manner. Additionally, we attempted to explain variance in previously found ADHD effects on neural activation during response inhibition using these DAT1 and COMT polymorphisms. The whole-brain analyses demonstrated large-scale neural activation changes in the medial and lateral prefrontal, subcortical and parietal regions of the response inhibition network in relation to DAT1 and COMT polymorphisms. Although these neural activation changes were associated with different task performance measures, no relationship was found between DAT1 or COMT variants and ADHD, nor did variants in these genes explain variance in the effects of ADHD on neural activation. These results suggest that dopamine-related genes play a role in the neurobiology of response inhibition. The limited associations between gene polymorphisms and task performance further indicate the added value of neural measures in linking genetic factors and behavioural measures.

  6. Epistatic interactions involving DRD2, DRD4, and COMT polymorphisms and risk of substance abuse in women with binge-purge eating disturbances.

    PubMed

    Steiger, Howard; Thaler, Lea; Gauvin, Lise; Joober, Ridha; Labbe, Aurelie; Israel, Mimi; Kucer, Audrey

    2016-06-01

    Substance abuse is common in individuals with bulimia-spectrum (binge-purge) eating disturbances, a co-occurrence that has been attributed to shared neurobiological substrates--notably alterations in dopaminergic activity. We examined the implications of variations of selected, dopamine-relevant polymorphisms (DRD2 Taq1A, DRD4 7R, and COMT) for risk of substance abuse in women with binge-purge eating syndromes. We genotyped 183 women (66.1% showing full-threshold BN and 33.9% showing sub-syndromic variants), and assessed lifetime presence of alcohol, cannabis, cocaine, and stimulant abuse or dependence using structured interviews. Tests for main and interaction effects of various allele combinations revealed that individuals who carried high function COMT and low-function DRD4 7R alleles (a combination expected to be associated with higher risk) did indeed show more lifetime substance abuse and, specifically, more cannabis abuse. Our findings suggest that a gene combination that, in theory, codes for low levels of dopaminergic neurotransmission coincides with sensitivity to substance abuse in a sample displaying binge-purge eating-disorder variants. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. ALA16VAL-MnSOD gene polymorphism and stroke: Association with dyslipidemia and glucose levels.

    PubMed

    Flores, Ariane Ethur; Pascotini, Eduardo Tanuri; Kegler, Aline; Gabbi, Patricia; Bochi, Guilherme Vargas; Barbisan, Fernanda; Duarte, Thiago; Prado, Ana Lucia Cervi; Duarte, Marta M M F; da Cruz, Ivana B M; Moresco, Rafael Noal; Santos, Adair Roberto Soares; Bresciani, Guilherme; Royes, Luiz Fernando Freire; Fighera, Michele Rechia

    2017-09-05

    Stroke risk has been associated to the progression of carotid plaques due to high glucose levels and lipid accumulation, which are greatly associated to cerebral injury, brain oxidative stress, and apoptosis. The ALA16VAL-MnSOD gene single nucleotide polymorphism (SNP) has shown to modulate risk factors of several metabolic and vascular diseases, such as blood glucose (GLU) and lipid levels. However, the association of these factors in stroke patients has not been studied to date. Thus, we evaluated the influence of the Ala16Val-MnSOD SNP on lipid profile, GLU levels, oxidative and DNA damage of 44 patients in a late phase of stroke (>6months). The statistical analysis showed a greater proportion of VV carries in stroke patients. The results also indicated that stroke patients had higher cholesterol (CHO) and GLU levels when compared to healthy counterparts. Interestingly, V allele carriers with stroke showed higher levels of CHO and GLU when compared to AA stroke and healthy counterparts. Our findings suggest that oxidative stress markers are still increased even after 6 months of cerebral injury. Furthermore, we propose that the Ala16Val-MnSOD SNPs may contribute to hypercholesterolemia and higher GLU levels, increasing the risk to neurovascular events that may lead to stroke. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Nonlinear modulation of interacting between COMT and depression on brain function.

    PubMed

    Gong, L; He, C; Yin, Y; Ye, Q; Bai, F; Yuan, Y; Zhang, H; Lv, L; Zhang, H; Zhang, Z; Xie, C

    2017-09-01

    The 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. Fifty 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. We 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). Our 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. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  9. Association of ghrelin Leu72Met polymorphism with type 2 diabetes mellitus in Chinese population.

    PubMed

    Liu, Jing; Liu, Jia; Tian, Li-min; Liu, Ju-xiang; Bing, Ya-jun; Zhang, Ji-ping; Wang, Yun-Fang; Zhang, Lu-yan

    2012-08-10

    Ghrelin, a novel endogenous ligand for the growth hormone secretagogue receptor, is considered to implicate the development of the type 2 diabetes mellitus (T2DM). The Leu72Met (+408C>A) polymorphism of the preproghrelin, has been linked to obesity, insulin resistance and diabetes. To investigate the distribution of ghrelin gene Leu72Met polymorphism and its association with the type 2 diabetes mellitus in Chinese population. We conducted a case-control study on 877 patients with T2DM and 864 controls, which were genotyped by the polymerase chain reaction (PCR) technique, denaturing high performance liquid chromatography (DHPLC) and DNA sequence analysis. Laboratory analyses were carried out in the hospital laboratory. No significant difference in the Leu72Met genotype distributions and allele frequency was observed between type 2 diabetes mellitus and controls (both P>0.05). The polymorphism was not associated with T2DM. However, among the T2DM group, the patients carrying Leu72Leu genotype had significantly increased levels of FPG and serum creatinine compared with variant genotypes (Leu72Met and Met72Met) (P<0.05). In the control group, the subjects with variant genotypes had significantly increased levels of FINS, HOMA-IR compared with Leu72Leu genotype (P<0.05). The Leu72Met polymorphism of the preproghrelin gene was not associated with T2DM in Chinese population. However, it may have some roles in the etiology of insulin resistance. Copyright © 2012 Elsevier B.V. All rights reserved.

  10. Serotonin transporter genotype (5-HTTLPR) and electrocortical responses indicating the sensitivity to negative emotional cues.

    PubMed

    Papousek, Ilona; Reiser, Eva M; Schulter, Günter; Fink, Andreas; Holmes, Emily A; Niederstätter, Harald; Nagl, Simone; Parson, Walther; Weiss, Elisabeth M

    2013-12-01

    Growing literature indicates that emotional reactivity and regulation are strongly linked to genetic modulation of serotonergic neurotransmission. However, until now, most studies have focused on the relationship between genotypic markers, in particular the serotonin transporter-linked polymorphic region (5-HTTLPR), and neural structures using MRI. The current study aimed to bridge the gap between the relevant MRI literature on the effects of the 5-HTTLPR genotype and the research tradition focusing on transient lateralized changes of electrocortical activity in the prefrontal cortex using electroencephalography (EEG). Lateral shifts of EEG alpha asymmetry in response to an aversive film consisting of scenes of real injury and death were assessed in healthy participants (n = 165). To evaluate the specificity of the 5-HTTLPR effect, participants were also tested for the COMT Val158Met polymorphism which is linked to dopamine inactivation. While viewing the film, individuals homozygous for the 5-HTTLPR short allele displayed a clear lateral shift of dorsolateral frontal activity to the right, which was virtually absent in participants carrying the long allele. The heightened electrocortical response to the aversive stimulation and its direction indicates a greater propensity of s/s homozygotes to experience withdrawal oriented affect in response to negative emotion cues in the environment. Moreover, together with previous research the findings support the notion of a link between the serotonergic system and self-regulation related to avoidance motivation, and a link between the dopaminergic system and self-regulation related to approach motivation.

  11. Genetic moderation of the association between regulatory focus and reward responsiveness: a proof-of-concept study.

    PubMed

    Goetz, Elena L; Hariri, Ahmad R; Pizzagalli, Diego A; Strauman, Timothy J

    2013-02-01

    Recent studies implicate individual differences in regulatory focus as contributing to self-regulatory dysfunction, particularly not responding to positive outcomes. How such individual differences emerge, however, is unclear. We conducted a proof-of-concept study to examine the moderating effects of genetically driven variation in dopamine signaling, a key modulator of neural reward circuits, on the association between regulatory focus and reward cue responsiveness. Healthy Caucasians (N=59) completed a measure of chronic regulatory focus and a probabilistic reward task. A common functional genetic polymorphism impacting prefrontal dopamine signaling (COMT rs4680) was evaluated. Response bias, the participants' propensity to modulate behavior as a function of reward, was predicted by an interaction of regulatory focus and COMT genotype. Specifically, self-perceived success at achieving promotion goals predicted total response bias, but only for individuals with the COMT genotype (Val/Val) associated with relatively increased phasic dopamine signaling and cognitive flexibility. The combination of success in promotion goal pursuit and Val/Val genotype appears to facilitate responding to reward opportunities in the environment. This study is among the first to integrate an assessment of self-regulatory style with an examination of genetic variability that underlies responsiveness to positive outcomes in goal pursuit.

  12. Conformational analysis of the N-terminal sequence Met1 Val60 of the tyrosine hydroxylase

    NASA Astrophysics Data System (ADS)

    Alieva, Irada N.; Mustafayeva, Narmina N.; Gojayev, Niftali M.

    2006-03-01

    Molecular mechanics method and molecular dynamics (MD) simulation techniques are used to study the behavior and the effect of the amino acids substitution on structure and molecular dynamics of the specific portion of Met1-Val60 amino acid residues from N-terminal regulatory domain of the tyrosine hydroxylase (TH) and its mutants in which the positively charged arginine residues at positions 37 and 38 were replaced by electrically neutral Gly and negatively charged Glu, and serine residue at position 40 was replaced by Ala or Asp residue. Our study allowed us to make the following conclusions: (i) the higher conformational flexibility of the Met1-Arg16 sequence is revealed in comparision to other part of the N-terminus; (ii) the stretch of amino acid residues Met30-Ser40 within the N-terminus forms β-turn so that two α-helices (residues 16-29 and residues 41-60) are paralel one another; (ii) the significant differences that are observed for the Arg37→Gly37, Arg37-Arg38→Glu37-Glu38 mutant segments indicates that the positive charge of the Arg37 and Arg38 residues is one of the main factor that maintains the characteristic of the turn; (ii) no major conformational changes are observed between Ser40→Ala40, and Ser40→Asp40 mutant segments.

  13. Identification of a G‐Protein Subunit‐α11 Gain‐of‐Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2)

    PubMed Central

    Piret, Sian E; Gorvin, Caroline M; Pagnamenta, Alistair T; Howles, Sarah A; Cranston, Treena; Rust, Nigel; Nesbit, M Andrew; Glaser, Ben; Taylor, Jenny C; Buchs, Andreas E; Hannan, Fadil M

    2016-01-01

    ABSTRACT Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia, inappropriately low serum parathyroid hormone concentrations and hypercalciuria. ADH is genetically heterogeneous with ADH type 1 (ADH1), the predominant form, being caused by germline gain‐of‐function mutations of the G‐protein coupled calcium‐sensing receptor (CaSR), and ADH2 caused by germline gain‐of‐function mutations of G‐protein subunit α‐11 (Gα11). To date Gα11 mutations causing ADH2 have been reported in only five probands. We investigated a multigenerational nonconsanguineous family, from Iran, with ADH and keratoconus which are not known to be associated, for causative mutations by whole‐exome sequencing in two individuals with hypoparathyroidism, of whom one also had keratoconus, followed by cosegregation analysis of variants. This identified a novel heterozygous germline Val340Met Gα11 mutation in both individuals, and this was also present in the other two relatives with hypocalcemia that were tested. Three‐dimensional modeling revealed the Val340Met mutation to likely alter the conformation of the C‐terminal α5 helix, which may affect G‐protein coupled receptor binding and G‐protein activation. In vitro functional expression of wild‐type (Val340) and mutant (Met340) Gα11 proteins in HEK293 cells stably expressing the CaSR, demonstrated that the intracellular calcium responses following stimulation with extracellular calcium, of the mutant Met340 Gα11 led to a leftward shift of the concentration‐response curve with a significantly (p < 0.0001) reduced mean half‐maximal concentration (EC50) value of 2.44 mM (95% CI, 2.31 to 2.77 mM) when compared to the wild‐type EC50 of 3.14 mM (95% CI, 3.03 to 3.26 mM), consistent with a gain‐of‐function mutation. A novel His403Gln variant in transforming growth factor, beta‐induced (TGFBI), that may be causing keratoconus was also identified, indicating likely digenic

  14. XRCC3 Thr241Met Polymorphism is not Associated with Lung Cancer Risk in a Romanian Population.

    PubMed

    Catana, Andreea; Pop, Monica; Marginean, Dragos Horea; Blaga, Ioana Cristina; Porojan, Mihai Dumitru; Popp, Radu Anghel; Pop, Ioan Victor

    2016-01-01

    Deoxyribonucleic Acid (DNA) repair mechanisms play a critical role in protecting the cellular genome against carcinogens. X-ray cross-complementing gene 3 (XRCC3) is involved in DNA repair and therefore certain genetic polymorphisms that occur in DNA repair genes may affect the ability to repair DNA defects and may represent a risk factor in carcinogenesis. The purpose of our study was to investigate the association between XRCC3 gene substitution of Threonine with Methionine in codon 241 of XRCC3 gene (Thr241Met) polymorphism and the risk of lung cancer, in a Romanian population. We recruited 93 healthy controls and 85 patients with lung cancer, all smokers. Thr241Met, XRCC3 gene genotyping was determined by multiplex Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Statistical analysis (OR, recessive model), did not revealed an increased risk for lung cancer, for the variant 241Met allele and Thr241Met genotypes (p=0.138, OR=0.634, CI=0.348-1.157; p=0.023, OR=0.257, CI=0.085-6.824). Also, there were no positive statistical associations between Thr241Met polymorphism of XRCC3 gene, gender, tobacco and various histopathological tumor type of lung cancer. In conclusion, the results of the study suggest that the XRCC3 gene Thr241Met polymorphism is not associated with an increased risk for the development of lung cancer in this Romanian group.

  15. LRP5 coding polymorphisms influence the variation of peak bone mass in a normal population of French-Canadian women.

    PubMed

    Giroux, Sylvie; Elfassihi, Latifa; Cardinal, Guy; Laflamme, Nathalie; Rousseau, François

    2007-05-01

    Bone mineral density has a strong genetic component but it is also influenced by environmental factors making it a complex trait to study. LRP5 gene was previously shown to be involved in rare diseases affecting bone mass. Mutations associated with gain-of-function were described as well as loss-of-function mutations. Following this discovery, many frequent LRP5 polymorphisms were tested against the variation of BMD in the normal population. Heel bone parameters (SOS, BUA) were measured by right calcaneal QUS in 5021 healthy French-Canadian women and for 2104 women, BMD evaluated by DXA at two sites was available (femoral neck (FN) and lumbar spine (LS)). Among women with QUS measures and those with DXA measures, 26.5% and 32.8% respectively were premenopausal, 9.2% and 10.7% were perimenopausal and 64.2% and 56.5% were postmenopausal. About a third of the peri- and postmenopausal women never received hormone therapy. Two single nucleotide coding polymorphisms (Val667Met and Ala1330Val) in LRP5 gene were genotyped by allele-specific PCR. All bone measures were tested individually for associations with each polymorphism by analysis of covariance with adjustment for non genetic risk factors. Furthermore, haplotype analysis was performed to take into account the strong linkage disequilibrium between the two polymorphisms. The two LRP5 polymorphisms were found to be associated with all five bone measures (L2L4 and femoral neck DXA as well as heel SOS, BUA and stiffness index) in the whole sample. Premenopausal women drove the association as expected from the proposed role of LRP5 in peak bone mass. Our results suggest that the Val667Met polymorphism is the causative variant but this remains to be functionally proven.

  16. Prion protein gene analysis in three kindreds with fatal familial insomnia (FFI): Codon 178 mutation and codon 129 polymorphism

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Medori, R.; Tritschler, H.J.

    1993-10-01

    Fatal familial insomnia (FFI) is a disease linked to a GAC(Asp) [yields] AAC(Asn) mutation in codon 178 of the prion protein (PrP) gene. FFI is characterized clinically by untreatable progressive insomnia, dysautonomia, and motor dysfunctions and is characterized pathologically by selective thalamic atrophy. The authors confirmed the 178[sup Asn] mutation in the PrP gene of a third FFI family of French ancestry. Three family members who are under 40 years of age and who inherited the mutation showed only reduced perfusion in the basal ganglia on single photon emission computerized tomography. Some FFI features differ from the clinical and neuropathologicmore » findings associated with 178[sup Asn] reported elsewhere. However, additional intragenic mutations accounting for the phenotypic differences were not observed in two affected individuals. In other sporadic and familial forms of Creutzfeldt-Jakob disease and Gerstmann-Straeussler syndrome, Met or Val homozygosity at polymorphic codon 129 is associated with a more severe phenotype, younger age at onset, and faster progression. In FFI, young and old individuals at disease onset had 129[sup Met/Val]. Moreover, of five 178[sup Asn] individuals who are above age-at-onset range and who are well, two have 129[sup Met] and three have 129[sup Met/Val], suggesting that polymorphic site 129 does not modulate FFI phenotypic expression. Genetic heterogeneity and environment may play an important role in inter- and intrafamilial variability of the 178[sup Asn] mutation. 32 refs., 5 figs., 1 tab.« less

  17. MCT1, MCT4 and CD147 gene polymorphisms in healthy horses and horses with myopathy.

    PubMed

    Mykkänen, A K; Koho, N M; Reeben, M; McGowan, C M; Pösö, A R

    2011-12-01

    Polymorphisms in human lactate transporter proteins (monocarboxylate transporters; MCTs), especially the MCT1 isoform, can affect lactate transport activity and cause signs of exercise-induced myopathy. Muscles express MCT1, MCT4 and CD147, an ancillary protein, indispensable for the activity of MCT1 and MCT4. We sequenced the coding sequence (cDNA) of horse MCT4 for the first time and examined polymorphisms in the cDNA of MCT1, MCT4 and CD147 of 16 healthy horses. To study whether signs of myopathy are linked to the polymorphisms, biopsy samples were taken from 26 horses with exercise-induced recurrent myopathy. Two polymorphisms that cause a change in amino acid sequence were found in MCT1 (Val(432)Ile and Lys(457)Gln) and one in CD147 (Met(125)Val). All polymorphisms in MCT4 were silent. Mutations in MCT1 or CD147 in equine muscle were not associated with myopathy. In the future, a functional study design is needed to evaluate the physiological role of the polymorphisms found. Copyright © 2010 Elsevier Ltd. All rights reserved.

  18. Correlation between genetic polymorphisms and stroke recovery: analysis of the GAIN Americas and GAIN International Studies.

    PubMed

    Cramer, S C; Procaccio, V

    2012-05-01

    Recovery after stroke occurs on the basis of specific molecular events. Genetic polymorphisms associated with impaired neural repair or plasticity might reduce recovery from stroke and might also account for some of the intersubject variability in stroke recovery. This study hypothesized that the ApoE ε4 polymorphism and the val(66) met polymorphism for brain-derived neurotrophic factor (BDNF) are each associated with poorer outcome after stroke. Associations with mitochondrial genotype were also explored. Genotypes were determined in 255 stroke patients who also received behavioral evaluations in the Glycine Antagonist In Neuroprotection (GAIN) clinical trials. The primary outcome measure was recovery during the first month post-stroke, as this is the time when neural repair is at a maximum and so when genetic influences might have their largest impact. Two secondary outcome measures at 3 months post-stroke were also examined.   Genotype groups were similar acutely post-stroke. Presence of the ApoE ε4 polymorphism was associated with significantly poorer recovery over the first month post-stroke (P = 0.023) and with a lower proportion of subjects with minimal or no disability (modified Rankin score 0-1, P = 0.01) at 3 months post-stroke. Indeed, those with this polymorphism were approximately half as likely to achieve minimal or no disability (18.2%) versus those with polymorphism absent (35.5%). Findings were confirmed in multivariate models. Results suggested possible effects from the val(66) met BDNF polymorphism and from the R0 mitochondrial DNA haplotype.   Genetic factors, particularly the ApoE ε4 polymorphism, might contribute to variability in outcomes after stroke. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS.

  19. BDNFval66met affects neural activation pattern during fear conditioning and 24 h delayed fear recall.

    PubMed

    Lonsdorf, Tina B; Golkar, Armita; Lindström, Kara M; Haaker, Jan; Öhman, Arne; Schalling, Martin; Ingvar, Martin

    2015-05-01

    Brain-derived neurotrophic factor (BDNF), the most abundant neutrophin in the mammalian central nervous system, is critically involved in synaptic plasticity. In both rodents and humans, BDNF has been implicated in hippocampus- and amygdala-dependent learning and memory and has more recently been linked to fear extinction processes. Fifty-nine healthy participants, genotyped for the functional BDNFval66met polymorphism, underwent a fear conditioning and 24h-delayed extinction protocol while skin conductance and blood oxygenation level dependent (BOLD) responses (functional magnetic resonance imaging) were acquired. We present the first report of neural activation pattern during fear acquisition 'and' extinction for the BDNFval66met polymorphism using a differential conditioned stimulus (CS)+ > CS- comparison. During conditioning, we observed heightened allele dose-dependent responses in the amygdala and reduced responses in the subgenual anterior cingulate cortex in BDNFval66met met-carriers. During early extinction, 24h later, we again observed heightened responses in several regions ascribed to the fear network in met-carriers as opposed to val-carriers (insula, amygdala, hippocampus), which likely reflects fear memory recall. No differences were observed during late extinction, which likely reflects learned extinction. Our data thus support previous associations of the BDNFval66met polymorphism with neural activation in the fear and extinction network, but speak against a specific association with fear extinction processes. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  20. Leu432Val polymorphism in CYP1B1 as a susceptible factor towards predisposition to primary open-angle glaucoma

    PubMed Central

    Banerjee, Deblina; Mookherjee, Suddhasil; Banerjee, Antara; Sen, Abhijit; Variation Consortium, the Indian Genome

    2008-01-01

    Purpose Defects in cytochrome P450 1B1 (CYP1B1) cause primary congenital glaucoma. However, defects in the gene have also been reported in primary open-angle glaucoma (POAG). Since POAG is primarily a complex disease, we examined the potential of coding single nucleotide polymorphisms (cSNPs) in the gene for association with the disease. Methods Five coding SNPs – c.514 C>G (Arg48Gly), c.727 G>T (Ala119Ser), c.1666 C>G (Leu432Val), c.1719 C>T (Asp449Asp), and c.1730 A>G (Asn453Ser) – were genotyped in 264 unrelated POAG patients and 95 controls. In addition, 542 normal individuals selected from various ethnic groups representing the Indian population were also genotyped for these cSNPs. The patterns of linkage disequilibrium between the SNPs and haplotype variations for comparison between POAG patients and controls as well as different ethnic groups of the Indian population were determined using Haploview. Allelic variants of Leu432Val were cloned by site-directed mutagenesis of normal CYP1B1 cDNA, which were used for transfection of retinal pigment epithelium (RPE) cells. The generation of reactive oxygen species (ROS) was quantified by measuring fluorescence emission by degradation of CM-H2DCFDA using a fluoremeter. Results The c.1666G allele of the Leu432Val in CYP1B1 showed a statistically significant higher representation among POAG patients compared to controls (p=0.0001; Odds ratio=6.027; 95% CI: 3.863–9.401) suggesting it to be a potential risk allele toward disease predisposition. Analysis of genotype frequencies of the polymorphism between the two groups demonstrated GG as a potential risk genotype (p=0.0001; Odds ratio=15.505; 95% CI: 5.529–43.474) for the disease. CYP1B1 Val432 was estimated to generate higher ROS in RPE cells compared to its allelic variant (Leu432; p=0.0245 for 15 min and p=0.0197 for 30 min). Comparison of haplotype diversities revealed CGGTA as the risk haplotype for the disease (p=0.0001, by Fisher’s exact test

  1. Anxiolytic effect of music exposure on BDNFMet/Met transgenic mice.

    PubMed

    Li, Wen-Jing; Yu, Hui; Yang, Jian-Min; Gao, Jing; Jiang, Hong; Feng, Min; Zhao, Yu-Xia; Chen, Zhe-Yu

    2010-08-06

    Brain-derived neurotrophic factor (BDNF) has been reported to play important roles in the modulation of anxiety, mood stabilizers, and pathophysiology of affective disorders. Recently, a single nucleotide polymorphism (SNP) in the BDNF gene (Val66Met) has been found to be associated with depression and anxiety disorders. The humanized BDNF(Met/Met) knock-in transgenic mice exhibited increased anxiety-related behaviors that were unresponsive to serotonin reuptake inhibitors, fluoxetine. Music is known to be able to elicit emotional changes, including anxiolytic effects. In this study, we found that music treatment could significantly decrease anxiety state in BDNF(Met/Met) mice, but not in BDNF(+/)(-), mice compared with white noise exposure in open field and elevated plus maze test. Moreover, in contrast to white noise exposure, BDNF expression levels in the prefrontal cortex (PFC), amygdala and hippocampus were significantly increased in music-exposed adult BDNF(Met/Met) mice. However, music treatment could not upregulate BDNF levels in the PFC, amygdala, and hippocampus in BDNF(+/)(-) mice, which suggests the essential role of BDNF in the anxiolytic effect of music. Together, our results imply that music may provide an effective therapeutic intervention for anxiety disorders in humans with this genetic BDNF(Met) variant. Copyright 2010 Elsevier B.V. All rights reserved.

  2. Genetics of Lesch's typology of alcoholism.

    PubMed

    Samochowiec, Jerzy; Kucharska-Mazur, Jolanta; Grzywacz, Anna; Pelka-Wysiecka, Justyna; Mak, Monika; Samochowiec, Agnieszka; Bienkowski, Przemyslaw

    2008-02-15

    It is widely accepted that dopamine and serotonin (5-HT) neurotransmission can be critically involved in the development of alcohol abuse and alcohol dependence. Lesch's typology of alcoholism has been gaining increasing popularity as it qualitatively differentiates patients into different treatment response subgroups. The aim of the present study was to evaluate a possible genetic background of Lesch's typology with special emphasis placed on dopamine- and serotonin-related genes. 122 alcoholics (the mean age: 35+/-9 years) were investigated. According to Lesch's typology, 58 patients were of type I, 36 patients of type II, 11 patients of type III, and 17 patients of type IV. Alcohol drinking and family history was assessed by means of a structured interview, based on the Semi-Structured Assessment for the Genetics of Alcoholism. 150 control subjects without psychiatric disorders were also recruited. The control group was ethnically-, age- and gender-matched to the patients. The DRD2 TaqIA, exon 8, and promoter -141C ins/del polymorphisms as well as COMT Val158Met, 5HTT 44 bp del in promoter, and DAT 40 bp VNTR polymorphisms were detected by means of PCR. No significant differences were observed when the whole group of alcoholics and the controls were compared. Similarly, there were no differences between either the Lesch type I or type II alcoholics and the control subjects. No significant differences were observed between type I and type II alcoholics. Alleles frequencies were not calculated for the Lesch type III and type IV alcoholics since the number of patients was too small. The present results argue against any major role of the investigated polymorphisms in either Lesch type I or type II alcoholism. More comprehensive studies are needed to define the role of the investigated polymorphisms in Lesch type III and type IV alcoholism.

  3. The Impact of BDNF Polymorphisms on Suicidality in Treatment-Resistant Major Depressive Disorder: A European Multicenter Study.

    PubMed

    Schosser, Alexandra; Carlberg, Laura; Calati, Raffaella; Serretti, Alessandro; Massat, Isabel; Spindelegger, Christoph; Linotte, Sylvie; Mendlewicz, Julien; Souery, Daniel; Zohar, Joseph; Montgomery, Stuart; Kasper, Siegfried

    2017-10-01

    Numerous studies have reported associations between the brain-derived neurotrophic factor (BDNF) gene and psychiatric disorders, including suicidal behavior, although with conflicting results. A total of 250 major depressive disorder patients were collected in the context of a European multicenter resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using the Mini International Neuropsychiatric Interview and Hamilton Rating Scale for Depression, and treatment response using the HAM-D. Genotyping was performed for the functional Val66Met polymorphism (rs6265) and 7 additional tagging single nucleotide polymorphisms within the BDNF gene. Neither BDNF single markers nor haplotypes were found to be associated with suicide risk and lifetime history of suicide attempts. Gender-specific analyses revealed nonsignificant single marker (rs908867) and haplotypic association with suicide risk in males after multiple testing correction. Analyzing treatment response phenotypes, the functional Val66Met polymorphism as well as rs10501087 showed significant genotypic and haplotypic association with suicide risk in remitters (n=34, 13.6%). Considering the sample size, the present findings need to be replicated in larger samples to confirm or refute a role of BDNF in the investigated suicidal behavior phenotypes. © The Author 2017. Published by Oxford University Press on behalf of CINP.

  4. Predicting change in symptoms of depression during the transition to university: the roles of BDNF and working memory capacity.

    PubMed

    LeMoult, Joelle; Carver, Charles S; Johnson, Sheri L; Joormann, Jutta

    2015-03-01

    Studies on depression risk emphasize the importance of both cognitive and genetic vulnerability factors. The present study has provided the first examination of whether working memory capacity, the BDNF Val66Met polymorphism, and their interaction predict changes in symptoms of depression during the transition to university. Early in the semester, students completed a self-report measure of depressive symptoms and a modified version of the reading span task to assess working memory capacity in the presence of both neutral and negative distractors. Whole blood was genotyped for the BDNF Val66Met polymorphism. Students returned at the end of the semester to complete additional self-report questionnaires. Neither working memory capacity nor the BDNF Val66Met polymorphism predicted change in depressive symptoms either independently or in interaction with self-reported semester difficulty. The BDNF Val66Met polymorphism, however, moderated the association between working memory capacity and symptom change. Among met carriers, lower working memory capacity in the presence of negative-but not neutral-distractors was associated with increased symptoms of depression over the semester. For the val/val group, working memory capacity did not predict symptom change. These findings contribute directly to biological and cognitive models of depression and highlight the importance of examining Gene × Cognition interactions when investigating risk for depression.

  5. Sex differences in verbal working memory performance emerge at very high loads of common neuroimaging tasks.

    PubMed

    Reed, Jessica L; Gallagher, Natalie M; Sullivan, Marie; Callicott, Joseph H; Green, Adam E

    2017-04-01

    Working memory (WM) supports a broad range of intelligent cognition and has been the subject of rich cognitive and neural characterization. However, the highest ranges of WM have not been fully characterized, especially for verbal information. Tasks developed to test multiple levels of WM demand (load) currently predominate brain-based WM research. These tasks are typically used at loads that allow most healthy participants to perform well, which facilitates neuroimaging data collection. Critically, however, high performance at lower loads may obscure differences that emerge at higher loads. A key question not yet addressed at high loads concerns the effect of sex. Thoroughgoing investigation of high-load verbal WM is thus timely to test for potential hidden effects, and to provide behavioral context for effects of sex observed in WM-related brain structure and function. We tested 111 young adults, matched on genotype for the WM-associated COMT-Val 108/158 Met polymorphism, on three classic WM tasks using verbal information. Each task was tested at four WM loads, including higher loads than those used in previous studies of sex differences. All tasks loaded on a single factor, enabling comparison of verbal WM ability at a construct level. Results indicated sex effects at high loads across tasks and within each task, such that males had higher accuracy, even among groups that were matched for performance at lower loads. Published by Elsevier Inc.

  6. Sleep duration, depression, and oxytocinergic genotype influence prepulse inhibition of the startle reflex in postpartum women.

    PubMed

    Comasco, Erika; Gulinello, Maria; Hellgren, Charlotte; Skalkidou, Alkistis; Sylven, Sara; Sundström-Poromaa, Inger

    2016-04-01

    The postpartum period is characterized by a post-withdrawal hormonal status, sleep deprivation, and susceptibility to affective disorders. Postpartum mothering involves automatic and attentional processes to screen out new external as well as internal stimuli. The present study investigated sensorimotor gating in relation to sleep duration, depression, as well as catecholaminergic and oxytocinergic genotypes in postpartum women. Prepulse inhibition (PPI) of the startle reflex and startle reactivity were assessed two months postpartum in 141 healthy and 29 depressed women. The catechol-O-methyltransferase (COMT) Val158Met, and oxytocin receptor (OXTR) rs237885 and rs53576 polymorphisms were genotyped, and data on sleep duration were collected. Short sleep duration (less than four hours in the preceding night) and postpartum depression were independently associated with lower PPI. Also, women with postpartum depression had higher startle reactivity in comparison with controls. The OXTR rs237885 genotype was related to PPI in an allele dose-dependent mode, with T/T healthy postpartum women carriers displaying the lowest PPI. Reduced sensorimotor gating was associated with sleep deprivation and depressive symptoms during the postpartum period. Individual neurophysiological vulnerability might be mediated by oxytocinergic genotype which relates to bonding and stress response. These findings implicate the putative relevance of lower PPI of the startle response as an objective physiological correlate of liability to postpartum depression. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  7. The Val66Met brain-derived neurotrophic factor gene variant interacts with early pain exposure to predict cortisol dysregulation in 7-year-old children born very preterm: Implications for cognition.

    PubMed

    Chau, C M Y; Cepeda, I L; Devlin, A M; Weinberg, J; Grunau, R E

    2017-02-07

    Early stress in the form of repetitive neonatal pain, in infants born very preterm, is associated with long-term dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and with poorer cognitive performance. Brain-derived neurotrophic factor (BDNF) which is important in synaptic plasticity and cognitive functions is reduced by stress. Therefore the BDNF Val66Met variant, which affects secretion of BDNF, may interact with early exposure to pain-related stress in children born very preterm, to differentially affect HPA regulation that in turn may be associated with altered cognitive performance. The aims of this study were to investigate whether in children born very preterm, the BDNF Val66Met variant modulates the association between neonatal pain-related stress and cortisol levels at age 7years, and if cortisol levels were related to cognitive function. Furthermore, we examined whether these relationships were sex-specific. Using a longitudinal cohort design, N=90 children born very preterm (24-32weeks gestation) were followed from birth to age 7years. Cortisol was assayed from hair as an index of cumulative stress and from saliva to measure reactivity to a cognitive challenge. BDNF Val66Met variant was genotyped at 7years using real-time polymerase chain reaction (PCR). Using generalized linear modeling, in boys with the Met allele, greater neonatal pain-related stress (adjusted for clinical risk factors) predicted lower hair cortisol (p=0.006) and higher reactivity salivary cortisol (p=0.002). In both boys and girls with the Met allele, higher salivary cortisol reactivity was correlated with lower IQ (r=-0.60; p=0.001) and poorer visual-motor integration (r=-0.48; p=0.008). Our findings show associations between lower BDNF availability (presence of the Met allele) and vulnerability to neonatal pain/stress in boys, but not girls. This exploratory study suggests new directions for research into possible mechanisms underlying how neonatal pain/stress is

  8. The Val66Met Brain-Derived Neurotrophic Factor Gene Variant Interacts with Early Pain Exposure to Predict Cortisol Dysregulation in 7-year-old Children Born Very Preterm: Implications for Cognition

    PubMed Central

    Chau, Cecil MY; Cepeda, Ivan L; Devlin, Angela M.; Weinberg, Joanne; Grunau, Ruth E

    2015-01-01

    Early stress in the form of repetitive neonatal pain, in infants born very preterm, is associated with long-term dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and with poorer cognitive performance. Brain-derived neurotrophic factor (BDNF) which is important in synaptic plasticity and cognitive functions is reduced by stress. Therefore the BDNF Val66Met variant, which affects secretion of BDNF, may interact with early exposure to pain-related stress in children born very preterm, to differentially affect HPA regulation that in turn may be associated with altered cognitive performance. The aims of this study were to investigate whether in children born very preterm, the BDNF val66met variant modulates the association between neonatal pain-related stress and cortisol levels at age 7 years, and if cortisol levels were related to cognitive function. Furthermore, we examined whether these relationships were sex-specific. Using a longitudinal cohort design, N=90 children born very preterm (24–32 weeks gestation) were followed from birth to age 7 years. Cortisol was assayed from hair as an index of cumulative stress and from saliva to measure reactivity to a cognitive challenge. BDNF Val66Met variant was genotyped at 7 years using real time PCR. Using generalized linear modeling, in boys with the Met allele, greater neonatal pain-related stress (adjusted for clinical risk factors) predicted lower hair cortisol (p=0·006) and higher reactivity salivary cortisol (p=0.002). In both boys and girls with the Met allele, higher salivary cortisol reactivity was correlated with lower IQ (r= −0.60; p=0.001) and poorer visual-motor integration (r= −0.48; p=0.008). Our findings show associations between lower BDNF availability (presence of the Met allele) and vulnerability to neonatal pain/stress in boys, but not girls. This exploratory study suggests new directions for research into possible mechanisms underlying how neonatal pain/stress is related to cognitive

  9. The Flavin-Containing Monooxygenase 3 Gene and Essential Hypertension: The Joint Effect of Polymorphism E158K and Cigarette Smoking on Disease Susceptibility

    PubMed Central

    Bushueva, Olga; Solodilova, Maria; Churnosov, Mikhail; Ivanov, Vladimir; Polonikov, Alexey

    2014-01-01

    Gene encoding flavin-containing monooxygenase 3 (FMO3), a microsomal antioxidant defense enzyme, has been suggested to contribute to essential hypertension (EH). The present study was designed to investigate whether common functional polymorphism E158K (rs2266782) of the FMO3 gene is associated with EH susceptibility in a Russian population. A total of 2 995 unrelated subjects from Kursk (1 362 EH patients and 843 healthy controls) and Belgorod (357 EH patients and 422 population controls) regions of Central Russia were recruited for this study. DNA samples from all study participants were genotyped for the FMO3 gene polymorphism through PCR followed by RFLP analysis. We found that the polymorphism E158K is associated with increased risk of essential hypertension in both discovery population from Kursk region (OR 1.36 95% CI 1.09–1.69, P = 0.01) and replication population from Belgorod region (OR 1.54 95% CI 1.07–1.89, P = 0.02) after adjustment for gender and age using logistic regression analysis. Further analysis showed that the increased hypertension risk in carriers of genotype 158KK gene occurred in cigarette smokers, whereas nonsmoker carriers of this genotype did not show the disease risk. This is the first study reporting the association of the FMO3 gene polymorphism and the risk of essential hypertension. PMID:25243081

  10. Association between the ghrelin Leu72Met polymorphism and type 2 diabetes risk: a meta-analysis.

    PubMed

    Liao, Ning; Xie, Zi-Kang; Huang, Jian; Xie, Zheng-Fu

    2013-04-01

    Data on the association between the ghrelin Leu72Met polymorphism and type 2 diabetes are conflicting. A meta-analysis was performed on this topic. We searched for case-control studies using electronic databases (Medline and PubMed) and reference lists of studies. Odds ratios (OR) and 95% confidence intervals (CI) assuming dominant, recessive and homozygote comparison genetic models were calculated. Six case-control studies involving a total of 3417 cases and 3081 controls were included in this meta-analysis. No association was found between the ghrelin Leu72Met polymorphism and type 2 diabetes risk in the overall population in dominant, recessive and homozygote comparison models. However, in subgroup analyses stratified by ethnicity, we found that the risk for type 2 diabetes was decreased in subjects with Met72+ genotypes in Caucasians (OR=0.79, 95% CI: 0.64-0.98, P(z)=0.030). The ghrelin Leu72Met polymorphism was protective against type 2 diabetes in Caucasians. Future studies performed in larger sample size are needed to allow a more definitive conclusion. Copyright © 2012 Elsevier B.V. All rights reserved.

  11. MB-COMT promoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls

    PubMed Central

    Walton, Esther; Liu, Jingyu; Hass, Johanna; White, Tonya; Scholz, Markus; Roessner, Veit; Gollub, Randy; Calhoun, Vince D; Ehrlich, Stefan

    2014-01-01

    Many genetic studies report mixed results both for the associations between COMT polymorphisms and schizophrenia and for the effects of COMT variants on common intermediate phenotypes of the disorder. Reasons for this may include small genetic effect sizes and the modulation of environmental influences. To improve our understanding of the role of COMT in the disease etiology, we investigated the effect of DNA methylation in the MB-COMT promoter on neural activity in the dorsolateral prefrontal cortex during working memory processing as measured by fMRI - an intermediate phenotype for schizophrenia. Imaging and epigenetic data were measured in 102 healthy controls and 82 schizophrenia patients of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia. Neural activity during the Sternberg Item Recognition Paradigm was acquired with either a 3T Siemens Trio or 1.5T Siemens Sonata and analyzed using the FMRIB Software Library (FSL). DNA methylation measurements were derived from cryo-conserved blood samples. We found a positive association between MB-COMT promoter methylation and neural activity in the left dorsolateral prefrontal cortex in a model using a region-of-interest approach and could confirm this finding in a whole-brain model. This effect was independent of disease status. Analyzing the effect of MB-COMT promoter DNA methylation on a neuroimaging phenotype can provide further evidence for the importance of COMT and epigenetic risk mechanisms in schizophrenia. The latter may represent trans-regulatory or environmental risk factors that can be measured using brain-based intermediate phenotypes. PMID:24837210

  12. The Leu72Met polymorphism of the ghrelin gene is associated with a decreased risk for type 2 diabetes.

    PubMed

    Berthold, Heiner K; Giannakidou, Eleni; Krone, Wilhelm; Mantzoros, Christos S; Gouni-Berthold, Ioanna

    2009-01-01

    Ghrelin is involved in several metabolic and cardiovascular processes. The Leu72Met polymorphism of its gene was associated with an increased risk of type 2 diabetes (DM2) in some, but not all studies. Its association with atherosclerosis is not known. We investigated 420 Caucasian subjects with DM2 and 430 controls without diabetes (56.6% male, age 62+/-10 years). The Leu72Leu genotype frequencies were 89.76/84.65%, the Leu72Met 9.52/15.12% and the Met72Met 0.71/0.23% (P=0.029) in the DM2 and controls groups, respectively. In subjects with Met72+ genotypes the risk of DM2 was significantly decreased (univariate OR 0.63, 95% CI 0.42-0.95, P=0.026). In a logistic regression model, body mass index, hypertension and a positive family history for diabetes were predictors of diabetes while the polymorphism remained negatively associated with the disease (OR 0.62, 95% CI 0.40-0.97, P=0.036). After adjusting for known risk factors for atherosclerosis, the Met72+ variant was not associated with atherosclerotic disease (OR 1.41, 95% CI 0.78-2.54, P=0.25). Ghrelin concentrations were not associated with the polymorphism, DM2 or atherosclerotic disease. The Leu72Met polymorphism of the ghrelin gene is associated with a decreased risk for DM2. There is no association between the variant and atherosclerotic disease or ghrelin concentrations.

  13. Manganese superoxide dismutase Ala-9Val polymorphism and risk of breast cancer in a population-based case–control study of African Americans and whites

    PubMed Central

    Millikan, Robert C; Player, Jon; de Cotret, Allan René; Moorman, Patricia; Pittman, Gary; Vannappagari, Vani; Tse, Chiu-Kit J; Keku, Temitope

    2004-01-01

    Introduction A polymorphism in the manganese superoxide dismutase (MnSOD) gene, Ala-9Val, has been examined in association with breast cancer risk in several epidemiologic studies. Results suggest that the Ala allele increases the risk of breast cancer and modifies the effects of environmental exposures that produce oxidative damage to DNA. Methods We examined the role of the MnSOD Ala-9Val polymorphism in a population-based case–control study of invasive and in situ breast cancer in North Carolina. Genotypes were evaluated for 2025 cases (760 African Americans and 1265 whites) and for 1812 controls (677 African Americans and 1135 whites). Results The odds ratio for MnSOD Ala/Ala versus any MnSOD Val genotypes was not elevated in African Americans (odds ratio = 0.9, 95% confidence interval = 0.7–1.2) or in whites (odds ratio = 1.0, 95% confidence interval = 0.8–1.2). Greater than additive joint effects were observed for the Ala/Ala genotype and smoking, radiation to the chest, and occupational exposure to ionizing radiation. Antagonism was observed between the Ala/Ala genotype and the use of nonsteroidal anti-inflammatory drugs. Conclusions The MnSOD genotype may contribute to an increased risk of breast cancer in the presence of specific environmental exposures. These results provide further evidence for the importance of reactive oxygen species and of oxidative DNA damage in the etiology of breast cancer. PMID:15217492

  14. The relationship between MnSOD Val16Ala gene polymorphism and the level of serum total antioxidant capacity with the risk of chronic kidney disease in type 2 diabetic patients: a nested case-control study in the Tehran lipid glucose study.

    PubMed

    Abbasi, Mehrnaz; Daneshpour, Maryam S; Hedayati, Mehdi; Mottaghi, Azadeh; Pourvali, Katayoun; Azizi, Fereidoun

    2018-01-01

    Several studies have shown significant associations between manganese superoxide dismutase (MnSOD) Val16Ala polymorphism and diabetic complications, but this association has not been explored in relation with chronic kidney disease (CKD) in Type 2 diabetes mellitus (T2DM) patients. Total antioxidant capacity (TAC) level changes in diabetic condition and may play important role in onset or progression of the disease and its complications. The present study investigated the association of MnSOD Val16Ala polymorphism and serum TAC with the risk of CKD in T2DM patients. This nested case-control study included 280 type 2 diabetic patients with CKD and 280 age, sex and diabetes duration-matched control subjects selected from the participants of the Tehran Lipid and Glucose Study. MnSOD val16Ala (rs4880) SNP was genotyped by the Tetra-Primer ARMS-polymerase chain reaction analysis. Serum TAC was measured using ferric-reducing antioxidant power assay. Statistical analysis was performed using STATA statistical package v.12.0 or SPSS (Version 22.0). The Ala allele of the MnSOD Val16Ala polymorphism was associated with a lower risk of CKD (odds ratio (OR), 0.55; 95% confidence interval (CI), 0.36-0.84; P  = 0.006). Median serum TAC in CKD group was 920 μmol/L and was significantly lower ( p  < 0.001) compared to the control group (1045 μmol/L). Using an adjusted conditional logistic regression, we didn't observe any significant interaction between MnSOD Val16Ala SNP with quartiles of serum TAC in relation to CKD. A significant association was found between the MnSOD Val16Ala polymorphism and CKD, but this association is not affected by serum TAC level in T2DM patients.

  15. [Association between HRE-2 gene polymorphism at codon 655 and genetic susceptibility of colorectal cancer].

    PubMed

    Liang, Xia; Zhang, Yong-jing; Liu, Bing; Ni, Qin; Jin, Ming-juan; Ma, Xin-yuan; Yao, Kai-yan; Li, Qi-long; Chen, Kun

    2009-06-01

    To explore the distribution of HER-2 genetic polymorphism at codon 655 and its association with susceptibility of colorectal cancer in Chinese. A population-based case-control study was carried out. 292 patients with colorectal cancer and 842 healthy controls were interviewed. Meanwhile, the genetic polymorphism of HRE-2 was detected using polymerase chain reaction-restriction fragment length polymorphism. The frequencies of Ile/Val+Val/Val genotypes and Val allele were both higher in cases (25.34% and 13.36%) than those in controls (18.41% and 9.74%) (P<0.05). Compared with Ile/Ile genotype, Ile/Val+Val/Val genotypes were significantly associated with colorectal cancer [ORadjusted=1.54, 95% CI: 1.11-2.14]. The adjusted odds ratio of interactions between this polymorphism and smoking, alcohol drinking were 1.43 (95%CI: 0.88-2.30) and 1.29 (95%CI: 0.73-2.29), respectively. The present findings suggest that HER-2 genetic polymorphism at codon 655 may be associated with the risk of colorectal cancer in Chinese. In addition, there are no interactions between this polymorphism and smoking, alcohol drinking, respectively.

  16. Alkaline transition of pseudoazurin Met16X mutant proteins: protein stability influenced by the substitution of Met16 in the second sphere coordination.

    PubMed

    Abdelhamid, Rehab F; Obara, Yuji; Kohzuma, Takamitsu

    2008-01-01

    Several blue copper proteins are known to change the active site structure at alkaline pH (alkaline transition). Spectroscopic studies of Met16Phe, Met16Tyr, Met16Trp, and Met16Val pseudoazurin variants were performed to investigate the second sphere role through alkaline transition. The visible electronic absorption and resonance Raman spectra of Met16Phe, Met16Tyr, and Met16Trp variants showed the increasing of axial component at pH approximately 11 like wild-type PAz. The visible electronic absorption and far-UV CD spectra of Met16Val demonstrated that the destabilization of the protein structure was triggered at pH>11. Resonance Raman (RR) spectra of PAz showed that the intensity-weighted averaged Cu-S(Cys) stretching frequency was shifted to higher frequency region at pH approximately 11. The higher frequency shift of Cu-S(Cys) bond is implied the stronger Cu-S(Cys) bond at alkaline transition pH approximately 11. The visible electronic absorption and far-UV CD spectra of Met16X PAz revealed that the Met16Val variant is denatured at pH>11, but Met16Phe, Met16Tyr, and Met16Trp mutant proteins are not denatured even at pH>11. These observations suggest that Met16 is important to maintain the protein structure through the possible weak interaction between methionine -SCH3 part and coordinated histidine imidazole moiety. The introduction of pi-pi interaction in the second coordination sphere may be contributed to the enhancement of protein structure stability.

  17. Family trios analysis of common polymorphisms in the obestatin/ghrelin, BDNF and AGRP genes in patients with Anorexia nervosa: association with subtype, body-mass index, severity and age of onset.

    PubMed

    Dardennes, Roland M; Zizzari, Philippe; Tolle, Virginie; Foulon, Christine; Kipman, Amélie; Romo, Lucia; Iancu-Gontard, Dana; Boni, Claudette; Sinet, Pierre-Marie; Thérèse Bluet, Marie; Estour, Bruno; Mouren, Marie-Christine; Guelfi, Julien-Daniel; Rouillon, Frédéric; Gorwood, Philip; Epelbaum, Jacques

    2007-02-01

    Anorexia nervosa (AN) affects 0.3% of young girls with a mortality of 6%/decade and is strongly familial with genetic factors. Ghrelin is an upstream regulator of the orexigenic peptides NPY and AgRP and acts as a natural antagonist to leptin's effects on NPY/AgRP-expressing neurons, resulting in an increase in feeding and body weight. Obestatin which counteracts ghrelin action on feeding is derived from the same propeptide than ghrelin. BDNF has been involved in body weight regulation and its Val66Met polymorphism associated with AN. We therefore re-investigated the association between AN and the Leu72Met and Gln90Leu polymorphisms of the prepro-ghrelin/obestatin gene, the Ala67Thr polymorphism of AgRP and the Val66Met polymorphism of BDNF taking into account clinical subtypes (restrictive--ANR--and bingeing/purging--ANB--subtypes). Family trios study of these 4 single nucleotide polymorphisms were performed in 114 probands with AN and both their parents recruited in two specialized French centres. A transmission disequilibrium was observed for the Leu72Met SNP of the preproghrelin gene and for the Ala67Thr SNP of the AgRP gene. When stratified by clinical subtype, these two polymorphisms were preferentially transmitted for the trios with a bingeing/purging proband. An excess of transmission of the Gln90Leu72 preproghrelin/obestatin haplotype in patients with AN was observed. These results do not provide evidence for a preferential transmission of the 66Met allele of BDNF but support the hypothesis that ghrelin and AGRP polymorphisms confers susceptibility to AN. Further simultaneous analysis of genetic variants of the biological determinants of energy metabolism and feeding behaviour in very large populations should contribute to the understanding of the high degree of heritability of eating disorders and to the description of pathophysiological patterns leading to life-threatening conditions in a highly redundant system.

  18. [Study of genetic variants in the BDNF, COMT, DAT1 and SERT genes in Colombian children with attention deficit disorder].

    PubMed

    Ortega-Rojas, Jenny; Arboleda-Bustos, Carlos E; Morales, Luis; Benítez, Bruno A; Beltrán, Diana; Izquierdo, Álvaro; Arboleda, Humberto; Vásquez, Rafael

    Attention deficit and hyperactive disorder (ADHD) is highly prevalent among children in Bogota City. Both genetic and environmental factors play a very important role in the etiology of ADHD. However, to date few studies have addressed the association of genetic variants and ADHD in the Colombian population. To test the genetic association between polymorphisms in the DAT1, HTTLPR, COMT and BDNF genes and ADHD in a sample from Bogota City. We genotyped the most common polymorphisms in DAT1, SERT, COMT and BDNF genes associated with ADHD using conventional PCR followed by restriction fragment length polymorphism (RFLP) in 97 trios recruited in a medical center in Bogota. The transmission disequilibrium test (TDT) was used to determine the association between such genetic variants and ADHD. The TDT analysis showed that no individual allele of any variant studied has a preferential transmission. Our results suggest that the etiology of the ADHD may be complex and involves several genetic factors. Further studies in other candidate polymorphisms in a larger sample size will improve our knowledge of the ADHD in Colombian population. Copyright © 2016 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

  19. Role of peroxisome proliferator-activated receptors gene polymorphisms in type 2 diabetes and metabolic syndrome

    PubMed Central

    Dong, Chen; Zhou, Hui; Shen, Chong; Yu, Lu-Gang; Ding, Yi; Zhang, Yong-Hong; Guo, Zhi-Rong

    2015-01-01

    Metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are the serious public health problems worldwide. Moreover, it is estimated that MetS patients have about five-fold greater risk of the T2DM development compared with people without the syndrome. Peroxisome proliferator-activated receptors are a subgroup of the nuclear hormone receptor superfamily of ligand-activated transcription factors which play an important role in the pathogenesis of MetS and T2DM. All three members of the peroxisome proliferator-activated receptor (PPAR) nuclear receptor subfamily, PPARα, PPARβ/δ and PPARγ are critical in regulating insulin sensitivity, adipogenesis, lipid metabolism, and blood pressure. Recently, more and more studies indicated that the gene polymorphism of PPARs, such as Leu162Val and Val227Ala of PPARα, +294T > C of PPARβ/δ, Pro12Ala and C1431T of PPARγ, are significantly associated with the onset and progressing of MetS and T2DM in different population worldwide. Furthermore, a large body of evidence demonstrated that the glucose metabolism and lipid metabolism were influenced by gene-gene interaction among PPARs genes. However, given the complexity pathogenesis of metabolic disease, it is unlikely that genetic variation of a single locus would provide an adequate explanation of inter-individual differences which results in diverse clinical syndromes. Thus, gene-gene interactions and gene-environment interactions associated with T2DM and MetS need future comprehensive studies. PMID:25987964

  20. Catechol-O-methyltransferase association with hemoglobin A1c

    PubMed Central

    Hall, Kathryn T.; Jablonski, Kathleen A.; Chen, Ling; Harden, Maegan; Tolkin, Benjamin R.; Kaptchuk, Ted J.; Bray, George A.; Ridker, Paul M.; Florez, Jose C.; Chasman, Daniel I.

    2016-01-01

    Aims Catecholamines have metabolic effects on blood pressure, insulin sensitivity and blood glucose. Genetic variation in catechol-O-methyltransferase (COMT), an enzyme that degrades catecholamines, is associated with cardiometabolic risk factors and incident cardiovascular disease (CVD). Here we examined COMT effects on glycemic function and type 2 diabetes. Methods We tested whether COMT polymorphisms were associated with baseline HbA1c in the Women’s Genome Health Study (WGHS), and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), and with susceptibility to type 2 diabetes in WGHS, DIAbetes Genetics Replication And Meta-analysis consortium (DIAGRAM), and the Diabetes Prevention Program (DPP). Given evidence that COMT modifies some drug responses, we examined association with type 2 diabetes and randomized metformin and aspirin treatment. Results COMT rs4680 high-activity G-allele was associated with lower HbA1c in WGHS (β = −0.032% [0.012], p = 0.008) and borderline significant in MAGIC (β = −0.006% [0.003], p = 0.07). Combined COMT per val allele effects on type 2 diabetes were significant (OR = 0.98 [0.96–0.998], p = 0.03) in fixed-effects analyses across WGHS, DIAGRAM, and DPP. Similar results were obtained for 2 other COMT SNPs rs4818 and rs4633. In the DPP, the rs4680 val allele was borderline associated with lower diabetes incidence among participants randomized to metformin (HR = 0.81 [0.65–1.00], p = 0.05). Conclusions COMT rs4680 high-activity G-allele was associated with lower HbA1c and modest protection from type 2 diabetes. The directionality of COMT associations was concordant with those previously observed for cardiometabolic risk factors and CVD. PMID:27282867

  1. Genetic polymorphisms involved in dopaminergic neurotransmission and risk for Parkinson's disease in a Japanese population

    PubMed Central

    2011-01-01

    Background Parkinson's disease (PD) is characterized by alterations in dopaminergic neurotransmission. Genetic polymorphisms involved in dopaminergic neurotransmission may influence susceptibility to PD. Methods We investigated the relationship of catechol-O-methyltransferase (COMT), monoamine oxidase B (MAOB), dopamine receptor (DR) D2 and DRD4 polymorphisms and PD risk with special attention to the interaction with cigarette smoking among 238 patients with PD and 369 controls in a Japanese population. Results Subjects with the AA genotype of MAOB rs1799836 showed a significantly increased risk of PD (odds ratio (OR) = 1.70, 95% confidence interval (CI) = 1.12 - 2.58) compared with the AG and GG genotypes combined. The AA genotype of COMT rs4680 was marginally associated with an increased risk of PD (OR = 1.86, 95% CI = 0.98 - 3.50) compared with the GG genotype. The DRD2 rs1800497 and DRD4 rs1800955 polymorphisms showed no association with PD. A COMT -smoking interaction was suggested, with the combined GA and AA genotypes of rs4680 and non-smoking conferring significantly higher risk (OR = 3.97, 95% CI = 2.13 - 7.41) than the AA genotype and a history of smoking (P for interaction = 0.061). No interactions of smoking with other polymorphisms were observed. Conclusions The COMT rs4680 and MAOB rs1799836 polymorphisms may increase susceptibility to PD risk among Japanese. Future studies involving larger control and case populations and better pesticide exposure histories will undoubtedly lead to a more thorough understanding of the role of the polymorphisms involved in the dopamine pathway in PD. PMID:21781348

  2. Dopaminergic foundations of schizotypy as measured by the German version of the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE)—a suitable endophenotype of schizophrenia

    PubMed Central

    Grant, Phillip; Kuepper, Yvonne; Mueller, Eva A.; Wielpuetz, Catrin; Mason, Oliver; Hennig, Juergen

    2013-01-01

    The concept of schizotypy or “psychosis proneness” captures individual differences in perceptual, cognitive, and affective experiences that may relate to a range of psychotic disorders. The concept is an important way to assess the contribution of pre-existing psychological and genetically based biological features to the development of illnesses such as schizophrenia (so called endophenotypes). The Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE) is a widely used multi-dimensional measure of the construct and consists of four scales which mirror several groups of psychotic symptoms: Unusual Experiences (UnEx; positive symptoms), Cognitive Disorganization (CogDis; cognitive symptoms), Introvertive Anhedonia (IntAn; negative symptoms), and Impulsive Nonconformity (ImpNon; impulsive and antisocial symptoms). For the purpose of evaluating the suitability of schizotypy as an endophenotype of schizophrenia the current version of the O-LIFE was translated into German: its psychometric properties (including re-test reliability and construct validity) were examined in a large sample (n > 1200) and compared to those of the English original. The German version was both highly reliable and consistent with the original. The study aimed to show that schizotypy as measured by the O-LIFE can indeed be regarded as an endophenotype of schizophrenia in terms of genetic associations regarding relevant dopamine-related candidate polymorphisms of schizotypy [i.e., Val158Met-polymorphism of the COMT gene, uVNTR of the MAOA gene, Taq1A-polymorphism of the DRD2 gene, VNTR of the SLC6A3 (DAT) gene]. We also wanted to compare the genetic associations of the O-LIFE to those published using other operationalizations of schizotypy. Our results show a large number of significant associations and borderline-significant trends between the O-LIFE sub-scales and a range of genes, thereby supporting using the O-LIFE in the search for endophenotypic markers. PMID:23355817

  3. Individual Differences in the Speed of Facial Emotion Recognition Show Little Specificity but Are Strongly Related with General Mental Speed: Psychometric, Neural and Genetic Evidence

    PubMed Central

    Liu, Xinyang; Hildebrandt, Andrea; Recio, Guillermo; Sommer, Werner; Cai, Xinxia; Wilhelm, Oliver

    2017-01-01

    Facial identity and facial expression processing are crucial socio-emotional abilities but seem to show only limited psychometric uniqueness when the processing speed is considered in easy tasks. We applied a comprehensive measurement of processing speed and contrasted performance specificity in socio-emotional, social and non-social stimuli from an individual differences perspective. Performance in a multivariate task battery could be best modeled by a general speed factor and a first-order factor capturing some specific variance due to processing emotional facial expressions. We further tested equivalence of the relationships between speed factors and polymorphisms of dopamine and serotonin transporter genes. Results show that the speed factors are not only psychometrically equivalent but invariant in their relation with the Catechol-O-Methyl-Transferase (COMT) Val158Met polymorphism. However, the 5-HTTLPR/rs25531 serotonin polymorphism was related with the first-order factor of emotion perception speed, suggesting a specific genetic correlate of processing emotions. We further investigated the relationship between several components of event-related brain potentials with psychometric abilities, and tested emotion specific individual differences at the neurophysiological level. Results revealed swifter emotion perception abilities to go along with larger amplitudes of the P100 and the Early Posterior Negativity (EPN), when emotion processing was modeled on its own. However, after partialling out the shared variance of emotion perception speed with general processing speed-related abilities, brain-behavior relationships did not remain specific for emotion. Together, the present results suggest that speed abilities are strongly interrelated but show some specificity for emotion processing speed at the psychometric level. At both genetic and neurophysiological levels, emotion specificity depended on whether general cognition is taken into account or not. These

  4. BDNF and LTP-/LTD-like plasticity of the primary motor cortex in Gilles de la Tourette syndrome.

    PubMed

    Marsili, L; Suppa, A; Di Stasio, F; Belvisi, D; Upadhyay, N; Berardelli, I; Pasquini, M; Petrucci, S; Ginevrino, M; Fabbrini, G; Cardona, F; Defazio, G; Berardelli, A

    2017-03-01

    Gilles de la Tourette syndrome (GTS) is characterized by motor and vocal tics and often associated with obsessive-compulsive disorder (OCD). Responses to intermittent/continuous theta-burst stimulation (iTBS/cTBS), which probe long-term potentiation (LTP)-/depression (LTD)-like plasticity in the primary motor cortex (M1), are reduced in GTS. ITBS-/cTBS-induced M1 plasticity can be affected by brain-derived neurotrophic factor (BDNF) polymorphism. We investigated whether the BDNF polymorphism influences iTBS-/cTBS-induced LTP-/LTD-like M1 plasticity in 50 GTS patients and in 50 age- and sex-matched healthy subjects. In GTS patients, motor and psychiatric (OCD) symptom severity was rated using the Yale Global Tic Severity Scale (YGTSS) and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). We compared M1 iTBS-/cTBS-induced plasticity in healthy subjects and in patients with GTS. We also compared responses to TBS according to BDNF polymorphism (Val/Val vs Met carriers) in patients and controls. Fourteen healthy subjects and 13 GTS patients were Met carriers. When considering the whole group of controls, as expected, iTBS increased whereas cTBS decreased MEPs. Differently, iTBS/cTBS failed to induce LTP-/LTD-like plasticity in patients with GTS. When comparing responses to TBS according to BDNF polymorphism, in healthy subjects, Met carriers showed reduced MEP changes compared with Val/Val individuals. Conversely, in patients with GTS, responses to iTBS/cTBS were comparable in Val/Val individuals and Met carriers. YGTSS and Y-BOCS scores were comparable in Met carriers and in Val/Val subjects. We conclude that iTBS and cTBS failed to induce LTP-/LTD-like plasticity in patients with GTS, and this was not affected by BDNF genotype.

  5. Association between a catechol-o-methyltransferase polymorphism and obsessive-compulsive disorder in the Afrikaner population.

    PubMed

    Niehaus, D J; Kinnear, C J; Corfield, V A; du Toit, P L; van Kradenburg, J; Moolman-Smook, J C; Weyers, J B; Potgieter, A; Seedat, S; Emsley, R A; Knowles, J A; Brink, P A; Stein, D J

    2001-06-01

    It has been proposed that the catechol-o-methyl transferase gene (COMT) may play a role in the pathogenesis of obsessive-compulsive disorder (OCD). Whereas studies in a North American population showed that the low activity (L) allele of a functional polymorphism in COMT was associated with OCD in male patients, this result was not supported by studies in a Japanese population. The present association study assessed the risk for OCD conferred by this COMT polymorphism in a geographically different patient group, namely, the relatively genetically homogeneous Afrikaner population of South Africa. Fifty-four unrelated OCD patients and fifty-four sex-matched controls were recruited from the same Afrikaner community. Patients and controls were phenotyped (DSM-IV) and genotyped for a NlaIII polymorphism with H (high activity) or L (low activity) alleles in the COMT gene. The H/L genotype was significantly more common than expected in the OCD patient group (P = 0.0017). Replication studies with related individuals may be useful in discovering factors underpinning the H/L genotype abundance in the Afrikaner population. These results emphasise the need for further studies in genetically homogeneous populations to help define the complex etiology of this disease.

  6. The role of genetic variation across IL-1β, IL-2, IL-6, and BDNF in antipsychotic-induced weight gain.

    PubMed

    Fonseka, Trehani M; Tiwari, Arun K; Gonçalves, Vanessa F; Lieberman, Jeffrey A; Meltzer, Herbert Y; Goldstein, Benjamin I; Kennedy, James L; Kennedy, Sidney H; Müller, Daniel J

    2015-01-01

    Antipsychotics with high weight gain-inducing propensities influence the expression of immune and neurotrophin genes, which have been independently related to obesity indices. Thus, we investigated whether variants in the genes encoding interleukin (IL)-1β, IL-2, and IL-6 and brain-derived neurotrophic factor (BDNF) Val66Met are associated with antipsychotic-induced weight gain (AIWG). Nineteen polymorphisms were genotyped using Taqman(®) assays in 188 schizophrenia patients on antipsychotic treatment for up to 14 weeks. Mean weight change (%) from baseline was compared across genotypic groups using analysis of covariance (ANCOVA). Epistatic effects between cytokine polymorphisms and BDNF Val66Met were tested using Model-Based Multifactor Dimensionality Reduction. In European patients, IL-1β rs16944*GA (P = 0.013, Pcorrected = 0.182), IL-1β rs1143634*G (P = 0.001, Pcorrected = 0.014), and BDNF Val66Met (Val/Val, P = 0.004, Pcorrected = 0.056) were associated with greater AIWG, as were IL-1β rs4849127*A (P = 0.049, Pcorrected = 0.784), and IL-1β rs16944*GA (P = 0.012, Pcorrected = 0.192) in African Americans. BDNF Val66Met interacted with both IL-1β rs13032029 (Val/Met+ TT, PPerm = 0.029), and IL-6 rs2069837 (Val/Val+ AA, PPerm = 0.021) in Europeans, in addition to IL-1β rs16944 (Val/Val+ GA, PPerm = 0.006) in African Americans. SNPs across IL-1β and BDNF Val66Met may influence AIWG. Replication of these findings in larger, independent samples is warranted.

  7. Hoarding in obsessive-compulsive disorder: clinical and genetic correlates.

    PubMed

    Lochner, Christine; Kinnear, Craig J; Hemmings, Sian M J; Seller, Cathlene; Niehaus, Dana J H; Knowles, James A; Daniels, Willie; Moolman-Smook, Johanna C; Seedat, Soraya; Stein, Dan J

    2005-09-01

    Hoarding may be an important symptom dimension in obsessive-compulsive disorder (OCD). Hoarding in OCD has been associated with poor insight, poorer response to selective serotonin reuptake inhibitors than other OCD symptom dimensions, and a distinctive psychobiological profile. The clinical and genetic correlates of hoarding in OCD therefore deserve additional investigation. Adult OCD patients (N = 315) underwent a comprehensive clinical assessment that included the Structured Clinical Interview for DSM-IV Axis I Disorders (Patient Edition) and for Diagnosis of Obsessive-Compulsive Spectrum Disorders. DNA extracted from venous blood (10-30 mL) in a Caucasian subset of the interviewed OCD patients (N = 204) and Caucasian controls (N = 169), including patients (N = 94) and controls (N = 138) of Afrikaner descent, was genotyped to investigate polymorphisms in genes involved in monoamine function and previously hypothesized to be relevant to OCD. Data were collected from 1998 through 2004. OCD patients with hoarding made up 18.1% of the total sample. Compared with nonhoarding OCD, OCD with hoarding was associated with a number of comorbid Axis I disorders, obsessive-compulsive personality disorder, significantly higher OCD severity scores, and more functional impairment. In subjects of Afrikaner descent, the L/L genotype of the COMT Val158Met polymorphism was significantly more common in the OCD hoarding group, with a preponderance of low activity alleles, compared with nonhoarding patients and controls. These data are consistent with the hypothesis that hoarding represents a unique symptom subtype in OCD with a distinctive clinical and psychobiological profile. Further work is needed to determine the psychobiological mechanisms responsible for hoarding and to replicate the genetic findings noted here.

  8. Glutathione S-Transferase Pi-Ile 105 Val Polymorphism and Susceptibility to T2DM in Population from Turabah Region of Saudi Arabia.

    PubMed

    Mergani, Adil; Mansour, Ahmed Abdelkhalik; Askar, Tamer; Zahran, Rasha Nabeel; Mustafa, Adil Musa; Mohammed, Mukhtar Ahmed; Saleh, Osama Mosailhy

    2016-08-01

    Type 2 diabetes mellitus is characterized by chronic hyperglycemia and associated with oxidative stress resulting from accumulation of free radicals in body's tissues, which especially affects beta cells in pancreas and is an important factor in the development of diabetes and its complications. Glutathione S-transferases (GSTs) are a family of antioxidant enzymes that play important roles in decreasing ROS species and act as a kind of antioxidant defense. In a case-control study, we investigated the role of GSTP1 Ile105Val polymorphism in predisposition to T2DM in patients from Tarabah province, Saudi Arabia. The polymorphism was screened by PCR-RFLP in 90 T2DM patients and 87 healthy controls. The genotypes and alleles frequencies in cases and controls were assessed using Cochran-Armitage trend test and odds ratios (ORs), and 95 % confidence intervals (CIs) in different genetic models of inheritance were calculated. Our data indicate that G allele (Val) is associated with an increased risk for T2DM in this population in any combination (OR 4.101, 95 % CI 1.986-8.469, P = 0.00008). This indicates that individuals who are carriers for the mutant allele, either in homozygous (GG) or heterozygous (AG) state, are at fourfold higher risk for development of T2DM than other subjects in this population.

  9. Corticospinal excitability in the non-dominant hand is affected by BDNF genotype.

    PubMed

    Chang, Won Hyuk; Hwang, Jung Min; Uhm, Kyeong Eun; Pascual-Leone, Alvaro; Kim, Yun-Hee

    2017-02-01

    The objective of this study was to assess the functional state of corticospinal projections in the non-dominant hand according to brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms. We investigated this in 34 healthy right-handed individuals (12 men, mean age 27.4 ± 3.4 years) who underwent two experimental sessions consisting of corticospinal excitability measurements with single-pulse transcranial magnetic stimulation (TMS) and hand motor function assessments with a sequential finger motor task of the non-dominant hand. Experimental sessions were separated by periods of at least 2 days to avoid carryover effects. Data were analyzed according to BDNF polymorphism (Val/Val vs. Val/Met vs. Met/Met group). Ten (29.4%), seventeen (50.0%), and seven (20.6%) participants were allocated to the Val/Val, Val/Met, and Met/Met groups, respectively. Motor thresholds to TMS did not differ among groups, but the amplitude of the motor-evoked potentials in the non-dominant hand induced by suprathreshold (120% of MT) TMS was significantly lower in the Met/Met group than in the other two groups (p < 0.05). Movement accuracy and reaction time in the sequential finger motor task showed no significant differences among groups. These results indicate that Met/Met BDNF homozygote status affects corticospinal excitability, and should be controlled for in studies of motor system function using brain stimulation. Our findings may have clinical implications regarding further investigation of the impact of BDNF genotype on the human motor system.

  10. Crystallographic Studies of Prion Protein (PrP) Segments Suggest How Structural Changes Encoded by Polymorphism at Residue 129 Modulate Susceptibility to Human Prion Disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Apostol, Marcin I.; Sawaya, Michael R.; Cascio, Duilio

    2010-09-23

    A single nucleotide polymorphism (SNP) in codon 129 of the human prion gene, leading to a change from methionine to valine at residue 129 of prion protein (PrP), has been shown to be a determinant in the susceptibility to prion disease. However, the molecular basis of this effect remains unexplained. In the current study, we determined crystal structures of prion segments having either Met or Val at residue 129. These 6-residue segments of PrP centered on residue 129 are 'steric zippers,' pairs of interacting {beta}-sheets. Both structures of these 'homozygous steric zippers' reveal direct intermolecular interactions between Met or Valmore » in one sheet and the identical residue in the mating sheet. These two structures, plus a structure-based model of the heterozygous Met-Val steric zipper, suggest an explanation for the previously observed effects of this locus on prion disease susceptibility and progression.« less

  11. MTHFR-Ala222Val and male infertility: a study in Iranian men, an updated meta-analysis and an in silico-analysis.

    PubMed

    Nikzad, Hossein; Karimian, Mohammad; Sareban, Kobra; Khoshsokhan, Maryam; Hosseinzadeh Colagar, Abasalt

    2015-11-01

    Methylenetetrahydrofolate reductase (MTHFR) functions as a main regulatory enzyme in folate metabolism. The association of MTHFR gene Ala222Val polymorphism with male infertility in an Iranian population was investigated by undertaking a meta-analysis and in-silico approach. A genetic association study included 497 men; 242 had unexplained infertility and 255 were healthy controls. Polymerase chain reaction restriction fragment length polymorphism was used for genotyping MTHFR-Ala222Val. OpenMeta[Analyst] software was used to conduct the analysis; 22 studies were identified by searching PubMed and the currently reported genetic association study. A novel in-silico approach was used to analyse the effects of Ala222Val substitution on the structure of mRNA and protein. Genetic association study revealed a significant association of MTHFR-222Val/Val genotype with oligozoospermia (OR 2.32; 95% CI, 1.12 to 4.78; P = 0.0451) and azoospermia (OR 2.59; 95% CI 1.09 to 6.17; P = 0.0314). Meta-analysis for allelic, dominant and codominant models showed a significant association between Ala222Val polymorphism and the risk of male infertility (P < 0.001). In silico-analysis showed MTHFR-Ala222Val affects enzyme structure and could also change the mRNA properties (P = 0.1641; P < 0.2 is significant). The meta-analysis suggested significant association of MTHFR-Ala222Val with risk of male infertility, especially in Asian populations. Copyright © 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  12. [Effects of anxiety and the COMT gene on cortical evoked potentials and performance effectiveness of selective attention].

    PubMed

    Alfimova, M V; Golimbet, V E; Lebedeva, I S; Korovaĭtseva, G I; Lezheĭko, T V

    2014-01-01

    We studied influence of the anxiety-related trait Harm Avoidance and the COMT gene, which is an important modulator of prefrontal functioning, on event-related potentials in oddball paradigm and performance effectiveness of selective attention. For 50 individuals accuracy and time of searching words among letters at any desired rate and then under an instruction to perform the task as quickly and accurate as possible were measured. Scores on the Harm Avoidance scale from Cloninger's Temperament and Character Inventory, N100 and P300 parameters, and COMTVa1158Met genotypes were obtained for them as well. Searching accuracy and time were mainly related to N100 amplitude. The COMT genotype and Harm Avoidance did not affect N100 amplitude; however, the N100 amplitude modulated their effects on accuracy and time dynamics. Harm Avoidance was positively correlated with P300 latency. The results suggest that anxiety and the COMT gene effects on performance effectiveness of selective attention depend on cognitive processes reflected in N100 parameters.

  13. The 5-HTTLPR and BDNF polymorphisms moderate the association between uncinate fasciculus connectivity and antidepressants treatment response in major depression.

    PubMed

    Tatham, Erica L; Hall, Geoff B C; Clark, Darren; Foster, Jane; Ramasubbu, Rajamannar

    2017-03-01

    Symptom improvement in depression due to antidepressant treatment is highly variable and clinically unpredictable. Linking neuronal connectivity and genetic risk factors in predicting antidepressant response has clinical implications. Our investigation assessed whether indices of white matter integrity, serotonin transporter-linked polymorphism (5-HTTLPR) and brain-derived neurotrophic factor (BDNF) val66met polymorphism predicted magnitude of depression symptom change following antidepressant treatment. Fractional anisotropy (FA) was used as an indicator of white matter integrity and was assessed in the uncinate fasciculus and superior longitudinal fasciculus using tract-based spatial statistics (TBSS) and probabilistic tractography. Forty-six medication-free patients with major depressive disorder participated in a diffusion tensor imaging scan prior to completing an 8-week treatment regime with citalopram or quetiapine XR. Indexed improvements in Hamilton Depression Rating Scale score from baseline to 8-week endpoint were used as an indicator of depression improvement. Carriers of the BDNF met allele exhibited lower FA values in the left uncinate fasciculus relative to val/val individuals [F(1, 40) = 7.314, p = 0.009]. Probabilistic tractography identified that higher FA in the left uncinate fasciculus predicted percent change in depression severity, with BDNF moderating this association [F(3, 30) = 3.923, p = 0.018]. An interaction between FA in the right uncinate fasciculus and 5-HTTLPR also predicted percent change in depression severity [F(5, 25) = 5.315, p = 0.002]. Uncorrected TBSS results revealed significantly higher FA in hippocampal portions of the cingulum bundle in responders compared to non-responders (p = 0.016). The predictive value of prefrontal and amygdala/hippocampal WM connectivity on antidepressant treatment response may be influenced by 5-HTTLPR and BDNF polymorphisms in MDD.

  14. Orientation and cellular distribution of membrane-bound catechol-O-methyltransferase in cortical neurons: implications for drug development.

    PubMed

    Chen, Jingshan; Song, Jian; Yuan, Peixiong; Tian, Qingjun; Ji, Yuanyuan; Ren-Patterson, Renee; Liu, Guangping; Sei, Yoshitasu; Weinberger, Daniel R

    2011-10-07

    Catechol-O-methyltransferase (COMT) is a key enzyme for inactivation and metabolism of catechols, including dopamine, norepinephrine, caffeine, and estrogens. It plays an important role in cognition, arousal, pain sensitivity, and stress reactivity in humans and in animal models. The human COMT gene is associated with a diverse spectrum of human behaviors and diseases from cognition and psychiatric disorders to chronic pain and cancer. There are two major forms of COMT proteins, membrane-bound (MB) COMT and soluble (S) COMT. MB-COMT is the main form in the brain. The cellular distribution of MB-COMT in cortical neurons remains unclear and the orientation of MB-COMT on the cellular membrane is controversial. In this study, we demonstrate that MB-COMT is located in the cell body and in axons and dendrites of rat cortical neurons. Analyses of MB-COMT orientation with computer simulation, flow cytometry and a cell surface enzyme assay reveal that the C-terminal catalytic domain of MB-COMT is in the extracellular space, which suggests that MB-COMT can inactivate synaptic and extrasynaptic dopamine on the surface of presynaptic and postsynaptic neurons. Finally, we show that the COMT inhibitor tolcapone induces cell death via the mechanism of apoptosis, and its cytotoxicity is dependent on dosage and correlated with COMT Val/Met genotypes in human lymphoblastoid cells. These results suggest that MB-COMT specific inhibitors can be developed and that tolcapone may be less hazardous at low doses and in specific genetic backgrounds.

  15. Schooling and variation in the COMT gene: The devil is in the details

    PubMed Central

    Campbell, Daniel; Bick, Johanna; Yrigollen, Carolyn M.; Lee, Maria; Joseph, Antony; Chang, Joseph T.; Grigorenko, Elena L.

    2013-01-01

    Background Schooling is considered to be one of the major contributors to the development of intelligence within societies and individuals. Genetic variation might modulate the impact of schooling and explain, at least partially, the presence of individual differences in classrooms. Method We studied a sample of 1502 children (mean age = 11.7 years) from Zambia. Approximately 57% of these children were enrolled in school, and the rest were not. To quantify genetic variation, we investigated a number of common polymorphisms in the catechol-O-methyltransferase (COMT) gene that controls the production of the protein thought to account for >60% of the dopamine degradation in the prefrontal cortex. Results Haplotype analyses generated results ranging from the presence to absence of significant interactions between a number of COMT haplotypes and indicators of schooling (i.e., in- vs. out-of-school and grade completed) in the prediction of nonverbal intelligence, depending on the parameter specification. However, an investigation of the distribution of corresponding p-values suggested that these positive results were false. Conclusions Convincing evidence that the variation in the COMT gene is associated with individual differences in nonverbal intelligence either directly or through interactions with schooling was not found. P-values produced by the method of testing for haplotype effects employed here may be sensitive to parameter settings, invalid under default settings, and should be checked for validity through simulation. PMID:23952646

  16. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction.

    PubMed

    Caspi, Avshalom; Moffitt, Terrie E; Cannon, Mary; McClay, Joseph; Murray, Robin; Harrington, HonaLee; Taylor, Alan; Arseneault, Louise; Williams, Ben; Braithwaite, Antony; Poulton, Richie; Craig, Ian W

    2005-05-15

    Recent evidence documents that cannabis use by young people is a modest statistical risk factor for psychotic symptoms in adulthood, such as hallucinations and delusions, as well as clinically significant schizophrenia. The vast majority of cannabis users do not develop psychosis, however, prompting us to hypothesize that some people are genetically vulnerable to the deleterious effects of cannabis. In a longitudinal study of a representative birth cohort followed to adulthood, we tested why cannabis use is associated with the emergence of psychosis in a minority of users, but not in others. A functional polymorphism in the catechol-O-methyltransferase (COMT) gene moderated the influence of adolescent cannabis use on developing adult psychosis. Carriers of the COMT valine158 allele were most likely to exhibit psychotic symptoms and to develop schizophreniform disorder if they used cannabis. Cannabis use had no such adverse influence on individuals with two copies of the methionine allele. These findings provide evidence of a gene x environment interaction and suggest that a role of some susceptibility genes is to influence vulnerability to environmental pathogens.

  17. The Influence of Genetic and Environmental Factors among MDMA Users in Cognitive Performance

    PubMed Central

    Cuyàs, Elisabet; Verdejo-García, Antonio; Fagundo, Ana Beatriz; Khymenets, Olha; Rodríguez, Joan; Cuenca, Aida; de Sola Llopis, Susana; Langohr, Klaus; Peña-Casanova, Jordi; Torrens, Marta; Martín-Santos, Rocío; Farré, Magí; de la Torre, Rafael

    2011-01-01

    This study is aimed to clarify the association between MDMA cumulative use and cognitive dysfunction, and the potential role of candidate genetic polymorphisms in explaining individual differences in the cognitive effects of MDMA. Gene polymorphisms related to reduced serotonin function, poor competency of executive control and memory consolidation systems, and high enzymatic activity linked to bioactivation of MDMA to neurotoxic metabolites may contribute to explain variations in the cognitive impact of MDMA across regular users of this drug. Sixty ecstasy polydrug users, 110 cannabis users and 93 non-drug users were assessed using cognitive measures of Verbal Memory (California Verbal Learning Test, CVLT), Visual Memory (Rey-Osterrieth Complex Figure Test, ROCFT), Semantic Fluency, and Perceptual Attention (Symbol Digit Modalities Test, SDMT). Participants were also genotyped for polymorphisms within the 5HTT, 5HTR2A, COMT, CYP2D6, BDNF, and GRIN2B genes using polymerase chain reaction and TaqMan polymerase assays. Lifetime cumulative MDMA use was significantly associated with poorer performance on visuospatial memory and perceptual attention. Heavy MDMA users (>100 tablets lifetime use) interacted with candidate gene polymorphisms in explaining individual differences in cognitive performance between MDMA users and controls. MDMA users carrying COMT val/val and SERT s/s had poorer performance than paired controls on visuospatial attention and memory, and MDMA users with CYP2D6 ultra-rapid metabolizers performed worse than controls on semantic fluency. Both MDMA lifetime use and gene-related individual differences influence cognitive dysfunction in ecstasy users. PMID:22110616

  18. Brain-derived neurotrophic factor--a major player in stimulation-induced homeostatic metaplasticity of human motor cortex?

    PubMed

    Mastroeni, Claudia; Bergmann, Til Ole; Rizzo, Vincenzo; Ritter, Christoph; Klein, Christine; Pohlmann, Ines; Brueggemann, Norbert; Quartarone, Angelo; Siebner, Hartwig Roman

    2013-01-01

    Repetitive transcranial magnetic stimulation (rTMS) of the human motor hand area (M1HAND) can induce lasting changes in corticospinal excitability as indexed by a change in amplitude of the motor-evoked potential. The plasticity-inducing effects of rTMS in M1HAND show substantial inter-individual variability which has been partially attributed to the val(66)met polymorphism in the brain-derived neurotrophic factor (BDNF) gene. Here we used theta burst stimulation (TBS) to examine whether the BDNF val(66)met genotype can be used to predict the expression of TBS-induced homeostatic metaplasticity in human M1HAND. TBS is a patterned rTMS protocol with intermittent TBS (iTBS) usually inducing a lasting increase and continuous TBS (cTBS) a lasting decrease in corticospinal excitability. In three separate sessions, healthy val(66)met (n = 12) and val(66)val (n = 17) carriers received neuronavigated cTBS followed by cTBS (n = 27), cTBS followed by iTBS (n = 29), and iTBS followed by iTBS (n = 28). Participants and examiner were blinded to the genotype at the time of examination. As expected, the first TBS intervention induced a decrease (cTBS) and increase (iTBS) in corticospinal excitability, respectively, at the same time priming the after effects caused by the second TBS intervention in a homeostatic fashion. Critically, val(66)met carriers and val(66)val carriers showed very similar response patterns to cTBS and iTBS regardless of the order of TBS interventions. Since none of the observed TBS effects was modulated by the BDNF val(66)met polymorphism, our results do not support the notion that the BDNF val(66)met genotype is a major player with regard to TBS-induced plasticity and metaplasticity in the human M1HAND.

  19. Brain-Derived Neurotrophic Factor – A Major Player in Stimulation-Induced Homeostatic Metaplasticity of Human Motor Cortex?

    PubMed Central

    Rizzo, Vincenzo; Ritter, Christoph; Klein, Christine; Pohlmann, Ines; Brueggemann, Norbert; Quartarone, Angelo; Siebner, Hartwig Roman

    2013-01-01

    Repetitive transcranial magnetic stimulation (rTMS) of the human motor hand area (M1HAND) can induce lasting changes in corticospinal excitability as indexed by a change in amplitude of the motor-evoked potential. The plasticity-inducing effects of rTMS in M1HAND show substantial inter-individual variability which has been partially attributed to the val66met polymorphism in the brain-derived neurotrophic factor (BDNF) gene. Here we used theta burst stimulation (TBS) to examine whether the BDNF val66met genotype can be used to predict the expression of TBS-induced homeostatic metaplasticity in human M1HAND. TBS is a patterned rTMS protocol with intermittent TBS (iTBS) usually inducing a lasting increase and continuous TBS (cTBS) a lasting decrease in corticospinal excitability. In three separate sessions, healthy val66met (n = 12) and val66val (n = 17) carriers received neuronavigated cTBS followed by cTBS (n = 27), cTBS followed by iTBS (n = 29), and iTBS followed by iTBS (n = 28). Participants and examiner were blinded to the genotype at the time of examination. As expected, the first TBS intervention induced a decrease (cTBS) and increase (iTBS) in corticospinal excitability, respectively, at the same time priming the after effects caused by the second TBS intervention in a homeostatic fashion. Critically, val66met carriers and val66val carriers showed very similar response patterns to cTBS and iTBS regardless of the order of TBS interventions. Since none of the observed TBS effects was modulated by the BDNF val66met polymorphism, our results do not support the notion that the BDNF val66met genotype is a major player with regard to TBS-induced plasticity and metaplasticity in the human M1HAND. PMID:23469118

  20. Smoking, genes encoding dopamine pathway and risk for Parkinson's disease.

    PubMed

    Gu, Zhuqin; Feng, Xiuli; Dong, Xiumin; Chan, Piu

    2010-09-20

    Smoking has been reported to be inversely associated with Parkinson's disease (PD) in many studies, but a recent study in China found that smoking increased the risk of PD. Variants in genes associated with dopamine metabolism found to increase the risk for PD have also been associated with smoking behavior. To investigate the association between smoking and PD in a Chinese population and determine whether the genetic variants of genes involved in dopamine metabolism influence the relationship between smoking and risk for PD. Chinese PD patients were recruited from Xuanwu Hospital. Controls were sampled from community. Detailed information on life-long smoking behavior was collected by face-to-face interview. Genotypes were determined for SLC6A3 VNTR, COMT Val108/158Met and MAO-B intron13 A/G polymorphisms by PCR-RFLP, DHPLC and sequencing. Chi-square and logistic regression model were used in the analysis. 176 PD cases and 354 controls were enrolled in this study. 23.9% cases are smokers, compared to 48.0% in controls. Ever smoking is inversely associated with PD (odds ratio=0.14, 95% CI 0.08-0.26, adjusted for age and gender). None of the above-mentioned genetic polymorphisms was associated with PD risk or smoking. When each variant was included in the logistic regression model, the inverse association between smoking and PD remained the same, and the interactions between smoking and variants were not significant in the model. Our data support a reduction of PD risk associated with smoking in a Chinese population. These variants of genes associated with DA uptake and metabolism do not affect the inverse association between smoking and PD. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  1. No association of the Arg51Gln and Leu72Met polymorphisms of the ghrelin gene and polycystic ovary syndrome.

    PubMed

    Wang, Kehua; Wang, Leiguang; Zhao, Yueran; Shi, Yuhua; Wang, Laicheng; Chen, Zi-Jiang

    2009-02-01

    Ghrelin plays a role in regulating glucose metabolism and energy balance. Polymorphisms in preproghrelin and ghrelin gene could be responsible for obesity, insulin resistance and low ghrelin levels observed in some individuals. The objective of this study was to evaluate the influence of two single-nucleotide polymorphisms (SNPs) of ghrelin gene on the clinical, the hormonal and metabolic features in women with polycystic ovary syndrome (PCOS) in a Chinese population. A large sample of Chinese PCOS (n = 271) women and a control group (n = 296) of healthy women matched for age were studied. Hormone and metabolic profiles were measured and blood samples were collected for genotype and allelic frequency analysis. Non-synonymous SNPs in the coding region (exon 2) of the preproghrelin gene (Arg51Gln (346 G>A) and Leu72Met (408 C>A) were studied using PCR and restriction fragment length polymorphism analysis. The polymorphism Arg51Gln was not found in the cohorts studied. The distribution of Leu72Met was similar in PCOS group and in healthy controls. There was no significant difference in age, BMI, waist-hip-ratio and levels of FSH, LH, estradiol, testosterone and prolactin between PCOS patients with different genotypes, and the level of plasma glucose and insulin was also similar. No association was found between Leu72Met and Arg51Gln polymorphisms in the ghrelin gene and PCOS in Chinese population.

  2. The Leu72Met polymorphism of the GHRL gene prevents the development of diabetic nephropathy in Chinese patients with type 2 diabetes mellitus.

    PubMed

    Zhuang, Langen; Li, Ming; Yu, Changhua; Li, Can; Zhao, Mingming; Lu, Ming; Zheng, Taishan; Zhang, Rong; Zhao, Weijing; Bao, Yuqian; Xiang, Kunsan; Jia, Weiping; Wang, Niansong; Liu, Limei

    2014-02-01

    The preproghrelin (GHRL) Leu72Met polymorphism (rs 696217) is associated with obesity, reduced glucose-induced insulin secretion in healthy or diabetic subjects, and reduced serum creatinine (Scr) levels in type 2 diabetes. We evaluated the association of the Leu72Met polymorphism with measures of insulin sensitivity in non-diabetic control individuals and type 2 diabetics, and whether this variation contributes to the development of diabetic nephropathy (DN) in type 2 diabetes. A case-control study was performed of 291 non-diabetic control subjects and 466 patients with type 2 diabetes, of whom 238 had DN with overt albuminuria (DN group; albuminuric excretion rate [AER] ≥ 300 mg/24 h) and 228 did not have DN, but had diabetes for more than 10 years (non-DN group). Genotyping was performed using a TaqMan PCR assay. The Leu/Leu, Leu/Met, and Met/Met genotype frequencies were significantly different between the non-DN and DN groups (p = 0.011). The frequency of the variant genotypes (Leu/Met, Met/Met) was significantly lower in the DN group than the non-DN group (23.5 vs. 36.0 %, p = 0.003). Met/Met non-diabetic control subjects had lower BMI and Scr levels and higher eGFR level than Leu/Leu or Leu/Met individuals (p < 0.05). Leu/Met and Met/Met type 2 diabetics had significantly lower AER and Scr levels and higher eGFR level than Leu/Leu type 2 diabetics (all p < 0.001). The GHRL Leu72Met polymorphism may help to maintain normal renal function and may protect against the development of DN by reducing albuminuria and improving renal function in Chinese patients with type 2 diabetes.

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

    PubMed

    Campbell, Daniel; Bick, Johanna; Yrigollen, Carolyn M; Lee, Maria; Joseph, Antony; Chang, Joseph T; Grigorenko, Elena L

    2013-10-01

    Schooling is considered one of the major contributors to the development of intelligence within societies and individuals. Genetic variation might modulate the impact of schooling and explain, at least partially, the presence of individual differences in classrooms. We studied a sample of 1,502 children (mean age = 11.7 years) from Zambia. Approximately 57% of these children were enrolled in school, and the rest were not. To quantify genetic variation, we investigated a number of common polymorphisms in the catechol-O-methyltransferase (COMT) gene that controls the production of the protein thought to account for >60% of the dopamine degradation in the prefrontal cortex. Haplotype analyses generated results ranging from the presence to absence of significant interactions between a number of COMT haplotypes and indicators of schooling (i.e., in- vs. out-of-school and grade completed) in the prediction of nonverbal intelligence, depending on the parameter specification. However, an investigation of the distribution of corresponding p-values suggested that these positive results were false. Convincing evidence that the variation in the COMT gene is associated with individual differences in nonverbal intelligence either directly or through interactions with schooling was not found. p-values produced by the method of testing for haplotype effects employed here may be sensitive to parameter settings, invalid under default settings, and should be checked for validity through simulation. © 2013 The Authors. Journal of Child Psychology and Psychiatry © 2013 Association for Child and Adolescent Mental Health.

  4. Molecular genetic mechanisms of allelic specific regulation of murine Comt expression

    PubMed Central

    Segall, Samantha K.; Shabalina, Svetlana A.; Meloto, Carolina B.; Wen, Xia; Cunningham, Danielle; Tarantino, Lisa M.; Wiltshire, Tim; Gauthier, Josée; Tohyama, Sarasa; Martin, Loren J.; Mogil, Jeffrey S.; Diatchenko, Luda

    2015-01-01

    Abstract A functional allele of the mouse catechol-O-methyltransferase (Comt) gene is defined by the insertion of a B2 short interspersed repeat element in its 3′-untranslated region (UTR). This allele has been associated with a number of phenotypes, such as pain and anxiety. In comparison with mice carrying the ancestral allele (Comt+), ComtB2i mice show higher Comt mRNA and enzymatic activity levels. Here, we investigated the molecular genetic mechanisms underlying this allelic specific regulation of Comt expression. Insertion of the B2 element introduces an early polyadenylation signal generating a shorter Comt transcript, in addition to the longer ancestral mRNA. Comparative analysis and in silico prediction of Comt mRNA potential targets within the transcript 3′ to the B2 element was performed and allowed choosing microRNA (miRNA) candidates for experimental screening: mmu-miR-3470a, mmu-miR-3470b, and mmu-miR-667. Cell transfection with each miRNA downregulated the expression of the ancestral transcript and COMT enzymatic activity. Our in vivo experiments showed that mmu-miR-667-3p is strongly correlated with decreasing amounts of Comt mRNA in the brain, and lentiviral injections of mmu-miR-3470a, mmu-miR-3470b, and mmu-miR-667 increase hypersensitivity in the mouse formalin model, consistent with reduced COMT activity. In summary, our data demonstrate that the Comt+ transcript contains regulatory miRNA signals in its 3′-untranslated region leading to mRNA degradation; these signals, however, are absent in the shorter transcript, resulting in higher mRNA expression and activity levels. PMID:26067582

  5. Candidate genes for alcohol dependence: A genetic association study from India.

    PubMed

    Malhotra, Savita; Basu, Debasish; Khullar, Madhu; Ghosh, Abhishek; Chugh, Neera

    2016-11-01

    Search for candidate genes for alcohol dependence (AD) has been inconsistent and inconclusive. Moreover, most of the research has been confined to a few specific ethnic groups. Hence, the aim of our study was to explore specific candidate genes for AD in north Indian male population. In this clinic-based genetic association study, 210 males with AD and 200 controls matched for age, gender and ethnicity were recruited from the clinic and the general population, respectively. Cases were diagnosed with Semi-structured Assessment for Genetics of Alcoholism-II (SSAGA-II). Single-nucleotide polymorphism genotyping was done by real-time quantitative-polymerase chain reaction (PCR) using Taq Man assay (ABI 7500) fast real-time PCR system. Both at the genotypic level and at allelic frequency, Met158 variant of catechol-O-methyl transferase (COMT) showed significant increase in cases as compared to controls. The frequency of heterozygous genotype (A/G) of gamma-aminobutyric acid receptor A1 (GABRA1) was significantly lower in cases as compared to controls. Likewise, for GABRA2, the frequency of homozygous recessive genotype (G/G) was significantly higher in the control group. With respect to the 5-hydroxytryptamine (5HT) transporter long promoter region (5HTTLPR), cholinergic receptor muscarinic (CHRM2) and alcohol dehydrogenase 1B (ADH1B) genes, there was no significant difference between the cases and the controls. Aldehyde dehydrogenase (ALDH2) gene was found to be monomorphic in our study population. Our study findings showed COMT polymorphism conferring risk and GABRA polymorphism as a protective genotype for Indian male with AD. Genes for alcohol metabolism, serotonin transporter and cholinergic receptor gene polymorphism were perhaps not contributory to AD for Indian population.

  6. Association between ghrelin gene (Leu72Met) polymorphism and ghrelin serum level with coronary artery diseases.

    PubMed

    Hedayatizadeh-Omran, Akbar; Rafiei, Alireza; Khajavi, Rezvan; Alizadeh-Navaei, Reza; Mokhberi, Vahid; Moradzadeh, Kambiz

    2014-02-01

    Research shows that ghrelin gene polymorphism has some association with coronary artery diseases (CAD). Due to genetic differences among nations and the high prevalence of CAD, we conducted this study to examine the possible association between the polymorphism of ghrelin gene Leu72Met and CAD among an Iranian population. This case-control study was undertaken with patients who were referred to referral heart center, in 2011, with chest pain or a positive exercise test. Patients with risk factors for heart disease or who were surgery candidates, who underwent angiography and echocardiography, were also included. DNA extractions were performed using a modified salting out method, and the ghrelin region was amplified using polymerase chain reaction. The presence of the Leu72Met polymorphism and the serum levels of ghrelin were determined using the restriction fragment length polymorphism method and the enzyme-linked immunosorbent assay, respectively. The results indicated that in CAD patients, the incidence of heart failure was significantly different between the groups with genotypes CC or AA+CA (p=0.041). Mean serum level of ghrelin in the CAD group was significantly higher than that in the control group (p<0.0001). Additionally, there was a significant relationship between the distribution of ghrelin genotypes and serum levels of ghrelin in both the CAD and control groups (p<0.0001). This study indicates that there was a significant association between heart failure in CAD patients and the presence of the polymorphism, as well as an increase in serum levels of ghrelin associated with genotype distribution such that ghrelin levels have an inverse relationship with the frequency of the CC genotype.

  7. Common Variants in LRP2 and COMT Genes Affect the Susceptibility of Gout in a Chinese Population

    PubMed Central

    Zhou, Jingru; Qian, Qiaoxia; Ma, Yanyun; He, Hongjun; Ji, Hengdong; Yang, Yajun; Wang, Xiaofeng; Xu, Xia; Pang, Yafei; Zou, Hejian; Jin, Li; Wang, Jiucun

    2015-01-01

    Gout is a common inflammation disease resulting from an increase in serum uric acid. Nearly 70% of uric acid is excreted via the kidneys. To date, evidence for an association between genetic loci and gout is absent, equivocal or not replicated. Our study aims to test variants in two genes abundantly expressed in the kidney, LRP2 and COMT, for their association with uric acid and gout. In total, 1318 Chinese individuals were genotyped for rs2544390 in LRP2 and rs4680 in COMT. These LRP2 and COMT gene polymorphisms showed no significant effect on uric acid (P = 0.204 and 0.188, separately); however, rs2544390 in LRP2 did influence uric acid levels in individuals with BMI ≥ 25 (P = 0.009). In addition, the allele frequency distributions of the two loci showed a significant difference between gout patients and healthy controls. A missense variation in rs4680 (G > A) decreased the risk of gout (OR = 0.77, P = 0.015), whereas the T allele of rs2544390 was associated with gout pathogenesis risk (OR = 1.26, P = 0.020). The present study provides the first evidence for an association between COMT and gout. Rs2544390 in LRP2 only influenced uric acid levels in individuals with BMI ≥ 25, which might explain the discrepant results among previous studies. In addition, we are the first to identify the association between LRP2 and gout in a Chinese population and to confirm this association in Asians. PMID:26147675

  8. Common Variants in LRP2 and COMT Genes Affect the Susceptibility of Gout in a Chinese Population.

    PubMed

    Dong, Zheng; Zhao, Dongbao; Yang, Chengde; Zhou, Jingru; Qian, Qiaoxia; Ma, Yanyun; He, Hongjun; Ji, Hengdong; Yang, Yajun; Wang, Xiaofeng; Xu, Xia; Pang, Yafei; Zou, Hejian; Jin, Li; Wang, Jiucun

    2015-01-01

    Gout is a common inflammation disease resulting from an increase in serum uric acid. Nearly 70% of uric acid is excreted via the kidneys. To date, evidence for an association between genetic loci and gout is absent, equivocal or not replicated. Our study aims to test variants in two genes abundantly expressed in the kidney, LRP2 and COMT, for their association with uric acid and gout. In total, 1318 Chinese individuals were genotyped for rs2544390 in LRP2 and rs4680 in COMT. These LRP2 and COMT gene polymorphisms showed no significant effect on uric acid (P = 0.204 and 0.188, separately); however, rs2544390 in LRP2 did influence uric acid levels in individuals with BMI ≥ 25 (P = 0.009). In addition, the allele frequency distributions of the two loci showed a significant difference between gout patients and healthy controls. A missense variation in rs4680 (G > A) decreased the risk of gout (OR = 0.77, P = 0.015), whereas the T allele of rs2544390 was associated with gout pathogenesis risk (OR = 1.26, P = 0.020). The present study provides the first evidence for an association between COMT and gout. Rs2544390 in LRP2 only influenced uric acid levels in individuals with BMI ≥ 25, which might explain the discrepant results among previous studies. In addition, we are the first to identify the association between LRP2 and gout in a Chinese population and to confirm this association in Asians.

  9. Polymorphisms in Dopamine System Genes Are Associated with Individual Differences in Attention in Infancy

    ERIC Educational Resources Information Center

    Holmboe, Karla; Nemoda, Zsofia; Fearon, R. M. Pasco; Csibra, Gergely; Sasvari-Szekely, Maria; Johnson, Mark H.

    2010-01-01

    Knowledge about the functional status of the frontal cortex in infancy is limited. This study investigated the effects of polymorphisms in four dopamine system genes on performance in a task developed to assess such functioning, the Freeze-Frame task, at 9 months of age. Polymorphisms in the catechol-O-methyltransferase ("COMT") and the…

  10. Three novel variants (p.Glu178Lys, p.Val245Met, p.Ser250Phe) of the phenylalanine hydroxylase (PAH) gene impair protein expression and function in vitro.

    PubMed

    Zong, Yanan; Liu, Ning; Ma, Shanshan; Bai, Ying; Guan, Fangxia; Kong, Xiangdong

    2018-08-20

    Phenylketonuria (PKU) is the most common inherited metabolic disease, an autosomal recessive disorder affecting >10,000 newborns each year globally. It can be caused by over 1000 different naturally occurring mutations in the phenylalanine hydroxylase (PAH) gene. We analyzed three novel naturally occurring PAH gene variants: p.Glu178Lys (c.532G>A), p.Val245Met (c.733G>A) and p.Ser250Phe (c.749C>T). The mutant effect on the PAH enzyme structure and function was predicted by bioinformatics software. Vectors expressing the corresponding PAH variants were generated for expression in E. coli and in HEK293T cells. The RNA expression of the three PAH variants was measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR). The mutant PAH protein levels were determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), western blot and enzyme-linked immunosorbent assay (ELISA). All three variants were predicted to be pathogenic by bioinformatics analysis. The transcription of the three PAH variants was similar to the wild type PAH gene in HEK293T cells. In contrast, the levels of mutant PAH proteins decreased significantly compared to the wild type control, in both E. coli and HEK293T cells. Our results indicate that the three novel PAH gene variants (p.Glu178Lys, p.Val245Met, p.Ser250Phe) impair PAH protein expression and function in prokaryotic and eukaryotic cells. Copyright © 2018. Published by Elsevier B.V.

  11. Childhood Abuse Experiences and the COMT and MTHFR Genetic Variants Associated With Male Sexual Orientation in the Han Chinese Populations: A Case-Control Study.

    PubMed

    Qin, Jia-Bi; Zhao, Guang-Lu; Wang, Feng; Cai, Yu-Mao; Lan, Li-Na; Yang, Lin; Feng, Tie-Jian

    2018-01-01

    Although it is widely acknowledged that genetic and environmental factors are involved in the development of male homosexuality, the causes are not fully understood. To explore the association and interaction of childhood abuse experiences and genetic variants of the catechol-O-methyltransferase (COMT) and methylenetetrahydrofolate reductase (MTHFR) genes with the development of male homosexuality. A case-control study of 537 exclusively homosexual men and 583 exclusively heterosexual men was conducted, with data collected from March 2013 to August 2015. Data were analyzed using χ 2 tests and logistic regression models. Sociodemographic characteristics, childhood abuse experiences, and polymorphisms of COMT at rs4680, rs4818, and rs6267 and MTHFR at rs1801133. More frequent occurrence of physical (adjusted odds ratio [aOR] = 1.78), emotional (aOR = 2.07), and sexual (aOR = 2.53) abuse during childhood was significantly associated with the development of male homosexuality. The polymorphisms of MTHFR at rs1801133 and COMT at rs4818 also were significantly associated with the development of male homosexuality in the homozygote comparisons (T/T vs C/C at rs1801133, aOR = 1.68; G/G vs C/C at rs4818, aOR = 1.75). In addition, significant interaction effects between childhood abuse experiences and the COMT and MTHFR genetic variants on the development of male homosexuality were found. This is the first time that an association of childhood abuse, COMT and MTHFR genetic variants, and their interactions with development of male homosexuality was exhaustively explored, which could help provide new insight into the etiology of male homosexuality. Because homosexual men are a relatively obscure population, it was impossible to select the study participants by random sampling, which could lead to selection bias. In addition, because this was a case-control study, recall bias was inevitable, and we could not verify causality. Childhood abuse and the COMT and MTHFR genetic

  12. Interactions among catechol-O-methyltransferase genotype, parenting, and sex predict children’s internalizing symptoms and inhibitory control: Evidence for differential susceptibility

    PubMed Central

    SULIK, MICHAEL J.; EISENBERG, NANCY; SPINRAD, TRACY L.; LEMERY-CHALFANT, KATHRYN; SWANN, GREGORY; SILVA, KASSONDRA M.; REISER, MARK; STOVER, DARYN A.; VERRELLI, BRIAN C.

    2015-01-01

    We used sex, observed parenting quality at 18 months, and three variants of the catechol-O-methyltransferase gene (Val158Met [rs4680], intron1 [rs737865], and 3′-untranslated region [rs165599]) to predict mothers’ reports of inhibitory and attentional control (assessed at 42, 54, 72, and 84 months) and internalizing symptoms (assessed at 24, 30, 42, 48, and 54 months) in a sample of 146 children (79 male). Although the pattern for all three variants was very similar, Val158Met explained more variance in both outcomes than did intron1, the 3′-untranslated region, or a haplotype that combined all three catechol-O-methyltransferase variants. In separate models, there were significant three-way interactions among each of the variants, parenting, and sex, predicting the intercepts of inhibitory control and internalizing symptoms. Results suggested that Val158Met indexes plasticity, although this effect was moderated by sex. Parenting was positively associated with inhibitory control for methionine–methionine boys and for valine–valine/valine–methionine girls, and was negatively associated with internalizing symptoms for methionine–methionine boys. Using the “regions of significance” technique, genetic differences in inhibitory control were found for children exposed to high-quality parenting, whereas genetic differences in internalizing were found for children exposed to low-quality parenting. These findings provide evidence in support of testing for differential susceptibility across multiple outcomes. PMID:25159270

  13. Analysis of Manganese Superoxide Dismutase and Glutathione Peroxidase 1 Gene Polymorphisms in Vitiligo.

    PubMed

    Seçkin, Havva Yıldız; Kalkan, Göknur; Bütün, İlknur; Akbaş, Ali; Baş, Yalçın; Karakuş, Nevin; Benli, İsmail

    2016-08-01

    Vitiligo is a hereditary/acquired progressive pigmentation disorder characterized by discoloration of skin as a result of melanocyte dysfunction. Recent studies have proposed that oxidant/antioxidant status plays an important role in vitiligo pathogenesis because of the toxic effects on melanocytes. In this study, we aimed to investigate possible associations of MnSOD Ala-9Val and GPx1 Pro198Leu polymorphisms with vitiligo with in Turkish population. The study group consists of 57 patients with vitiligo and 69 healthy controls. Genotyping is performed to identify MnSOD Ala-9Val and GPx1 Pro198Leu polymorphisms. The method used for genotyping was based on the PCR amplification and detection of polymorphisms by hybridization probes labeled with fluorescent dyes. Both the genotype and allele frequencies of MnSOD Ala-9Val (p = 0.817 and p = 0.553, respectively) and GPx1 Pro198Leu polymorphisms (p = 0.422 and p = 0.673, respectively) were not significantly different between vitiligo patients and the control group. Although no significant difference was found, this is the first report investigating the possible associations between the MnSOD Ala-9Val and GPx1 Pro198Leu polymorphisms in Turkish population. Further studies with large populations will be able to clarify the association better.

  14. Dopaminergic influences on executive function and impulsive behaviour in impulse control disorders in Parkinson's disease.

    PubMed

    Leroi, Iracema; Barraclough, Michelle; McKie, Shane; Hinvest, Neal; Evans, Jonathan; Elliott, Rebecca; McDonald, Kathryn

    2013-09-01

    The development of impulse control disorders (ICDs) in Parkinson's disease (PD) may arise from an interaction among cognitive impairment, impulsive responding and dopaminergic state. Dopaminergic state may be influenced by pharmacologic or genotypic (catechol-O-methyltransferase; COMT) factors. We sought to investigate this interaction further by comparing those with (n = 35) and without (n = 55) ICDs on delay-discounting in different pharmacologic conditions (ON or OFF dopaminergic medication) and on response inhibition as well as aspects of executive functioning in the ON state. We then undertook an exploratory sub-group analysis of these same tasks when the overall PD group was divided into different allelic variants of COMT (val/val vs. met/met). A healthy control group (HC; n = 20) was also included. We found that in those with PD and ICDs, 'cognitive flexibility' (set shifting, verbal fluency, and attention) in the ON medication state was not impaired compared with those without ICDs. In contrast, our working memory, or 'cognitive focus', task was impaired in both PD groups compared with the HC group when ON. During the delay-discounting task, the PD with ICDs group expressed greater impulsive choice compared with the PD group without ICDs, when in the ON, but not the OFF, medication state. However, no group difference on the response inhibition task was seen when ON. Finally, the met homozygous group performed differently on tests of executive function compared with the val homozygous group. We concluded that the disparity in levels of impairment among different domains of executive function and impulsive decision-making distinguishes those with ICD in PD from those without ICD, and may in part be affected by dopaminergic status. Both pharmacologic and genotypic influences on dopaminergic state may be important in ICD. © 2013 The British Psychological Society.

  15. Aplastic crisis revealing the diagnosis of Hb Evans [alpha62(E11)Val-->Met, GTG-->ATG (alpha2)] in a Hispanic kindred: case report and review.

    PubMed

    Steiner, Laurie A; Van Hoff, Jack; Kutlar, Ferdane; Gallagher, Patrick G

    2007-01-01

    This report describes a Hispanic girl who presented in aplastic crisis due to parvovirus infection. She was subsequently found to have a chronic hemolytic anemia secondary to an unstable hemoglobinopathy. Genetic testing revealed that the girl and two symptomatic family members had Hb Evans [alpha62(E11)Val-->Met, GTG-->ATG (alpha2)], an unstable hemoglobin (Hb) variant due to a mutation in the alpha2-globin chain. Hb Evans has been described only once previously, in a Caucasian kindred. Literature review indicates aplastic crisis is a rare initial presentation of unstable hemoglobinopathies and that these disorders are infrequent but important causes of hemolytic anemia in Hispanic patients.

  16. Association of genetic polymorphism of glutathione S-transferase (GSTM1, GSTT1, GSTP1) with bladder cancer susceptibility.

    PubMed

    Safarinejad, Mohammad Reza; Safarinejad, Saba; Shafiei, Nayyer; Safarinejad, Shiva

    2013-10-01

    The glutathione-S-transferases (GSTs) comprise a class of enzymes that detoxify carcinogenic compounds by conjugating glutathione to facilitate their removal. Polymorphisms in GSTM1, GSTT1, and GSTP1 genes have been related to risk for bladder cancer. Studies focusing on GSTs gene variants relationship with the risk of bladder cancer have produced conflicting and inconsistent results. We examine the association between genetic polymorphism of glutathione S-transferase P1, GSTM1, GSTT1 genes and development of bladder transitional cell carcinoma (TCC). The study population consisted of 166 histologically confirmed male bladder TCC cases and 332 healthy male controls. Genotyping was done using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method and also investigated combined gene interactions. The GSTP1 Val/Val genotype was significantly associated with bladder cancer (OR = 4.32, 95% CI: 2.64-6.34), whereas the association observed for GSTM1 null (OR = 1.32, 95% CI: 0.82-2.62; P = 0.67) and GSTT1 null genotype (OR = 1.18, 95% CI: 0.79-1.67; P = 0.74) did not reach statistical significance. There was a significant multiple interaction between GSTM1, GSTT1, and GSTP1 genotypes in risk of bladder cancer (P for interaction = 0.02). The risk associated with the concurrent presence of GSTM1 positive and GSTP1 Ile/Val or Val/Val (OR = 3.71, 95% CI: 2.34-5.54) and GSTT1 positive and GSTP1 Ile/Val or Val/Val (OR = 2.66, 95% CI: 1.54-4.72) was statistically significant. Patients carrying GSTP1 Val/Val genotype were at increased risk for developing high-grade (OR = 7.68, 95% CI: 4.73-19.25) and muscle invasive (OR = 10.67, 95% CI: 6.34-21.75) bladder cancer. High risk for bladder TCC also was observed with respect to combined GSTT1 null/GSTP1 Ile/Val or Val/Val (OR = 4.76, 95% CI: 2.68-18.72) and GSTM1 null/GSTT1 null/GSTP1 Ile/Val or Val/Val (OR = 6.42, 95% CI: 4.76-14.72) genotype variant. This study suggests that the GSTP1 polymorphism

  17. Dietary carotenoid-rich oil supplementation improves exercise-induced anisocytosis in runners: influences of haptoglobin, MnSOD (Val9Ala), CAT (21A/T) and GPX1 (Pro198Leu) gene polymorphisms in dilutional pseudoanemia (sports anemia).

    PubMed

    Miranda-Vilela, Ana L; Akimoto, Arthur K; Alves, Penha C Z; Pereira, Luiz C S; Klautau-Guimarães, Maria N; Grisolia, Cesar K

    2010-04-01

    Physical training induces beneficial adaptation, whereas exhaustive exercises increase reactive oxygen-species generation, thereby causing oxidative damage in plasma and erythrocytes, fractions susceptible to lipid peroxidation. Pequi (Caryocar brasiliense Camb.) is a Brazilian Cerrado fruit containing a carotenoid-rich oil. The aim was to investigate the effects of pequi-oil on exercise-induced oxidative damage in plasma and erythrocytes, after running in the same environment and undergoing weekly training under the same conditions as to type, intensity and length. Evaluations were accomplished after outdoor running on flat land before and after ingestion of 400 mg pequi-oil capsules for 14 days. Blood samples were taken after running and submitted to TBARS assay and erythrogram analysis. Haptoglobin, MnSOD (Val9Ala), CAT (21A/T) and GPX1 (Pro198Leu) gene polymorphisms were priorly investigated, so as to estimate genetic influence The reduction in erythrocytes, hemoglobin and hematocrit after pequi-oil treatment was notably associated with higher plasma expansion. Except for MCHC (mean corpuscular hemoglobin concentration) and RDW (red cell distribution width), the results were influenced by the polymorphisms studied. The best response to pequi-oil was presented by MnSOD Val/Val, CAT AA or AT genotypes and the GPX1 Pro allele. The significantly lower RDW and higher MHCH values were related to pequi-oil protective effects. Pequi oil, besides possessing other nutritional properties, showed protective blood effects.

  18. Polymorphisms in O-methyltransferase genes are associated with stover cell wall digestibility in European maize (Zea mays L.).

    PubMed

    Brenner, Everton A; Zein, Imad; Chen, Yongsheng; Andersen, Jeppe R; Wenzel, Gerhard; Ouzunova, Milena; Eder, Joachim; Darnhofer, Birte; Frei, Uschi; Barrière, Yves; Lübberstedt, Thomas

    2010-02-12

    OMT (O-methyltransferase) genes are involved in lignin biosynthesis, which relates to stover cell wall digestibility. Reduced lignin content is an important determinant of both forage quality and ethanol conversion efficiency of maize stover. Variation in genomic sequences coding for COMT, CCoAOMT1, and CCoAOMT2 was analyzed in relation to stover cell wall digestibility for a panel of 40 European forage maize inbred lines, and re-analyzed for a panel of 34 lines from a published French study. Different methodologies for association analysis were performed and compared. Across association methodologies, a total number of 25, 12, 1, 6 COMT polymorphic sites were significantly associated with DNDF, OMD, NDF, and WSC, respectively. Association analysis for CCoAOMT1 and CCoAOMT2 identified substantially fewer polymorphic sites (3 and 2, respectively) associated with the investigated traits. Our re-analysis on the 34 lines from a published French dataset identified 14 polymorphic sites significantly associated with cell wall digestibility, two of them were consistent with our study. Promising polymorphisms putatively causally associated with variability of cell wall digestibility were inferred from the total number of significantly associated SNPs/Indels. Several polymorphic sites for three O-methyltransferase loci were associated with stover cell wall digestibility. All three tested genes seem to be involved in controlling DNDF, in particular COMT. Thus, considerable variation among Bm3 wildtype alleles can be exploited for improving cell-wall digestibility. Target sites for functional markers were identified enabling development of efficient marker-based selection strategies.

  19. Polymorphisms in O-methyltransferase genes are associated with stover cell wall digestibility in European maize (Zea mays L.)

    PubMed Central

    2010-01-01

    Background OMT (O-methyltransferase) genes are involved in lignin biosynthesis, which relates to stover cell wall digestibility. Reduced lignin content is an important determinant of both forage quality and ethanol conversion efficiency of maize stover. Results Variation in genomic sequences coding for COMT, CCoAOMT1, and CCoAOMT2 was analyzed in relation to stover cell wall digestibility for a panel of 40 European forage maize inbred lines, and re-analyzed for a panel of 34 lines from a published French study. Different methodologies for association analysis were performed and compared. Across association methodologies, a total number of 25, 12, 1, 6 COMT polymorphic sites were significantly associated with DNDF, OMD, NDF, and WSC, respectively. Association analysis for CCoAOMT1 and CCoAOMT2 identified substantially fewer polymorphic sites (3 and 2, respectively) associated with the investigated traits. Our re-analysis on the 34 lines from a published French dataset identified 14 polymorphic sites significantly associated with cell wall digestibility, two of them were consistent with our study. Promising polymorphisms putatively causally associated with variability of cell wall digestibility were inferred from the total number of significantly associated SNPs/Indels. Conclusions Several polymorphic sites for three O-methyltransferase loci were associated with stover cell wall digestibility. All three tested genes seem to be involved in controlling DNDF, in particular COMT. Thus, considerable variation among Bm3 wildtype alleles can be exploited for improving cell-wall digestibility. Target sites for functional markers were identified enabling development of efficient marker-based selection strategies. PMID:20152036

  20. Glutathion-S-Transferase P1 polymorphisms association with broncopulmonary dysplasia in preterm infants

    PubMed Central

    Karagianni, P; Rallis, D; Fidani, L; Porpodi, M; Kalinderi, K; Tsakalidis, C; Nikolaidis, N

    2013-01-01

    Background: Oxidative stress, characterized by the excretion of pre-oxidative and anti-oxidative proteases, has a key role in the pathogenesis of bronchopulmonary dysplasia (BPD). One of the many host anti-oxidant enzymes is glutathione-S-transferase P1 (GSTP1), with three polymorphic alleles having been identified: homozygous ile, heterozygous ile/val and homozygous val isomorph. The aim of this study was to examine the genetic predisposition to BPD in the GSTP1 polymorphisms. Methods: A prospective case-control study was carried out in the 2nd Neonatal Intensive Care Unit of Aristotle University in Thessaloniki, Greece during 2008. The genetic polymorphisms of GSTP1 in 28 preterms <32 weeks gestational age (GA) with BPD compared to 74 controls (33 preterms without BPD and 41 healthy terms) were examined. Results: The homozygous ile isomorph was predominant in all groups (preterms with BPD: 82%, preterms without BPD: 70%, healthy terms: 78%), followed by the heterozygous ile/val (14%, 18% and 20% respectively) and the homozygous val isomorph (4%, 12% and 2% respectively). The homozygous ile isomorph was also identified in the majority of preterms with mild (80%), moderate (100%) and severe (73%) BPD. The GSTP1 genetic distribution did not differ between the groups and GSTP1 polymorphisms were not associated with the severity of BPD. Conclusions: This study could not confirm an association between GSTP1 polymorphisms and the development of BPD or the severity of the disease. PMID:25031518

  1. Glutathion-S-Transferase P1 polymorphisms association with broncopulmonary dysplasia in preterm infants.

    PubMed

    Karagianni, P; Rallis, D; Fidani, L; Porpodi, M; Kalinderi, K; Tsakalidis, C; Nikolaidis, N

    2013-10-01

    Oxidative stress, characterized by the excretion of pre-oxidative and anti-oxidative proteases, has a key role in the pathogenesis of bronchopulmonary dysplasia (BPD). One of the many host anti-oxidant enzymes is glutathione-S-transferase P1 (GSTP1), with three polymorphic alleles having been identified: homozygous ile, heterozygous ile/val and homozygous val isomorph. The aim of this study was to examine the genetic predisposition to BPD in the GSTP1 polymorphisms. A prospective case-control study was carried out in the 2nd Neonatal Intensive Care Unit of Aristotle University in Thessaloniki, Greece during 2008. The genetic polymorphisms of GSTP1 in 28 preterms <32 weeks gestational age (GA) with BPD compared to 74 controls (33 preterms without BPD and 41 healthy terms) were examined. The homozygous ile isomorph was predominant in all groups (preterms with BPD: 82%, preterms without BPD: 70%, healthy terms: 78%), followed by the heterozygous ile/val (14%, 18% and 20% respectively) and the homozygous val isomorph (4%, 12% and 2% respectively). The homozygous ile isomorph was also identified in the majority of preterms with mild (80%), moderate (100%) and severe (73%) BPD. The GSTP1 genetic distribution did not differ between the groups and GSTP1 polymorphisms were not associated with the severity of BPD. This study could not confirm an association between GSTP1 polymorphisms and the development of BPD or the severity of the disease.

  2. Time-Resolved Influences of Functional DAT1 and COMT Variants on Visual Perception and Post-Processing

    PubMed Central

    Bender, Stephan; Rellum, Thomas; Freitag, Christine; Resch, Franz; Rietschel, Marcella; Treutlein, Jens; Jennen-Steinmetz, Christine; Brandeis, Daniel; Banaschewski, Tobias; Laucht, Manfred

    2012-01-01

    Background Dopamine plays an important role in orienting and the regulation of selective attention to relevant stimulus characteristics. Thus, we examined the influences of functional variants related to dopamine inactivation in the dopamine transporter (DAT1) and catechol-O-methyltransferase genes (COMT) on the time-course of visual processing in a contingent negative variation (CNV) task. Methods 64-channel EEG recordings were obtained from 195 healthy adolescents of a community-based sample during a continuous performance task (A-X version). Early and late CNV as well as preceding visual evoked potential components were assessed. Results Significant additive main effects of DAT1 and COMT on the occipito-temporal early CNV were observed. In addition, there was a trend towards an interaction between the two polymorphisms. Source analysis showed early CNV generators in the ventral visual stream and in frontal regions. There was a strong negative correlation between occipito-temporal visual post-processing and the frontal early CNV component. The early CNV time interval 500–1000 ms after the visual cue was specifically affected while the preceding visual perception stages were not influenced. Conclusions Late visual potentials allow the genomic imaging of dopamine inactivation effects on visual post-processing. The same specific time-interval has been found to be affected by DAT1 and COMT during motor post-processing but not motor preparation. We propose the hypothesis that similar dopaminergic mechanisms modulate working memory encoding in both the visual and motor and perhaps other systems. PMID:22844499

  3. Time-resolved influences of functional DAT1 and COMT variants on visual perception and post-processing.

    PubMed

    Bender, Stephan; Rellum, Thomas; Freitag, Christine; Resch, Franz; Rietschel, Marcella; Treutlein, Jens; Jennen-Steinmetz, Christine; Brandeis, Daniel; Banaschewski, Tobias; Laucht, Manfred

    2012-01-01

    Dopamine plays an important role in orienting and the regulation of selective attention to relevant stimulus characteristics. Thus, we examined the influences of functional variants related to dopamine inactivation in the dopamine transporter (DAT1) and catechol-O-methyltransferase genes (COMT) on the time-course of visual processing in a contingent negative variation (CNV) task. 64-channel EEG recordings were obtained from 195 healthy adolescents of a community-based sample during a continuous performance task (A-X version). Early and late CNV as well as preceding visual evoked potential components were assessed. Significant additive main effects of DAT1 and COMT on the occipito-temporal early CNV were observed. In addition, there was a trend towards an interaction between the two polymorphisms. Source analysis showed early CNV generators in the ventral visual stream and in frontal regions. There was a strong negative correlation between occipito-temporal visual post-processing and the frontal early CNV component. The early CNV time interval 500-1000 ms after the visual cue was specifically affected while the preceding visual perception stages were not influenced. Late visual potentials allow the genomic imaging of dopamine inactivation effects on visual post-processing. The same specific time-interval has been found to be affected by DAT1 and COMT during motor post-processing but not motor preparation. We propose the hypothesis that similar dopaminergic mechanisms modulate working memory encoding in both the visual and motor and perhaps other systems.

  4. C957T polymorphism of the dopamine D2 receptor gene is associated with motor learning and heart rate.

    PubMed

    Huertas, E; Bühler, K-M; Echeverry-Alzate, V; Giménez, T; López-Moreno, J A

    2012-08-01

    Genetic variants that are related to the dopaminergic system have been frequently found to be associated with various neurological and mental disorders. Here, we studied the relationships between some of these genetic variants and some cognitive and psychophysiological processes that are implicated in such disorders. Two single nucleotide polymorphisms were chosen: one in the dopamine D2 receptor gene (rs6277-C957T) and one in the catechol-O-methyltransferase gene (rs4680-Val158Met), which is involved in the metabolic degradation of dopamine. The performance of participants on two long-term memory tasks was assessed: free recall (declarative memory) and mirror drawing (procedural motor learning). Heart rate (HR) was also monitored during the initial trials of the mirror-drawing task, which is considered to be a laboratory middle-stress generator (moderate stress), and during a rest period (low stress). Data were collected from 213 healthy Caucasian university students. The C957T C homozygous participants showed more rapid learning than the T allele carriers in the procedural motor learning task and smaller differences in HR between the moderate- and the low-stress conditions. These results provide useful information regarding phenotypic variance in both healthy individuals and patients. © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

  5. Impact of the Ile105Val Polymorphism of the Glutathione S-transferase P1 (GSTP1) Gene on Obesity and Markers of Cardiometabolic Risk in Young Adult Population.

    PubMed

    Chielle, E O; Trott, A; da Silva Rosa, B; Casarin, J N; Fortuna, P C; da Cruz, I B M; Moretto, M B; Moresco, R N

    2017-05-01

    The aim of the study was to investigate the association between Glutathione S-transferase P1 (GSTP1) gene polymorphism with obesity and markers of cardiometabolic risk. A cross-sectional study was carried out in individuals aged≥18 and ≤30 years. The study included 54 normal weight, 27 overweight and 68 obese volunteers. Anthropometric measurements and biochemical parameters were evaluated, the DNA was extracted from blood samples and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to measure GSTP1 Ile 105 Val gene polymorphism of the study participants. Also, biochemical analysis and hormone assays were carried out. A positive association between GSTP1 polymorphism and obesity was observed on subjects carrying at least one G allele (AG and GG). GG genotype was found only in the obese group. The G allele carriers presented 2.4 times higher chance of obesity when compared to those with the AA genotype. These results were independent of sex and age. We suggest that despite a study in population regional (south of Brazil), the GSTP1 gene polymorphism may play a significant role in the increase of susceptibility of obesity and contribute to identify the cardiovascular risk in young adults. © Georg Thieme Verlag KG Stuttgart · New York.

  6. Association of interactions between dietary salt consumption and hypertension-susceptibility genetic polymorphisms with blood pressure among Japanese male workers.

    PubMed

    Imaizumi, Takahiro; Ando, Masahiko; Nakatochi, Masahiro; Maruyama, Shoichi; Yasuda, Yoshinari; Honda, Hiroyuki; Kuwatsuka, Yachiyo; Kato, Sawako; Kondo, Takaaki; Iwata, Masamitsu; Nakashima, Toru; Yasui, Hiroshi; Takamatsu, Hideki; Okajima, Hiroshi; Yoshida, Yasuko; Matsuo, Seiichi

    2017-06-01

    Blood pressure is influenced by hereditary factors and dietary habits. The objective of this study was to examine the effect of dietary salt consumption and single-nucleotide polymorphisms (SNPs) on blood pressure (BP). This was a cross-sectional analysis of 2728 male participants who participated in a health examination in 2009. Average dietary salt consumption was estimated using electronically collected meal purchase data from cafeteria. A multivariate analysis, adjusting for clinically relevant factors, was conducted to examine whether the effect on BP of salt consumption, SNPs, and interaction between salt consumption and each SNP. This study examined the SNPs AGT rs699 (Met235Thr), ADD1 rs4961 (Gly460Trp), NPPA rs5063 (Val32Met), GPX1 rs1050450 (Pro198Leu), and AGTR1 rs5186 (A1166C) in relation to hypertension and salt sensitivity. BP was not significantly associated with SNPs or salt consumption. The interaction between salt consumption and SNPs with systolic BP showed a significant association in NPPA rs5063 (Val32Met) (P = 0.023) and a marginal trend toward significance in rs4961 and rs1050450 (P = 0.060 and 0.067, respectively). The effect of salt consumption on BP differed by genotype. Dietary salt consumption and genetic variation can predict a high risk of hypertension.

  7. [The dentistry of Blainville and the positivism of Comte].

    PubMed

    Gysel, C

    1989-01-01

    COMTE improved BLAINVILLE's acquaintance when he was the secretary of SAINT-SIMON. They became friends. BLAINVILLE aided COMTE in his illness and financial troubles, taught him biology and was one of the first to support his philosophical ideas, through which he became self-conscious of his own value and scientific methods.

  8. Pathways to age of onset of heroin use: a structural model approach exploring the relationship of the COMT gene, impulsivity and childhood trauma.

    PubMed

    Li, Ting; Du, Jiang; Yu, Shunying; Jiang, Haifeng; Fu, Yingmei; Wang, Dongxiang; Sun, Haiming; Chen, Hanhui; Zhao, Min

    2012-01-01

    The interaction of the association of dopamine genes, impulsivity and childhood trauma with substance abuse remains unclear. To clarify the impacts and the interactions of the Catechol -O-methyltransferase (COMT) gene, impulsivity and childhood trauma on the age of onset of heroin use among heroin dependent patients in China. 202 male and 248 female inpatients who meet DSM-IV criteria of heroin dependence were enrolled. Impulsivity and childhood trauma were measured using BIS-11 (Barratt Impulsiveness Scale-11) and ETISR-SF (Early Trauma Inventory Self Report-Short Form). The single nucleotide polymorphism (SNP) rs737866 on the COMT gene-which has previously been associated with heroin abuse, was genotyped using a DNA sequence detection system. Structural equations model was used to assess the interaction paths between these factors and the age of onset of heroin use. Chi-square test indicated the individuals with TT allele have earlier age of onset of heroin use than those with CT or CC allele. In the correlation analysis, the severity of childhood trauma was positively correlated to impulsive score, but both of them were negatively related to the age of onset of heroin use. In structure equation model, both the COMT gene and childhood trauma had impacts on the age of onset of heroin use directly or via impulsive personality. Our findings indicated that the COMT gene, impulsive personality traits and childhood trauma experience were interacted to impact the age of onset of heroin use, which play a critical role in the development of heroin dependence. The impact of environmental factor was greater than the COMT gene in the development of heroin dependence.

  9. Meta- and Pooled Analysis of GSTP1 Polymorphism and Lung Cancer: A HuGE-GSEC Review

    PubMed Central

    Chen, Wei; Smith, Daryn W.; Benhamou, Simone; Bouchardy, Christine; Butkiewicz, Dorota; Fong, Kwun M.; Gené, Manuel; Hirvonen, Ari; Kiyohara, Chikako; Larsen, Jill E.; Lin, Pinpin; Raaschou-Nielsen, Ole; Povey, Andrew C.; Reszka, Edyta; Risch, Angela; Schneider, Joachim; Schwartz, Ann G.; Sorensen, Mette; To-Figueras, Jordi; Tokudome, Shinkan; Pu, Yuepu; Yang, Ping; Wenzlaff, Angela S.; Wikman, Harriet; Taioli, Emanuela

    2009-01-01

    Lung cancer is the most common cancer worldwide. Polymorphisms in genes associated with carcinogen metabolism may modulate risk of disease. Glutathione S-transferase pi (GSTP1) detoxifies polycyclic aromatic hydrocarbons found in cigarette smoke and is the most highly expressed glutathione S-transferase in lung tissue. A polymorphism in the GSTP1 gene, an A-to-G transition in exon 5 (Ile105Val, 313A → 313G), results in lower activity among individuals who carry the valine allele. The authors present a meta- and a pooled analysis of case-control studies that examined the association between this polymorphism in GSTP1 and lung cancer risk (27 studies, 8,322 cases and 8,844 controls and 15 studies, 4,282 cases and 5,032 controls, respectively). Overall, the meta-analysis found no significant association between lung cancer risk and the GSTP1 exon 5 polymorphism. In the pooled analysis, there was an overall association (odds ratio = 1.11, 95% confidence interval: 1.03, 1.21) between lung cancer and carriage of the GSTP1 Val/Val or Ile/Val genotype compared with those carrying the Ile/Ile genotype. Increased risk varied by histologic type in Asians. There appears to be evidence for interaction between amount of smoking, the GSTP1 exon 5 polymorphism, and risk of lung cancer in whites. PMID:19240225

  10. Hb Koln [β98(FG5) [GTG → ATG, ValMet]: the first report from India.

    PubMed

    Warang, Prashant; Nair, Sona; Nadkarni, Anita; Kedar, Prabhakar; Bhave, Abhay; Ghosh, Kanjaksha; Colah, Roshan

    2014-06-01

    The group of unstable hemoglobins are associated with congenital non-spherocytic hemolytic anemia due to instability of the hemoglobin molecule. They often lead to formation of the characteristic inclusion bodies or Heinz bodies. To identity the cause of mild anemia, reticulocytosis, and hepatosplenomegly in a case of non-spherocytic hemolytic anemia. A 34-year-old female patient originating from Maharashtra, western India presented with mild anemia and jaundice which had persisted since childhood. Investigations included a complete blood count, screening for red cell membrane protein defects, Hb analysis by high-performance liquid chromatography (HPLC) and cellulose acetate electrophoresis (pH 8.9), heat instability test and DNA sequencing. Hemoglobin analysis by HPLC showed an abnormal peak in the Hb C window (9.8%) with a retention time of 4.90 minutes. Cellulose acetate electrophoresis (pH 8.9) showed a slow moving band (6.15%) between Hb A2 and Hb S. The heat instability test was positive. DNA analysis of α globin genes showed absence of both deletional and non- deletional α thalassemia. DNA sequencing of the β globin gene revealed heterozygosity for a mutation at codon 98 [GTG → ATG, ValMet], which gives rise to Hb-Koln. Hb Koln is the commonest unstable Hb variant reported from many populations in the world. However, this is the first report of this unstable Hb variant from India.

  11. The influence of CHRNA4, COMT, and maternal sensitivity on orienting and executive attention in 6-month-old infants.

    PubMed

    Quan, Jeffry; Ong, Mei-Lyn; Bureau, Jean-Francois; Sim, Lit Wee; Sanmugam, Shamini; Abdul Malik, Adam B; Wong, Eric; Wong, Johnny; Chong, Yap-Seng; Saw, Seang Mei; Kwek, Kenneth; Qiu, Anqi; Holbrook, Joanna D; Rifkin-Graboi, Anne

    2017-08-01

    Despite claims concerning biological mechanisms sub-serving infant attention, little experimental work examines its underpinnings. This study examines how candidate polymorphisms from the cholinergic (CHRNA4 rs1044396) and dopaminergic (COMT rs4680) systems, respectively indicative of parietal and prefrontal/anterior cingulate involvement, are related to 6-month-olds' (n=217) performance during a visual expectation eye-tracking paradigm. As previous studies suggest that both cholinergic and dopaminergic genes may influence susceptibility to the influence of other genetic and environmental factors, we further examined whether these candidate genes interact with one another and/or with early caregiving experience in predicting infants' visual attention. We detected an interaction between CHRNA4 genotype and observed maternal sensitivity upon infants' orienting to random stimuli and a CHRNA4-COMT interaction effect upon infants' orienting to patterned stimuli. Consistent with adult research, we observed a direct effect of COMT genotype on anticipatory looking to patterned stimuli. Findings suggest that CHRNA4 genotype may influence susceptibility to other attention-related factors in infancy. These interactions may account for the inability to establish a link between CHRNA4 and orienting in infant research to date, despite developmental theorizing suggesting otherwise. Moreover, findings suggest that by 6months, dopamine, and relatedly, the prefrontal cortex/anterior cingulate, may be important to infant attention. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Association of GSTs polymorphisms with risk of gestational diabetes mellitus.

    PubMed

    Li, Yan; Li, Shaoru; Zhai, Qianqian; Hai, Jie; Wang, Di; Cao, Meng; Zhang, Qinggui

    2015-01-01

    We conducted a case-control study to investigate the association between GSTM1, GSTT1 and GSTP1 IIe105Val polymorphisms and development of gestational diabetes mellitus in a Chinese population. A total of 320 patients with gestational diabetes mellitus and 358 pregnancy subjects were consecutively collected between January 2013 and December 2014. Genotyping for detection of GSTM1, GSTT1 and GSTP1 IIe105Val was conducted by using PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphisms) method. By Fisher's exact test, we found that the genotype distributions of GSTP1 IIe105Val were in line with the Hardy-Weinberg equilibrium in control subjects (P=0.57). By Chi-square test, we found significant differences in the genotype distributions of GSTM1 (χ(2)=11.49, P=0.001) and GSTT1 (χ(2)=18.50, P<0.001). Using unconditional logistic analysis, individuals carrying the null genotypes of GSTM1 and GSTT1 were associated with an increased risk of gestational diabetes mellitus when compared with the present genotype, and the adjusted Ors (95% CI) were 1.71 (1.24-2.36) and 2.00 (1.44-2.79), respectively. However, the GSTP1 IIe105Val polymorphism was not associated with an elevated risk of gestational diabetes mellitus. In conclusion, we suggest that the GSTM1 null genotype and GSTT1 null genotype are correlated with an increased risk of gestational diabetes mellitus in a Chinese population.

  13. Structural Perturbations in the Ala → Val Polymorphism of Methylenetetrahydrofolate Reductase: How Binding of Folates May Protect against Inactivation†‡

    PubMed Central

    Pejchal, Robert; Campbell, Elizabeth; Guenther, Brian D.; Lennon, Brett W.; Matthews, Rowena G.; Ludwig, Martha L.

    2006-01-01

    In human methylenetetrahydrofolate reductase (MTHFR) the Ala222Val (677C → T) polymorphism encodes a heat-labile gene product that is associated with elevated levels of homocysteine and possibly with risk for cardiovascular disease. Generation of the equivalent Ala to Val mutation in Escherichia coli MTHFR, which is 30% identical to the catalytic domain of the human enzyme, creates a protein with enhanced thermolability. In both human and E. coli MTHFR, the A → V mutation increases the rate of dissociation of FAD, and in both enzymes, loss of FAD is linked to changes in quaternary structure [Yamada, K., Chen, Z., Rozen, R., and Matthews, R. G. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 14853–14858; Guenther, B. D., Sheppard, C. A., Tran, P., Rozen, R., Matthews, R. G., and Ludwig, M. L. (1999) Nat. Struct. Biol. 6, 359–365]. Folates have been shown to protect both human and bacterial enzymes from loss of FAD. Despite its effect on affinity for FAD, the A → V mutation is located at the bottom of the (βα)8 barrel of the catalytic domain in a position that does not contact the bound FAD prosthetic group. Here we report the structures of the Ala177Val mutant of E. coli MTHFR and of its complex with the 5,10-dideazafolate analogue, LY309887, and suggest mechanisms by which the mutation may perturb FAD binding. Helix α5, which immediately precedes the loop bearing the mutation, carries several residues that interact with FAD, including Asn168, Arg171, and Lys172. In the structures of the mutant enzyme this helix is displaced, perturbing protein–FAD interactions. In the complex with LY309887, the pterin-like ring of the analogue stacks against the si face of the flavin and is secured by hydrogen bonds to residues Gln183 and Asp120 that adjoin this face. The direct interactions of bound folate with the cofactor provide one mechanism for linkage between binding of FAD and folate binding that could account in part for the protective action of folates

  14. The Influence of the Brain‐Derived Neurotropic Factor Val66Met ‐Genotype and HMG‐CoA Reductase Inhibitors on Insulin Resistance in the Schizophrenia and Bipolar Populations

    PubMed Central

    Burghardt, K.J.; Pop‐Busui, R.; Bly, M.J.; Grove, T.B.; Taylor, S.F.; Ellingrod, V.L.

    2012-01-01

    Abstract Introduction: The brain‐derived neurotrophic factor (BDNF) Val66Met variant and HMG‐COA reductase inhibitors (statins) have been implicated in insulin resistance with a possible increased risk of diabetes. We sought to determine the effect of the BDNF Met variant and statin medication use on insulin resistance in schizophrenia and bipolar disorder using the homeostasis model assessment of insulin resistance (HOMA‐IR). Methods: A cross‐sectional design was used and patients with diabetes or on any medications affecting glucose regulation were ‐excluded. Associations between insulin resistance and genotype were then analyzed by ANOVA and regression analysis. Subjects were grouped by BDNF genotype as well as presence of statin. Results: Two hundred fifty‐two subjects with a mean age of 44 years were included. The group was 53% male and 41% had a diagnosis of bipolar disorder; 78% and 19% were receiving atypical antipsychotics (AAPs) and statin medications, respectively. Analysis showed schizophrenia subjects with the BDNF met allele as well as schizophrenia subjects with both the BDNF met allele and were receiving a statin had significantly higher HOMA‐IR values compared to the other groups (p= 0.046 and p= 0.016, respectively). Conclusions: Our results suggest that in the metabolically high‐risk population of schizophrenia the BDNF met allele alone and in combination with statin medications is associated with higher insulin resistance values. This was not seen in the bipolar population. Further validation of these associations remains necessary. Clin Trans Sci 2012; Volume 5: 486–490 PMID:23253673

  15. The Contribution of Matrix Metalloproteinase-8 Promoter Polymorphism to Oral Cancer Susceptibility.

    PubMed

    Hung, Yi-Wen; Tsai, Chia-Wen; Wu, Cheng-Nan; Shih, Liang-Chun; Chen, Yen-Yu; Liu, Yen-Fang; Hung, Huey-Shan; Shen, Ming-Yi; Chang, Wen-Shin; Bau, DA-Tian

    2017-01-01

    Metalloproteinases (MMPs) are a family of multifunctional proteins reported to be overexpressed in several types of cancers. However, the contribution of MMP8 genotype to oral cancer has not been elucidated. In this study, we focused on the contribution of polymorphisms in the promoter region of MMP-8 (C-799T) and two non-synonymous polymorphisms (Val436Ala and Lys460Thr) to Taiwanese oral cancer. In this case-control study, MMP-8 genotype, was examined among 788 patients with oral cancer and 956 gender- and age-matched healthy controls regarding its potential to determine oral cancer risk. The distributions of MMP-8 C-799T, Val436Ala and Lys460Thr genotypes were not different between the oral cancer and non-cancer control groups. We also analyzed the allelic frequency distributions and no significant difference was found. As for gene-environment interaction analysis, there was an increased risk for smokers, alcohol drinkers or betel quid chewers with variant MMP-8 C-799T or Val436Ala genotypes. Our findings suggest that the polymorphisms at MMP-8 C-799T or Val436Ala may not play a major role in mediating personal risk of oral cancer; however, the detailed mechanisms require further investigation. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  16. Hb Valletta [beta87(F3)Thr-->Pro] and Hb Marseille/Long Island [beta2(NA2)His-->Pro; (-1)Met-(+1)Val-(+2)Pro-Leu], in a unique compound heterozygote with a normal hemoglobin phenotype.

    PubMed

    Galdies, Ruth; Cassar, Wilhelmina; Pizzuto, Monica; Scerri, Christian A; Felice, Nicholas; Cassar, Olivianne A; Buttigieg, George; Felice, Alex E

    2010-01-01

    This study refers to the quantitative hemoglobin (Hb) phenotype of a 19-year-old female with Hb Valletta [beta87(F3)Thr-->Pro] in association with Hb Marseille/Long Island [beta2(NA2)His-->Pro; (-1)Met-(+1)Val-(+2)Pro-Leu] and a normal Hb electrophoretogram. The data serve to alert investigators to the possibility that relatives with apparently normal Hb phenotypes may be transmitting mutant alleles and suggest methods for identification.

  17. White matter integrity in major depressive disorder: Implications of childhood trauma, 5-HTTLPR and BDNF polymorphisms.

    PubMed

    Tatham, Erica L; Ramasubbu, Rajamannar; Gaxiola-Valdez, Ismael; Cortese, Filomeno; Clark, Darren; Goodyear, Bradley; Foster, Jane; Hall, Geoffrey B

    2016-07-30

    This study examined the impact of childhood neglect, serotonin transporter (5-HTTLPR) and brain derived neurotrophic factor (BDNF) polymorphisms on white matter (WM) integrity in major depressive disorder (MDD) using diffusion tensor imaging (DTI). Fifty-five medication-free MDD patients and 18 controls underwent diffusion tensor imaging scanning, genotyping and completed the Childhood Trauma Questionnaire. Tract based spatial statistics (TBSS) findings revealed reduced fractional anisotropy (FA) in the MDD group in the anterior internal capsule. 5-HTTLPR-S'L' heterozygotes in the MDD group exhibited reduced FA in the internal capsule relative to S'S' and reduced FA in corona radiata compared to L'L'. Probabilistic tractography revealed higher FA in the uncinate fasciculus (UF) for BDNF val/val genotype relative to met-carriers, particularly in individuals with high depression severity. High depression severity and experiences of childhood physical or emotional neglect predicted higher FA in the UF and superior longitudinal fasciculus. Reductions in FA were identified for subgroups of MDD patients who were 5-HTTLPR heterozygotes and BDNF-met carriers. An association between emotional/physical neglect and FA was observed in subjects with high depressive symptoms. Our findings suggest that WM connectivity within frontal and limbic regions are affected by depression and influenced by experiences of neglect and genetic risk factors. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  18. Plasma urotensin-2 level and Thr21Met but not Ser89Asn polymorphisms of the urotensin-2 gene are associated with migraines.

    PubMed

    Geyik, Sırma; Ergun, Sercan; Kuzudişli, Samiye; Şensoy, Figen; Temiz, Ebru; Altunışık, Erman; Korkmaz, Murat; Dağlı, Hasan; Kul, Seval; Akçalı, Aylin; Neyal, Ayşe Münife

    2016-01-01

    Urotensin-II (U-II) is a peptide recognized by its potent vasoconstrictor activity in many vascular events, however the role of urotensin-II in migraine has not been considered yet. The molecular mechanisms and genetics of migraine have not been fully clarified yet, but it is well-known that vascular changes considerably contribute in pathophysiology of migraine and also its complications. The aim of this study was to analyze the plasma U-II levels along with genotype distributions and allele frequencies for UTS2 Thr21Met and Ser89Asn polymorphisms among the patients with migraine without aura (MWoA). One hundred eighty-six patients with MWoA and 171 healthy individuals were included in this study. Plasma U-II levels were measured in attack free period. The genotype and allele frequencies for the Thr21Met (T21M) and Ser89Asn (S89N) polymorphisms in the UTS2 gene were analyzed. Plasma U-II levels were significantly higher in MWoA patients (p = 0.002). We detected a significant association between the T21M polymorphism in the UTS2 gene and migraine (53.8 % in patients, 40.4 % in controls, p = 0.035), but not with S89N polymorphism (p = 0.620). A significant relationship was found between U-II levels and MIDAS score (β = 0.508, p = 0.001). Our study suggests that U-II may play a role in migraine pathogenesis; also Thr21Met polymorphism was associated with the risk of migraine disease. Further studies are needed for considering the role of U-II in migraine pathophysiology and for deciding if UTS2 gene may be a novel candidate gene in migraine cases.

  19. Unexpected combined effects of NADH dehydrogenase subunit-2 237 Leu/Met polymorphism and green tea consumption on renal function in male Japanese health check-up examinees: a cross-sectional study.

    PubMed

    Kokaze, Akatsuki; Ishikawa, Mamoru; Matsunaga, Naomi; Karita, Kanae; Yoshida, Masao; Ohtsu, Tadahiro; Ochiai, Hirotaka; Shirasawa, Takako; Nanri, Hinako; Hoshino, Hiromi; Takashima, Yutaka

    2013-11-20

    NADH dehydrogenase subunit-2 237 leucine/methionine (ND2-237 Leu/Met) polymorphism is associated with longevity in Japanese. A previous study has shown that ND2-237 Leu/Met polymorphism modulates the effects of green tea consumption on risk of hypertension. For men with ND2-237Leu, habitual green tea consumption may reduce the risk of hypertension. Moreover, there is a combined effect of ND2-237 Leu/Met polymorphism and alcohol consumption on risk of mildly decreased estimated glomerular filtration rate (eGFR) (<90 ml/min/1.73 m2). Several beneficial effects of green tea on the kidney have been reported. The objective of this study was to investigate whether ND2-237 Leu/Met polymorphism modifies the effects of green tea consumption on risk of mildly decreased eGFR in male Japanese health check-up examinees. For ND2-237Leu genotypic men, after adjustment for confounding factors, green tea consumption may increase the risk of mildly decreased eGFR (P for trend = 0.016). The adjusted odds ratio (OR) for mildly decreased eGFR was significantly higher in subjects with ND2-237Leu who consume ≥6 cups of green tea per day than those who consume ≤1 cup of green tea per day (adjusted OR = 5.647, 95% confidence interval: 1.528-20.88, P = 0.009). On the other hand, for ND2-237Met genotypic men, green tea consumption does not appear to determine the risk of mildly decreased eGFR. The present results suggest that ND2-237 Leu/Met polymorphism unexpectedly modifies the effects of green tea consumption on eGFR and the risk of mildly decreased eGFR in male Japanese subjects.

  20. Unexpected combined effects of NADH dehydrogenase subunit-2 237 Leu/Met polymorphism and green tea consumption on renal function in male Japanese health check-up examinees: a cross-sectional study

    PubMed Central

    2013-01-01

    Background NADH dehydrogenase subunit-2 237 leucine/methionine (ND2-237 Leu/Met) polymorphism is associated with longevity in Japanese. A previous study has shown that ND2-237 Leu/Met polymorphism modulates the effects of green tea consumption on risk of hypertension. For men with ND2-237Leu, habitual green tea consumption may reduce the risk of hypertension. Moreover, there is a combined effect of ND2-237 Leu/Met polymorphism and alcohol consumption on risk of mildly decreased estimated glomerular filtration rate (eGFR) (<90 ml/min/1.73 m2). Several beneficial effects of green tea on the kidney have been reported. The objective of this study was to investigate whether ND2-237 Leu/Met polymorphism modifies the effects of green tea consumption on risk of mildly decreased eGFR in male Japanese health check-up examinees. Results For ND2-237Leu genotypic men, after adjustment for confounding factors, green tea consumption may increase the risk of mildly decreased eGFR (P for trend = 0.016). The adjusted odds ratio (OR) for mildly decreased eGFR was significantly higher in subjects with ND2-237Leu who consume ≥6 cups of green tea per day than those who consume ≤1 cup of green tea per day (adjusted OR = 5.647, 95% confidence interval: 1.528-20.88, P = 0.009). On the other hand, for ND2-237Met genotypic men, green tea consumption does not appear to determine the risk of mildly decreased eGFR. Conclusion The present results suggest that ND2-237 Leu/Met polymorphism unexpectedly modifies the effects of green tea consumption on eGFR and the risk of mildly decreased eGFR in male Japanese subjects. PMID:24252463