Functional Val158Met Polymorphism Research Articles

A Novel Mutation in the MAP7D3 Gene in Two Siblings with Severe Intellectual Disability and Autistic Traits: Concurrent Assessment of BDNF Functional Polymorphism, X-Inactivation and Oxidative Stress to Explain Disease Severity.

Intellectual disabilities (ID) and autism spectrum disorders (ASD) are characterized by extreme genetic and phenotypic heterogeneity. However, understanding this heterogeneity is difficult due to the intricate interplay among multiple interconnected genes, epigenetic factors, oxidative stress, and environmental factors. Employing next-generation sequencing (NGS), we revealed the genetic cause of ID and autistic traits in two patients from a consanguineous family followed by segregation analysis. Furthermore, in silico prediction methods and 3D modeling were conducted to predict the effect of the variants. To establish genotype-phenotype correlation, X-chromosome inactivation using Methylation-specific PCR and oxidative stress markers were also investigated. By analyzing the NGS data of the two patients, we identified a novel frameshift mutation c.2174_2177del (p.Thr725MetfsTer2) in the MAP7D3 gene inherited from their mother along with the functional BDNF Val66Met polymorphism inherited from their father. The 3D modeling demonstrated that the p.Thr725MetfsTer2 variant led to the loss of the C-terminal tail of the MAP7D3 protein. This change could destabilize its structure and impact kinesin-1's binding to microtubules via an allosteric effect. Moreover, the analysis of oxidative stress biomarkers revealed an elevated oxidative stress in the two patients compared to the controls. To the best of our knowledge, this is the first report describing severe ID and autistic traits in familial cases with novel frameshift mutation c.2174_2177del in the MAP7D3 gene co-occurring with the functional polymorphism Val66M in the BDNF gene. Besides, our study underlines the importance of investigating combined genetic variations, X-chromosome inactivation (XCI) patterns, and oxidative stress markers for a better understanding of ID and autism etiology.

Association between Val158Met polymorphism in the COMT gene with anxiety and heart rate variability in children with irritable bowel syndrome

The aim of this study was to examine the peculiarities of trait anxiety and heart rate variability parameters as well as their relationship depending on the catechol O-methyltransferase (COMT) gene Val158Met polymorphism in children with irritable bowel syndrome. Materials and methods. A total of 26 children aged 6–12 years with a verified diagnosis of irritable bowel syndrome according to the Rome IV criteria were examined. Beforehand, all the patients underwent molecular genetic testing for the COMT Val158met single nucleotide polymorphism by using the polymerase chain reaction-restriction fragment length polymorphism method. Heart rate variability was analyzed via cardiointervalography (Neurosoft) based on short five-minute resting-state ECG recordings. The CMAS (Children’s Manifest Anxiety Scale) test was used to measure trait anxiety levels. The Pearson’s test was used to assess correlations between heart rate variability parameters and anxiety levels. Data were processed using Microsoft Excel 2016 and analyzed with GraphPad (Prism 5.0). Results. Depending on the functional COMT Val158met polymorphism, all the patients were allocated to 3 groups: 8 children with 472 GA (Val/Met) COMT genotype; 10 children with 472 AA (Met/Met) genotype; 8 children with 472 GG (Val/Val) genotype. Time and frequency domain parameters of heart rate variability were significantly different in each group. The highest level of anxiety and the largest percentage of LF component (mainly sympathetic activity) in the structure of heart rate variability was noted among Met/Met carriers. Val/Val carriers had a significantly lower anxiety level and an autonomic imbalance with a higher percentage of HF component (parasympathetic activity). Positive correlations between trait anxiety and heart rate variability parameters were found only in Val/Val and Val/Met groups. Conclusions. Our study has revealed the influence of the COMT Val158met polymorphism on the level of trait anxiety and heart rate variability parameters. It is important for a better understanding of the gut-brain axis dysregulation and impaired stress resilience in children with irritable bowel syndrome. Also, these data could be used to improve current schemes for the treatment of irritable bowel syndrome, supplementing them with activation therapy, psychotherapy, psychopharmacotherapy.

How can ketamine be used to manage suicidal risk?

In France, suicidal behaviors remain a major public health issue. Depressed patients with suicidal ideation have more severe depressive symptoms, a more unfavorable disease course, and a greater number of suicide attempts than patients without suicidal ideation. Unfortunately, conventional antidepressants tend to be less effective in patients with suicidal tendencies than in those without. Nevertheless, promising advancements have emerged with the use of ketamine, which has shown significant and rapid efficacy in reducing the intensity of suicidal ideation in depressed patients within the first 72 h after its administration. Several mechanisms are potentially involved: (1) reduction of anhedonia. It has been demonstrated that ketamine reduces both anhedonia and suicidal ideation. In depressed patients, the reduction of anhedonia observed 2 h after ketamine administration is associated with metabolic changes in the anterior cingulate cortex involved in suicidal ideation; (2) activation of neuroplasticity cascades. The reduction in suicidal ideation within 24 h following ketamine administration is correlated with changes in plasma BDNF levels and is modulated by the Val66Met functional polymorphism of the BDNF gene. Moreover, preclinical and clinical studies have shown that ketamine induces functional and connectivity changes in the prefrontal and anterior cingulate regions, which are strongly implicated in suicidal behaviors; (3) reduction of inflammation. It is now widely accepted that suicidal behaviors are associated with low-grade inflammation, and with elevated quinolinic acid and reduced kynurenic acid levels. Interestingly, predictors of a reduction in suicidal ideation after ketamine infusion include initial severity of suicidal thoughts and depression, as well as baseline blood levels of kynurenic acid; (4) involvement of the opioidergic system. Post-mortem studies have indicated alterations in the opioidergic system related to suicidal behaviors. A recent study suggested that the antisuicidal effect of ketamine may depend on this system because naltrexone, an antagonist of mu opioid receptors, abolished the typical antidepressant effect and reduction in suicidal ideation observed following ketamine administration. In conclusion, ketamine exhibits promising potential in mitigating suicidal ideation - its effects are specific, rapid, albeit temporary. The suggested mechanisms driving its efficacy are multifaceted. Nevertheless, it is yet to be determined whether ketamine administration can effectively prevent suicidal behaviors.

Interaction between COMT Val158 Met polymorphism and childhood trauma predicts risk for depression in men.

Depression is a disabling illness with complex etiology. While the catechol-O-methyltransferase (COMT) gene, in particular the functional Val158 Met polymorphism, has been related to depression, the mechanisms underlying this gene-disease association are not completely understood. Therefore, we explore the association of COMT Val158 Met polymorphism with depression as well as its interaction with childhood trauma in 1136 young adults from a population-based study carried out in the city of Pelotas, Brazil. The diagnosis was performed through the Mini International Neuropsychiatric Interview 5.0 (MINI 5.0), and trauma was assessed with the Childhood Trauma Questionnaire (CTQ). Total DNA was extracted and genotyped by real-time PCR, and the QTLbase dataset was queried to perform large-scale quantitative trait locus (QTL) analysis. Our research showed no direct association between the Val158 Met polymorphism and the diagnosis of depression (women: χ2 =0.10, d= 1, p= 0.751; men: χ2 =0.003, df =1, p= 0.956). However, the Met-allele of the Val158 Met polymorphism modified the effect of childhood trauma in men (OR =2.58 [95% CI: 1.05-6.29]; p= 0.038) conferring risk for depression only on those who suffer from trauma. The conditional effect from moderation analysis showed that trauma impacts the risk of depression only in men carrying the Met-allele (effect: 0.9490, standard error [SE]: 0.2570; p= 0.0002). QTLbase and dataset for Val158 Met polymorphism were consistent for markers that influence chromatin accessibility transcription capacity including histone methylation and acetylation. The changes caused in gene regulation by childhood trauma exposure and polymorphism may serve as evidence of the mechanism whereby the interaction increases susceptibility to this disorder in men.

Catechol-O-methyltransferase activity does not influence emotional processing in men.

Background:Catechol-O-methyltransferase (COMT) regulates cortical dopaminergic transmission and prefrontal-dependent cognitive function. However, its role in other cognitive processes, including emotional processing, is relatively unexplored. We therefore investigated the separate and interactive influences of COMT inhibition and Val158Met (rs4680) genotype on performance on an emotional test battery.Methods:We recruited 74 healthy men homozygous for the functional COMT Val158Met polymorphism. Volunteers were administered either a single 200 mg dose of the brain-penetrant COMT inhibitor tolcapone or placebo in a double-blind, randomised manner. Emotional processing was assessed using the emotional test battery, and mood was rated using visual analogue scales and the Profile of Mood States (POMS) questionnaire across the test day.Results:There were no main or interactive effects of Val158Met genotype or tolcapone on any of the emotional processing measures or mood ratings.Conclusions:Our findings suggest that, at least in healthy adult men, COMT has little or no effect on emotional processing or mood. These findings contrast with several neuroimaging studies that suggest that COMT modulates neural activity during emotional processing. Thus, further studies are required to understand how COMT impacts on the relationship between behavioural output and neural activity during emotional processing. Nevertheless, our data suggest that novel COMT inhibitors under development for treating cognitive dysfunction are unlikely to have acute off target effects on emotional behaviours.

Dopaminergic modulation of regional cerebral blood flow: An arterial spin labelling study of genetic and pharmacological manipulation of COMT activity

Dopamine has direct and complex vasoactive effects on cerebral circulation. Catechol-O-methyltransferase (COMT) regulates cortical dopamine, and its activity can be influenced both genetically and pharmacologically. COMT activity influences the functional connectivity of the PFC at rest, as well as its activity during task performance, determined using blood oxygen level-dependent (BOLD) fMRI. However, its effects on cerebral perfusion have been relatively unexplored. Here, 76 healthy males, homozygous for the functional COMT Val158Met polymorphism, were administered either the COMT inhibitor tolcapone or placebo in a double-blind, randomised design. We then assessed regional cerebral blood flow at rest using pulsed arterial spin labelling. Perfusion was affected by both genotype and drug. COMT genotype affected frontal regions (Val158 > Met158), whilst tolcapone influenced parietal and temporal regions (placebo > tolcapone). There was no genotype by drug interaction. Our data demonstrate that lower COMT activity is associated with lower cerebral blood flow, although the regions affected differ between those affected by genotype compared with those altered by acute pharmacological inhibition. The results extend the evidence for dopaminergic modulation of cerebral blood flow. Our findings also highlight the importance of considering vascular effects in functional neuroimaging studies, and of exercising caution in ascribing group differences in BOLD signal solely to altered neuronal activity if information about regional perfusion is not available.

The importance of identifying functional Val158Met polymorphism in catechol-O- Methyltransferase when assessing MRI-based volumetric measurements in major depressive disorder.

Many studies have shown volumetric differences in the hippocampus between COMT gene polymorphisms and other studies have shown differences between depressed patients and controls; yet, few studies have been completed to identify the volumetric differences when taking both factors into consideration. Using voxel-based morphology (VBM) we investigated, in major depressive disorder (MDD) patients and healthy controls, the relationship between COMT gene polymorphism and volumetric abnormalities. Data from 60 MDD patients and 25 healthy controls were included in this study. Volumetric measurements and genotyping of COMTval158met polymorphism were conducted to determine its impact on gray matter volume (GMV) in the hippocampus and amygdala using a Met dominant model (Val/Val vs Met/Val & Met/Met). In the analysis, a significant difference in the right hippocampus (p = 0.015), right amygdala (p = 0.003) and entire amygdala (p = 0.019) was found between the interaction of diagnosis and genotype after MRI scanner, age and sex correction. Healthy controls (HC) with the Met dominant genotype exhibited a larger right hippocampal, right amygdalar and entire amydgalar volume than MDD patients with the Met dominant genotype. Conversely, HC with the Val/Val genotype displayed a lower right hippocampal, right amygdalar and entire amygdalar volume than their MDD counterparts. This study shows that COMT polymorphism and depression may have a confounding effect on neuroimaging studies.

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

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

The extra virgin olive oil phenolic oleacein is a dual substrate-inhibitor of catechol-O-methyltransferase

Catechol-containing polyphenols present in coffee and tea, while serving as excellent substrates for catechol-O-methyltransferase (COMT)-catalyzed O-methylation, can also operate as COMT inhibitors. However, little is known about the relationship between COMT and the characteristic phenolics present in extra virgin olive oil (EVOO). We here selected the EVOO dihydroxy-phenol oleacein for a computational study of COMT-driven methylation using classic molecular docking/molecular dynamics simulations and hybrid quantum mechanical/molecular mechanics, which were supported by in vitro activity studies using human COMT. Oleacein could be superimposed onto the catechol-binding site of COMT, maintaining the interactions with the atomic positions involved in methyl transfer from the S-adenosyl-L-methionine cofactor. The transition state structure for the meta-methylation in the O5 position of the oleacein benzenediol moiety was predicted to occur preferentially. Enzyme analysis of the conversion ratio of catechol to O-alkylated guaiacol confirmed the inhibitory effect of oleacein on human COMT, which remained unaltered when tested against the protein version encoded by the functional Val158Met polymorphism of the COMT gene. Our study provides a theoretical determination of how EVOO dihydroxy-phenols can be metabolized via COMT. The ability of oleacein to inhibit COMT adds a new dimension to the physiological and therapeutic utility of EVOO secoiridoids.

P.2.034 - Genotype-dependent deterioration of sustained attention by the COMT inhibitor tolcapone after sleep deprivation

Introduction Elevated sleepiness and impaired vigilance due to medical disorders, is often treated by drugs that enhance dopaminergic neurotransmission, including modafinil, caffeine or cocaine [1]. Tolcapone is a brain penetrant selective inhibitor of catechol-O-methyltransferase (COMT) devoid of psychostimulant properties that leads to relatively specific increases in prefrontal cortex (PFC) dopamine signaling [2,3]. Because it hardly affects striatal domapinergic transmission, tolcapone may mitigate subjective and behavioral consequences of sleep deprivation without unwanted psychostimulant adverse effects [2]. Tolcapone also improves cognition and cortical information processing in rested volunteers, depending on the genotype of the functional Val158Met polymorphism of COMT [3]. The impact of this common genetic variant for efficient treatment of hypersomnolence and behavioral markers of increased sleep need after sleep loss is controversial. Here we investigated the potential usefulness of tolcapone to mitigate consequences of sleep deprivation on lapses of sustained attention, and tested the hypothesis that dopamine signaling in the prefrontal cortex (PFC) causally contributes to neurobehavioral and neurophysiological markers of human sleep homeostasis. Methods We first quantified the impact of COMT genotype (SNP-Id: rs4680) on the evolution of attentional lapses during two days of extended wakefulness in a non-tolcapone treated group of 73 volunteers. Subsequently, in an independent group of 30 healthy male study participants, we tested whether selective inhibition of COMT activity by tolcapone counteracts attentional and neurophysiological markers of elevated sleep need in a COMT genotype-dependent manner. 2 x 100 mg tolcapone were administered after 11 and 23 hours, in a randomized, double-blind, placebo-controlled, cross-over design. The psychomotor Vigilance Test (PVT) and objective electroencephalogram (EEG) recordings were carried out in three-hour intervals among all 103 volunteers across the 40 hours of prolonged wakefulness. Repeated measure linear mixed-models were applied, followed by multiple comparison corrected post-hoc testing when appropriate. Results Both COMT genotype and tolcapone modulated the sleep-loss induced impairment of vigilant attention. More specifically, data from the non-tolcapone treated group revealed that Val/Met heterozygotes produced twice as many lapses after a night without sleep compared to Met/Met homozygotes (p Conclusions The current results demonstrate that PFC dopaminergic neurotransmission regulates attentional lapses during sleep deprivation without changing neurophysiological markers of sleep homeostasis. Intriguingly, selective inhibition of COMT can even reverse the expected beneficial effects of pharmacologically enhanced dopaminergic tone after prolonged wakefulness. These findings may have important implications, given the increased use of stimulants in healthy people aimed at improving vigilance and cognitive functions [1,4].

Val66Met functional polymorphism and serum protein level of brain-derived neurotrophic factor (BDNF) in acute episode of schizophrenia and depression.

Brain-derived neurotrophic factor (BDNF) influences neuron differentiation during development as well as the synaptic plasticity and neuron survival in adulthood. BDNF has been implicated in the pathogenesis of schizophrenia and depression. Val66Met polymorphism and BDNF serum level are potential biomarkers in neuropsychiatric disorders. The aim of this study was to determine the effect of BDNF gene Val66Met functional polymorphism on serum BDNF concentration in patients with schizophrenia, during depression episode and in healthy control group. 183 participants were recruited (61 patients with depressive episode, 56 females with schizophrenia, 66 healthy controls) from Polish population. Serum BDNF levels were measured using ELISA method. Val66Met polymorphism was genotyped using PCR- RFLP method. Serum BDNF levels were not associated with Val66Met polymorphism in either of the groups. A significant increase of BDNF level in schizophrenia (p = 0.0005) and depression (p = 0.026) comparing to the control group has been observed. Our results suggest that the functional Val66Met BDNF polymorphism is not associated with BDNF serum levels, which is in line with previous findings. Replication studies on larger groups are needed.

The Impact of BDNF Polymorphisms on Suicidality in Treatment-Resistant Major Depressive Disorder: A European Multicenter Study.

BackgroundNumerous studies have reported associations between the brain-derived neurotrophic factor (BDNF) gene and psychiatric disorders, including suicidal behavior, although with conflicting results.MethodsA 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.ResultsNeither 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%).ConclusionsConsidering 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.

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

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.

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

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.

The correlation between plasma brain-derived neurotrophic factor and cognitive function in bipolar disorder is modulated by the BDNF Val66Met polymorphism

ObjectivesBrain-derived neurotrophic factor (BDNF) may be involved in the pathogenesis of bipolar disorder (BD). The functional BDNF Val66Met polymorphism (rs6265) is associated with secretion of BDNF. The current study aimed to explore the correlation between changes of plasma BDNF and cognitive function after 12 week of treatment, considering the influence of the BDNF val66Met polymorphism. The correlation of changes of plasma BDNF with quality of life (QOL) was explored.MethodsFirst diagnosed patients with BD were recruited. Symptom severity, plasma BDNF levels were examined during weeks 0, 1, 2, 4, 8, and 12. QOL, Wisconsin Card Sorting Test (WCST) and the Conners’ Continuous Performance Test (CPT) were assessed at baseline and endpoint. The genotype of the BDNF Val66Met polymorphism was determined. The change of cognitive function and QOL measures over 12 weeks were reduced by factor analysis. Pearson's correlation was used to investigate the association between change of plasma BDNF levels with cognitive function and QOL.ResultsFive hundred and forty-one BP patients were recruited. Three hundred and fifty-five (65.6%) patients completed the 12-week follow-up. A significant negative correlation was found between changes of plasma BDNF level with factor 1 (WCST) (r = −0.25, P < 0.001). After further stratification according to subtypes of BD and the BDNF genotypes, above significant correlation was found only in those with BP-I and the BDNF Val66Met Val/Met genotype (r = −0.54, P < 0.008).ConclusionWe conclude that changes in plasma BDNF significantly correlated with changes in WCST in patients with BD; such correlation is moderated by the BDNF Val66Met polymorphism and subtype of BD.Disclosure of interestThe author has not supplied his declaration of competing interest.

Genes of the dopaminergic system selectively modulate top-down but not bottom-up attention.

Cognitive performance is modulated by the neurotransmitter dopamine (DA). Recently, it has been proposed that DA has a strong impact on top-down but not on bottom-up selective visual attention. We tested this assumption by analyzing the influence of two gene variants of the dopaminergic system. Both the catechol O-methyltransferase (COMT) protein and the dopamine transporter (DAT) protein are crucial for the degradation and inactivation of DA. These metabolizing proteins modulate the availability of DA, especially in the prefrontal cortex and basal ganglia. The functional COMT Val158Met polymorphism of the COMT gene represents two coding variants, valine and methionine. In Met allele carriers, the COMT activity is reduced three- to fourfold. A variable number of tandem repeats (VNTR) polymorphism exists in the DAT1 gene, which encodes DAT. The DAT density was reported to be about 50% higher for the DAT1 10-repeat than the DAT1 9-repeat allele. We assessed attention via two experimental tasks that predominantly measure either top-down processing (the Stroop task) or bottom-up processing (the Posner-Cuing task). Carriers of the Met allele of the COMT Val158Met polymorphism displayed better performance in the Stroop task, but did not outperform the other participants in the Posner-Cuing task. The same result was noted for carriers of the DAT1 10-repeat allele. From these findings, we suggest that normal variations of the dopaminergic system impact more strongly on top-down than on bottom-up attention.

Identification of BDNF sensitive electrophysiological markers of synaptic activity and their structural correlates in healthy subjects using a genetic approach utilizing the functional BDNF Val66Met polymorphism.

Increasing evidence suggests that synaptic dysfunction is a core pathophysiological hallmark of neurodegenerative disorders. Brain-derived neurotropic factor (BDNF) is key synaptogenic molecule and targeting synaptic repair through modulation of BDNF signalling has been suggested as a potential drug discovery strategy. The development of such “synaptogenic” therapies depend on the availability of BDNF sensitive markers of synaptic function that could be utilized as biomarkers for examining target engagement or drug efficacy in humans. Here we have utilized the BDNF Val66Met genetic polymorphism to examine the effect of the polymorphism and genetic load (i.e. Met allele load) on electrophysiological (EEG) markers of synaptic activity and their structural (MRI) correlates. Sixty healthy adults were prospectively recruited into the three genetic groups (Val/Val, Val/Met, Met/Met). Subjects also underwent fMRI, tDCS/TMS, and cognitive assessments as part of a larger study. Overall, some of the EEG markers of synaptic activity and brain structure measured with MRI were the most sensitive markers of the polymorphism. Met carriers showed decreased oscillatory activity and synchrony in the neural network subserving error-processing, as measured during a flanker task (ERN); and showed increased slow-wave activity during resting. There was no evidence for a Met load effect on the EEG measures and the polymorphism had no effects on MMN and P300. Met carriers also showed reduced grey matter volume in the anterior cingulate and in the (left) prefrontal cortex. Furthermore, anterior cingulate grey matter volume, and oscillatory EEG power during the flanker task predicted subsequent behavioural adaptation, indicating a BDNF dependent link between brain structure, function and behaviour associated with error processing and monitoring. These findings suggest that EEG markers such as ERN and resting EEG could be used as BDNF sensitive functional markers in early clinical development to examine target engagement or drug related efficacy of synaptic repair therapies in humans.

Investigation of Brain‐Derived Neurotrophic Factor (BDNF) Gene Variants in Migraine

A number of observations have suggested that brain-derived neurotrophic factor (BDNF) plays a role in migraine pathophysiology. This study investigates whether variants in the BDNF gene are associated with migraine in an Australian case-control population. BDNF has an important role in neural growth, development, and survival in the central nervous system and is an important modulator of central and peripheral pain responses. Variants in BDNF, in particular the functional Val66Met polymorphism (rs6265), have been found to be associated with a number of psychiatric disorders, cognitive function, and obesity. As BDNF has been found to be differentially expressed in a number of aspects related to migraine, we tested for association between single nucleotide polymorphisms (SNPs) in BDNF and migraine. Five SNPs in the BDNF locus (rs1519480, rs6265, rs712507, rs2049046, and rs12273363) were genotyped initially in a cohort of 277 migraine cases, including 172 diagnosed with migraine with aura (MA) and 105 with migraine without aura (MO), and 277 age- and sex-matched controls. Three of these SNPs (rs6265, rs2049046, and rs12273363) were subsequently genotyped in a second cohort of 580 migraineurs, including 473 diagnosed with MA and 105 with MO, and 580 matched controls. BDNF SNPs rs1519480, rs6265, rs712507, and rs12273363 were not significantly associated with migraine. However, rs2049046 showed a significant association with migraine, and in particular, MA in the first cohort. In the second cohort, although an increase in the rs2049046 T-allele frequency was observed in migraine cases, and in both MA and MO subgroups, it was not significantly different from controls. Analysis of data combined from both cohorts for rs2049046 showed significant differences in the genotypic and allelic distributions for this marker in both migraine and the MA subgroup. This study confirmed previous studies that the functional BDNF SNP rs6265 (Val66Met) is not associated with migraine. However, we found that rs2049046, which resides at the 5' end of one the BDNF transcripts, may be associated with migraine, suggesting that further investigations of this SNP may be warranted.

Brain‐derived neurotrophic factor gene polymorphism predicts interindividual variation in the sleep electroencephalogram

Previous studies have suggested that brain-derived neurotrophic factor (BDNF) participates in the homeostatic regulation of sleep. The objective of this study was to investigate the influence of the Val66Met functional polymorphism of the BDNF gene on sleep and sleep EEG parameters in a large population-based sample. In total 337 individuals participating in the São Paulo Epidemiologic Sleep Study were selected for analysis. None of the participants had indications of a sleep disorder, as measured by full-night polysomnography and questionnaire. Spectral analysis of the EEG was carried out in all individuals using fast Fourier transformation of the oscillatory signals for each EEG electrode. Sleep and sleep EEG parameters in individuals with the Val/Val genotype were compared with those in Met carriers (Val/Met and Met/Met genotypes). After correction for multiple comparisons and for potential confounding factors, Met carriers showed decreased spectral power in the alpha band in stage one and decreased theta power in stages two and three of nonrapid-eye-movement sleep, at the central recording electrode. No significant influence on sleep macrostructure was observed among the genotype groups. Thus, the Val66Met polymorphism seems to modulate the electrical activity of the brain, predicting interindividual variation of sleep EEG parameters. Further studies of this and other polymorphic variants in potential candidate genes will help the characterization of the molecular basis of sleep.

Genetic variation in brain-derived neurotrophic factor val66met allele is associated with altered serotonin-1A receptor binding in human brain

Brain Derived Neurotrophic Factor (BDNF) regulates brain synaptic plasticity. BDNF affects serotonin signaling, increases serotonin levels in brain tissue and prevents degeneration of serotonin neurons. These effects have hardly been studied in human brain. We examined the relationship of the functional val66met polymorphism of the BDNF gene to serotonin 1A (5-HT1A) receptor binding in vivo. 50 healthy volunteers (HV) and 50 acutely depressed, unmedicated patients with major depressive disorder (MDD) underwent PET scanning with the 5-HT1A receptor ligand, [11C]WAY-100635 and a metabolite corrected arterial input function. A linear mixed effects model compared 5-HT1A receptor binding potential (BPF, proportional to the number of available receptors) in 13 brain regions of interest between met allele carriers (met/met and val/met) and noncarriers (val/val) using sex and C-1019G genotype of the 5-HT1A receptor promoter functional polymorphism as covariates. There was an interaction between diagnosis and allele (F=4.23, df=1, 94, p=0.042), such that met allele carriers had 17.4% lower BPF than non-met carriers in the HV group (t=2.6, df=96, p=0.010), but not in the MDD group (t=−0.4, df=96, p=0.58). These data are consistent with a model where the met allele of the val66met polymorphism causes less proliferation of serotonin synapses, and consequently fewer 5-HT1A receptors. In MDD, however, the effect of the val66met polymorphism is not detectable, possibly due to a ceiling effect of over-expression of 5-HT1A receptors in mood disorders.