Influence of BDNF and COMT polymorphisms on emotional decision making

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.     

Association between the Val66Met polymorphism (rs6265/G196A) of the BDNF gene and cognitive performance with SSRI use in Arab Alzheimer’s disease patients

Brain derived neutrophic factor (BDNF) is a protein and a member of the neurotrophin family of growth factors, supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses. The BDNF gene Val66Met polymorphism (rs6265/G196A) is responsible for BDNF synthesis that impact BDNF function that includes memory and cognition.This study investigated whether the BDNF gene Val66Met polymorphism (rs6265/G196A) is associated with cognitive function changes in both Alzheimer disease (AD) patients and elderly participants. In addition the impact of SSRI use on cognition improvement will be assessed. Healthy young, middle ages (25–59 years old) and elderly (more than 60 years old) participants (140) as well as 40 AD patients of whom are both of Saudi Arabian origin were recruited. The genotyping for the association study was performed by real-time PCR using Taqman chemistry in the ABI Prism 7900HT Sequence Detection System. Both Mini-Mental Status Examination (MMSE) and Clinical Dementia Rating (CDR) were used to assess cognitive function of healthy and AD participants, respectively.The findings showed that the BDNF Val66Met genotype distributions and allele frequencies have significant association with cognitive performance in both elderly control group and AD patients. The main findings showed that carriers of GG homozygotes (Val/Val) have superior cognitive performance among AD patients and elderly control subjects. In addition the use of SSRIs in 13 AD patients and 17 elderly participants positively improved cognitive function in elderly (p > 0.001) but not in AD patients (p = 0.1).     

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

Background

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.

Association between the Val66Met polymorphism (rs6265/G196A) of the BDNF gene and cognitive performance with SSRI use in Arab Alzheimer’s disease patients

Brain derived neutrophic factor (BDNF) is a protein and a member of the neurotrophin family of growth factors, supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses. The BDNF gene Val66Met polymorphism (rs6265/G196A) is responsible for BDNF synthesis that impact BDNF function that includes memory and cognition.This study investigated whether the BDNF gene Val66Met polymorphism (rs6265/G196A) is associated with cognitive function changes in both Alzheimer disease (AD) patients and elderly participants. In addition the impact of SSRI use on cognition improvement will be assessed. Healthy young, middle ages (25–59 years old) and elderly (more than 60 years old) participants (140) as well as 40 AD patients of whom are both of Saudi Arabian origin were recruited. The genotyping for the association study was performed by real-time PCR using Taqman chemistry in the ABI Prism 7900HT Sequence Detection System. Both Mini-Mental Status Examination (MMSE) and Clinical Dementia Rating (CDR) were used to assess cognitive function of healthy and AD participants, respectively.The findings showed that the BDNF Val66Met genotype distributions and allele frequencies have significant association with cognitive performance in both elderly control group and AD patients. The main findings showed that carriers of GG homozygotes (Val/Val) have superior cognitive performance among AD patients and elderly control subjects. In addition the use of SSRIs in 13 AD patients and 17 elderly participants positively improved cognitive function in elderly (p > 0.001) but not in AD patients (p = 0.1).     

Interaction between BDNF Val66Met and dopamine transporter gene variation influences anxiety-related traits.

The involvement in neural plasticity and the mediation of effects of repeated stress exposure and long-term antidepressant treatment on hippocampal neurogenesis supports a critical role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of affective and other stress-related disorders. A previously reported valine to methionine substitution at amino-acid position 66 (BDNF Val66Met) seems to account for memory disturbance and hippocampal dysfunction. In the present study, we evaluated the impact of the BDNF Val66Met polymorphism on individual differences in personality traits in a sample of healthy volunteers in relation to other common gene variants thought to be involved in the pathophysiology of affective disorders, such as the serotonin transporter promoter polymorphism (5-HTTLPR) and a variable number of tandem repeat polymorphism of the dopamine transporter gene (DAT VNTR). Personality traits were assessed using the NEO personality inventory (NEO-PI-R) and Tridimensional Personality Questionnaire (TPQ). There was a significant DAT VNTR-dependent association between NEO-PI-R Neuroticism and the BDNF Val66Met polymorphism. Among individuals with at least one copy of the DAT 9-repeat allele, carriers of the BDNF Met allele exhibited significantly lower Neuroticism scores than noncarriers. This interaction was also observed for TPQ Harm Avoidance, a personality dimension related to Neuroticism. Our results support the notion that allelic variation at the BDNF locus--in interaction with other gene variants--influences anxiety- and depression-related personality traits.     

Alteration of the Centromedial Amygdala Glutamatergic Synapses by the BDNF Val66Met Polymorphism

Fear expression is mediated by an activation of the centromedial amygdala (CEm), the major output nucleus of the amygdaloid complex. Consistently, fear extinction is associated with an increased synaptic inhibition as well as a suppression of the excitability of the CEm neurons. However, little is known about the role of CEm glutamatergic synapses in fear regulation and anxiety-like behaviors. The BDNF Val66Met, a single-nucleotide polymorphism in the human BDNF gene, impairs fear extinction and leads to anxiety-like symptoms. To determine whether the BDNF Val66Met polymorphism affects the CEm excitatory synapses, we examined basal glutamatergic synaptic transmission and plasticity in the CEm neurons of BDNF Val66Met knock-in (BDNF^Met/Met) mice. The BDNF Val66Met single-nucleotide polymorphism exerted an opposite effect on non-NMDA and NMDA receptor transmission with a potentiation of the former and a suppression of the latter. In addition, the decay time of NMDA currents was decreased in BDNF^Met/Met mice, suggesting a modification of NMDA receptor subunit composition. Unlike the wild-type mice that exhibited a potentiation of non-NMDA receptor transmission following fear conditioning and a depotentiation upon fear extinction, BDNF^Met/Met mice failed to show this experience-dependent synaptic plasticity in the CEm neurons. Our results suggest that the elevated non-NMDA receptor transmission, the suppression of NMDA receptor transmission, and an impairment of synaptic plasticity in the CEm neurons might contribute to the fear extinction deficit and increased anxiety-like symptoms in BDNF Val66Met carriers.     

Association of a functional BDNF polymorphism and anxiety-related personality traits

Rationale Converging lines of evidence point to brain-derived neurotrophic factor (BDNF) as a factor in the pathophysiology of depression. Recently, it was shown that the Val allele of the BDNF Val66Met substitution polymorphism showed a significant association with higher mean neuroticism scores of the NEO-Five Factor Inventory (NEO-FFI) in healthy subjects, and previous studies suggested the Val allele to be increased in bipolar disorder families. The association to anxiety-related traits has not been investigated so far.Methods We tested a total of 343 unrelated subjects of German descent (171 male, 172 female, age: 39.0±14.6 years) who were carefully screened for psychiatric health. The self-ratable State–Trait Anxiety Inventory (STAI), which allows anxiety to be quantified as a comparatively stable personality trait, and the NEO-Five Factor Inventory (NEO-FFI) was applied.Results In the trait-related anxiety score, a significant (F=3.2, df=2, p<0.042) effect of the genotype was observed with higher levels of trait anxiety in Val/Val (35.0±7.4) compared to Val/Met (33.4±6.5) and Met/Met (32.0±4.6) genotypes. The NEO neuroticism scores were also higher in Val/Val (29.5±7.0) than in Val/Met (28.4±6.5) or Met/Met (26.8±5.8) genotype, but not at a significant rate.Conclusions Our findings support the hypothesis that anxiety- and depression-related personality traits are associated with the BDNF polymorphism although the explained variance is low.     

Meta-analysis of BDNF Val66Met polymorphism association with treatment response in patients with major depressive disorder

The aim of our meta-analysis was to assess the association between BDNF Val66Met polymorphism and treatment response in patients with MDD. 8 studies that included data from 1115 subjects were identified. We tested two phenotypes: response rate and remission rate. OR was used as a measure of the effect of the association in a fixed/random effect model. Meta-analysis was performed for genotypes Met/Met versus Val/Val, Val/Met versus Val/Val, Met/Met versus Val/Met, Val/Met + Met/Met versus Val/Val, Met/Met versus Val/Val + Val/Met, and Met allele versus Val allele. When all groups were pooled, a significant association of Val/Met genotype and increased response rate was found in comparison to Val/Val in overall population (OR = 1.66, 95%CI = 1.07–2.57, P = 0.02). In the subgroup analysis, similar result was shown in Asian population (OR = 1.83, 95%CI = 1.03–3.26, P = 0.04), but not in Caucasian population. We didn't observe a significant association of BDNF Val66Met polymorphism with remission rate. This meta-analysis demonstrates the association between BDNF Val66Met polymorphism and treatment response in patients with MDD, and Val66Met heterozygous patients have a better response rate in comparison to Val/Val homozygote patients, especially in Asian population.     

BDNF Val66Met Impairs Fluoxetine-Induced Enhancement of Adult Hippocampus Plasticity

Recently, a single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene (BDNF Val66Met) has been linked to the development of multiple forms of neuropsychiatric illness. This SNP, when genetically introduced into mice, recapitulates core phenotypes identified in human BDNF Val66Met carriers. In mice, this SNP also leads to elevated expression of anxiety-like behaviors that are not rescued with the prototypic selective serotonin reuptake inhibitor (SSRI), fluoxetine. A prominent hypothesis is that SSRI-induced augmentation of BDNF protein expression and the beneficial trophic effects of BDNF on neural plasticity are critical components for drug response. Thus, these mice represent a potential model to study the biological mechanism underlying treatment-resistant forms of affective disorders. To test whether the BDNF Val66Met SNP alters SSRI-induced changes in neural plasticity, we used wild-type (BDNF^Val/Val) mice, and mice homozygous for the BDNF Val66Met SNP (BDNF^Met/Met). We assessed hippocampal BDNF protein levels, survival rates of adult born cells, and synaptic plasticity (long-term potentiation, LTP) in the dentate gyrus either with or without chronic (28-day) fluoxetine treatment. BDNF^Met/Met mice had decreased basal BDNF protein levels in the hippocampus that did not significantly increase following fluoxetine treatment. BDNF^Met/Met mice had impaired survival of newly born cells and LTP in the dentate gyrus; the LTP effects remained blunted following fluoxetine treatment. The observed effects of the BDNF Val66Met SNP on hippocampal BDNF expression and synaptic plasticity provide a possible mechanistic basis by which this common BDNF SNP may impair efficacy of SSRI drug treatment.     

Impact of variation in the BDNF gene on social stress sensitivity and the buffering impact of positive emotions: Replication and extension of a gene–environment interaction

A previous study reported that social stress sensitivity is moderated by the brain-derived-neurotrophic-factor^Val66Met (BDNF rs6265) genotype. Additionally, positive emotions partially neutralize this moderating effect. The current study aimed to: (i) replicate in a new independent sample of subjects with residual depressive symptoms the moderating effect of BDNF^Val66Met genotype on social stress sensitivity, (ii) replicate the neutralizing impact of positive emotions, (iii) extend these analyses to other variations in the BDNF gene in the new independent sample and the original sample of non-depressed individuals.Previous findings were replicated in an experience sampling method (ESM) study. Negative Affect (NA) responses to social stress were stronger in “Val/Met” carriers of BDNF^Val66Met compared to “Val/Val” carriers. Positive emotions neutralized the moderating effect of BDNF^Val66Met genotype on social stress sensitivity in a dose–response fashion. Finally, two of four additional BDNF SNPs (rs11030101, rs2049046) showed similar moderating effects on social stress-sensitivity across both samples. The neutralizing effect of positive emotions on the moderating effects of these two additional SNPs was found in one sample.In conclusion, ESM has important advantages in gene–environment (GxE) research and may attribute to more consistent findings in future GxE research. This study shows how the impact of BDNF genetic variation on depressive symptoms may be explained by its impact on subtle daily life responses to social stress. Further, it shows that the generation of positive affect (PA) can buffer social stress sensitivity and partially undo the genetic susceptibility.     

BDNF levels and genotype are associated with antipsychotic-induced weight gain in patients with chronic schizophrenia.

Recent evidence suggests that centrally released brain-derived neurotrophic factor (BDNF) modulates eating behavior and metabolism that is responsible for body weight fluctuation. BDNF also may play an important role in the therapeutic action of antipsychotic medications. We investigated whether the Val66Met polymorphism of the BDNF gene affected weight gain after long-term antipsychotic treatment in schizophrenia. The polymorphism was genotyped in 196 Chinese patients with schizophrenia on long-term antipsychotic medication. Serum BDNF was measured in all patients and 50 normal controls. Mean body mass index (BMI) change was evaluated retrospectively by means of clinical records. The results showed that there was a significant relationship between the three BDNF Val/Met genotypes and mean BMI gain, with genotype having a strong effect on BMI gain in male but not female patients. BDNF levels were significantly lower in patients than normal controls, and negatively correlated with BMI gain in female but not male patients. Our results suggest that variation in the BDNF gene may be a risk factor for weight gain in male patients with schizophrenia on long-term antipsychotic treatment, and decreased BDNF levels may be associated with weight gain in females.     

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

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.     

The relationship between childhood abuse and dissociation. Is it influenced by catechol-O-methyltransferase (COMT) activity?

Dissociation is a failure of perceptual, memorial and emotional integration that is associated with a variety of psychiatric disorders. Dissociative processes are usually attributed to the sequelae of childhood trauma although there are data to suggest that genetic influences are also important. Bipolar disorder (BD), a condition with a strong genetic basis, has also been associated with early psychological trauma. Since childhood trauma is a risk factor for both BD and dissociation, we tested for potential gene-childhood abuse interactions on dissociation in a pilot sample of BD probands and their affected and unaffected relatives (n=178). Dissociation was measured with the Dissociative Experiences Scale (DES II) and childhood maltreatment with the Childhood Trauma Questionnaire (CTQ). The BD and recurrent unipolar depression (MDE-R) groups showed higher levels of self-reported abuse and dissociation than their unaffected relatives. The low-activity Met allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene was associated with lower levels of self-reported dissociation. Further, the functional catechol-O-methyltransferase (COMT) Val158Met polymorphism interacted significantly with total CTQ abuse scores to impact perceived dissociation. The Val/Val genotype was associated with increasing levels of dissociation in participants exposed to higher levels of childhood trauma. The opposite was observed in people with Met/Met genotypes who displayed decreased dissociation with increasing self-reported childhood trauma. The current findings support the involvement of the COMT Val158Met polymorphism in mediating the relationship between trauma and psychopathology.     

The BDNF Val66Met Polymorphism Modulates the Generalization of Cued Fear Responses to a Novel Context

Brain-derived neurotrophic factor (BDNF) has a crucial role in activity-dependent synaptic plasticity and learning and memory. The human functional single-nucleotide BDNF rs6265 (Val66Met) polymorphism has been found to be associated with alteration in neural BDNF release and function correlating with altered emotional behavior. Here, we investigated for the first time the hypothesis that this polymorphism in humans modulates the context dependency of conditioned fear responses. Applying a new paradigm examining generalization of cued fear across contexts, 70 participants stratified for BDNF Val66Met polymorphism were guided through two virtual offices (context) in which briefly illuminated blue and yellow lights served as cues. In the fear context, one light (conditioned stimulus, CS+) but not the other light (CS−) was associated with an electric shock (unconditioned stimulus, US). In the safety context, both lights were presented too, but no US was delivered. During the test phase, lights were presented again both in learning contexts and in a novel generalization context without any US. All participants showed clear fear conditioning to the CS+ in the fear context as indicated by potentiation of startle responses and reports of fear. No fear reactions were found for the CS+ in the safety context. Importantly, generalization of fear responses indicated by the potentiation of startle response to the CS+ compared with the CS− in the novel context was evident only in the Met-carrying group. These are the first results to provide evidence in humans that BDNF modulates the generalization of fear responses. Such context-dependent generalization processes might predispose Met carriers for affective and anxiety disorders.     

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

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.     

Brain-derived neurotrophic factor gene polymorphisms: influence on treatment response phenotypes of major depressive disorder

Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor family of neurotrophins, has pivotal roles in neuronal survival, proliferation, and synaptic plasticity in the brain. Both clinical and pharmacological studies have implicated the common single nucleotide polymorphism (SNP) at position 196, Val66Met in the pathophysiology of major depressive disorder (MDD), and antidepressant response. However, inconsistent results were found between Val66Met (rs6265) polymorphism and treatment response phenotypes in genetic association studies. The functional Val66Met polymorphism and seven other tagging SNP markers selected to capture the major allelic variations across BDNF locus were analyzed in depressed patients, treated with antidepressants, and 76 control patients. Two hundred and six patients with Diagnostic and Statistical Manual of Mental Disorders-IV MDD were recruited for this study and genotyped for eight BDNF tagging SNPs (rs11030096, rs925946, rs10501087,rs6265, rs12273363, rs908867, rs1491850, and rs1491851)to investigate the functional impact of genotypes/haplotypes in the susceptibility of depression and on treatment response. None of the eight SNPs, including the rs6265, were significantly associated with MDD after permutation correction. However, we found an association for rs10501087, rs6265 with nonresponse to antidepressant treatment (corrected permutation P:0.03599; 0.0399 and power: 0.1420; 0.1492, respectively).Analysis of each two-marker, three-marker, and four-marker sliding window haplotypes showed significance in haplotype combinations. Especially rs10501087 (C), rs6265 (A), and rs149,1850 (C) together or with the other SNP haplotypes showed a similar pattern in all treatment response phenotypes. Despite the limited power of analysis, our results suggest that these three SNPs may play a role in antidepressant treatment response phenotypes in MDD.     

Attention-deficit hyperactivity disorder and intellectual disability: a study of association with brain-derived neurotrophic factor gene polymorphisms

Symptoms of attention-deficit hyperactivity disorder (ADHD) have been found in several studies of children with intellectual disabilities (ID) but the two diseases are not always associated. Several lines of evidence implicate the involvement of brain-derived neurotrophic factor (BDNF) in ADHD, and it may also be relevant in ID due to its known involvement in the development of the central nervous system (CNS) and in learning/memory functions. We genotyped paediatric patients with ADHD and ID for the Val66Met and 270 C/T polymorphisms in BDNF. Diagnosis of ADHD and ID was confirmed by the clinicians in accordance with DSM-IV criteria. The G/A genotype of the Val66Met SNP was associated with both ADHD and ID, and the G allele was significantly associated with ADHD. The C/C genotype of the C270T SNP was significantly overrepresented in both ADHD and ID groups compared with the controls. Data suggest that both BDNF polymorphisms could play a role in the etiology of ADHD. In addition, we present the first results suggesting that these BDNF SNPs are significantly associated with ID.     

抑郁症 185例自杀意念、行为的危险因素分析

目的 分析抑郁症病人自杀意念、行为的危险因素。方法 选取商丘市第二人民医院2020年1月至2021年8月185例抑郁症初诊病人（研究组）,采用倾向值匹配法另选取185例健康志愿者（对照组）。采用聚合酶链式反应-限制性片段长度多态性（PCR-RFLP）检测两组脑源性神经营养因子（BDNF）基因多态性并比较;分别采用自杀意念自评量表（SIOSS）和专家访谈方式调查研究组的自杀意念、行为,采用logistic多元回归法分析自杀意念、行为的影响因素。结果 两组BDNF第66个氨基酸处的缬氨酸突变为蛋氨酸（Val66Met）基因型分布与等位基因频率比较差异无统计学意义（P>0.05）,且均符合遗传平衡规律（P>0.05）;研究组离婚/丧偶病人SIOSS评分高于未婚、已婚[（12.86±3.05）分比（8.73±1.98）分、（10.02±2.01）分]（P<0.05）,无业病人SIOSS评分高于在编人员、普通职员/个体户[（13.63±3.04）分比（8.04±1.95）分、（9.78±2.04）分]（P<0.05）,收入水平<3 000元/月SIOSS评分高于3 ...     

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

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.