The brain-derived neurotrophic factor (BDNF) polymorphism Val66Met is associated with neither serum BDNF level nor response to selective serotonin reuptake inhibitors in depressed Japanese patients

Background

We investigated the relationship between a brain-derived neurotrophic factor (BDNF) polymorphism (Val66Met) and the clinical response of patients with major depressive disorder to selective serotonin reuptake inhibitors (SSRIs; here, paroxetine and sertraline). In addition, serum BDNF levels in these patients were considered together with the clinical response.

Methods

A total of 132 patients who met the DSM-IV criteria for major depressive disorder were enrolled in the study. 54 of these patients were male and 78 were female (age range, 20-74 years; mean ± S.D., 51 ± 15). The patients' clinical improvement was evaluated using the 17-item Hamilton Rating Scale for Depression (HAMD-17) before (T0) and at 8 weeks after the administration of SSRI treatment (T8). Patients with at least a 50% decrease in the HAMD-17 score were classified as responders.

Results

No correlation was observed between the BDNF Val66Met polymorphism and response to SSRIs or between the BDNF Val66Met polymorphism and serum BDNF levels at T0. An inverse correlation was found between serum BDNF levels and HAMD-17 scores at T0.

Conclusions

These results suggest that the BDNF Val66Met polymorphism is independent of both the response to SSRI treatment and serum BDNF levels. The findings in the present study reconfirm that the serum BDNF level is a state biomarker for depression.     

Genetic Role of BDNF Val66Met and 5-HTTLPR Polymorphisms on Depressive Disorder

Objective

We investigated possible association between depressive disorders and BDNF Val66Met and 5-HTTLPR. Brain derived neurotrophic factor (BDNF) gene and serotonin transporter (SLC6A4) gene are promising candidate genes for depressive disorders. It has been suggested that BDNF promotes the survival and differentiation of serotonergic neurons and that serotonergic transmission exerts powerful control over BDNF gene expression.

Methods

Final analyses were performed on 186 patients with depressive disorders and 1032 controls. Val66Met polymorphism of BDNF gene and 5-HTTLPR polymorphism of serotonin transporter gene were genotyped and allele and genotypic associations on the diagnosis of depression and age at onset of depression were analyzed.

Results

The 5-HTTLPR was positively associated with depressive affected status in the total sample and in females (p=0.038 for allelewise, p=0.015 for genotype-wise associations), but, not in males. The BDNF Val66Met showed no association with depression. BDNF Val66Met and 5-HTTLPR alone were not associated with age at onset of depression. Additional analysis on the interaction between BDNF Val66Met and 5-HTTLPR found a significant association with age at onset of depression in the entire patient group. This association was also found in the female but not in the male patient group. None of the positive results survived Bonferroni correction for multiple testing.

Conclusion

This result suggested that BDNF Val66Met and 5-HTTLPR may contribute to depressive disorders in a complex way and that the genetic effect could differ by gender. Further studies with large number of patients will be necessary.     

The study of BDNF Val66Met polymorphism in Chinese schizophrenic patients

Accumulating evidence showed that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. Recent studies have reported that the Val66Met polymorphism of the BDNF gene may be associated with susceptibility for schizophrenia and age of onset of this disease, with mix results. In the present study, the BDNF Val66Met gene polymorphism was examined in 387 inpatients (259 men and 128 women) meeting the DSM-IV criteria for schizophrenia and unrelated 365 healthy controls (255 men and 110 women). The schizophrenia symptomatology was assessed by the Positive and Negative Syndrome Scale (PANSS). Age of onset was defined as the age at which the psychotic symptoms first appeared. Our results showed that genotype frequency distributions and allelic frequencies did not differ between patients and controls. No interaction was found between sex and genotypes. Analysis of covariance (ANCOVA) showed a significance of the BDNF Val66Met genotypes on the age of onset (F = 3.76, p < 0.02), after adjusting sex, age and duration of illness. Furthermore, ANCOVA showed that the significance of the BDNFVal66Met genotypes on age of onset was increased comparing the Val66Met heterozygotes with the combination of Val66Val and Met66Met homozygotes (F = 5.85, p < 0.01). Our results suggest that the BDNF Val66Met polymorphism may not contribute directly to the susceptibility to schizophrenia, but to the onset of the disease. Furthermore, our results show the heterozygous effect of the BDNF Val66Met gene on the clinical variability of schizophrenia phenotype.     

The association between brain-derived neurotrophic factor Val66Met variants and psychotic symptoms in posttraumatic stress disorder

Abstract

Objectives. Psychotic symptoms frequently occur in veterans with combat-related posttraumatic stress disorder (PTSD). Brain-derived neurotrophic factor (BDNF) plays a major role in neurodevelopment, neuro-regeneration, neurotransmission, learning, regulation of mood and stress responses. The Met allele of the functional polymorphism, BDNF Val66Met, is associated with psychotic disorders. This study intended to assess whether the Met allele is overrepresented in unrelated Caucasian male veterans with psychotic PTSD compared to veteran controls. Methods. The BDNF Val66Met variants were genotyped in 576 veterans: 206 veterans without PTSD and 370 veterans with PTSD subdivided into groups with or without psychotic features. Results. Veterans with psychotic PTSD were more frequently carriers of one or two Met alleles of the BDNF Val66Met polymorphism than veterans with PTSD without psychotic features and veterans without PTSD. Conclusions. The study shows that veterans with psychotic PTSD carried more Met alleles of the BDNF Val66Met than non-psychotic veterans with PTSD or veterans without PTSD. The results might add further support to the hypothesis that psychotic PTSD is a more severe subtype of PTSD.     

Serotonergic functioning as measured by the loudness dependence of auditory evoked potentials is related to a haplotype in the brain-derived neurotrophic factor (BDNF) gene

Objectives

The serotonergic system plays an important pathophysiological role in various psychiatric disorders. Brain-derived neurotrophic factor (BDNF) is involved in the differentiation and survival of serotonergic neurons. A previous study showed that low serum BDNF levels were associated with strong loudness dependence of auditory evoked potentials (LDAEP) as a reflection of low central serotonergic activity. To evaluate the genetic basis of this relationship, we studied whether the LDAEP is correlated with genetic variants within the BDNF gene.

Methods

Ninety five healthy subjects (41 males, 54 females) received electrophysiological recording of LDAEP and blood drawing for BDNF genotyping. Three BDNF markers (including the single nucleotide polymorphism rs6265(Val66Met)) were analyzed.

Results

Haplotype analysis revealed stronger LDAEP values in carriers of the G(Val)-C-T [rs6265(Val66Met)-rs2030324-rs1491850] haplotype within the BDNF gene in comparison to other haplotype carriers. These findings were demonstrated for the LDAEP of both left and right primary auditory cortices as well as for the vertex electrode (Cz).

Conclusion

Subjects with the BDNF haplotype G(Val)-C-T seem to be characterized by low serotonergic activity as well as possibly by low serum BDNF levels. These findings need replication in independent samples.     

Association among aggressiveness, neurocognitive function, and the Val66Met polymorphism of brain-derived neurotrophic factor gene in male schizophrenic patients

Background

The aim of this study was to investigate the association among aggressive behavior, neuropsychological function, and the Val66Met functional polymorphism of brain-derived neurotrophic factor (BDNF) gene in male schizophrenic patients.

Methods

We examined 51 male patients with schizophrenia who had committed homicide (ie, H-SCZ), 50 male patients with schizophrenia who had not committed homicide (ie, NH-SCZ), and 50 healthy male controls. Patients were evaluated using the Positive and Negative Syndrome Scale, Life History of Aggression, and the Overt Aggression Scale. In addition, patients were given neurocognitive function tests, including Korean-Wechsler Adult Intelligence Scale short form, the Korean version of the Rey Memory Test, the Stroop Test, and the Wisconsin Card Sorting Test. The Val66Met polymorphism of the BDNF gene was also genotyped in all schizophrenic patients.

Results

We observed no significant difference between patients in the H-SCZ and NH-SCZ groups, with regard to Positive and Negative Syndrome Scale scores. Total Life History of Aggression (P < .01) and Overt Aggression Scale scores for the most severe episode (P < .01) or for the previous month (P < .05) were higher in the H-SCZ group than in the NH-SCZ group. There were no significant differences in the genotype distribution or allelic frequency of the Val66Met polymorphism between the schizophrenic groups. In addition, we observed no significant differences between H-SCZ and NH-SCZ groups with regard to performance on neuropsychological tests. The Met allele of the Val66Met polymorphism was associated with poor intelligence quotient, memory quotient), learning, and delayed recall in the H-SCZ group. However, genotype did not seem to influence neurocognitive function in schizophrenic patients who had committed homicide.

Conclusions

The neurocognitive tests used in our study were unable to distinguish between violent and nonviolent schizophrenic patients. Furthermore, the Val66Met polymorphism was not associated with aggressiveness in patients with schizophrenia.     

Influence of the BDNF Val66Met polymorphism on coping response to stress in patients with advanced gastric cancer

Objective

Coping with cancer is an important determinant of psychological morbidity, quality of life, and treatment adherence in cancer patients. The aim of this study was to elucidate the association between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and coping response to stress in patients diagnosed with advanced gastric cancer.

Methods

Ninety-one subjects (60 males, 31 females) recently diagnosed with advanced gastric cancer were recruited. Coping style and distress level were examined using the Mini-Mental Adjustment to Cancer (Mini-MAC) scale and Hospital Anxiety and Depression Scale, and genotyping was evaluated. To examine the temporal stability of the Mini-MAC scores, a 6-week follow-up evaluation was conducted in 72 patients, after completion of two chemotherapy cycles.

Results

Coping style to cancer significantly differed between the Met carriers of BDNF Val66Met and the Val/Val homozygotes. The Met carriers were significantly more anxious than the Val/Val homozygotes.

Conclusion

The present findings suggest that the BDNF Val66Met polymorphism may be involved in individual coping responses to cancer. The Met allele of BDNF Val66Met may be predictive of an anxious coping style in patients with advanced cancer.     

Association between the BDNF Val66Met Polymorphism and Chronicity of Depression

Objective

Both clinical and biological factors influence the course of depressive disorders. This study tested for associations between the brain-derived neurotrophic factor (BDNF) gene at the Val66Met locus and the course of major depressive disorder (MDD).

Methods

Three hundred ten Korean subjects (209 patients, 101 controls) were genotyped for rs6265 at nucleotide 196 (G/A), which produces an amino acid substitution at codon 66 (Val66Met) of the gene for BDNF. Course of illness was evaluated both by chronicity of current episode (episode duration >24 months) and by the lifetime history of recurrences.

Results

Patients with the Met/Met BDNF genotype had a significantly higher rate of chronic depression than all others. There was a significant dose effect of the Met allele on chronicity. Compared with the Val/Val genotype, the relative risk of chronicity was 1.67 for the Val/Met genotype, and 2.58 for the Met/Met genotype. Lifetime history of recurrent episodes was not related to BDNF genotypes but was significantly associated with younger age of onset and with a history of depression in first degree relatives.

Conclusion

BDNF genotyping may be informative for anticipating chronicity in major depression.     

Association analysis of brain-derived neurotrophic factor Val66Met polymorphisms with Alzheimer's disease and age of onset

Because of a decrease in central brain-derived neurotrophic factor (BDNF) levels in Alzheimer's disease (AD) and the important role of BDNF in neuronal survival, BDNF may represent a candidate gene conferring susceptibility to AD. Recently, a functional BDNF Val66Met polymorphism has been associated with AD in an Italian population. In the present study, we investigated a possible role of this BDNF polymorphism in the susceptibility of AD or AD onset in a Chinese population. Comparing AD patients and controls, the distribution of the BDNF genotypes and alleles did not differ significantly. The onset age was not significantly different comparing the three BDNF genotype groups. Our negative findings suggest that it is unlikely that the BDNF Val66Met polymorphism plays a major role in the pathogenesis of AD in the Chinese population and do not support previous findings that homozygosity for the 66Val allele confers an increased risk for AD. Further studies with genetic variations in BDNF relating either to AD-associated depression or to the AD treatment response are suggested.     

Plasma BDNF levels are correlated with aggressiveness in patients with amnestic mild cognitive impairment or Alzheimer disease

In the present study, we examined whether neuropsychiatric symptoms were correlated with plasma brain-derived neurotrophic factor (BDNF) levels as a state marker or were associated with the BDNF polymorphism Val66Met in patients with amnestic mild cognitive impairment (A-MCI) or Alzheimer disease (AD). One hundred and seventy-six outpatients with AD (n = 129) or A-MCI (n = 47) were selected and their plasma BDNF concentrations measured. Next, we investigated the correlation between the plasma BDNF level and the Behavioral Pathology in Alzheimer Disease (Behave-AD) subscale scores, which reflect neuropsychiatric symptoms. We also compared the plasma BDNF level and the Behave-AD subscale scores among the BDNF Val66Met genotypic groups. Among the seven Behave-AD subscale scores, aggressiveness was positively correlated with the plasma BDNF level (ρ = 0.237, P < 0.005), but did not differ significantly among the three BDNF Val66Met genotypic groups. The Behave-AD total and other subscale scores did not differ significantly among the BDNF Val66Met genotypic groups and were not associated with the plasma BDNF level. Moreover, the plasma BDNF level did not differ significantly among the three BDNF Val66Met genotypic groups or between patients with A-MCI and those with AD. The plasma BDNF level was robustly correlated with aggressiveness, implying that the plasma BDNF level might be useful as a behavioral state marker in patients with AD or A-MCI.     

The brain-derived neurotrophic factor Val66Met polymorphism and rate of decline in Alzheimer's disease

It is largely unknown why some patients with Alzheimer's disease (AD) decline cognitively more rapidly than others. Genetic differences among patients could influence rate of decline. Brain-derived neurotrophic factor (BDNF) is a neurotrophin important in the survival neurons and in memory function. BDNF levels are reduced in the brain in AD. The Val66Met polymorphism in the BDNF gene modifies neuronal BDNF secretion, and affects hippocampal function and memory performance. We tested the hypothesis that the BDNF Val66Met polymorphism influences rate of cognitive decline in AD. In a sample of 149 AD patients followed for an average of 3.9 years, we found no effect of BDNF Val66Met genotype on rate of change in the Mini Mental State Examination. Results were similar when we excluded patients taking an acetylcholinesterase inhibitor, those placed in a nursing home during the study, or those with a neuropathological diagnosis that included AD plus an entity other than AD. We also found no evidence that the effects of the BDNF Val66Met genotype depend on APOE genotype, which itself had no effect on rate of cognitive change. These findings suggest that the functional BDNF Val66Met variant is not a major determinant of rate of cognitive decline in AD.     

Polymorphism of the brain-derived neurotrophic factor gene and performance on a cognitive prefrontal test in bipolar patients

Objectives:  The aim of the study was to test a possible association between the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene and performance on a neurocognitive test, the Wisconsin Card Sorting Test (WCST), in bipolar patients.
Methods:  Fifty-four bipolar patients were studied, 18 male and 36 female, aged 18–72 (mean 46 years). The number of perseverative errors (WCST-P), non-perseverative errors (WCST-NP), completed corrected categories (WCST-CC), conceptual level responses (WCST-%CONC) and set to the first category (WCST-1st CAT) were measured in relation to the Val66Met genotypes of BDNF.
Results:  The percentages of subjects with Val/Val, Val/Met and Met/Met genotypes were respectively 81.5, 16.7 and 1.8%. Subjects with Val/Val and Val/Met genotypes did not differ on clinical factors except for the age of onset of the illness, which was earlier in Val/Val than Val/Met genotype (27 years versus 38 years). The performance in all domains of WCST was significantly better in subjects with Val/Val BDNF genotype compared with Val/Met genotype.
Conclusions:  The results suggest a role of BDNF in prefrontal cognitive function in bipolar illness. The tests of prefrontal cognition may be considered as endophenotypic markers in bipolar illness.     

The effect of depression, BDNF gene val66met polymorphism and gender on serum BDNF levels

Objective

To determine the effect of BDNF gene val66met polymorphism on serum BDNF levels in drug-free patients with major depressive disorder (MDD) and healthy subjects, that differ by gender.

Methods

Sixty-six drug-free patients (19 males + 47 females) with non-psychotic MDD and fifty-six healthy controls (18 males + 38 females) were recruited. Three-way ANOVA was employed to analyze the effect of mental health status, met-carriage and gender on Hamilton Depression Rating Scale (HDRS) scores and serum BDNF levels, by using the MIXED Procedure (SAS).

Results

Patients had a lower serum BDNF level than healthy subjects (22.47 vs. 27.49; p < 0.0001). Met-carrier patients had a higher HDRS score than Val homozygote's (25.99 vs. 22.99, p < 0.02). Serum BDNF level for met-carrier subjects (patients + controls) was lower than Val homozygote subjects (23.08 vs. 26.87; p < 0.002). However, there were no effects of two-way interactions of met-carriage and mental health status on HDRS scores and serum BDNF levels. There was no gender effect on HDRS scores in the patients. Overall, male subjects (patients + controls) had a higher serum BDNF level than female subjects (26.87 vs. 23.08; p < 0.002). However, there were no effects of two-way interactions of gender with mental health status and met-carriage on serum BDNF levels.

Conclusions

We replicated the previous findings of lower serum BDNF levels during depression and in females. In addition, we found that met-carriage had an effect in reducing serum BDNF levels, regardless of gender and depression. Further animal and human studies with a larger sample size should investigate whether BDNF val66met polymorphism could alter brain and serum BDNF levels.     

The role of brain-derived neurotrophic factor (BDNF) gene variants in antipsychotic response and antipsychotic-induced weight gain

Background

Brain-derived neurotrophic factor (BDNF) has extensive effects on the nervous system including cell survival, differentiation, neuronal growth and maintenance, as well as cell death. Moreover, it promotes synaptic plasticity and interacts with dopaminergic and serotonergic neurons, suggesting an important role on the alteration of brain function with antipsychotic medications and induced weight gain in schizophrenia patients. The differential effects of BDNF gene variants could lead to changes in brain circuitry that would in turn cause variable response to antipsychotic medication. Therefore, we hypothesized that genetic variation in this candidate gene helps in explaining the inter-individual variation observed in antipsychotic drug treatment with respect to response and induced weight gain.

Method

We examined four single-nucleotide polymorphisms across the BDNF gene, including Val66Met (rs6265). Prospective BPRS change scores and weight change after six weeks were obtained from a total of 257 schizophrenia patients of European ancestry.

Results

The markers rs11030104 and Val66Met were associated with antipsychotic response (P = 0.04; 0.007, respectively). On the other hand, marker rs1519480 was associated with weight gain (P = 0.04). Moreover, a two-marker haplotype across rs6265 and rs1519480 was associated with weight change (P = 0.001). Results with Val66Met in response, and results with rs6265-rs1519480 haplotypes remained significant at the modified Bonferroni corrected alpha of 0.017.

Conclusion

BDNF genetic variants might play an important role in predicting antipsychotic response and antipsychotic-induced weight gain. However, replication in larger and independent samples is required.     

Interaction of the DRD3 and BDNF gene variants in subtyped bipolar disorder

Objectives

Bipolar disorder is a severe mental disorder with prominent genetic etiologic factors. Dopaminergic dysfunction has been implicated in the pathogenesis of bipolar disorder, which suggests that the dopamine D3 receptor gene (DRD3) is a strong candidate gene. The brain-derived neurotrophic factor (BDNF) gene has been implicated in the etiology of bipolar disorder. We examined the association between the BDNF Val66Met and DRD3 Ser9Gly polymorphisms with two subtypes of bipolar disorder: bipolar-I and -II. Because BDNF regulates DRD3 expression (1), we also examined possible interactions between these genes.

Methods

We recruited 964 participants: 268 with bipolar-I, 436 with bipolar-II, and 260 healthy controls. The genotypes of the BDNF Val66Met and DRD3 Ser9Gly polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis.

Results

Logistic regression analysis showed a significant main effect for the Val/Val genotype of the BDNF Val66Met polymorphism (P = 0.020), which predicted bipolar-II patients. Significant interaction effects for the BDNF Val66Met Val/Val genotype and both DRD3 Ser9Gly Ser/Ser and Ser/Gly genotypes were found only in bipolar-II patients (P = 0.027 and 0.006, respectively).

Conclusion

We provide initial evidence that the BDNF Val66Met and DRD3 Ser9Gly genotypes interact only in bipolar-II disorder and that bipolar-I and bipolar-II may be genetically distinct.     

Impact of the BDNF Val66Met Polymorphism on Regional Brain Gray Matter Volumes: Relevance to the Stress Response

Objective

Genetic imaging is used to investigate the mechanism by which genetic variants influence brain structure. In a previous study, a structural change of the dorsolateral prefrontal cortex was associated with symptom modulation in post-traumatic stress disorder patients. This study examined the effect of a polymorphism in the gene encoding brain-derived neurotrophic factor (BDNF) on regional gray matter (GM) volumes and the correlations between the dorsolateral prefrontal GM volume and the stress level in healthy volunteers.

Methods

Sixty-one volunteers underwent genotyping for the BDNF Val66Met single nucleotide polymorphism (SNP) and completed the Stress Response Inventory (SRI). Magnetic resonance images were also acquired, and the effect of each subject''s BDNF genotype and SRI subscore on his or her dorsolateral prefrontal GM volume was evaluated.

Results

The Val/Val homozygotes had significantly larger GM volumes in the prefrontal cortex and the precuneus, the uncus, and the superior temporal and occipital cortices than Met carriers. The Met homozygotes demonstrated a higher stress response in depression domain than Val/Val and Val/Met groups. A negative correlation between the middle frontal cortex GM volume and the SRI depression subscore was found.

Conclusion

These findings indicate an interaction between genes and brain structure, and they suggest that differences in dorsolateral prefrontal GM volume related to the BDNF Val66Met SNP are associated with resilience to stressful life events, particularly in the dimension of emotion.     

Sex differences in prepsychotic “prodromal” symptomatology and its association with Positive and Negative Syndrome Scale active phase psychopathology in male and female patients

Background

A wide spectrum of prodromal symptoms has been reported, but their association with the severity of the active phase psychopathology in relationship to sex is unknown.

Method

Seventy-three (47 male) Diganostic and Statistical Manual (DSM) schizophrenia patients were subjected to the structured clinical interview for Positive and Negative Syndrome Scale (PANSS). Prodromal symptoms were recorded retrospectively after psychotic phase had subsided.

Results

Thirty-eight prodromal symptoms were identified. All symptoms appeared in both sexes. However, there was a significantly greater frequency of 3 symptoms (odd beliefs/magical thinking, over elaborate speech, hyperacusia) in female patients and of 2 symptoms (marked peculiar behavior, aggressiveness) in male patients. In the female patients, 9 symptoms were associated with an increased risk for severe total and components of the PANSS psychopathology in the psychotic phase; 2 symptoms were associated with a mild negative subscale psychopathology. In the male patients, 6 symptoms were associated with the severity of the PANSS psychopathology; 5 carried an increase risk for severe and 1 was associated with mild psychopathology. Also, the risk for severe PANSS positive, general, and total psychopathology increased with the increasing number of total and less specific symptoms in the female but not in the male patients.

Conclusions

Sex differences in schizophrenia are extended into the prepsychotic stage. Also, the presence of certain prodromal symptoms, different in men and women, and the number of symptoms in female patients are associated with the severity of the psychotic phase psychopathology. Evaluation of early therapeutic interventions in prodromal phase should consider sex and spectrum of prodromal symptoms.     

Interaction between catechol-O-methyltransferase (COMT) Val108/158Met and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms in age at onset and clinical symptoms in schizophrenia

Summary. Catechol-O-methyltransferase (COMT) gene is one of the candidate genes for schizophrenia because it codes an enzyme that participates in the metabolic inactivation of dopamine and noradrenaline and a limiting factor of dopamine metabolism in the prefrontal cortex. COMT gene lies on chromosome 22q11.2, which has been associated with schizophrenia susceptibility. A single-nucleotide polymorphism of COMT gene at position 108/158 results in an amino acid substitution from valine (val) to methionine (met), which modifies its enzymatic activity and may change the brain morphology and expressional behaviors. On the other hand, brain-derived neurotrophic factor (BDNF) plays a critical role in the development of mesolimbic dopaminergic- related systems. BDNF also contains a functional single-nucleotide polymorphism at codon 66 (Val66Met) of its prodomain and this polymorphism is responsible for schizophrenia susceptibility. In this study, we first investigated the relationship between COMT Val108/158Met polymorphism and age at onset as well as levels of clinical symptoms in 158 of chronic schizophrenia inpatients and then we investigated the gene-by-gene interaction between COMT Val108/158Met polymorphism and BDNF Val66Met polymorphism with age- and sex-matched control subjects (n = 318). We concluded that the COMT Val108/158Met polymorphism was not related to either the onset at age or the levels of clinical symptoms after long-term antipsychotic treatment in schizophrenia.     

A role for the BDNF gene Val66Met polymorphism in schizophrenia? A comprehensive review

Schizophrenia is believed to arise from complex gene–environment interactions. Brain-derived neurotrophic factor (BDNF) is involved in neuronal development, differentiation and plasticity. A functional single nucleotide polymorphism that results in a valine (Val) to methionine (Met) substitution at codon 66 (Val66Met) results in the aberrant sorting and release of mature BDNF through the activity-dependent secretion pathway. The Val66Met polymorphism has been linked to impaired neurocognitive function in healthy adults, and identified as a locus of risk for a range of neuropsychiatric disorders including schizophrenia. Here we provide a comprehensive review of the relationship between the BDNF Val66Met polymorphism and schizophrenia, integrating evidence from the fields of genetic epidemiology, clinical psychiatry, behavioral neuroscience and neuroimaging. We argue that while the Val66Met polymorphism may not be a major risk-conferring agent for the development of schizophrenia per se, there is mounting evidence that the polymorphism modulates a range of clinical features of the illness, including age of onset, symptoms, therapeutic responsiveness, neurocognitive function and brain morphology.     

The impact of glycogen synthase kinase 3β gene on psychotic mania in bipolar disorder patients

Objective

The aim of this study was to examine the relationships between glycogen synthase 3β gene polymorphisms and bipolar I disorder, manic in a Korean sample.

Methods

Patients with bipolar disorder (n = 118) and a control group (n = 158) were assessed by genotyping for GSK3β single nucleotide polymorphisms (SNPs) − 1727A/T and − 50C/T. The patients were divided into two groups according to the presence of psychotic symptoms (psychotic mania, n = 92; non-psychotic mania, n = 26) and also divided based on gender and age of onset. The severity of symptoms was measured using the Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS).

Results

There were no significant differences in the genotype distributions or allelic frequencies of GSK3β polymorphisms and gender between patients with bipolar disorder and a normal control group. According to haplotype analysis, there was no association between these two groups. However, analysis of the age of onset of bipolar disorder revealed significant differences in genotype and allele distributions among the patients. Patients who were homozygous for the wild-type variant (TT) had an older age of onset than carriers of the mutant allele (A/A: 27.4 ± 9.1; A/T: 30.1 ± 11.8; T/T: 42.3 ± 19.9; p = 0.034). We detected differences in allele frequencies of the GSK3β − 1727A/T polymorphism between the psychotic mania group and the non-psychotic mania group.

Conclusion

This study suggests that GSK3β polymorphisms are not associated with bipolar disorder. However, the GSK3β SNP − 1727A/T is associated with age of onset and presence of psychotic symptoms in bipolar disorder.