Genetic epistasis between the brain-derived neurotrophic factor Val66Met polymorphism and the 5-HTT promoter polymorphism moderates the susceptibility to depressive disorders after childhood abuse

Background

Based on biological interactions between the serotonergic system and the brain-derived neurotrophic factor (BDNF), BDNF is a plausible candidate for a gene–gene–environment interaction moderating the interaction between the s/l- promoter polymorphism of the serotonin transporter (5-HTTLPR) and childhood abuse. We tested the hypothesis of a three-way interaction with respect to depressive symptoms.

Methods

2035 Caucasian subjects from the Study of Health in Pomerania (German general population) completed the Beck Depression Inventory (BDI-II) and the Childhood Trauma Questionnaire. All subjects were genotyped for the BDNF Val66Met (rs6265) and the s/l 5-HTTLPR polymorphisms.

Results

Tobit regression analyses revealed a three-way-interaction between the three genotypes of 5-HTTLPR and the BDNF genotypes and overall childhood abuse for the BDI-II score (p = 0.02). Emotional abuse carried the main effect of the interaction (p = 0.008). The s/s genotype of the 5-HTTLPR exerted its negative impact on mental health after childhood abuse only in the presence of the BDNF Val/Val genotype but not in the presence of the BDNF Met allele. In contrast, the l allele of the 5-HTTLPR also emerged as a genetic risk factor for depression in carriers of one or two Met alleles.

Conclusions

Our results point to a gene–gene–environment interaction that relevantly impacts on the role of the s/s genotype of the 5-HTTLPR in childhood abuse: Depending on the BDNF background (Val/Val versus Met allele) the s/s genotype showed either protective or risk properties with regard to depressive symptoms.     

Association study of polymorphisms in leptin and leptin receptor genes with antipsychotic-induced body weight gain

Background

Antipsychotic-induced weight gain (AIWG) is a serious side-effect of antipsychotic medication leading to metabolic syndrome and increased cardiovascular morbidity. Unfortunately, there are still no valid predictors to assess an individual's risk to gain weight. Previous studies have indicated an impact of genetic variation in the genes encoding leptin, LEP, and leptin receptor, LEPR, on AIWG, but results have not been conclusive. Thus, we investigated polymorphisms in both genes for an association with AIWG.

Methods

A total of 181 schizophrenic and schizoaffective patients treated with various antipsychotics were included. In a small subset of patients, leptin plasma levels were additionally obtained. Five polymorphisms in LEP and LEPR (LEP: rs7799039 (-2548G/A polymorphism), rs10954173, rs3828942; LEPR: rs1327120, rs1137101 (Q223R polymorphism) were genotyped using TaqMan assays. Statistical association with % weight change from baseline weight was performed using ANCOVA with baseline weight as covariate.

Results

ANCOVA showed a non-significant trend for genotype association of the rs7799039 marker (p = .068). No significant association of the other LEP and LEPR SNPs with AIWG was detected. However, we found a significant association between a haplotype of LEP rs7799039G–rs10954173G–rs3828942G (p = .035) and AIWG. The rs7799039 G-allele (p = .042) and G-allele of rs3828942 (p = .032) were associated with higher weight gain.

Conclusion

Our study supports the hypothesis of an impact of LEP gene variation on AIWG. Limitations of our study include heterogeneous samples, short treatment duration and multiple comparisons. Our findings were compared to previous studies in detail in order to provide the readers with a more conclusive picture. However, further studies are warranted including more gene variants and interaction analyses with other genes of the leptin–melanocortin pathway.     

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.     

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.     

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 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.     

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.     

BDNF plasma levels and genotype in depression and the response to electroconvulsive therapy

Background

Brain derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression and the antidepressant response. Electroconvulsive therapy (ECT) is reported to increase BDNF levels in blood, though only a small number of studies have been conducted to date.

Brain derived neurotrophic factor Val66Met polymorphism and psychotic symptoms in Alzheimer's disease

Objective

Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disorder with a high prevalence. Since behavioral disturbances, such as psychotic symptoms, represent a key feature of AD, genes related to dopamine, serotonin and brain derived neurotrophic factor (BDNF), are considered as candidate genes for AD. BDNF is a neurotrophin that regulates neurodevelopment, neuroplasticity, and neuronal functions. BDNF is involved in the etiopathogenesis of psychiatric and neurodegenerative disorders. A single base pair polymorphism (BDNF Val66Met) was reported to be associated with AD and/or schizophrenia, as well as other psychoses, although some studies failed to replicate these findings. The aim of the study was to evaluate the association between BDNF Val66Met variants and AD, as well as onset of AD or presence of psychotic symptoms in AD.

Method

BDNF Val66Met was analyzed in 211 patients with AD and in 402 aged healthy control subjects. All subjects were ethnically homogenous Caucasians from Croatia, and were subdivided according to the gender, onset of AD, and presence of psychotic symptoms. A χ² test, with Bonferroni correction and standardized residuals were used to evaluate the data.

Results

Distribution of the BDNF Val66Met genotypes differed significantly between male and female AD patients with or without psychotic symptoms. This difference was due to the significant contribution of the Met/Val genotype and the combined Met/Met and Met/Val genotypes between psychotic and non-psychotic symptoms in male, but not in female patients with AD. The frequency of the gene variants of the BDNF Val66Met did not differ significantly among male and female patients with AD and control subjects, or between male and female patients with early or late onset AD. There were significant sex related differences in age, duration of illness and scores of dementia between patients with AD.

Conclusion

Our male patients were younger, had shorter duration of illness, and had less severe dementia and higher cognitive performance than female AD patients. The gene variants of the BDNF Val66Met polymorphism were significantly associated with the presence of psychotic symptoms in male, but not in female patients with AD. The results had adequate statistical power to suggest that BDNF Val66Met was not related to susceptibility to AD or the onset of AD, but that presence of one or two Met alleles of BDNF Val66Met polymorphism might present a risk factor for psychosis in AD.     

Increased levels of plasma brain-derived neurotrophic factor (BDNF) in children with attention deficit-hyperactivity disorder (ADHD)

Background

Recent reports have suggested a pathophysiological role of brain-derived neurotrophic factor (BDNF) in attention deficit-hyperactivity disorder (ADHD). We evaluated the plasma levels of BDNF in patients with ADHD.

Methods

Plasma BDNF levels were measured in 41 drug naive ADHD patients and 107 normal controls. The severity of ADHD symptoms was determined by patient scores on the ADHD rating scale (ARS) and the computerized ADHD diagnostic system (ADS).

Results

ANCOVA with age and gender as covariates showed that the mean plasma BDNF levels were significantly higher in ADHD patients than in normal controls (F = 16.968, p < 0.001). There were also significant differences in plasma BDNF levels of ADHD patients and those of normal controls for males and females (Mann–Whitney U-test, p = 0.001 and 0.041, respectively). We also found a significant correlation between plasma BDNF levels and omission errors in ADS outcome-variable T-scores (p < 0.001).

Conclusions

Our study suggests that there is an increase of plasma BDNF levels in untreated ADHD patients, and that plasma BDNF levels had a significant positive correlation with the severity of inattention symptoms. Further studies are required to elucidate the source and role of circulating BDNF in ADHD.     

No genetic association between NCAM1 gene polymorphisms and schizophrenia in the Chinese population

Background

The neural cell adhesion molecule 1(NCAM1, aliases NCAM and CD56) is a cell-surface molecule which makes homophilic adhesion between neural cells involved in cell migration, axon outgrowth and synaptic plasticity. Recent studies reported that NCAM1 might act as a candidate schizophrenia susceptibility gene.

Method

We genotyped five SNPs (rs1943620, rs1836796, rs1821693, rs686050, rs584427) within the NCAM1 gene and conducted a case-control study in 288 schizophrenic patients and 288 healthy subjects in the Chinese Han population. We compared allele and genotype frequencies and haplotype distributions between cases and controls.

Result

No significant differences in allele and genotype frequencies were found for each single SNP between schizophrenic patients and healthy subjects. Moreover, there were no significant differences in haplotype distributions between cases and controls (global χ² = 1.318, P = 0.725, df = 3).

Conclusion

Our study suggests that the five SNPs within NCAM1 gene we studied may not play a major role in the schizophrenia susceptibility in the Chinese Han population.     

Manganese superoxide dismutase gene Ala-9Val polymorphism might be related to the severity of abnormal involuntary movements in Korean schizophrenic patients

Objective

This study examined whether the manganese superoxide dismutase (MnSOD) gene Ala–9Val single-nucleotide polymorphism (SNP) is associated with neuroleptic-induced tardive dyskinesia (TD) and the severity of the abnormal involuntary movements in Korean schizophrenic patients.

Method

We investigated whether the MnSOD gene Ala–9Val SNP is associated with TD in Korean schizophrenic patients with (n = 83) and without (n = 126) TD who were matched for exposure to antipsychotics and other relevant variables.

Results

Logistic regression analysis revealed that being older (p = 0.026) was a risk factor for TD, but that there was no significant association between MnSOD gene and TD. Abnormal involuntary movements were more severe in carriers of the Ala allele than in noncarriers (p = 0.044).

Conclusion

These findings do not support that the MnSOD gene Ala–9Val SNP is associated with TD in Korean schizophrenic patients. However, this polymorphism might be related to the severity of abnormal involuntary movements in this population.     

Association Study of Brain-Derived Neurotrophic Factor Gene Polymorphisms and Body Weight Change in Schizophrenic Patients Under Long-Term Atypical Antipsychotic Treatment

Schizophrenic patients treated with atypical antipsychotics (AAPs) often develop excessive body weight gain, which may lead to further morbidity and poor treatment compliance. This study examined whether genetic variants in the brain-derived neurotrophic factor (BDNF) gene may be associated with body weight change after AAP treatment. The study included 481 schizophrenic patients treated with clozapine (n = 266), olanzapine (n = 79), or risperidone (n = 136) for an average of 49.2 ± 28.2 months. Three common single-nucleotide polymorphisms (SNPs) of the BDNF gene were chosen as tagging SNPs. In single-marker-based analysis, the BDNF rs11030101-T homozygous genotype was found to be associated with significantly increased body weight gain (P = 0.037). The BDNF Val66Met (rs6265) polymorphism was not found to be associated with body weight gain. Haplotype analysis further showed that the rs11030101-T-allele-related haplotype is also associated with increased body weight gain (P = 0.047). Our findings suggest that there is a nominal association with rs11030101 but did not replicate the previously found relationship between the BDNF Val66Met polymorphism and body weight gain during long-term AAP treatment.     

No influence of brain-derived neurotrophic factor (BDNF) polymorphisms on treatment response in a naturalistic sample of patients with major depression

The role of the brain-derived neurotrophic factor (BDNF) in the pathophysiology of major depressive disorder (MDD) remains to be elucidated. Recent post hoc analyses indicated a potential association of three polymorphisms in the BDNF gene with worse treatment outcome in patients with the subtype of melancholic depression. We aimed at replicating these findings in a German naturalistic multicenter follow-up. Three polymorphisms in the BDNF gene (rs7103411, rs6265 (Val66Met) and rs7124442) were genotyped in 324 patients with MDD and 470 healthy controls. We applied univariate tests and logistic regression models stratifying for depression subtype and gender. The three polymorphisms were not associated with MDD as diagnosis. Further, no associations were found in univariate tests. With logistic regression, we only found a tendency towards an association of the rs6265 (Val66Met) polymorphism with overall response to treatment (response rates: GG (val/val) < GA (val/met) < AA (met/met); p = 0.0129) and some gender differences for the rs6265 (Val66Met) and rs7103411 polymorphisms. Treatment outcome stratified for subtypes of depression did not differ significantly between the investigated polymorphisms or using haplotype analyses. However, results showed a tendency towards significance. At this stage, we cannot support an influence of these three polymorphisms. Further studies in larger patient samples to increase sample sizes of subgroups are warranted.     

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.     

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.     

Interaction of serotonin-related genes affects short-term antidepressant response in major depressive disorder

Background

Four serotonin-related genes including guanine nucleotide binding protein beta polypeptide 3 (GNB3), 5-hydroxytryptamine receptor 1A (HTR1A; serotonin receptor 1A), 5-hydroxytryptamine receptor 2A (HTR2A; serotonin receptor 2A), and solute carrier family 6 member 4 (SLC6A4; serotonin neurotransmitter transporter) have been suggested to be candidate genes for influencing antidepressant treatment outcome. The aim of this study was to explore whether interaction among these genes could contribute to the pharmacogenomics of short-term antidepressant response in a Taiwanese population with major depressive disorder (MDD).

Methods

Included in this study were 101 MDD patients who were treated with antidepressants, 35 of whom were rapid responders and 66 non-responders after 2 weeks of treatment. We genotyped four single nucleotide polymorphisms (SNPs), including GNB3 rs5443 (C825T), HTR1A rs6295 (C-1019G), HTR2A rs6311 (T102C), and SLC6A4 rs25533, and employed the generalized multifactor dimensionality reduction (GMDR) method to investigate gene–gene interactions.

Results

Single-locus analyses showed the GNB3 rs5443 polymorphism to be associated with short-term antidepressant treatment outcome (P-value = 0.029). We did not correct for multiple testing in these multiple exploratory analyses. Finally, the GMDR approach identified a significant gene–gene interaction (P-value = 0.025) involving GNB3 and HTR2A, as well as a significant 3-locus model (P-value = 0.015) among GNB3, HTR2A, and SLC6A4.

Conclusions

These results support the hypothesis that GNB3, HTR2A, and SLC6A4 may play a role in the outcome of short-term antidepressant treatment for MDD in an interactive manner. Future research with independent replication using large sample sizes is needed to confirm the functions of the candidate genes identified in this study as being involved in short-term antidepressant treatment response.     

Epistatic effects between variants of kappa-opioid receptor gene and A118G of mu-opioid receptor gene increase susceptibility to addiction in Indian population

Objective

Unequivocal evidence suggests contribution of κ-opioid receptor (KOR) in addiction to drugs of abuse. A study was undertaken to identify the single nucleotide polymorphisms (SNP) at selective areas of kappa opioid receptor 1 (OPRK1) gene in heroin as well as in alcohol addicts and to compare them with that in control population. The potential interaction of the identified KOR SNPs with A118G of μ opioid receptor was also investigated.

Methods

Two hundred control subjects, one hundred thirty heroin and one hundred ten alcohol addicts, all male and residing in Kolkata, a city in eastern India, volunteered for the study. Exons 3 and 4 of OPRK1 and the SNP, A118G of mu opioid receptor 1 (OPRM1) in the DNA samples were genotyped by sequencing and restriction fragment length polymorphism respectively. The SNPs identified in the population were analyzed by odds ratio and its corresponding 95% confidence interval was estimated using logistic regression models. SNP–SNP interactions were also investigated.

Results

Three SNPs of OPRK1, rs16918875, rs702764 and rs963549, were identified in the population, none of which showed significant association with addiction. On the other hand, significant association was observed for A118G with heroin addiction (χ² = 7.268, P = 0.0264) as well as with alcoholic addition (χ² = 6.626, P = 0.0364). A potential SNP–SNP interaction showed that the odds of being addicted was 2.51 fold in heroin subjects [CI (95%) = 1.1524 to 5.4947, P = 0.0206] and 2.31 fold in alcoholics [CI (95%) = 1.025 to 5.24, P = 0.0433] with the OPRK1 (rs16918875) and A118G risk alleles than without either. A significant interaction was also identified between GG/AG of A118G and GG of rs702764 [O.R (95%) = 2.04 (1.279 to 3.287), P = 0.0029] in case of opioid population.

Conclusion

Our study suggests that set associations of polymorphisms may be important in determining the risk profile for complex diseases such as addiction.     

Oxidative stress in tardive dyskinesia: Genetic association study and meta-analysis of NADPH quinine oxidoreductase 1 (NQO1) and Superoxide dismutase 2 (SOD2, MnSOD) genes

Introduction

Tardive dyskinesia (TD) is a potentially irreversible side effect of antipsychotic medication treatment that occurs in approximately 25% of chronically treated schizophrenia patients. Oxidative stress has been one of the proposed mechanisms influencing TD risk. Pae et al. (2004) originally reported a significant association between TD and the NADPH quinine oxidoreductase 1 (NQO1) gene Pro187Ser (C609T, rs1800566) polymorphism in Korean schizophrenia patients; however, subsequent studies have not consistently replicated these findings. Similarly, Hori et al. (2000) reported an association between TD and the Manganese superoxide dismutase SOD2 (MnSOD) gene Ala9Val (rs4880) polymorphism in a Japanese sample, but most research groups failed to replicate their positive findings.

Aims

We investigated the role of the NQO1 polymorphism Pro187Ser and SOD2 (Ala9Val) in a group of well-characterized schizophrenia patients (N = 223) assessed for TD. We also performed a meta-analysis of all the previously published TD studies, including data from our sample, on these polymorphisms, Pro187Ser (N = 5 studies) and Ala9Val (N = 9 studies).

Results

We did not observe a significant association of the Pro187Ser or Ala9Val polymorphism with TD occurrence or AIMS scores in our Caucasian and African American samples when analyzed independently. Meta-analysis did not reveal a significant association of the Pro187Ser/Ala9Val alleles or genotypes with TD occurrence.

Conclusions

Neither the NQO1 Pro187Ser nor the SOD2 Ala9Val appear to play a major role in TD risk, although additional polymorphisms should be tested before the role of NQO1 and SOD2 in TD can be completely excluded.