Association analysis of genes in serotonin pathway with attention and executive function in patients with bipolar affective disorder

Background

The reason why it is difficult to identify susceptibility genes attributed to bipolar disorder (BPD) is the phenotypic heterogeneity. The use of endophenotypes has been advocated as one possible strategy to discovery cause variants of BPD.

Methods

A total of 164 patients with BPD and 164 matched controls were employed in the present research. Fifty-two single nucleotide polymorphisms (SNPs) within the genes in serotonin pathway were selected for genotyping using the GoldenGate genotyping assay. All participants completed three neurocognitive tests including the tower of Hanoi (TOH), the Wisconsin card sorting test (WCST) and Trail making tests (TMTA and TMTB-M).

Results

Patients with BPD demonstrated a wide range of deficits in mental activities of attention and speed of information processing, and executive function. Significant interactions between rs2760347 in 5HTR2A gene and diagnosis were found for the executive time of TOH, with β = 11.82 and P = 0.002 (adjusted P = 0.03 after Bonferroni correction).

Conclusions

Cognitive impairments existing in BPD may be particularly notable in certain domains of attention and executive function, and 5HTR2A gene may be involved in modulating executive function of BP-I patients.     

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.     

SRD5A2 is associated with increased cortisol metabolism in schizophrenia spectrum disorders

Objective

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is documented in bipolar disorder and schizophrenia, but the mechanism is unclear; recently, increased activity of cortisol metabolizing enzymes was indicated in these disorders. We investigated whether five genes involved in cortisol metabolism were associated with altered activity of cortisol metabolizing enzymes in bipolar disorder (BD) and schizophrenia spectrum disorders (SCZ).

Methods

A case–control sample of subjects with BD (N = 213), SCZ (N = 274) and healthy controls (N = 370) from Oslo, Norway, were included and genotyped from 2003 to 2008. A sub-sample (healthy controls: N = 151; SCZ: N = 40; BD: N = 39) had estimated enzyme activities based on measurements of urinary free cortisol, urinary free cortisone and metabolites. A total of 102 single nucleotide polymorphisms (SNPs) in the SRD5A1, SRD5A2, AKR1D1, HSD11B1 and HSD11B2 genes were genotyped, and significant SNPs analyzed in the sub-sample.

Results

There was a significant association of rs6732223 in SRD5A2 (5α-reductase) with SCZ (p = 0.0043, Bonferroni corrected p = 0.030, T risk allele). There was a significantly increased 5α-reductase activity associated with rs6732223 (T allele) within the SCZ group (p = 0.011).

Conclusions

The present data suggest an interaction between SCZ and SRD5A2 variants coding for the enzyme 5α-reductase, giving rise to increased 5α-reductase activity in SCZ. The findings may have implications for cortisol metabolizing enzymes as possible drug targets.     

A common polymorphism in the 3′-UTR of the NOS1 gene was associated with completed suicides in Japanese male population

Background

Suicidal behavior has been widely accepted as familial. Its transmission cannot be explained by the transmission of psychiatric disorder alone and seems to be partly explained by the transmission of impulsive–aggressive behavior. Studies in laboratory animal have shown that mice lacking NOS1 manifest significant aggressive behavior. Further, several polymorphisms of neuronal nitric oxide synthase (NOS1) gene have been reported to be associated with impulsivity, aggression and suicide attempts. To further clarify the possible involvement of NOS1 with suicide, we carried out an association study of NOS1 gene polymorphisms with completed suicide.

Methods

We examined 7 single nucleotide polymorphisms (SNPs) of the NOS1 gene which were previously studied in several neuropsychiatric disorders (rs2682826, rs6490121, rs3782206, rs561712, rs3782219, rs3782221, and rs41279104), in age and gender matched 287 healthy control subjects and 284 completed suicides using the TaqMan probe assays.

Results

We found that both the genotypic distribution and the allelic frequencies of rs2682826 SNP were significantly different between the completed suicide and control groups (P = 0.0007 and 0.0005, respectively). The odd ratio for the minor allele of the SNP was 0.653 (95% CI 0.513–0.832). The significance was remained even after correction for multiple testing. Gender-based analysis showed that the significances were appeared in males only.

Conclusion

Our study raises a possibility that a genetic variation of NOS1 may be implicated in the pathophysiology of suicide in Japanese population, especially in males. Further studies on more NOS1 genetic variants are needed to confirm our observations.     

Association of genetic polymorphisms in the type II deiodinase gene with bipolar disorder in a subset of Chinese population

Objective

Genetic factors play a critical role in the etiology of bipolar disorder (BPAD). Previous studies suggested an association between thyroid dysfunction and BPAD. We hypothesize that genetic variations in the type II deiodinase (DIO2) gene that possibly alter the bioactivity of thyroid hormones are associated with BPAD.

Method

A case–control association study was conducted in a subset of Chinese Han population. Two single nucleotide polymorphisms (SNP), open reading frame a (ORFa)-Gly3Asp (rs12885300) and Thr92Ala (rs225014) with potential functions on the activity of DIO2, were selected. The frequencies of allele, genotype and haplotype of the two SNPs were compared between the BPAD patients and the control group.

Results

Statistical significance between the BPAD patients and the control group was observed for the allele (χ² = 7.746, P = 0.005, df = 1) and genotype frequencies (χ² = 8.158, P = 0.017, df = 2) at the locus of ORFa-Gly3Asp, and for the allele (χ² = 15.838, P = 7.00e−005, df = 1) and genotype frequencies (χ² = 17.236, P = 0.0002, df = 2) at Thr92Ala. Distribution of allele 3Gly and 92Ala were significantly higher in the BPAD patients, with odds ratios of 1.489 [95% confidence interval (CI) = 1.124–1.973] and 1.616 [95% CI = 1.275–2.048], respectively. Individuals with two copies of the variant 3Gly or 92Ala were at greater risk of BPAD than individuals with one copy (dose–response manner). Haplotypes ORFa-3Asp-92Ala and ORFa-3Gly-92Ala indicated higher susceptibility for BPAD with odds ratios of 3.759 (95% CI = 2.013–7.020) and 1.292 (95% CI = 1.017–1.642), respectively, while ORFa-3Asp-92Thr probably played a protective role with an odds ratio of 0.395 (95% CI = 0.284–0.549).

Conclusion

Data generated from this study supported our hypothesis that genetic variations of the DIO2 gene were associated with BPAD and suggested further consideration on the possible involvement of these functionally active variants in the pathophysiology of BPAD.     

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.     

Genetic epistasis in female suicide attempters

Background

Complex behaviors such as suicidal behavior likely exhibit gene–gene interactions. The main aim of this study is to explore potential single nucleotide polymorphisms combinations with epistatic effect in suicidal behavior using a data mining tool (Multifactor Dimensionality Reduction).

Methods

Genomic DNA from peripheral blood samples was analyzed using SNPlex Technology. Multifactor Dimensionality Reduction was used to detect epistatic interactions between single nucleotide polymorphisms from the main central nervous system (CNS) neurotransmitters (dopamine: 9; noradrenaline: 19; serotonin: 23; inhibitory neurotransmitters: 60) in 889 individuals (417 men and 472 women) aged 18 years or older (585 psychiatric controls without a history of suicide attempts, and 304 patients with a history of suicide attempts). Individual analysis of association between single nucleotide polymorphisms and suicide attempts was estimated using logistic regression models.

Results

Multifactor Dimensionality Reduction showed significant epistatic interactions involving four single nucleotide polymorphisms in female suicide attempters with a classification test accuracy of 60.7% (59.1%–62.4%, 95% CI): rs1522296, phenylalanine hydroxylase gene (PAH); rs7655090, dopamine receptor D5 gene (DRD5); rs11888528, chromosome 2 open reading frame 76, close to diazepam binding inhibitor gene (DBI); and rs2376481, GABA-A receptor subunit γ3 gene (GABRG3). The multivariate logistic regression model confirmed the relevance of the epistatic interaction [OR(95% CI) = 7.74(4.60–13.37)] in females.

Conclusions

Our results suggest an epistatic interaction between genes of all monoamines and GABA in female suicide attempters.     

Positive association between the PDLIM5 gene and bipolar disorder in the Chinese Han population

Background

Bipolar disorder is a widespread and severe brain disorder that is strongly affected by genetic factors. The PDZ and LIM domain 5 (PDLIM5) gene encodes a protein as an Enigma homologue LIM domain protein, which has been widely reported as being expressed in various brain regions. The analysis of DNA microarrays in the frontal lobes of patients with bipolar disorder has indicated changes in the expression level of PDLIM5, and subsequent studies have suggested that PDLIM5 might play a role in susceptibility to bipolar disorder. We sought to examine the association between PDLIM5 and bipolar disorder.

Methods

We recruited 502 patients with bipolar disorder and 507 controls from Anhui Province, China. We conducted a case–control study of 4 single-nucleotide polymorphisms (SNPs) of PDLIM5 that have been reported to be significantly associated with bipolar disorder in the Japanese and Chinese population: rs10008257, rs2433320, rs2433322 and rs2438146.

Results

We found that rs2433322 showed significantly different frequencies between patients and controls (p = 0.002). Three of the SNPs, rs10008257, rs2433320 and rs2438146, showed no statistical association with bipolar disorder; however, haplotypes constructed from 3 SNPs, rs2433320, rs2433322 and rs2438146, were significantly associated with bipolar disorder (global p = 0.004 after Bonferroni correction).

Limitations

Our genetic association study only offered evidence for susceptibility of PDLIM5 to bipolar disorder, but the positive SNP rs2433322 could not indicate a direct cause of this complicated brain disorder. In addition, the 4 tagged SNPs that we selected could not cover the whole region of PDLIM5, thus additional reproducible studies of more SNPS in large non-Asian populations are needed.

Conclusion

Our results suggest that PDLIM5 might play a role in susceptibility to bipolar disorder among the Chinese Han population.     

Association study of the SLC25A12 gene and autism in Han Chinese in Taiwan

Purpose

Autism is a childhood-onset neurodevelopmental disorder with a strong genetic component in its etiology. Several studies reported that the solute carrier family 25 member A12 (SLC25A12) gene was associated with autism. This study aimed to replicate this finding in a Han Chinese sample from Taiwan using a population-based case–control approach.

Methods

We genotyped two single nucleotide polymorphisms (SNPs, rs2056202 and rs2292813) of the SLC25A12 gene that were previously reported to be associated with autism in 465 patients (402 males and 63 females) and 450 control subjects (227 males and 223 females) from Taiwan. Differences in the genotype, allele, and haplotype frequencies between the two groups were compared.

Results

We found no differences in the allele, genotype, or haplotype frequencies of these two SNPs between patients and controls.

Conclusions

Our data do not support that the SLC25A12 gene is associated with autism in our population. The discrepant results of other studies may come from the clinical heterogeneity of patients recruited for studies, or the genetic heterogeneity of autism in different populations.     

Genetic Association Study of the Alpha 7 Nicotinic Receptor (CHRNA7) with the Development of Schizophrenia and Bipolar Disorder in Korean Population

Objective

CHRNA7 has been shown to be a strong candidate gene for schizophrenia and bipolar disorder. It is located on chromosome 15q13-q14, which is one of the replicated linkage spots for schizophrenia and bipolar disorder.

Methods

We conducted an association study to determine whether previous positive association is replicable in the Korean population. We included 254 patients with schizophrenia, 193 patients with bipolar disorder type I, 38 patients with bipolar disorder type II, 64 schizoaffective disorder patients, and 349 controls. All subjects were ethnically Korean. A total of 898 subjects were included, and genotyping was done for three single nucleotide polymorphisms (SNPs) of CHRNA7. These three intronic SNPs were rs2337506 (A/G), rs6494223 (C/T), and rs12916879 (A/G).

Results

There was only one marginally significant association; this association was between rs12916879 and bipolar disorder type I in the male subgroup. In both the allele and genotype distributions, we found a weak signal (Chi-squared=3.57, df=1, p=0.06 for allele, Chi-squared=7.50, df=2, p=0.02 for genotype) only. Unphased haplotype analysis could not provide additional support for this finding. No SNP was associated with schizophrenia or any other affected groups in this Korean sample. The associative finding is marginal and inconclusive.

Conclusion

We could not replicate positive association in other ethnic groups previously studied. This suggests possible heterogeneity in the genes associated with schizophrenia and bipolar disorders. Because of structural complexity of the CHRNA7 gene and the limited statistical power of this study, further genetic studies with more SNPs and larger samples covering various populations, along with more fine molecular exploration of the CHRNA7 gene structure, are required.     

Suicide attempts and clinical risk factors in patients with bipolar and unipolar affective disorders

Background

Suicide is an important clinical problem in psychiatric patients. The highest risk of suicide attempts is noted in affective disorders.

Objective

The aim of the study was to look for suicide risk factors among sociodemographic and clinical factors, family history and stressful life events in patients with diagnosis of unipolar and bipolar affective disorder (597 patients, 563 controls).

Method

In the study, the Structured Clinical Interview for DSM-IV Axis I Disorders and the Operational Criteria Diagnostic Checklist questionnaires, a questionnaire of family history, and a questionnaire of personality disorders and life events were used.

Results

In the bipolar and unipolar affective disorders sample, we observed an association between suicidal attempts and the following: family history of psychiatric disorders, affective disorders and psychoactive substance abuse/dependence; inappropriate guilt in depression; chronic insomnia and early onset of unipolar disorder. The risk of suicide attempt differs in separate age brackets (it is greater in patients under 45 years old). No difference in family history of suicide and suicide attempts; marital status; offspring; living with family; psychotic symptoms and irritability; and coexistence of personality disorder, anxiety disorder or substance abuse/dependence with affective disorder was observed in the groups of patients with and without suicide attempt in lifetime history.     

Facial emotion triggered cerebral potentials in treatment-resistant depression and borderline personality disorder patients of both genders

Background

Processing facial expressions of emotion is deteriorated in depression, which might be more pronounced in treatment-resistant depression (TRD), especially when the latter is comorbid with borderline personality disorder (BPD). Neurophysiologically, both early perceptual and late cognitive cerebral processes of facial emotions can be illustrated by event-related potentials (ERPs).

Methods

We therefore tried the ERPs to facial expressions of Neutral, Anger, Happiness, and Sadness in 25 patients with TRD, 15 with BPD, 22 with their comorbidity (TRD + BPD), as well as in 37 healthy volunteers. The depression levels of participants were measured with the Plutchik–van Praag Depressive Inventory (PVP).

Results

There was no group difference regarding either N1 (N170), P2, N2, P3a or P3b latency or amplitude to the four facial emotions. Reaction times (RTs) to Anger (p < .01), Happiness (p < .01), and Sadness (p < .001) in TRD, and those to Anger (p < .01) and Happiness (p < .01) in TRD + BPD patients were longer than those in the healthy volunteers. RTs to the four facial expressions were positively correlated (p < .01) with their depressive moods in all participants. In addition, PVP was positively correlated with the P2 latency to Anger in TRD + BPD patients (Fz, p < .01; Cz, p < .01; Pz, p < .01).

Conclusions

BPD contributed little to TRD or TRD + BPD regarding cerebral processing of facial emotions, however, other cognitive and behavioral data suggest a generalized impairment when responding to facial emotions in TRD and TRD + BPD patients, and a deteriorated perceptual processing of Anger in TRD + BPD patients.     

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.     

Correlates of psychiatric hospitalization in a clinical sample of Canadian adolescents with bipolar disorder

Objective

To identify factors associated with psychiatric hospitalization among adolescents with bipolar disorder (BD).

Methods

Participants were 100 adolescents, ages 13–19, who fulfilled DSM-IV criteria for bipolar I disorder [(BD-I), n = 26], bipolar II disorder [(BD-II), n = 40], or operationalized criteria for BD not otherwise specified [(BD-NOS), n = 34], via the Schedule for Affective Disorders and Schizophrenia, Present and Lifetime version (KSADS-PL). Demographic, clinical, and family history variables were measured via clinical interview with the participant and a parent or guardian.

Results

The lifetime prevalence of psychiatric hospitalization was 50%. Significant predictors of psychiatric hospitalization in univariate analyses included older age, BD-I, history of suicide attempt, psychosis, lifetime use of second generation antipsychotics (SGAs), lithium, SSRI antidepressants and any medication. BD-II was negatively associated with psychiatric hospitalization. In multivariable analyses, older age, history of suicide attempt, psychosis and use of SGAs were positively associated with hospitalization, whereas BD-II was negatively associated with hospitalization.

Conclusions

Psychiatric hospitalization in adolescents with BD is highly prevalent and associated with older age and proxies for greater illness severity. Further studies are needed to identify strategies for reducing the need for psychiatric hospitalizations among adolescents with BD.     

Association between TNF-α promoter -308A/G polymorphism and tardive dyskinesiain Chinese Han patients with schizophrenia

Objective

Previous studies have indicated that the immune may be involved in the pathogenesis of tardive dyskinesia (TD). Some genetic polymorphisms in the human leukocyte antigen (HLA) I and II regions have been associated with TD, and the tumor necrosis factor-α (TNF-α) gene is located in the HLA III region. TNF-α levels in the striatum significantly increased in haloperidol-induced TD in rats. The TNF-α gene −308A/G single nucleotide polymorphism (SNP) has been shown to directly influence TNF-α expression. The genetic association between the TNF-α gene −308A/G SNP and TD is unclear. The present study investigated whether this variation is associated with clinical phenotypes and TD in schizophrenia in a genetically homogeneous northern Chinese Han population.

Methods

We genotyped the TNF-α gene −308A/G SNP in patients with schizophrenia with TD (n = 350) and without TD (n = 410). The Abnormal Involuntary Movement Scale (AIMS) and Positive and Negative Syndrome Scale (PANSS) were used to assess the severity of TD and psychopathology of schizophrenia, respectively.

Results

The allele and genotype frequencies did not significantly differ between patients with schizophrenia with and without TD (p > 0.05). No significant difference was found in the total AIMS score between the genotypes (p > 0.05). However, the PANSS negative symptom subscore was associated with risk for TD (p = 0.004), and a significant difference was found in total AIMS score between the genotypes in TD patients (p = 0.013).

Conclusion

The TNF-α gene −308A/G polymorphism does not appear to play a major role in the susceptibility to TD in patients with schizophrenia in a northern Chinese Han population. However this polymorphism may play a role in the TD severity.     

Hopelessness and suicidal risk in bipolar disorder. A study in clinically nonsyndromal patients

Objective

Attempted suicide and death due to suicide are not uncommon among patients with bipolar disorder. Although some risk factors for suicidality in bipolar patients have been identified, little is known about hopelessness and other possible trait or diathesis-related factors. Consequently, the objective of this study was to investigate variables associated with suicidal risk in clinically nonsyndromal bipolar patients.

Methods

A sample of 102 outpatients with a diagnosis of bipolar disorder according to International Classification of Diseases, 10th Revision criteria during nonsyndromal stage were evaluated. On the basis of suicidal history, patients were divided into suicide attempt, suicidal ideation, and nonsuicidal groups. Sociodemographic, clinical, and psychopathological variables were assessed.

Results

As compared with the nonsuicidal group, female sex, combined psychopharmacologic treatment, and hopelessness were independently associated with suicide attempt. Hopelessness and insight into having a mental disorder were independently associated with history of suicidal ideation.

Conclusions

Patients with bipolar disorder and suicidal history are characterized by the presence of hopelessness, which probably confers greater vulnerability for suicidal behavior in the presence of stress factors. This identification of the risk profile for suicidal behavior in nonsyndromal bipolar patients adds complementary information to risk factors established for suicidality during acute phases of the disease, allows for differentiated preventive and treatment approaches of patients at risk, and suggests psychotherapy as an advisable intervention in this group of patients.     

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.     

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.     

Association Study of <Emphasis Type="Italic">VMAT1</Emphasis> Polymorphisms and Suicide Behavior

Genetic association studies have linked suicide behavior with genes encoding transporters of monoamine. Variants in the vesicular monoamine transporter 1 (VMAT1) have been previously shown to be associated with several psychiatric disorders including schizophrenia and bipolar disorder. However, their association with suicide behavior has not been explored. In the present study, we genotyped three single-nucleotide polymorphisms (rs2270637, rs1390938, and rs2279709) within this gene in 100 individuals who attempted suicide, 236 suicide victims, and 300 control subjects without any history of psychiatric disorders or suicide ideation. We demonstrated no difference in genotype, allele, or haplotype frequencies of theses single-nucleotide polymorphisms between the study groups. Consequently, contribution of VMAT1 in risk of psychiatric disorders might be independent of suicide behavior. Future studies with larger sample sizes are needed to confirm our results.