DISC1 exon 11 rare variants found more commonly in schizoaffective spectrum cases than controls

We previously performed a linkage study using families identified through probands meeting criteria for DSM‐IV schizoaffective disorder, bipolar type (SABP) and observed a genome‐wide significant signal (LOD = 3.54) at chromosome 1q42 close to DISC1. An initial sequencing study of DISC1 using 14 unrelated DSM‐IV SABP samples from the linkage study identified 2 non‐synonymous coding SNPs in exon 11 in 2 separate individuals. Here we provide evidence of additional rare coding SNPs within exon 11. In sequencing exon 11 in 506 cases and 1,211 controls for variants that occurred only once, 4 additional rare variants were found in cases (P‐value = 0.008, Fisher's exact trend test). © 2011 Wiley‐Liss, Inc.     

No evidence for association between bipolar disorder risk gene variants and brain structural phenotypes

Background

While recent genome-wide association studies have identified several new bipolar disorder (BD) risk variants, structural imaging studies have reported enlarged ventricles and volumetric reductions among the most consistent findings. We investigated whether these genetic risk variants could explain some of the structural brain abnormalities in BD.

Methods

In a sample of 517 individuals (N=121 BD cases, 116 SZ cases, 61 other psychosis cases and 219 healthy controls), we tested the potential association between nine SNPs in the genes CACNA1C, ANK3, ODZ4 and SYNE1 and eight brain structural measures found to be altered in BD, and if these were specifically affecting the BD sample. We also assessed the polygenic effect of all these 9 SNPs on the brain phenotypes.

Results

Our most significant result was an association between the risk allele A in CACNA1C SNP rs4775913 and decreased cerebellar volume (p_nom.=0.0075) in the total sample, which did not remain significant after multiple testing correction (p_threshold<0.0064). There was no evidence for diagnostic specificity for this association in the BD group. Further, no polygenic effect of these 9 SNPs was observed.

Limitations

Low statistical power might increase our type II error rate.

Conclusions

The present findings indicate that these risk SNPs do not explain a large proportion of the structural brain alterations in BD. Thus, these genes which are all related to neuronal functions must be involved in other pathophysiological aspects of BD development.     

Association analysis of Neuregulin 1 candidate regions in schizophrenia and bipolar disorder

Schizophrenia (SCZ) and bipolar disorder (BPD) are severe heritable psychiatric disorders involving a complex genetic aetiology. Neuregulin 1 (NRG1) is a leading candidate gene for SCZ, and has recently been implicated in BPD. We previously reported association of two NRG1 haplotypes with SCZ and BPD in a Scottish case–control sample. One haplotype is located at the 5′ end of the gene (region A), and the other is located at the 3′ end (region B). Here, association to haplotypes within regions A and B was assessed in patients with SCZ and BPD in a second Scottish case–control sample and in the two Scottish samples combined. Association to region B was also assessed in patients with SCZ and BPD in a German case–control sample, and in all three samples combined. No evidence was found for association in the new samples when analysed individually; however, in the joint analysis of the two Scottish samples, a region B haplotype comprising two SNPs (rs6988339 and rs3757930) was associated with SCZ and the combined case group (SCZ: p = 0.0037, OR = 1.3, 95% CI: 1.1–1.6; BPD + SCZ: p = 0.0080, OR = 1.2, 95% CI: 1.1–1.5), with these associations withstanding multiple testing correction at the single-test level (SCZ: p_st = 0.022; BPD + SCZ: p_st = 0.044). This study supports the involvement of NRG1 variants in the less well studied 3′ region in conferring susceptibility to SCZ and BPD in the Scottish population.     

Association study of polymorphisms between DISC1 and schizophrenia in a Korean population

To further clarify schizophrenia (SCZ), disrupted in schizophrenia 1 (DISC1) is a promising candidate gene expressed predominantly within the hippocampus. Several lines of evidence suggest that DISC1 may be involved in susceptibility to SCZ. In this study, we investigated whether genetic polymorphisms in the coding region of DISC1 were associated with several SCZ clinical phenotypes in a Korean population. To examine any association between DISC1 and SCZ, we genotyped three clinical single nucleotide polymorphisms (SNPs) (rs3738401, R264Q; rs3738402, L465L; rs821616, S704C) in the coding region of the DISC1 gene using the Illumina Sentrix Array Matrix chip and direct sequencing in 303 patients with SCZ and 300 healthy controls. Our case-control analysis showed that none of these SNPs was associated with SCZ. In further endophenotype stratification, however, we found a significant association between rs821616 and the poor concentration subgroup of SCZ, determined using the Operational Criteria Checklist (codominant model, p=0.015). Our results suggest that DISC1 may be a susceptibility gene for poor concentration among Korean patients with SCZ.     

High frequency of neurexin 1beta signal peptide structural variants in patients with autism

Neuroligins are postsynaptic membrane cell-adhesion molecules which bind to beta-neurexins, a family of proteins that act as neuronal cell surface receptors. To explore the possibility that structural variants in the beta-neurexin genes predispose to autism, the coding regions and associated splice junctions of three beta-neurexin genes were scanned with detection of virtually all mutations-SSCP (DOVAM-S) in 72 Caucasian patients with autism. In addition, segments of the neurexin 1beta gene were sequenced in 131 additional Caucasian and 61 Afro-American patients with autism from South Carolina and the Midwest. Two putative missense structural variants were identified in the neurexin 1beta gene in four Caucasian patients with autism and not in 535 healthy Caucasian controls (4/203 vs. 0/535, P=0.0056). Initial family data suggest that incomplete penetrance may occur. In addition, no structural variant was found in the neurexin 2beta gene and the neurexin 3beta gene. In the context of all available data, we conclude that mutations of the neurexin 1beta gene may contribute to autism susceptibility.     

Jumonji domain containing 1C (JMJD1C) sequence variants in seven patients with autism spectrum disorder,intellectual disability and seizures

The Jumonji domain containing 1C (JMJD1C) gene encodes the Jumonji domain-containing protein 1C (JMJD1C) and is a member of the jmJC domain-containing protein family involved in histone demethylation that is expressed in the brain. We report seven, unrelated patients with developmental delays or intellectual disability and heterozygous, de novo sequence variants in JMJD1C. All patients had developmental delays, but there were no consistent additional findings. Two patients were reported to have seizures for which there was no other identified cause. De novo, deleterious sequence variants in JMJD1C have previously been reported in patients with autism spectrum disorder and a phenotype resembling classical Rett syndrome, but only one JMJD1C variant has undergone functional evaluation. In all of the seven patients in this report, there was a plausible, alternative explanation for the neurocognitive phenotype or a modifying factor, such as an additional potentially pathogenic variant, presence of the variant in a population database, heteroplasmy for a mitochondrial variant or mosaicism for the JMJD1C variant. Although the de novo variants in JMJD1C are likely to be relevant to the developmental phenotypes observed in these patients, we conclude that further data supporting the association of JMJD1C variants with intellectual disability is still needed.     

Dysbindin gene variants are associated with bipolar I disorder in a Korean population

The dysbindin gene (DTNBP1) has been associated with schizophrenia in several populations. Because the clinical characteristics of schizophrenia and bipolar disorder overlap in many respects and findings from genetic studies have suggested common genes between them, we conducted a case control association study of bipolar disorder in Korea to investigate the genetic association between DTNBP1 and bipolar disorder. In total, 163 patients with bipolar disorder and 350 controls were evaluated. We genotyped three single nucleotide polymorphisms of DTNBP1 (SNP A, P1763, and P1320) and analyzed the allele, genotype, and haplotype associations with bipolar disorder. We found significant genotypic associations with P1763 and P1320, but no association with SNP A in the bipolar I group. When we included bipolar II and schizoaffective disorder in the affected phenotype, the significance decreased. A positive association was observed between the SNP A-P1763 haplotype and the bipolar I phenotype. This haplotype association was lost when we either broadened our phenotype or included P1320 in a haplotype. The positive results of the present study lost significance after a Bonferroni correction for multiple testing. These findings are consistent with previous findings that showed a positive association of DTNBP1 with bipolar disorders. Moreover, our results suggest that DTNBP1 may contribute more to bipolar I disorder than bipolar II disorder or schizoaffective disorder. Further comprehensive studies will be required to clarify these association, however, it seems likely that DTNBP1 is a susceptibility gene for bipolar disorder.     

Diagnoses in school-age children of bipolar affective disorder patients and normal controls

A family study of psychiatric diagnoses was performed in 29 children of bipolar patients and 37 children of normal controls, ages 6-17. There were no differences in major or minor affective diagnoses between the patient and control groups, but there was an increase of non-specific diagnoses in the patient group. Using DSM-III criteria, 10% of patients' children and 14% of controls' children had had at least one episode of major depression. This suggests that major depression in children is not familially related to adult bipolar major affective disorder. The observed prevalence of depression in childhood is increased when both direct interview of children and interview of parents are performed.     

No association of the MCP-1 promoter A-2518G polymorphism with bipolar disorder in the Korean population

It has been suggested that bipolar disorder is associated with altered immune function. Monocyte chemoattractant protien-1 (MCP-1) is a chemokine that influences both neural and immune functions. We thus hypothesized that MCP-1 may be related to the development or pathophysiology of bipolar disorder. In this case–control study, we investigated the association between the A-2518G single nucleotide polymorphism (SNP) of the MCP-1 promoter and bipolar disorder. Patients with bipolar disorder (n = 183; bipolar I = 145, bipolar II = 38) and healthy controls (350) were recruited for the study. No significant allelic or genotypic association was detected between the A-2518G polymorphism and any sample of bipolar disorder patients. When we pooled the healthy controls and the cases of bipolar I disorder from previous Korean studies and this study, we again found no significant association. No significant difference in either allele frequency or genotype distribution was observed between bipolar I and bipolar II disorders. There was no difference in the age at onset of bipolar disorder among the three genotype groups. Our data suggest that the A-2518G polymorphism of MCP-1 is not a major susceptibility factor for bipolar disorder in the Korean population. However, the physiological role of MCP-1 is highly suggestive of its being associated with bipolar disorder, and further analyses of other SNPs of MCP-1 remain to be performed.     

Elevated C-reactive protein and cognitive deficits in individuals with bipolar disorder

Background

Some individuals with bipolar disorder have cognitive deficits even when euthymic. In previous studies, we found an association between elevated levels of C-reactive protein (CRP), a marker of inflammation, and reduced cognitive functioning in schizophrenia. This issue has not been examined in bipolar disorder.

Methods

We measured the levels of high sensitivity CRP in serum samples from 107 individuals with bipolar disorder. Cognitive functioning was measured with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Trail Making Test Part A and WAIS Information and Letter Number Sequencing. We estimated the odds of RBANS scores <=70 for participants whose CRP levels were above the 75th and the 90th percentile of the level of non-psychiatric controls. We also examined the association between cognitive scores and CRP levels. Covariates included demographic factors, mood symptom severity, cigarette smoking status, and body mass index.

Results

There was a significantly increased odds of low RBANS total score for individuals who had a CRP level higher than the 90th percentile (OR=4.32, p=.018) and the 75th percentile (OR=3.07, p=.04)) of the control group. There was an inverse relationship between CRP levels and performance on RBANS total (t=−2.48, p=.015); RBANS immediate memory (t=−2.16, p=.033); RBANS attention (t=−2.18, p=.032); RBANS language (t=−2.13, p=.036); Trail Making A (t=−2.39, p=.019).

Limitations

Factors which we did not measure such as diet, allergen exposure, and underlying autoimmune disorders may contribute to CRP levels.

Conclusions

Inflammation may play a major role in the cognitive deficits associated with bipolar disorder.     

Increased risk of developing stroke among patients with bipolar disorder after an acute mood episode: a six-year follow-up study

BACKGROUND: Despite cerebrovascular diseases having been reported as one of the major causes of death among patients with bipolar disorder, there is scant information on the risk of stroke among this patient population. This study estimated the relative risk of developing stroke among patients with bipolar disorder in 6 years following hospitalization for an acute mood episode compared with patients undergoing appendectomy. METHODS: Two study cohorts were identified from the Taiwan National Health Insurance Research Database for the year 1998: patients hospitalized with bipolar disorder, and patients undergoing an appendectomy. Follow-up was undertaken to determine whether sampled patients had utilized emergency medical services for the management of any type of stroke in the period 1998-2003. RESULTS: Stroke occurred among 2.97% of patients with bipolar disorder and 1.50% of patients undergoing appendectomy between 1998 and 2003. The adjusted odds ratio of developing stroke, by cohort, shows that after adjusting for demographic characteristics, comorbid medical disorder, and substance or alcohol dependence, patients with bipolar disorder were more likely to develop stroke (OR=2.05; 95% CI=1.73-3.54). LIMITATIONS: The validity of diagnoses, lacking of information on smoking, body mass index, and socioeconomic status, and possible selection bias might compromise the findings. CONCLUSIONS: During the six-year follow-up period, the likelihood of developing stroke was twice as great amongst patients with bipolar disorder as patients undergoing an appendectomy. A requirement exists for the initiation of research providing an understanding of the pathophysiological mechanisms of the association between stroke and bipolar disorder.     

Tyrosine kinase B protein expression is reduced in the cerebellum of patients with bipolar disorder

Background

The role of the cerebellum in coordinating mental activity is supported by its connections with cerebral regions involved in cognitive/affective functioning, with decreased activities on functional neuroimaging observed in the cerebellum of schizophrenia patients performing mental tasks. Brain-derived neurotrophic factor (BDNF)-induced activation of tyrosine kinase B (TrkB) is essential to synaptic plasticity. We hypothesized that alterations in BDNF and TrkB expression in the cerebellum were associated with schizophrenia and affective disorders.

Methods

We employed immunohistochemistry and immunoblotting to quantify protein expression of BDNF and TrkB in the cerebellum of patients with schizophrenia, bipolar disorder, and major depression compared to controls (n = 15 each).

Results

While TrkB immunoreactivity in each of the molecular and granule-cell layers was reduced in all 3 disease groups (12-34%) compared to the control (P = 0.018 and 0.038, respectively, ANOVA), only the reduction in bipolar disorder remained statistically significant upon Tukey-Kramer post hoc analyses (P = 0.019 and 0.021, respectively). Apparent decreases in BDNF immunoreactivity in all 3 disease groups (12-30%) compared to the control were not statistically significant. TrkB immunoreactivity was not significantly associated with any of the demographic, clinical, and postmortem variables. Immunoblotting displayed an 85-kDa TrkB-immunoreactive band, consistent with a truncated isoform, in all 60 cases.

Limitations

On immunoblotting, apparent decreases in 85-kDa-TrkB levels in all 3 disease groups compared to the control were not statistically significant.

Conclusions

Our finding of reduced TrkB expression in bipolar disorder suggests that dysregulation of TrkB-mediated neurotrophin signaling in the cerebellum may play a role in the pathophysiology of this disease.     

A prospective,longitudinal study of metabolic syndrome in patients with bipolar disorder and schizophrenia

Background

Although cross sectional studies have evaluated the prevalence of metabolic syndrome (MetS) in patients with bipolar patients (BPAD), data from longitudinal studies are limited.

Aim

To assess the prevalence of MetS in patients with BPAD, to observe the change in prevalence rate over a period of 6 months, to assess the prevalence of sub-threshold MetS (i.e., patients fulfilling one or two criteria of MetS) and to compare patients with BPAD and schizophrenia on the above mentioned parameters.

Methodology

Seventy five patients with BPAD and 53 patients with schizophrenia were initially evaluated for MetS and then followed up for a period of 6 months.

Results

According to consensus definition, prevalence of MetS at baseline was 40% in BPAD group and 32% in schizophrenia group. Over 6 months of follow-up the prevalence of MetS increased by 8% and 9.4% in the BPAD and the schizophrenia groups respectively. There was no significant difference between the two groups on any of the assessments. Another 28–32% of patients in the BPAD group also fulfilled two criteria and 13–17% fulfilled at least one criterion of MetS at different points of assessment. Similarly, 19–26% of the patients with schizophrenia met at least two and 23–26% of the patients fulfilled at least one criterion of MetS.

Limitation

The study was limited by small sample size, inclusion and the relatively short follow-up period.

Conclusion

40% patients with BPAD and 32% with schizophrenia have MetS and the prevalence of MetS increases by 8–9.4% over 6 months.     

Association of genetic variation in CACNA1C with bipolar disorder in Han Chinese

Background

A growing body of evidence highlights the existence of shared genetic susceptibility to both major depressive disorder (MDD) and bipolar disorder (BD), suggesting some potential genetic overlap between the disorders. Genome-wide association studies have identified consistent association of single nucleotide polymorphisms of the α-1 C subunit of the L-type voltage-gated calcium channel gene (CACNA1C) with MDD and BD, suggesting CACNA1C as a promising candidate gene for susceptibility to mood disorders. In the present study, we tested the association of CACNA1C with MDD and BD in Han Chinese.

Methods

We genotyped three potentially functional polymorphisms in 635 MDD patients, 286 BD patients and 730 normal, control patients.

Results

The genotype frequencies of SNP rs1051375 showed statistically significant differences between the BD and control groups (P=0.005). At the allele level, the difference of G allele frequency of rs1051375 between BD patients and control subjects was also significant (P=0.011; OR=1.30, 95% CI: 1.06–1.58). We found that GG genotype of rs1051375 carriers had a lower age at onset than those with the AG or AA genotype, and the mean±standard deviation ages at onset of GG, AG and AA carriers were 24.04±4.22, 25.76±4.75 and 25.78±4.33 years, respectively. Neither genotype nor allele frequencies of the three polymorphisms were found to be significantly different between the MDD patients and control subjects.

Limitations

The relative small sample size in BD group should be considered a limitation of this study.

Conclusions

Our initial findings support a potential association of CACNA1C as a genetic risk factor for BD susceptibility.     

The use of the GBI in a population of adolescent offspring of parents with a bipolar disorder

Objective: To assess the psychometric properties and the usefulness of the General Behavior Inventory (GBI) in the adolescent age range. Method: The GBI, the Schedule for Affective Disorders and Schizophrenia for School Age Children, Kiddie-SADS-Present and Lifetime Version (K-SADS-PL) and the Youth Self-Report (YSR) were used to assess 117 adolescents of a bipolar parent twice with an interval of 14 months. Based on the K-SADS results, the bipolar offspring were assigned to one of three groups: with mood disorders, with non-mood disorders, and with no disorders. Results: Principal component analyses resulted in the same two-factor solution as reported for adults. The Depression scale of the GBI discriminated between adolescents with a DSM-IV mood disorder, a non-mood disorder and no disorder on Axis I. Significant correlations between GBI scales and the corresponding Internalizing and Externalizing scales of the YSR showed convergent validity. Conclusions: The GBI can be used in the adolescent age range as a self-report to discriminate mood disorders from non-mood disorders or no disorders.     

Correlates of preferring a passive role in decision-making among patients with schizophrenia or bipolar disorder

ObjectiveTo assess the factors associated with the persistence of clinician-led style in the therapeutic relationship in cases of serious mental illness, and the conditioning factors that the patients identify as determinants of their health.MethodAssessment of preferences in the decision-making process and health-related control locus of 107 outpatients with DSM-5 diagnosis of schizophrenia or bipolar disorder. Demographic and clinical information was also obtained through review of available records and using several scales.Results64.4 % patients preferred to adopt a passive role in the therapeutic relationship. In the multivariate analysis, the preference of playing a passive role in the decision-making process was significantly associated with the elderly, being disabled, or the view that one’s health depends on doctors (AUC ROC value: 0.80).ConclusionsPatients with severe mental illness more frequently preferred a passive role in the decision-making process. We found several factors associated with a preference for the “expert role” model.Practice implicationsThe identified factors may permit care to be tailored to the most probable expectations as regard decision-making. Since the populations concerned may be vulnerable and suffer inequalities in the provision of health services, promoting participation in the care process could help improve clinical parameters ethically.     

Serum levels of brain-derived neurotrophic factor in patients with schizophrenia and bipolar disorder

There is evidence that major psychiatric discords such as schizophrenia (SZ) and bipolar disorder (BD) are associated with dysregulation of synaptic plasticity with downstream alterations of neurotrophins. Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the central nervous system (CNS), and performs many biological functions such as promoting the survival, differentiation, and plasticity of neurons. Variants in the BDNF gene increase the risk of SZ and bipolar disorder. Chronic administration of drugs used to treat SZ and BD, such as lithium, valproate, quetiapine, clozapine, and olanzapine, increases BDNF expression in rat brain. To examine serum BDNF, three groups of chronically medicated DSM-IV SZ patients, on treatment with clozapine (n = 27), typical (n = 14), and other atypical antipsychotics (n = 19), 30 euthymic BD patients, and 26 healthy control had 5 ml blood samples collected by venipuncture. Serum BDNF levels were significantly higher in SZ patients (p < 0.001) when compared to either controls or euthymic BD patients. Increased BDNF in SZ patients might be related to the course of illness or to treatment variables. Prospective studies are warranted.     

Reduced expression of glyoxalase-1 mRNA in mood disorder patients

Glyoxalase-1 (Glo1) is an antioxidant enzyme which detoxifies alpha-ketoaldehydes to prevent the accumulation of pro-oxidant compounds, such as methylglyoxal, in all cell types. Glo1 has been suggested to be involved in anxiety disorders, autism, and Alzheimer's disease. Mood disorders have a high rate of comorbidity with anxiety disorders although, to date, little is known of the involvement of Glo1 in the pathophysiology of these conditions. In the present study, we examined the expression levels of Glo1 mRNA in peripheral white blood cells of mood disorder patients to understand the role of Glo1 in mood disorders. Quantitative real-time polymerase chain reaction experiments revealed that reduced expression of Glo1 mRNA was observed in major depressive and bipolar disorder patients in a current depressive state, as compared with healthy control subjects. In contrast, the expression of Glo1 mRNA in major depressive and bipolar patients, in a remissive state, showed no significant alteration when compared with healthy control subjects. These results suggest that the aberrant expression of Glo1 might be involved in the pathophysiology of mood disorders.