Assessment of risk factors related to suicide attempts in patients with bipolar disorder.

We compared the characteristics of patients with bipolar disorder with and without a history of suicide attempts to identify the risk factors of suicide in this disorder. Among 212 patients with bipolar disorder, 44 (21.2%) patients had histories of suicide attempts. Suicide attempters were younger and more likely to be diagnosed with bipolar II. The variables that differentiated those who did from those who did not attempt suicide included age at first contact, lifetime history of antidepressant use, major depressive episode, mixed episode, auditory hallucinations, rapid cycling, the number of previous mood episodes, age of first depressive episode, and age of first psychotic symptoms. Strong predictors of suicide attempts were younger age at onset, lifetime history of auditory hallucinations, and history of antidepressant use. Antecedent depressive episodes and psychotic symptoms predicted the first suicide attempt in patients with bipolar disorder. This study could help clinicians to understand the major risk factors of suicidal behavior in bipolar disorder.

No association of functional polymorphisms in methlylenetetrahydrofolate reductase and the risk and minor physical anomalies of schizophrenia in Korean population.

Methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate metabolism, plays an important role in DNA methylation. It has been suggested that abnormal DNA methylation contributes to the pathogenesis of schizophrenia and congenital anomalies. The previous findings regarding the genetic relationship between MTHFR and schizophrenia are controversial. This study investigated the association of the two functional polymorphisms of MTHFR, C677T and A1298C, with the risk for schizophrenia. Furthermore, we conducted an updated meta-analysis on the two polymorphisms. In addition, we investigated the relationship between the polymorphisms and minor physical anomaly (MPA), which may represent neurodevelopmental aberrations in 201 schizophrenia patients and 350 normal control subjects. There was no significant association between either of the two polymorphisms and the risk of schizophrenia (chi-square = 0.001, df = 1, P = 0.971 for C677T; chi-square = 1.319, df = 1, P = 0.251 for A1298C). However, in meta-analysis, the C677T polymorphism showed a significant association in the combined and Asian populations (OR = 1.13, P = 0.005; OR = 1.21, P = 0.011, respectively) but not in the Korean and Caucasian populations alone. Neither polymorphism was associated with MPAs measured by the Waldrop scale (chi-square = 2.513, df = 2, P = 0.285). In conclusion, the present findings suggest that in the Korean population, the MTHFR polymorphisms are unlikely to be associated with the risk for schizophrenia and neurodevelopmental abnormalities related to schizophrenia.

Association of ANK3 with bipolar disorder confirmed in East Asia.

Results of genome-wide association studies (GWASs) for bipolar disorder (BD) have indicated ANK3 as one of the most promising candidates for a susceptibility gene. In this study, we performed genetic association analysis of two single-nucleotide polymorphisms (SNPs) in ANK3 (rs1938526 and rs10994336), whose genome-wide significant associations were reported in a previous meta-analysis of GWASs, using genotyping data of Korean and Japanese case-control samples and a part of data from a GWAS in Han-Chinese from Taiwan. The total number of participants was 2,212 cases (352 from Korea, 860 from Japan, and 1,000 from Taiwan) and 2,244 controls (349 from Korea, 895 from Japan, and 1,000 from Taiwan). We could not detect any significant difference of allele frequency in individual analyses using each of the three populations. However, when we combined the three data sets and performed a meta-analysis, rs1938526 showed nominally significant association (P = 0.048, odds ratio = 1.09). The over-represented allele in BD was same as that reported in Caucasian GWASs. On the other hand, any significant association was not detected in rs10994336. This discrepancy between two SNPs may be explained by the different degree of linkage disequilibrium between Asian and Caucasian. These findings further supported the association between ANK3 and BD, and also suggested the genomic region around rs1938526 as a common risk locus across ethnicities.

EGR3 as a potential susceptibility gene for schizophrenia in Korea.

Early growth response (EGR) genes play critical roles in signal transduction in the brain, which is involved in neuronal activation, brain development, and synaptic plasticity. EGR genes, including EGR2, EGR3, and EGR4, showed significant association with schizophrenia in Japanese schizophrenic pedigrees. In particular, EGR3, which resides at the chromosomal location 8p21.3, was suggested to be a potential susceptibility gene in schizophrenia based on a study of Japanese cases. However, this requires further replication with an independent sample set. We investigated the association of the EGR3 and EGR2 genes, which were suggested as potential susceptibility genes for schizophrenia supported by both genetic association and postmortem brain expression studies, with schizophrenia in Korean patients. Along with 350 healthy individuals, 244 schizophrenic patients were analyzed. Among the four examined single-nucleotide polymorphisms (SNPs) of EGR3 (rs1008949, rs7009708, rs35201266, and rs3750192), SNP rs35201266 in intron 1 of the EGR3 gene showed a significant association with schizophrenia (P = 0.0008, χ(2) = 11.156, OR = 1.493), which withstands multiple testing correction. In addition, the "T-G-C-G" haplotype of EGR3 was under-represented in the patients with schizophrenia (P = 0.0073, χ(2) = 7.188, OR = 0.697). However, an association between the SNPs of EGR2 (rs2295814 and rs2297488) and schizophrenia was not found. These findings are consistent with the previous genetic association of the EGR3 gene in Japanese cohorts, which is the first replication concerning the association of EGR3 with schizophrenia in an independent cohort. Taken together, EGR3 could be suggested as a compelling susceptibility gene in schizophrenia.

Dose-dependent effect of intracerebroventricular injection of ouabain on the phosphorylation of the MEK1/2-ERK1/2-p90RSK pathway in the rat brain related to locomotor activity.

Intracerebroventricular (ICV) injection of ouabain, a specific Na-K ATPase inhibitor, induced behavioral changes in rats, a putative animal model for bipolar disorder. The binding of ouabain to Na-K ATPase is known to affect signaling molecules in vitro such as extracellular signal-regulated kinase1/2 (ERK1/2). Although ERK has been suggested to be related to the behavioral alterations induced by various psychotomimetics, the effect of ouabain on ERK in the brain related to behavioral changes has not been examined. After ICV injection of ouabain in rats, we investigated changes in the phosphorylation of mitogen-activated protein kinase kinase1/2 (MEK1/2), ERK1/2, and p90 ribosomal s6 kinase (p90RSK) in rat striatum, frontal cortex, and hippocampus along with changes in locomotor activity. Ouabain induced the following biphasic dose-dependent changes in locomotor activity: no change with 10(-6) M, a statistically significant decrease with 10(-5) M, no change with 10(-4) M, and a statistically significant increase with 0.5x10(-3) and 10(-3) M. The phosphorylation level of MEK1/2, ERK1/2, and p90RSK in rat striatum showed dose-dependent changes similar to those observed in locomotor activity with relatively high correlation. The phosphorylation of these molecules in rat frontal cortex and hippocampus also changed in a similar dose-dependent pattern. Taken together, ouabain induced biphasic dose-dependent changes in locomotor activity and the phosphorylation of the ERK1/2 pathway. These findings suggest a possible relationship between ouabain-induced behavioral changes and ERK activity in the brain and suggest an important role of ERK in regulating locomotor activity and mood state.

Associations between DRDs and schizophrenia in a Korean population: multi-stage association analyses.

The dysregulation of the dopaminergic system has been implicated in the pathophysiology of major psychosis, including schizophrenia, with dopamine receptor genes (DRDs) presently targeted as the most promising candidate genes. We investigated DRD1-5 for association with schizophrenia using a multi-stage approach in a Korean sample. One hundred forty-two SNPs in DRD1-5 were selected from the dbSNP, and the associations of each SNP were then screened and typed by MALDI-TOF mass spectrometry using pooled DNA samples from 150 patients with major psychosis and 150 controls. Each of the suggested SNPs was then genotyped and tested for an association within the individual samples comprising each pool. Finally, the positively associated SNPs were genotyped in an extended sample of 270 patients with schizophrenia and 350 controls. Among the 142 SNPs, 88 (62%) SNPs in our Korean population were polymorphic. At the pooling stage, 10 SNPs (DRD1: 2, DRD2: 3, and DRD4: 5) were identified (P<0.05). SNPs rs1799914 of DRD1 (P=0.046) and rs752306 of DRD4 (P=0.017) had significantly different allele frequencies in the individually genotyped samples comprising the pool. In the final stage, with the extended sample, the suggestive association of DRD4 with rs752306 was lost, but the association of DRD1 with rs1799914 gained greater significance (P=0.017). In these large-scale multi-stage analyses, we were able to find a possible association between DRD1 and schizophrenia. These findings suggested the potential contribution of a multi-step strategy for finding genes related to schizophrenia.

Association between CLOCK 3111T/C and preferred circadian phase in Korean patients with bipolar disorder.

Genes associated with circadian rhythms have been suggested to play an important role in the pathophysiology of bipolar disorder. A single nucleotide polymorphism (SNP) in the 3'-flanking region of CLOCK (3111T/C; rs1801260) has been reported to be associated with sleep disturbances and an increased recurrence rate in patients with bipolar disorder. We examined the association of CLOCK 3111T/C with bipolar disorder in 260 patients and 350 controls in a Korean population. CLOCK 3111T/C showed significant allelic and genotypic associations with bipolar disorder (P=0.012, P=0.033, respectively). Morningness/eveningness (M/E) was evaluated using the Composite Scale of Morningness (CSM) in 108 patients with bipolar disorder. In the subgroup analysis of the highest and lowest 25th percentile of M/E scores, significantly more C allele carriers were found among extreme evening types than among extreme morning types (P=0.041). After correcting for age, C allele carriers had lower M/E scores than those carrying the T/T genotype, but the association was not statistically significant. We also analyzed the association between age at onset (AAO) and CLOCK 3111T/C in the bipolar disorder group, and no association was found. Despite the relatively small sample sizes, these results support a possible role of the CLOCK 3111T/C SNP in bipolar disorder. Further studies with larger samples and more polymorphisms are necessary.

No association between AKT1 polymorphism and schizophrenia: a case-control study in a Korean population and a meta-analysis.

V-akt murine thymoma viral oncogene homolog 1 (AKT1) has been suggested to be involved in the pathophysiology of schizophrenia. Recent, independent studies in Caucasian, Japanese, Iranian, and Chinese populations have reported that the AKT1 gene may be associated with schizophrenia, but these results have yet to be replicated in other populations. In the present study, we performed a case-control association study between AKT1 and schizophrenia in a Korean population. We genotyped six single nucleotide polymorphisms (SNP1 (rs3803300), SNP2 (rs1130214), SNP3 (rs3730358), SNP4 (rs1130233), SNP5 (rs2494732), SNP A (rs2498804)) of AKT1, selected from previous reports, in a sample of 283 subjects with schizophrenia and 350 controls. No significant difference in single marker polymorphisms or haplotype frequencies of the six SNPs in the AKT1 gene was observed between controls and subjects with schizophrenia. In addition, we carried out an updated meta-analysis of the six SNPs, and found no evidence for an association between the six SNPs and schizophrenia. Taken together, our results do not support the hypothesis that AKT1 is a susceptibility gene for schizophrenia.