A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder.

Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10-9), a region known to contain regulatory genes for plasma lipid levels (FADS1/2/3). A subsequent meta-analysis of Phase I/II and the Psychiatric GWAS Consortium for BD (PGC-BD) identified another novel BD gene, NFIX (Pbest=5.8 × 10-10), and supported three regions previously implicated in BD susceptibility: MAD1L1 (Pbest=1.9 × 10-9), TRANK1 (Pbest=2.1 × 10-9) and ODZ4 (Pbest=3.3 × 10-9). Polygenicity of BD within Japanese and trans-European-Japanese populations was assessed with risk profile score analysis. We detected higher scores in BD cases both within (Phase I/II) and across populations (Phase I/II and PGC-BD). These were defined by (1) Phase II as discovery and Phase I as target, or vice versa (for 'within Japanese comparisons', Pbest~10-29, R2~2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for 'trans-European-Japanese comparison,' Pbest~10-13, R2~0.27%). This 'trans population' effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates~0.7). These results indicate that (1) two novel and three previously implicated loci are significantly associated with BD and that (2) BD 'risk' effect are shared between Japanese and European populations.

Increased protein and mRNA expression of resistin after dexamethasone administration.

Synthetic glucocorticoids such as dexamethasone are widely used to treat a variety of inflammatory and autoimmune conditions, but they may induce adverse events including hyperglycemia. To shed light on the effect and action mechanism of dexamethasone, we examined the alterations of gene expression levels caused by dexamethasone.Microarray analysis was performed on whole blood collected from 24 physically healthy subjects at baseline and after dexamethasone administration. The expression levels of resistin mRNA were found to be significantly increased after the dexamethasone administration. In a separate sample of 12 subjects, we examined plasma resistin protein levels and found that they were increased after dexamethasone administration. Furthermore, the plasma mRNA and protein levels of resistin were significantly higher in individuals who carried the A allele of RETN single nucleotide polymorphism rs3219175 than in those who did not carry the allele. There was no significant interaction between the genotype and dexamethasone administration. No significant correlation was found between plasma levels of cortisol and resistin. Consistent with previous studies, the genotype of RETN rs3219175 was a strong determinant of resistin levels. The present study showed that oral administration of dexamethasone increases the protein and mRNA levels of resistin irrespective of the rs3219175 genotype.

Possible association of CUX1 gene polymorphisms with antidepressant response in major depressive disorder.

Association between response to antidepressant treatment and genetic polymorphisms was examined in two independent Japanese samples of patients with major depressive disorder (MDD). Genome-wide approach using the Illumina Human CNV370-quad Bead Chip was utilized in the analysis of the 92 MDD patients in the first sample. In all, 11 non-intergenic single-nucleotide polymorphisms with uncorrected allelic P-value <0.0001 were selected for the subsequent association analyses in the second sample of 136 MDD patients. Difference in allele distribution between responders and nonresponders were found in the second-stage sample for rs365836 and rs201522 of the CUX1 gene (P=0.005 and 0.004, respectively). The allelic P-values for rs365836 and rs201522 in both samples combined were 0.0000023 and 0.0000040, respectively. Our results provide the first evidence that polymorphisms of the CUX1 gene may be associated with response to antidepressant treatment in Japanese patients with MDD.

Inhibition of olanzapine-induced weight gain by the retinoid analog AM-80.

INTRODUCTION: Weight gain and metabolic abnormalities are common side effects of antipsychotic treatment. Retinoids have been suggested as promising substances to suppress obesity. This study has investigated the effects of a retinoid agonist AM-80 on olanzapine-induced weight gain and metabolic changes in rats. METHODS: Female Sprague-Dawley rats (7 weeks) were treated with AM-80 (1 mg/kg/day, subcutaneously) and/or olanzapine (4 mg/kg/day, intraperitoneally) for 21 days. Body weight and food/water intake were measured daily. The open field (OFT) and prepulse inhibition (PPI) tests were done on days 18 and 21, respectively. Animals were sacrificed on day 22 to measure weight of adipose tissues and serum levels of adiponectin and leptin levels. RESULTS: Olanzapine significantly increased body weight, food/water intake and the mass of inguinal adipose tissue (IAT) compared to vehicle-treated rats. AM-80 demonstrated significant inhibition of weight gain. No significant effect of olanzapine or AM-80 was found on behaviors or serum adiponectin/leptin levels. CONCLUSION: These findings suggests that AM-80 is a potential therapeutic agent to attenuate weight gain and metabolic side effects associated with olanzapine.

Glutamatergic changes in the cerebral white matter associated with schizophrenic exacerbation.

OBJECTIVE: Glutamatergic dysfunction in the brain has been implicated in the pathophysiology of schizophrenia. This study was aimed to examine several brain chemical mediators, including Glx (glutamate + glutamine), using (1)H magnetic resonance spectroscopy (MRS) in medicated patients with schizophrenia, with and without psychotic exacerbation. METHOD: (1)H MRS was acquired in 24 patients with schizophrenia, with psychotic exacerbation; 22 patients without exacerbation; and 27 age- and sex-matched healthy volunteers. The levels of metabolites were measured in the left frontal and inferior parietal white matter and compared across the three groups. RESULTS: The Glx level was significantly elevated in the left inferior parietal white matter in the patients with psychotic exacerbation in comparison with that in the healthy volunteers and the patients without exacerbation (P < 0.05). We also detected that there was a significant correlation between Positive and Negative Syndrome Scale-positive scale and Glx level in the left parietal white matter (r = 0.51, P < 0.001). CONCLUSION: Higher than normal Glx levels indicate glutamatergic overactivity in the left inferior parietal white matter with schizophrenic exacerbation, a finding that is in accordance with the glutamatergic hypothesis in schizophrenia. The Glx level measured by (1)H MRS could be a biomarker for exacerbation in schizophrenia.

Pharmacotherapeutic determinants for QTc interval prolongation in Japanese patients with mood disorder.

An increased incidence of sudden death has been observed among patients treated with antidepressants. A prolonged QTc interval is a known prognostic factor for fatal arrhythmia, and several studies have shown that the use of antidepressants can cause a prolonged QTc interval. However, few studies, especially in Japan, have compared the effects of multiple drugs on QTc interval or examined dose relationships in a clinical setting.We compared the effects of antidepressants on QT interval, corrected to QTc by Bazett's formula, in 729 Japanese patients who were diagnosed with mood disorder.Using stepwise multiple linear regression analysis, we found that the use of tricyclic antidepressants (P<0.01) and concomitant use of antipsychotics (P<0.05), as well as advanced age and being female (known factors for prolonged QTc interval; both P<0.01), significantly prolonged the QTc interval. Analysis of individual antidepressants also revealed that the use of clomipramine (P<0.01) and amitriptyline (P<0.05) significantly prolonged the QTc interval.Our results reveal that tricyclic antidepressants, especially clomipramine and amitriptyline, confer a risk of prolonged QTc interval in a dose-dependent manner. The selective serotonin reuptake inhibitors investigated (fluvoxamine, paroxetine, sertraline) were not indicated as risk factors for QTc prolongation.

Plasma levels of vascular endothelial growth factor and fibroblast growth factor 2 in patients with major depressive disorders.

We investigated the plasma levels of VEGF and FGF-2, important factors for regulation of neuroplasticity such as neurogenesis, in patients in remission from major depressive disorders (MDD). The plasma VEGF levels were significantly higher in the MDD patients than in the matched control subjects, while no significant difference in plasma FGF-2 levels was found. In particular, the MDD patients with family history of psychiatric disorders, but not patients without such a family history, showed significantly higher values of plasma VEGF than the controls. Although this is a preliminary study, altered VEGF levels might be involved in the pathophysiology of MDD.

The neuroprotective effects and possible mechanism of action of a methanol extract from Asparagus cochinchinensis: In vitro and in vivo studies.

Extracts of Asparagus cochinchinensis (AC) have antitumor, anti-inflammatory, and immunostimulant effects. The neurobiological mechanisms underlying the effects of AC have not been sufficiently explored. Thus we performed in vivo and in vitro experiments to further characterize potential therapeutic effects and to clarify the underlying mechanisms. In the tail suspension test immobility time was significantly reduced after administration of AC which suggests antidepressant-like activity without effect on body core temperature. Moreover, in animals pretreated with AC infarct size after occlusion of the middle cerebral artery was reduced. In vitro experiments confirmed neuroprotective effects. Total saponin obtained from AC significantly inhibited H2O2-induced cell death in cultured cortical neurons. The survival-promoting effect by AC saponins was partially blocked by inhibitors for extracellular signal-regulated kinase (ErK) and phosphoinositide 3-kinase Akt (PI3K/Akt) cascades, both of which are known as survival-promoting signaling molecules. Furthermore, phosphorylation of Scr homology-2 (SH2) domain-containing phosphatase 2 (Shp-2) was induced by AC, and the protective effect of AC was abolished by NSC87877, an inhibitor for Shp-2, suggesting an involvement of Shp-2 mediated intracellular signaling in AC saponins. Moreover, AC-induced activation of pShp-2 and ErK1/2 were blocked by NSC87877 indicating that activation of these signaling pathways was mediated by the Shp-2 signaling pathway. These effects appear to be associated with activation of the Shp-2, ErK1/2 and Akt signaling pathways. Our results suggest that AC has antidepressant-like and neuroprotective (reducing infarct size) effects and that activation of pShp-2 and pErK1/2 pathways may be involved in the effects.

Low serum cholesterol in suicide attempters.

Previous studies have shown an association between low serum cholesterol concentration and suicide; however, conflicting results have also been reported. To examine this potential association, cholesterol levels in 99 patients admitted to an emergency ward following an attempted suicide were compared with those in 74 nonsuicidal psychiatric inpatients, and those in 39 psychiatrically normal individuals with accidental injuries. Cholesterol concentrations in suicide attempters were found to be significantly lower compared with both psychiatric and normal controls, when sex, age, psychiatric diagnosis, and physical conditions (serum total protein and red blood cell count) were adjusted for. This significant relationship was observed in mood disorders and personality or neurotic disorders, but not in schizophrenia spectrum disorders. These results support the previous claim that lower cholesterol level is associated with an increased risk of suicidal behavior.

Pericentric region of chromosome 9 is a possible candidate region for linkage study of schizophrenia.

We have undertaken a systematic G-banding survey to find structural chromosomal abnormalities among patients with schizophrenia. Of 120 patients with DSM-III-R schizophrenia, four (3.3%) had a pericentric inversion of chromosome 9 and three (2.5%) had a X/XX mosaicism. The frequency of pericentric inversion of chromosome 9 among patients with schizophrenia was statistically higher than those among newborns and Asian populations. Our results indicate that the pericentric region of chromosome 9 might be one of the potential regions of interest for linkage analysis of schizophrenia.

Changes of immunological functions after acute exacerbation in schizophrenia.

We investigated the changes of immunological functions in 14 schizophrenic patients (DSM-III-R; six men and eight women) who were hospitalized due to acute exacerbation of schizophrenia. The following immunological functions were studied on admission, 4 and 8 weeks after admission: serum immunoglobulins (Ig)G, A, and M; serum complement CH50; lymphocyte responses to mitogens (phytohemagglutinin, concanavalin A, and pokeweed mitogen); lymphocyte subpopulations (CD3%, 4%, 8%, 16%, 20%, 25%, and 56%); and natural killer cell (NK) activity. Psychological status of the patients, which was assessed by using Brief Psychiatric Rating Scale, improved gradually after admission. Changes in immune functions were analyzed using one-way analysis of variance and a randomized block analysis of variance with multiple comparison. NK activity on admission was significantly lower than those at 4 and 8 weeks after admission (p < .03). Serum IgG levels on admission and at 4 weeks after admission were significantly decreased as compared with those at 8 weeks after admission (p < .05); they were also lower than those in controls (p < .05). CD56% on admission and CD25% 4 weeks after admission were significantly increased as compared with controls (p < .05). These results indicate that several immunological functions might change related to time course after acute exacerbation. It is suggested that clinical conditions be carefully taken into consideration to evaluate immunological studies in schizophrenia.

Association between serotonin transporter gene polymorphism and anxiety-related traits.

BACKGROUND: Polymorphism in the serotonin transporter promoter gene has been recently reported to be associated with the personality trait known as anxiety-related traits. We have attempted to replicate these findings in 101 healthy Japanese subjects. METHODS: The personality traits of the subjects were assessed with the tridimensional personality questionnaire. RESULTS: An association was observed in the present study between individuals grouped according to the transporter gene and harm avoidance scores. CONCLUSIONS: These data supported that there was an association between the serotonin transporter gene and anxiety.

The monoamine oxidase-A gene and major psychosis in Japanese subjects.

BACKGROUND: Monoamine oxidase (MAO) is a critical enzyme in deamination of biogenic amines and may be involved in the pathophysiology of major psychosis, including mood disorder and schizophrenia. Recently, evidence for genetic association between the MAO-A gene and bipolar mood disorder was obtained in Caucasians. METHODS: We investigated the polymorphisms of the MAO-A gene, which may be related to enzyme activity (T/941/G, A/1609/G), with amino-acid change (A/1609/G), in Japanese patients with bipolar disorder patients (n = 132), unipolar major depression (n = 43), or schizophrenia (n = 95), and controls (n = 169). RESULTS: No difference in the allele frequencies or genotype distribution of the T/941/G variation was observed between any disease group and the control group. As for the A/1609/G variation, no G allele was found in the Japanese subjects. CONCLUSIONS: No evidence for the genetic association between the MAO-A gene and major psychosis was obtained in the Japanese subjects.

No evidence for an association of affective disorders with high- or low-activity allele of catechol-o-methyltransferase gene.

Catechol-o-methyltransferase (COMT) is an enzyme that inactivates biologically active or toxic catechols. Previous studies have yielded inconsistent results on the relationship between erythrocyte COMT activity and affective disorders. Recently an amino acid change (Val-108-Met) of the COMT protein was shown to determine high- and low-activity alleles of the enzyme. Using polymerase chain reaction and the restriction enzyme NLaIII, we genotyped 107 patients with bipolar disorder, 62 with unipolar depression, and 121 controls. Neither bipolar nor unipolar patients differ significantly in the genotypic or allelic frequency from the control group. Even when the bipolar and unipolar patients were pooled into a single group, the distributions of both the genotypes and the alleles for the patient group were similar to those for the controls. We conclude that genetic variation that determines high and low activities of COMT does not have a major effect on the vulnerability to affective disorders in our sample.

Schizophrenia following in utero exposure to the 1957 influenza epidemics in Japan.

OBJECTIVE: Studies in Finland, England, and Denmark have reported that individuals exposed to the 1957 A2 influenza pandemic during their second trimester in utero are at greater risk for later schizophrenia. However, other studies in England, the United States, and Holland reported no such association. The authors' goal was to shed light on these conflicts. METHOD: They compared the number of individuals who later developed schizophrenia who were born in the 5 months after the peak prevalence of three distinct 1957 influenza epidemics in Japan with the mean number of individuals who later developed schizophrenia who were born in the corresponding months of the 4 years surrounding the epidemics. RESULTS: A significantly greater number of females but not males who later developed schizophrenia were born during the risk exposure months than in the non-risk-exposure months. CONCLUSIONS: These findings, although weak, lend support to the claim that in utero exposure to influenza epidemics is a risk factor for adult schizophrenia.

No evidence for an association of polymorphisms of the tryptophan hydroxylase gene with affective disorders or attempted suicide among Japanese patients.

OBJECTIVE: Tryptophan hydroxylase is the rate-limiting enzyme in the biosynthesis of serotonin. The authors examined whether polymorphisms A218C and A779C in intron 7 of the tryptophan hydroxylase gene are associated with a risk for affective disorders or suicidal behavior. METHOD: Subjects were 141 patients with bipolar disorder and 73 patients with unipolar affective disorder, 46 of whom had a history of attempted suicide, and 208 healthy volunteers. All subjects were unrelated to each other, and all were Japanese. Genotyping was performed by polymerase chain reaction amplification followed by digestion by a restriction enzyme and single-strand conformational polymorphism analysis. RESULTS: There was no significant genotypic or allelic association of the A218C polymorphism with bipolar disorder, unipolar depression, or history of attempted suicide. In nearly 100% of the subjects, genotypes for the A779C were identical to those for the A218C. CONCLUSIONS: The authors conclude that the examined polymorphisms are unlikely to have major relevance to the pathogenesis of affective disorders or suicidal behavior.

Association of bipolar disorder with the 5178 polymorphism in mitochondrial DNA.

Parent-of-origin effect in transmission of bipolar disorder and abnormal phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) findings in the brain in patients with bipolar disorder implicate pathophysiological role of mitochondrial DNA in bipolar disorder. The authors examined possible association of bipolar disorder with the 5178 polymorphism in mitochondrial DNA. Genotype frequencies of the 5178 polymorphism were examined by polymerase chain reaction-restriction fragment length polymorphism method in 145 patients with bipolar disorder and 184 controls. The rate of 5178C genotype was significantly higher in patients with bipolar disorder (81/125 (64.8%), P < 0.05) compared with controls (98/184 (53.2%)) when paternally transmitted cases were excluded. This effect was more prominent in patients with bipolar II disorder (5178C: 28/37, 75.6%, P < 0.02 to controls). Bipolar II patients with 5178A genotype without family history had significantly later age at onset (56.0 +/- 14.7 years, P < 0.05) than other bipolar patients. Brain intracellular pH measured by (31)P-MRS was significantly higher in bipolar patients with 5178A (7.04 +/- 0.03, n = 7, P < 0.05) than those with 5178C (7.00 +/- 0.03, n = 7). There was no difference of subcortical hyperintensity scores by magnetic resonance imaging between patients with 5178A and those with 5178C. These results suggest that the 5178 polymorphism in mitochondrial DNA may regulate vulnerability to bipolar disorder via alteration of brain energy metabolism. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:182-186, 2000.

Genes for interleukin-2 receptor beta chain, interleukin-1 beta, and schizophrenia: no evidence for the association or linkage.

We studied a CA repeat polymorphism of the interleukin-2 receptor beta chain (IL-2RB) gene and a C/-514/T variation of the interleukin-1 beta (IL-1B) gene in Japanese schizophrenia patients. Both a case-control association study (54 patients and 54 controls) and a linkage study using six multiplex families (the number of the affected > or =4 in each family) were employed. No evidence for the association or the linkage was obtained either for the IL-2RB or IL-1B gene.

Novel polymorphism in the promoter region of the tumor necrosis factor alpha gene: No association with narcolepsy.

The striking evidence of almost 100% association of narcolepsy with human leukocyte antigens (HLA) DR2(DR15) antigen is an important clue to elucidate the molecular basis of this sleep disorder. The gene for tumor necrosis factor alpha (TNF alpha) is located in the HLA class II gene cluster. Recent studies have indicated that TNF alpha plays an important role in the regulation of normal human sleep, and regulation of this cytokine may be disturbed in narcolepsy. We searched for a mutation associated with narcolepsy in the promoter region of the TNF alpha gene by single-strand conformation polymorphism analysis. A novel polymorphism, C-850T, was found in narcoleptic patients. Genotype frequency was examined by restriction fragment length polymorphism method. No significant difference of genotype distribution was found between 92 patients with narcolepsy and 91 normal controls. These results do not support our hypothesis that genetic abnormality of TNF alpha production is pathogenetic for narcolepsy.

Association study of structural mutations of the tyrosine hydroxylase gene with schizophrenia and Parkinson's disease.

Tyrosine hydroxylase (TH) gene is the rate-limiting enzyme in the synthesis of catecholamines. Functional polymorphisms of the TH gene may be involved in the pathogenesis of neuropsychiatric diseases such as schizophrenia, affective disorders, and Parkinsonism. This study examined a possible association of two polymorphisms, both of which result in an amino acid change of the TH protein, with schizophrenia and Parkinson's disease (PD). The Val81Met polymorphism is a common variation, although its effect on the enzyme expression is unclear. Leu205Pro polymorphism is a rare mutation that is reported to cause Parkinsonism in infancy for individuals who are homozygous for the mutated type. We genotyped a Japanese sample of 194 schizophrenics, 99 patients with PD, and 161 controls for the Val81Met polymorphism by using mis-match PCR and digestion by the restriction enzyme BalI. There was no significant allelic or genotypic association of the Val81Met polymorphism with schizophrenia or PD. The Leu205Pro polymorphism was examined by using PCR and digestion by AluI; however, there was no individual who carried the mutated type of Pro205 among 50 schizophrenics or 50 patients with PD. Thus we obtained no evidence for the involvement of the two structural mutations of the TH gene in the pathogenesis of schizophrenia or PD.