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ABSTRACT: Fat-mass and obesity-associated (FTO) gene is known to be involved in the pathophysiology of obesity and a single-nucleotide polymorphism (SNP) rs9939609 of FTO gene is repeatedly confirmed to be associated with body mass index (BMI) and obesity. The aim of this study is to elucidate effects of FTO gene polymorphism on BMI in Japanese patients with schizophrenia and healthy subjects.
Three hundred fifty one patients with schizophrenia and 342 age- and sex-matched healthy subjects participated in the study. Information on BMI and antipsychotic medication was also collected from patients and healthy subjects. Genotype of the FTO SNP rs9939609 was determined by TaqMan SNP Genotyping Assays.
There was no significant difference in BMI between patients and healthy subjects. No significant difference in BMI was observed among any medications. We observed no significant difference in rs9939609 allele frequencies between patients and healthy subjects. There was a significant difference in BMI between healthy subjects with risk (AA or TA) genotypes and those with TT genotype. We also observed a significant positive correlation between the number of risk allele (A allele) and BMI in healthy subjects.
Our study suggested that FTO rs9939609 polymorphism might have some impacts on the BMI in healthy subjects, but might not have same impacts on the BMI of patients with schizophrenia.
Clinical Psychopharmacology and Neuroscience 12/2012; 10(3):185-9.
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Tsunehiko Tanaka,
Masahito Tomotake,
Yoshinori Ueoka,
Yasuhiro Kaneda,
Kyoko Taniguchi,
Masahito Nakataki, Shusuke Numata,
Shinya Tayoshi,
Ken Yamauchi,
Satsuki Sumitani,
Takashi Ohmori,
Shu-Ichi Ueno,
Tetsuro Ohmori
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ABSTRACT: The purpose of the present study was to investigate the correlation between cognitive function and clinical variables in people with schizophrenia.
The subjects were 61 stabilized outpatients with schizophrenia (DSM-IV). Their mean age was 40.1 (SD = 12.2) years. All subjects gave written informed consent to participate in the research. Cognitive function was evaluated using the Brief Assessment of Cognition in Schizophrenia. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale, the Calgary Depression Scale for Schizophrenia, and the Drug-Induced Extrapyramidal Symptoms Scale.
The Positive and Negative Syndrome Scale Negative syndrome score was significantly correlated with verbal memory score (r = -0.37, P < 0.01), working memory score (r = 0.38, P < 0.01), attention and speed of information processing score (r = -0.51, P < 0.01), verbal fluency score (r = -0.39, P < 0.01), and composite score (r = -0.54, P < 0.01). In addition, the Drug-Induced Extrapyramidal Symptoms Scale score was significantly correlated with attention and speed of information processing (r = -0.45, P < 0.01), and composite score (r = -0.41, P < 0. 01). Dose of antipsychotics and anti-Parkinson drugs was not significantly correlated with the Brief Assessment of Cognition in Schizophrenia scores.
These results indicate that cognitive dysfunction of people with schizophrenia might be associated with negative and drug-induced extrapyramidal symptoms, suggesting that their minimization would be important for improving cognitive dysfunction.
Psychiatry and Clinical Neurosciences 10/2012; 66(6):491-8. · 2.13 Impact Factor
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Makoto Kinoshita, Shusuke Numata,
Atsushi Tajima,
Shinji Shimodera,
Shinji Ono,
Akira Imamura,
Jun-Ichi Iga,
Shinya Watanabe,
Kumiko Kikuchi,
Hiroko Kubo,
Masahito Nakataki,
Satsuki Sumitani,
Issei Imoto,
Yuji Okazaki,
Tetsuro Ohmori
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ABSTRACT: Schizophrenia (SCZ) is a complex psychiatric disease with a lifetime morbidity rate of 0.5-1.0 %. To date, aberrant DNA methylation in SCZ has been reported in several studies. However, no comprehensive studies using medication-free subjects with SCZ have been conducted. In addition, most of these studies have been limited to the analysis of the CpG sites in CpG islands (CGIs) in the gene promoter regions, so little is known about the DNA methylation signatures across the whole genome in SCZ. Genome-wide DNA methylation profiling (485,764 CpG sites) of peripheral leukocytes was conducted in the first set of samples (24 medication-free patients with SCZ and 23 non-psychiatric controls) using Infinium HumanMethylation450 Beadchips. Second, a monozygotic twin study was performed using three pairs of monozygotic twins that were discordant for SCZ. Finally, the data from these two independent cohorts were compared. A total of 234 differentially methylated CpG sites that were common between these two cohorts were identified. Of the 234 CpG sites, 153 sites (65.4 %) were located in the CGIs and in the regions flanking CGIs (CGI: 40.6 %; CGI shore: 13.3 %; CGI shelf: 11.5 %). Of the 95 differently methylated CpG sites in the CGIs, most of them were located in the promoter regions (promoter: 75.8 %; gene body: 14.7 %; 3'-UTR: 2.1 %). Aberrant DNA methylation in SCZ was identified at numerous loci across the whole genome in peripheral leukocytes using two independent sets of samples. These findings support the notion that altered DNA methylation could be involved in the pathophysiology of SCZ.
Neuromolecular medicine 09/2012; · 5.00 Impact Factor
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Biological Psychiatry 08/2012; 141(2-3):271-3. · 8.28 Impact Factor
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Kazutaka Ohi,
Ryota Hashimoto,
Yuka Yasuda,
Motoyuki Fukumoto,
Hidenaga Yamamori,
Satomi Umeda-Yano,
Takeya Okada,
Kouzin Kamino,
Takashi Morihara,
Masao Iwase,
Hiroaki Kazui, Shusuke Numata,
Masashi Ikeda,
Tohru Ohnuma,
Nakao Iwata,
Shu-ichi Ueno,
Norio Ozaki,
Tetsuro Ohmori,
Heii Arai,
Masatoshi Takeda
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ABSTRACT: Genome-wide association and follow-up studies have reported an association between schizophrenia and rs12807809 of the NRGN gene on chromosome 11q24.2. We investigated the association of five linkage disequilibrium-tagging SNPs and haplotypes that cover the NRGN gene with schizophrenia in a Japanese sample of 2,019 schizophrenia patients and 2,574 controls to determine whether rs12807809 is the most strongly associated variant for schizophrenia in the vicinity of the NRGN gene. We found that the rs12807809-rs12278912 haplotype of the NRGN gene was associated with schizophrenia (global P = 0.0042). The frequencies of the TG and TA haplotypes of rs12807809-rs12278912 in patients were higher (OR = 1.14, P = 0.0019) and lower (OR = 0.85, P = 0.0053), respectively, than in the controls. We did not detect any evidence of association of schizophrenia with any SNPs; however, two nominal associations of rs12278912 (OR = 1.10, P = 0.057) and rs2075713 (OR = 1.10, P = 0.057) were observed. Furthermore, we detected an association between the rs12807809-rs12278912 haplotype and NRGN expression in immortalized lymphoblasts derived from 45 HapMap JPT subjects (z = 2.69, P = 0.007) and confirmed the association in immortalized lymphoblasts derived from 42 patients with schizophrenia and 44 healthy controls (z = 3.09, P = 0.002). The expression of the high-risk TG haplotype was significantly lower than the protective TA haplotype. The expression was lower in patients with schizophrenia than in controls; however, this difference was not statistically significant. This study provides further evidence of the association of the NRGN gene with schizophrenia, and our results suggest that there is a link between the TG haplotype of rs12807809-rs12278912, decreased expression of NRGN and risk of developing schizophrenia.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 03/2012; 159B(4):405-13. · 3.70 Impact Factor
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ABSTRACT: Objectives
Vascular endothelial growth factor (VEGF) is thought to be involved in the pathophysiology of mood disorders and the target of antidepressants. The aim of this study was to elucidate molecular effects of lithium on VEGF expression by using leukocytes of healthy subjects and patients with bipolar disorder.Methods
Eight healthy male subjects participated in the first study. Lithium was prescribed for 2 weeks, enough to reach therapeutic serum concentration. Leukocyte counts and serum lithium concentrations were determined at baseline, at 1- and 2-week medication, and at 2 weeks after stopping medication. VEGF mRNA levels were also examined in nine lithium-treated bipolar patients and healthy controls in the second study.ResultsIn the first study, leukocyte counts were significantly increased at 2 weeks compared with those at baseline and were normalized after 2 weeks. VEGF mRNA levels were significantly decreased at 2 weeks and after 2 weeks compared with those at baseline. Consistent with the first study, VEGF mRNA levels were significantly decreased in the lithium-treated bipolar patients compared with healthy controls.Conclusions
Our investigation suggests that VEGF mRNA expression may be useful as a peripheral marker of the effects of lithium. Copyright © 2011 John Wiley & Sons, Ltd.
Human Psychopharmacology Clinical and Experimental 06/2011; 26(4-5):358 - 363. · 2.48 Impact Factor
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Ryota Hashimoto,
Kazutaka Ohi,
Yuka Yasuda,
Motoyuki Fukumoto,
Hidenaga Yamamori,
Kouzin Kamino,
Takashi Morihara,
Masao Iwase,
Hiroaki Kazui, Shusuke Numata,
Masashi Ikeda,
Shu-Ichi Ueno,
Tetsuro Ohmori,
Nakao Iwata,
Norio Ozaki,
Masatoshi Takeda
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ABSTRACT: Alterations in centrosomal function have been suggested in the pathology of schizophrenia. The molecule pericentriolar material 1 (PCM1) is involved in maintaining centrosome integrity and in the regulation of the microtubule cytoskeleton. PCM1 forms a complex at the centrosome with the disrupted-in-schizophrenia 1 (DISC1) protein, which is a major susceptibility factor for schizophrenia. The association between genetic variants in the PCM1 gene and schizophrenia has been reported by several case-control studies, linkage studies and a meta-analysis. The aims of this study are to replicate the association between four single-nucleotide polymorphisms (SNPs) in the PCM1 gene and schizophrenia in a Japanese population (1496 cases and 1845 controls) and to perform a meta-analysis of the combined sample groups (3289 cases and 3567 controls). We failed to find a significant association between SNPs or haplotypes of the PCM1 gene and schizophrenia in the Japanese population (P>0.28). The meta-analysis did not reveal an association between the four examined SNPs and schizophrenia. Our data did not support genetic variants in the PCM1 gene as a susceptibility locus for schizophrenia.
Biological Psychiatry 06/2011; 129(1):80-4. · 8.28 Impact Factor
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ABSTRACT: The epithelial membrane protein 1 (EMP1) plays a role in neuronal differentiation and neurite outgrowth, which are involved in the pathogenesis of major depressive disorder (MDD). We sought to determine whether the EMP1 gene is implicated in MDD. We determined the mRNA expression levels of the EMP1 gene in peripheral-blood leukocytes of patients and control subjects (n=27 each). Next, we performed case-control association analyses (MDD, n=182; controls, n=350) in the Japanese population. The level of expression of the EMP1 mRNA was significantly lower in medication-free patients compared with control subjects (P<0.001). The association analysis revealed an absence of association between the polymorphisms studied and MDD, whereas a gender-specific association was observed between male controls and male patients for marker rs7315725 (permutation P=0.039). Our results suggest that the EMP1 gene may be implicated in the pathophysiology of MDD in the Japanese population.
Neuroscience Letters 02/2011; 489(2):126-30. · 2.11 Impact Factor
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Yoshinori Ueoka,
Masahito Tomotake,
Tsunehiko Tanaka,
Yasuhiro Kaneda,
Kyoko Taniguchi,
Masahito Nakataki, Shusuke Numata,
Shinya Tayoshi,
Ken Yamauchi,
Satsuki Sumitani,
Takashi Ohmori,
Shu-ichi Ueno,
Tetsuro Ohmori
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ABSTRACT: The main purpose of the present study was to examine the relationship between quality of life (QOL) and cognitive dysfunction in schizophrenia. Subjects were 61 stabilized outpatients. Quality of life and cognitive function were assessed using the Quality of Life Scale (QLS) and the Brief Assessment of Cognition in Schizophrenia (BACS), respectively. Clinical symptoms were evaluated with the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS). The BACS composite score and the BACS Verbal memory score were positively correlated with the QLS total score and two subscales. The BACS Attention and speed of information processing score had positive correlation with the QLS total and all the subscales scores. The PANSS Positive and Negative syndrome scores also had significant correlations with the QLS total score and all of the subscales. In addition, the CDSS score was negatively correlated with the QLS total score and some of the subscales. Stepwise regression analysis showed that the BACS Attention and speed of information processing score was an independent predictor of the QLS total score but it was less associated with the QLS than the PANSS Negative syndrome score and the CDSS score. The results suggest that negative and depressive symptoms are important factors on patients' QOL and also support the view that cognitive performance provides a determinant of QOL in patients with schizophrenia.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 01/2011; 35(1):53-9. · 3.25 Impact Factor
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Kazutaka Ohi,
Ryota Hashimoto,
Yuka Yasuda,
Tetsuhiko Yoshida,
Hidetoshi Takahashi,
Naomi Iike,
Masao Iwase,
Kouzin Kamino,
Ryouhei Ishii,
Hiroaki Kazui, [......], Shusuke Numata,
Masashi Ikeda,
Toshihisa Tanaka,
Takashi Kudo,
Shu-Ichi Ueno,
Takeo Yoshikawa,
Tetsuro Ohmori,
Nakao Iwata,
Norio Ozaki,
Masatoshi Takeda
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ABSTRACT: The chitinase 3-like 1 (CHI3L1) gene acts as a cellular survival factor in response to several environmental and psychosocial stresses. The expression level of CHI3L1 was increased in the hippocampus and prefrontal cortex regions of patients with schizophrenia. Genetic variants of the CHI3L1 gene have been significantly associated with schizophrenia in two distinct ethnic groups, the Chinese and Irish populations. The aims of this study are to confirm the association between the CHI3L1 gene and schizophrenia in a Japanese population using the largest sample size to date (1463 cases and 1795 controls) and perform a meta-analysis of the combined samples (3005 cases, 3825 controls and 601 trios). We found significant associations between single nucleotide polymorphism (SNP) 4/rs4950928 (p=0.009), which is located in the promoter region of the CHI3L1 gene, and haplotypes including this SNP and schizophrenia (the most significant global p<0.001). As the meta-analysis of the combined samples showed significant heterogeneity among studies of SNP3/rs10399805 (p=0.026) and SNP4 (p<0.001), we performed meta-analyses separately in the Japanese (2033 cases and 2365 controls) and Chinese populations (412 cases, 464 controls and 601 trios), the major groups analyzed in association studies of the CHI3L1 gene. The meta-analysis in Japanese populations showed stronger evidence for the association of schizophrenia with SNP4 (p=0.003), while the meta-analysis in Chinese populations showed an association with a different variant (SNP3) (p=0.003). We conclude that the genetic variants in the CHI3L1 gene have ethnic heterogeneity and confer a susceptibility to schizophrenia in Asian populations.
Biological Psychiatry 02/2010; 116(2-3):126-32. · 8.28 Impact Factor
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ABSTRACT: Gamma-amino butyric acid (GABA) is thought to play a role in the pathophysiology of schizophrenia. High magnetic field proton magnetic resonance spectroscopy ((1)H-MRS) provides a reliable measurement of GABA in specific regions of the brain. This study measured GABA concentration in the anterior cingulate cortex (ACC) and in the left basal ganglia (ltBG) in 38 patients with chronic schizophrenia and 29 healthy control subjects. There was no significant difference in GABA concentration between the schizophrenia patients and the healthy controls in either the ACC (1.36+/-0.45 mmol/l in schizophrenia patients and 1.52+/-0.54 mmol/l in control subjects) or the ltBG (1.13+/-0.26 mmol/l in schizophrenia patients and 1.18+/-0.20 mmol/l in control subjects). Among the right handed schizophrenia patients, the GABA concentration in the ltBG was significantly higher in patients taking typical antipsychotics (1.25+/-0.24 mmol/l) than in those taking atypical antipsychotics (1.03+/-0.24 mmol/l, p=0.026). In the ACC, the GABA concentration was negatively correlated with the dose of the antipsychotics (rs=-0.347, p=0.035). In the ltBG, the GABA concentration was positively correlated with the dose of the anticholinergics (rs=0.403, p=0.015). To the best of our knowledge, this is the first study to have directly measured GABA concentrations in schizophrenia patients using (1)H-MRS. Our results suggest that there are no differences in GABA concentrations in the ACC or the ltBG of schizophrenia patients compared to healthy controls. Antipsychotic medication may cause changes in GABA concentration, and atypical and typical antipsychotics may have differing effects. It is possible that medication effects conceal inherent differences in GABA concentrations between schizophrenia patients and healthy controls.
Biological Psychiatry 12/2009; 117(1):83-91. · 8.28 Impact Factor
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Shusuke Numata,
Masahito Nakataki,
Jun-ichi Iga,
Toshihito Tanahashi,
Yoshihiro Nakadoi,
Kazutaka Ohi,
Ryota Hashimoto,
Masatoshi Takeda,
Mitsuo Itakura,
Shu-ichi Ueno,
Tetsuro Ohmori
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ABSTRACT: Disrupted-in-schizophrenia 1 (DISC1), a known genetic risk factor for schizophrenia (SZ) and major depressive disorder (MDD), interacts with several proteins and some of them are reported to be genetically associated with SZ. Pericentrin (PCNT) also interacts with DISC1 and recently single-nucleotide polymorphisms (SNPs) within the PCNT gene have been found to show significant associations with SZ and MDD. In this study, case-controlled association analysis was performed to determine if the PCNT gene is implicated in SZ. Nine SNPs were analyzed in 1,477 individuals (726 patients with SZ and 751 healthy controls). No significant difference was observed between the controls and the patients in allelic frequencies or genotypic distributions of eight SNPs. Although allelic distribution of rs11702684 was different between the two groups (P = 0.042), the difference did not reach statistical significance after permutation correction for multiple comparisons. In the haplotypic analysis, we could not find any significant association in our subjects, either. This gene may not play a major role independently in the etiology of SZ in the Japanese population.
Neuromolecular medicine 11/2009; 12(3):243-7. · 5.00 Impact Factor
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Psychiatric genetics 07/2009; 19(3):162. · 2.33 Impact Factor
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ABSTRACT: Pericentrin (PCNT) interacts with disruption-in-schizophrenia 1 (DISC1), a known genetic risk factor for schizophrenia, bipolar disorder and major depressive disorder (MDD). We sought to determine whether the PCNT gene is implicated in MDD.
We performed case-control association analyses in the Japanese population. We analyzed 9 single nucleotide polymorphisms (SNPs) in 173 patients with MDD and 348 healthy controls.
We found a significant allelic association between 3 SNPs (rs3788265, rs2073376 and rs2073380) of the PCNT gene and MDD (p = 0.006, 0.005 and 0.021, respectively). After correction for multiple testing, 2 SNPs (rs3788265 and rs2073376) retained significant allelic associations with MDD. In addition, we found a significant association between the 2 marker haplotypes (r3788265 and rs2073376) and MDD (permutation p = 0.011).
Our sample was small and comprised only Japanese participants. In addition, owing to the late onset of MDD, it is possible that the disorder will develop in at least some participants in our control group. Finally, we did not show how SNPs of the PCNT gene alter its function.
Our results suggest that genetic variations in the PCNT gene may play a significant role in the etiology of MDD in the Japanese population.
Journal of psychiatry & neuroscience: JPN 06/2009; 34(3):195-8. · 5.34 Impact Factor
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Kazutaka Ohi,
Ryota Hashimoto,
Yuka Yasuda,
Tetsuhiko Yoshida,
Hidetoshi Takahashi,
Naomi Iike,
Motoyuki Fukumoto,
Hironori Takamura,
Masao Iwase,
Kouzin Kamino, [......],
Tohru Ohnuma,
Shu-Ichi Ueno,
Tomoko Fukunaga,
Toshihisa Tanaka,
Takashi Kudo,
Heii Arai,
Tetsuro Ohmori,
Nakao Iwata,
Norio Ozaki,
Masatoshi Takeda
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ABSTRACT: G72 is one of the most widely tested genes for association with schizophrenia. As G72 activates the D-amino acid oxidase (DAO), G72 is termed D-amino acid oxidase activator (DAOA). The aim of this study is to investigate the association between G72 and schizophrenia in a Japanese population, using the largest sample size to date (1774 patients with schizophrenia and 2092 healthy controls). We examined eight single nucleotide polymorphisms (SNPs), which had been associated with schizophrenia in previous studies. We found nominal evidence for association of alleles, M22/rs778293, M23/rs3918342 and M24/rs1421292, and the genotype of M22/rs778293 with schizophrenia, although there was no association of allele or genotype in the other five SNPs. We also found nominal haplotypic association, including M15/rs2391191 and M19/rs778294 with schizophrenia. However, these associations were no longer positive after correction for multiple testing. We conclude that G72 might not play a major role in the risk for schizophrenia in the Japanese population.
Schizophrenia Research 03/2009; 109(1-3):80-5. · 4.75 Impact Factor
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Toshiyuki Yasui,
Masayo Yamada,
Hirokazu Uemura,
Shu-Ichi Ueno, Shusuke Numata,
Tetsuro Ohmori,
Naoko Tsuchiya,
Masamichi Noguchi,
Mitsutoshi Yuzurihara,
Yoshio Kase,
Minoru Irahara
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ABSTRACT: The aim of the present study was to compare the effects on serum cytokine concentrations of paroxetine, a selective serotonin re-uptake inhibitor, and kamishoyosan, a Japanese traditional medicine, in midlife women with psychological symptoms.
Seventy-six women with psychological symptoms such as anxiety and mild depression as menopausal symptoms were enrolled in this study. Thirty-eight women received oral administration of 10mg paroxetine every day, and 38 women received oral administration of kamshoyosan every day for 6 months. Overall climacteric symptoms were assessed using Greene's climacteric scale. Serum levels of cytokines were measured using a multiplexed human cytokine assay.
Greene's total scores in both women treated with paroxetine and in women treated with kamishoyosan decreased significantly. Percentage decreases in Greene's total, psychological and vasomotor scores during the 6-month period in the paroxetine group were significantly greater than those in the kamishoyosan group. Serum IL-6 concentration in women treated with paroxetine decreased significantly. Serum concentrations of IL-8, IL-10, macrophage inflammatory protein (MIP)-1beta and monocyte chemoattractant protein-1 in women treated with paroxetine decreased significantly. On the other hand, serum IL-6 concentration in women treated with kamishoyosan decreased significantly, but other serum concentrations did not change significantly.
Decrease in IL-6 concentration may be involved in the mechanism of the actions of both paroxetine and kamishoyosan in women with psychological symptoms, and IL-6 may therefore be useful as a marker of treatment. The action of paroxetine may also be associated with decreases in IL-8, IL-10, MIP-1beta.
Maturitas 02/2009; 62(2):146-52. · 2.77 Impact Factor
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ABSTRACT: A change in the glutamatergic system is thought to play an important role in the pathophysiology of schizophrenia. The aim of this study was to investigate the changes in metabolites, including glutamate (Glu), in the anterior cingulate cortex (ACC) and the left basal ganglia (ltBG) of patients with chronic schizophrenia using proton magnetic resonance spectroscopy ((1)H-MRS). In addition, since gender differences in this illness were known, we examined the effects of gender on these metabolites. The (1)H-MRS was performed on the ACC and ltBG of 30 patients with schizophrenia and 25 healthy individuals who acted as the control group. The levels of Glu, glutamine (Gln), creatine plus phosphocreatine (Cre), myo-inositol (mI), N-acetylaspartate (NAA), and choline-containing compounds (Cho) were measured. Two-way analysis of variance revealed that the illness significantly affected the levels of Glu and mI in the ACC; both metabolites were lower in the patients with schizophrenia as compared to the control subjects. The results also revealed that gender significantly affected the level of Gln in the ACC and the levels of Cre and NAA in the ltBG; the level of Gln in the ACC were higher in male subjects versus female subjects, whereas Cre and NAA levels in the ltBG were lower in male subjects as compared to female subjects. These results confirmed a change in the glutamatergic system and suggested an involvement of mI in the pathophysiology of schizophrenia.
Schizophrenia Research 01/2009; 108(1-3):69-77. · 4.75 Impact Factor
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Kiyoshi Kunika,
Toshihito Tanahashi, Shusuke Numata,
Shu-ichi Ueno,
Tetsuro Ohmori,
Naoto Nakamura,
Kazue Tsugawa,
Katsuyuki Miyawaki,
Maki Moritani,
Hiroshi Inoue,
Mitsuo Itakura
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ABSTRACT: Genetic variants of the transcription factor 7-like 2 (TCF7L2) gene affect the risk of type 2 diabetes in populations with multiple ethnic groups. However, a comprehensive survey of this gene has not been done for a Japanese population. Thus, we conducted this gene-based association study, in which the common genetic variants were analyzed. Using 24 Japanese type 2 diabetic subjects, we first screened a 9.5 kb region, which included the entire coding sequence, to assess potential functional variants of TCF7L2. Sequencing revealed a common coding variant (Pro477Thr) in exon 14 of TCF7L2 that was not enrolled in the public SNP database. Nineteen SNPs and the microsatellite DG10S478 were genotyped across the gene in 2,877 unrelated Japanese subjects. This independent screen identified the previously reported rs7903146 with a strongest association (allele P = 0.0001, odds ratio = 1.59 [95% confidence interval 1.25-2.01]), but there was no significant association between Pro477Thr and type 2 diabetes (allele P = 0.64). Expression of the Pro477Thr variant did not alter TCF7L2 expression in 30 lymphoblast cells. Although a genotypic effect of Pro477Thr on expression of TCF7L2 was not apparent, Pro477Thr was identified as a common variant of TCF7L2 in 2,877 Japanese subjects. Further functional studies are required to determine the possible effect of this coding variant on type 2 diabetes.
Journal of Human Genetics 12/2008; 53(11-12):972-82. · 2.57 Impact Factor
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Shusuke Numata,
Jun-Ichi Iga,
Masahito Nakataki,
Shin'ya Tayoshi,
Kyoko Taniguchi,
Satsuki Sumitani,
Masahito Tomotake,
Toshihito Tanahashi,
Mitsuo Itakura,
Yoko Kamegaya,
Masahiko Tatsumi,
Akira Sano,
Takashi Asada,
Hiroshi Kunugi,
Shu-Ichi Ueno,
Tetsuro Ohmori
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ABSTRACT: The phosphodiesterase 4B (PDE4B) interacts with disrupted-in-schizophrenia 1 (DISC1), which is a known genetic risk factor for schizophrenia, bipolar disorder and major depressive disorder (MDD). PDE4B is also important in the regulation of cAMP signaling, a second messenger implicated in learning, memory, and mood. In this study, we determined mRNA expression levels of the PDE4B gene in the peripheral blood leukocytes of patients with MDD and control subjects (n = 33, each). Next we performed two-stage case-controlled association analyses (first set; case = 174, controls = 348; second set; case = 481, controls = 812) in the Japanese population to determine if the PDE4B gene is implicated in MDD. In the leukocytes, a significantly higher expression of the PDE4B mRNA was observed in the drug-naïve MDD patients compared with control subjects (P < 0.0001) and the expression of the MDD patients significantly decreased after antidepressant treatment (P = 0.030). In the association analysis, we observed significant allelic associations of four SNPs (the most significant, rs472952; P = 0.002) and a significant haplotypic association (permutation P = 0.019) between the PDE4B gene and MDD in the first-set samples. However, we could not confirm these significant associations in the following independent second-set of samples. Our results suggest that the PDE4B gene itself does not link to MDD but the elevated mRNA levels of PDE4B might be implicated in the pathophysiology of MDD.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 09/2008; 150B(4):527-34. · 3.70 Impact Factor
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ABSTRACT: TGFBR2 gene is a tumor suppressor gene located at chromosome 3p22, and the locus is reported to be linked with schizophrenia susceptibility. According to the previous studies, a reduced incidence of cancer is observed in schizophrenic patients compared with the general population and tumor suppressor genes may be associated with schizophrenia. We measured the mRNA expression of TGFBR2 gene in the peripheral leukocytes from 19 medication-free schizophrenics and 25 medication-free major depressive patients compared with age- and sex-matched control subjects using a quantitative real-time PCR method. We also followed up the TGFBR2 mRNA expression levels from 13 schizophrenics after several weeks - antipsychotic treatments. The TGFBR2 mRNA levels of medication free schizophrenics were significantly higher than those of control subjects and decreased to almost the same level as controls after antipsychotic treatment. On the other hand, the TGFBR2 mRNA levels of medication-free major depressive patients were not significantly different from controls. In genetic studies, we failed to find any association between the TGFBR2 gene and schizophrenia with 10 SNPs of TGFBR2 gene in Japanese subjects (279 subjects each) and there was no significant difference with haplotype analysis, either. Our results suggest that the TGFBR2 gene itself does not link to schizophrenia but that the TGFBR2 mRNA levels in the peripheral leukocytes may be a potential state marker for schizophrenia.
Journal of Psychiatric Research 06/2008; 42(6):425-32. · 4.66 Impact Factor
