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ABSTRACT: 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.The Pharmacogenomics Journal advance online publication, 15 May 2012; doi:10.1038/tpj.2012.18.
The Pharmacogenomics Journal 05/2012; · 4.54 Impact Factor
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R Hashimoto,
H Hashimoto,
N Shintani,
S Chiba,
S Hattori,
T Okada,
M Nakajima,
K Tanaka,
N Kawagishi,
K Nemoto, [......],
N Iwata,
N Ozaki,
T Nakabayashi,
O Saitoh,
A Kosuga, M Tatsumi,
K Kamijima,
D R Weinberger,
H Kunugi,
A Baba
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ABSTRACT: Pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1: adenylate cyclase-activating polypeptide 1), a neuropeptide with neurotransmission modulating activity, is a promising schizophrenia candidate gene. Here, we provide evidence that genetic variants of the genes encoding PACAP and its receptor, PAC1, are associated with schizophrenia. We studied the effects of the associated polymorphism in the PACAP gene on neurobiological traits related to risk for schizophrenia. This allele of the PACAP gene, which is overrepresented in schizophrenia patients, was associated with reduced hippocampal volume and poorer memory performance. Abnormal behaviors in PACAP knockout mice, including elevated locomotor activity and deficits in prepulse inhibition of the startle response, were reversed by treatment with an atypical antipsychotic, risperidone. These convergent data suggest that alterations in PACAP signaling might contribute to the pathogenesis of schizophrenia.
Molecular Psychiatry 12/2007; 12(11):1026-32. · 13.67 Impact Factor
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H Kunugi,
R Hashimoto,
T Okada,
H Hori,
T Nakabayashi,
A Baba,
K Kudo,
M Omori,
S Takahashi,
R Tsukue,
K Anami,
N Hirabayashi,
A Kosuga, M Tatsumi,
K Kamijima,
T Asada,
S Harada,
K Arima,
O Saitoh
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ABSTRACT: We examined, for the first time, the possible association between schizophrenia and the anaplastic lymphoma kinase (ALK) gene which plays an important role in neurodevelopment. When two nonsynonymous polymorphisms (Arg1491Lys and Glu1529Asp) were examined, there were significant differences in genotype and allele distributions between patients and controls. Individuals homozygous for the minor allele (1491Lys-1529Asp) were more common in patients than in controls (p = 0.0064, odds ratio 2.4, 95% CI 1.3-4.6). These results suggest that genetic variations of the ALK gene might confer susceptibility to schizophrenia.
Acta Neurovegetativa 11/2006; 113(10):1569-73. · 2.73 Impact Factor
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ABSTRACT: Previous studies have suggested that genetic variations in the brain-derived neurotrophic factor (BDNF) gene may be associated with several neuropsychiatric diseases including bipolar disorder. The present study examined a microsatellite polymorphism located approximately 1.0 kb upstream of the translation initiation site of the BDNF gene for novel sequence variations, association with bipolar disorder, and effects on transcriptional activity. Detailed sequencing analysis revealed that this polymorphism is not a simple dinucleotide repeat, but it is highly polymorphic with a complex structure containing three types of dinucleotide repeats, insertion/deletion, and nucleotide substitutions that gives rise to a total of 23 novel allelic variants. We obtained evidence supporting the association between this polymorphic region (designated as BDNF-linked complex polymorphic region (BDNF-LCPR)) and bipolar disorder. One of the major alleles ('A1' allele) was significantly more common in patients than in controls (odds ratio 2.8, 95% confidential interval 1.5-5.3, P=0.001). Furthermore, a luciferase reporter gene assay in rat primary cultured neurons suggests that this risk allele (A1) has a lower-transcription activity, compared to the other alleles. Our results suggest that the BDNF-LCPR is a functional variation that confers susceptibility to bipolar disorder and affects transcriptional activity of the BDNF gene.
Molecular Psychiatry 08/2006; 11(7):695-703. · 13.67 Impact Factor
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ABSTRACT: Two research groups have recently reported a significant association between schizophrenia and genetic variants of Frizzled-3 (FZD3) gene. We examined a possible association in a Japanese sample of schizophrenia, bipolar disorder, unipolar depression and controls with four single nucleotide polymorphisms (SNPs), tested in previous reports. We failed to find significant association in the four SNPs or haplotype analysis. The FZD3 gene might not play a role in conferring susceptibility to major psychosis in our sample.
Acta Neurovegetativa 03/2005; 112(2):303-7. · 2.73 Impact Factor
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ABSTRACT: Two research groups have thus far reported a significant association between schizophrenia and a promoter polymorphism (-308G > A) of the gene encoding tumor necrosis factor alpha (TNF-alpha), while contradictive negative results have also been reported. We examined the possible association in a Japanese sample of 297 schizophrenia cases and 458 controls. Allele frequencies of both the patients and controls were very low (1.5% and 0.8%, respectively), and the difference was not statistically significant. We conclude that the effect of the -308G > A polymorphism on the development of schizophrenia is, if any, weak and the majority of Japanese schizophrenics are unrelated to the -308G > A polymorphism of the TNF-alpha gene.
Acta Neurovegetativa 03/2004; 111(2):217-21. · 2.73 Impact Factor
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ABSTRACT: Growing evidence has implicated the possible involvement of neurotrophins in the pathogenesis of functional psychoses such as schizophrenia and bipolar disorder. Previous studies reported a significant association of a dinucleotide repeat polymorphism of the neurotrophin-3 (NTF3) gene with schizophrenia. The aims of the present study were to examine whether this polymorphism is associated with bipolar disorder and whether the polymorphic region has an enhancer/silencer effect on transcriptional activity in an allele-dependent manner. In an association analysis between the polymorphism and bipolar disorder in a Japanese sample of 88 patients and 98 controls matched for age, sex, and ethnicity, the distribution of alleles did not differ significantly between the two groups. pGL3-promoter luciferase reporter vectors containing the polymorphic region increased luciferase activity relative to empty pGL3-promoter vector in HeLa, IMR-32 (neuroblastoma) and Hs683 (glioma) cell lines; however, no significant difference was detected between alleles for either cell line. Our results suggest that the examined polymorphism has no major role in giving susceptibility to bipolar disorder. Although the polymorphic region may have an enhancer-like effect on transcriptional activity, we obtained no evidence for allele-dependent differential effects.
Neuropsychobiology 02/2004; 50(3):206-10. · 2.67 Impact Factor
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ABSTRACT: Alterations of G proteins have been implicated in major psychiatric illnesses. A C825T polymorphism of a gene encoding the beta3 subunit of heterotrimeric G proteins (GNB3) was reported to be associated with several pathological conditions, such as hypertension and depressive disorder. We examined whether this polymorphism is associated with functional psychoses in a Japanese sample of 370 schizophrenics, 164 bipolars, 68 depressive patients, and 198 controls. We obtained no evidence for an association of the polymorphism with any diagnostic group.
Acta Neurovegetativa 03/2002; 109(2):213-8. · 2.73 Impact Factor
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ABSTRACT: A polymorphism of a variable number tandem repeat (VNTR), that was recently found in the promoter region of the monoamine oxidase-A (MAOA) gene, was shown to be associated with its transcriptional activity. This study examined whether this functional polymorphism of the MAOA gene is associated with the risk of developing mood disorders in a Japanese sample of 161 patients with bipolar disorder, 98 with unipolar depression, and 258 controls. There was no significant genotypic or allelic association, suggesting that the functional VNTR polymorphism in the MAOA gene is unlikely to play a major role in the pathogenesis of bipolar disorder or unipolar depression. Furthermore, we found no association between the polymorphism and a history of suicide attempt.
Molecular Psychiatry 08/1999; 4(4):393-5. · 13.67 Impact Factor
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ABSTRACT: 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.
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.
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.
The authors conclude that the examined polymorphisms are unlikely to have major relevance to the pathogenesis of affective disorders or suicidal behavior.
American Journal of Psychiatry 06/1999; 156(5):774-6. · 12.54 Impact Factor
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ABSTRACT: A common missense mutation of the methylenetetrahydrofolate reductase (MTHFR) gene (C677T) has been shown to be a risk factor for premature cardiovascular disease and neural tube defect. Deficient activity of MTHFR has also been implicated in the pathogenesis of psychiatric conditions such as schizophrenia and affective disorders. Arinami et al found an increased frequency of homozygosity for the mutated type (T677) of the MTHFR gene in schizophrenia and depression. We tried to replicate this finding in a sample of 343 patients with schizophrenia, 143 with bipolar disorder, 71 with unipolar depression, and 258 controls; however, there was no significantly increased frequency of homozygosity for the T677 allele in any of the diagnostic groups, compared to the controls. Our results suggest that homozygosity for the T677 allele of the MTHFR gene is unlikely to play a major role in the pathogenesis of schizophrenia or affective disorders in our sample.
Molecular Psychiatry 10/1998; 3(5):435-7. · 13.67 Impact Factor
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ABSTRACT: The ciliary neurotrophic factor (CNTF) gene is considered a candidate gene for schizophrenia, in view of the neurodevelopmental hypothesis of the disorder. Recently, controversial results regarding an association between psychiatric disorders; mainly schizophrenia, and a null mutation of the CNTF gene were reported. We investigated this mutation in 138 Japanese patients with schizophrenia and 140 healthy control subjects. No significant difference was observed in allele frequencies or genotype distribution between the patients and control subjects. Our results did not provide evidence for the involvement of the null mutation of the CNTF gene in the development of schizophrenia.
Psychiatry Research 07/1997; 71(1):7-10. · 2.52 Impact Factor
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ABSTRACT: 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.
American Journal of Medical Genetics 05/1997; 74(3):338-41.
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The Lancet 09/1996; 348(9023):336. · 38.28 Impact Factor
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The Lancet 06/1996; 347(9011):1340. · 38.28 Impact Factor
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ABSTRACT: In this study we investigated the one-year outcome of panic disorder. The subjects were 169 panic disorder patients (69 males, 100 females; mean age 36.5 years), who attended the outpatient clinic of the Department of Psychiatry, Showa University Hospital, from September to December 1993. The outcome study was performed from October to December 1994. Patients who were being treated at Showa University Hospital during the outcome study were interviewed in person, and those who were not were interviewed by telephone. The one-year outcome of 100 patients (32 interviewed in person and 68 interviewed by telephone; 37 males, 63 females; mean age 39.5 years) was assessed. That of the remaining 69 patients was not assessed because they did not provide informed consent or had moved during the last year. The patients who were assessed (N = 100) were older and exhibited less severe phobic avoidance on their first visit to the clinic than those who were not assessed (N = 69). The frequency of panic attacks, and the severity of phobic avoidance and anticipatory anxiety decreased significantly between the time of the patients' first visit to the clinic and the time of the outcome study. Panic attacks, phobic avoidance and anticipatory anxiety disappeared in 27.0%, 32.9% and 13.6% and decreased in frequency or severity in 61.8%, 62.0% and 61.4% of the cases, respectively. Seventy-three patients felt that the severity of their panic disorder symptoms decreased between the time of the outcome study and the time of their first visit to the clinic, 20 felt that it had not changed and 7 felt that it had increased worse. The phobic avoidance and anticipatory anxiety at the time of the patients' first visit to the clinic were more severe, and the Global Assessment of Functioning Scale score was lower in the case of the former group of patients than in that of the latter two groups.
Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica 02/1996; 98(9):667-79.
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ABSTRACT: There is some evidence suggesting that a polymorphism of variable number of tandem repeats (VNTR) in the second intron of the serotonin transporter (5-HTT) gene and another variation which lies 1.2 kb upstream of the promoter of the gene (5-HTTLPR) are associated with affective disorders. However, conflicting results have also been reported. We examined an allelic association of these two polymorphisms in a Japanese sample of 191 patients with affective disorders (142 bipolar and 49 unipolar) and 212 controls. Substantial differences in the number and frequency of alleles between Caucasians and Japanese were observed for both polymorphisms. A significant association between the VNTR polymorphism and bipolar disorder (genotypic association: odds ratio 2.2, 95% CI 1.2-4.0; allelic association: odds ratio 1.7, 95% CI 1.0-3.0) was found, but not between the 5-HTTLPR polymorphism and bipolar disorder. No significant association with unipolar depression was detected using either genetic marker, although this may be attributable to the relatively small number of subjects with unipolar depression. Our results suggest that the VNTR itself or another unknown functional polymorphism which would be in linkage disequilibrium to the VNTR has an effect on susceptibility to bipolar disorder.
Molecular Psychiatry 2(6):457-62. · 13.67 Impact Factor
