Association between chromogranin A gene polymorphism and schizophrenia in the Japanese population

It has been reported that expression of the chromogranin A (CHGA) gene is reduced in the prefrontal cortex and cerebrospinal fluid of patients with schizophrenia. Single-marker and haplotype analyses of SNPs within the CHGA gene were performed in 633 subjects with schizophrenia and 589 healthy controls. A significant association with schizophrenia was observed to one SNP marker, rs9658635 (p=0.0269), and with a 2 marker haplotype (p=0.0016). Significant association of rs9658635 was then replicated in a second independent cohort (377 schizophrenia and 338 control samples) (p=0.007). These results suggest that the CHGA gene is associated with the risk of developing schizophrenia in the Japanese population.     

Association between PNPO and schizophrenia in the Japanese population

Accumulating evidence suggests that both homocysteine metabolism and monoaminergic neurotransmitter systems are important in schizophrenia pathology. We hypothesized that the gene PNPO (pyridoxine 5'-phosphatase oxidase gene) might be a candidate for susceptibility to schizophrenia because PNPO encodes pyridoxamine 5'-phosphate oxidase (EC 1.4.3.5), a rate-limiting enzyme in pyridoxal 5'-phosphate (PLP, vitamin B(6)) synthesis. PLP is a metabolically-active form of vitamin B(6) and thus, is required as a co-factor for enzymes involved in both homocysteine metabolism and synthesis of neurotransmitters such as catecholamine. We examined 8 single nucleotide polymorphisms (SNPs) in PNPO and its 5'-flanking regions in 359 schizophrenia patients and 582 control subjects. Four marker regions of PNPO showed significant levels of allelic associations with schizophrenia (the highest was rs2325751, P=0.004). In addition, the haplotype case-control study revealed a significant association (permutation P<0.00001) between PNPO and schizophrenia. These findings suggest that variations in PNPO may contribute to overall genetic risk for schizophrenia in the Japanese population.     

Association between chromogranin b gene polymorphisms and schizophrenia in the Japanese population.

BACKGROUND: We found in previous work a significant association between schizophrenia and D20S95 on chromosome 20p12.3. In this study, we analyzed 10 microsatellite markers and found an association of schizophrenia with D20S882 and D20S905 that flank D20S95. The chromogranin B gene (CHGB) is 30 kb from D20S905. The chromogranin B (secretogranin I) belongs to a series of acidic secretory proteins that are widely expressed in endocrine and neuronal cells, and its cerebrospinal fluid levels have been reported to decrease in patients with chronic schizophrenia. METHODS: We screened for polymorphisms in CHGB with polymerase chain reaction direct sequencing methods in 24 Japanese schizophrenic patients and identified a total of 22 polymorphisms. Allelic and genotypic distributions of detected polymorphisms were compared between unrelated Japanese schizophrenic patients (n = 192) and healthy control subjects (n = 192). RESULTS: Statistically significant differences in the allelic distributions were found between schizophrenic patients and control subjects for 1058C/G (A353G) (corrected p = 7.7 x 10(-5)) and 1104A/G (E368E) (corrected p = 8.1 x 10(-6)). The 1058C/G and 1104A/G alleles were in almost complete linkage disequilibrium and were in linkage disequilibrium with D20S95. CONCLUSIONS: Results suggest that the CHGB variations are involved in the susceptibility to schizophrenia in our study population.     

Association study of clock gene (CLOCK) and schizophrenia and mood disorders in the Japanese population

Recently the clock genes have been reported to play some roles in neural transmitter systems, including the dopamine system, as well as to regulate circadian rhythms. Abnormalities in both of these mechanisms are thought to be involved in the pathophysiology of major mental illness such as schizophrenia and mood disorders including bipolar disorder (BP) and major depressive disorder (MDD). Recent genetic studies have reported that CLOCK, one of the clock genes, is associated with these psychiatric disorders. Therefore, we investigated the association between the six tagging SNPs in CLOCK and the risk of these psychiatric disorders in Japanese patients diagnosed with schizophrenia (733 patients), BP (149) and MDD (324), plus 795 Japanese controls. Only one association, with schizophrenia in females, was detected in the haplotype analysis (P = 0.0362). However, this significance did not remain after Bonferroni correction (P = 0.0724). No significant association was found with BP and MDD. In conclusion, we suggest that CLOCK may not play a major role in the pathophysiology of Japanese schizophrenia, BP and MDD patients. However, it will be important to replicate and confirm these findings in other independent studies using large samples. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. T. Kishi and T. Kitajima have contributed equally to this work.     

微卫星DNA vWA的多态性与精神分裂症的关联研究

目的　通过对微卫星DNAvWA多态性的分析 ,了解精神分裂症与vWA有关“等位基因”的关联情况。方法　对 32例精神分裂症患者和 12 3名随机人群采用PEProfilerplus系统进行PCR复合扩增 ,然后用ABI310型基因分析系统对扩增产物进行电泳和基因检测。结果　两组vWA“等位基因”频率符合Hardy Weinberg平衡定律 (P >0 0 5 ) ;精神分裂症组vWA 14的检出率为 17 2 % ,对照组的检出率为 33 3% ,两组有显著性差异 (P <0 0 5 ) ;精神分裂症组vWA 17的检出率为 31 2 % ,对照组检出率为 19 5 % ,两组有显著性差异 (P <0 0 5 ) ;其他各“等位基因”检出率两组无统计学显著差异 (P >0 0 5 )。结论　vWA“等位基因”vWA 14和vWA 17与精神分裂症的发病有关 ,在第 12号染色体上可能存在与精神分裂症相关的基因     

精神分裂症与微卫星DNA D3S1358的多态性的关联研究

目的　通过对微卫星DNAD3S135 8多态性的分析 ,了解精神分裂症与D3S135 8有关等位基因的关联情况。方法　对 32名精神分裂症患者和 12 3名随机人群采用PEProfilerplus系统进行PCR复合扩增 ,然后用ABI310型基因分析系统对扩增产物进行电泳和基因检测。结果　两组D3S135 8等位基因频率符合Hardy Weinberg平衡定律 (P >0 .0 5 ) ;精神分裂症组D3S135 8 14的检出率为 12 .5 % ,对照组的检出率为 4 .4 7% ,两者有统计学显著差异 (P <0 .0 5 ) ;精神分裂症组D3S135 8 17的检出率为 9.38% ,对照组检出率为 2 0 .73% ,显著低于对照组 (P <0 .0 5 ) ;其他各等位基因检出率两组无统计学显著差异(P >0 .0 5 )。结论　D3S135 8某些等位基因与精神分裂症的发病有关 ,在第 3号染色体上可能存在与精神分裂症相关的易感或抗性基因。     

No association between the brain-derived neurotrophic factor gene and schizophrenia in a Japanese population

Brain-derived neurotrophic factor (BDNF) plays important roles in the survival, maintenance and growth of neurons. Several studies have indicated that BDNF is likely to be related to the pathogenesis of schizophrenia. Recent genetic analyses have revealed that BDNF gene polymorphisms are associated with schizophrenia, although contradictory negative findings have also been reported. To assess whether three BDNF gene polymorphisms (rs988748, C132T and rs6265) could be implicated in vulnerability to schizophrenia, we conducted a case-control association analysis (349 patients and 423 controls) in Japanese subjects. We found no association between these BDNF gene polymorphisms and schizophrenia using both single-marker and haplotype analyses. The results of the present study suggest that these three BDNF gene polymorphisms do not play major roles in conferring susceptibility to schizophrenia in a Japanese population. However, further studies assessing the associations between these BDNF gene polymorphisms and schizophrenia should be performed in several other ethnic populations.     

Association study of the vesicular monoamine transporter 1 (VMAT1) gene with schizophrenia in a Japanese population

Background  

Vesicular monoamine transporters (VMATs) mediate accumulation of monoamines such as serotonin, dopamine, adrenaline, and noradrenaline from the cytoplasm into storage organelles. The VMAT1 (alternatively solute carrier family 18: SLC18A1) regulates such biogenic amines in neuroendocrine systems. The VMAT1 gene maps to chromosome 8p21.3, a locus with strong evidence of linkage with schizophrenia. A recent study reported that a non-synonymous single nucleotide polymorphism (SNP) of the gene (Pro4Thr) was associated with schizophrenia.     

Possible association between Interleukin-1beta gene and schizophrenia in a Japanese population

Background

Disrupted-in-Schizophrenia 1 (DISC1) gene is one of the most promising candidate genes for major mental disorders. In a previous study, a Finnish group demonstrated that DISC1 polymorphisms were associated with autism and Asperger syndrome. However, the results were not replicated in Korean population. To determine whether DISC1 is associated with autism in Chinese Han population, we performed a family-based association study between DISC1 polymorphisms and autism.

Methods

We genotyped seven tag single nucleotide polymorphisms (SNPs) in DISC1, spanning 338 kb, in 367 autism trios (singleton and their biological parents) including 1,101 individuals. Single SNP association and haplotype association analysis were performed using the family-based association test (FBAT) and Haploview software.

Results

We found three SNPs showed significant associations with autism (rs4366301: G > C, Z = 2.872, p = 0.004; rs11585959: T > C, Z = 2.199, p = 0.028; rs6668845: A > G, Z = 2.326, p = 0.02). After the Bonferroni correction, SNP rs4366301, which located in the first intron of DISC1, remained significant. When haplotype were constructed with two-markers, three haplotypes displayed significant association with autism. These results were still significant after using the permutation method to obtain empirical p values.

Conclusions

Our study provided evidence that the DISC1 may be the susceptibility gene of autism. It suggested DISC1 might play a role in the pathogenesis of autism.     

Lack of association between the interleukin-1 gene complex and schizophrenia in a Japanese population

Interleukin-1 (IL1) is an inflammatory cytokine and exerts neurodegenerative effects in the brain. Several studies have indicated that IL1 is likely to be involved in the pathogenesis of schizophrenia. Recent genetic studies have revealed that the IL1 gene complex (IL,1 alpha, IL1, beta and IL1 receptor antagonist) was associated with schizophrenia, although contradictory findings have also been reported. To assess whether the IL1 gene complex was implicated in vulnerability to schizophrenia, the authors conducted a case-control association study (416 patients with schizophrenia and 440 control subjects) for nine polymorphisms in Japanese subjects. The authors found no association between the IL1 gene complex polymorphisms and schizophrenia using either single-marker or haplotype analyses. The results of the present study suggest that the IL1 gene complex does not play a major role in conferring susceptibility to schizophrenia in the Japanese population.     

Association study of the DISC1/TRAX locus with schizophrenia in a Japanese population

Disrupted-in-Schizophrenia-1 (DISC1), identified by cytogenetic approaches in a pedigree with familial psychosis, is considered a candidate susceptibility gene for schizophrenia in some populations. In the pedigree, the TRAX gene, located adjacent to DISC1 on the disrupted chromosome 1, may also contribute to the pathophysiology of the familial schizophrenia. We studied association of the DISC1 and TRAX genes with schizophrenia in 338 Japanese by analyzing 15 single nucleotide polymorphisms (SNPs), including 12 SNPs in DISC1 and three in TRAX, respectively. No significant difference was observed between the patients and controls in allelic frequencies or genotypic distributions of 15 SNPs. A weak trend for the association in genotypic distribution of one SNP in TRAX (major homo/hetero/minor homo: 0.324/0.431/0.245 vs. 0.293/0.526/0.181 for patients vs controls, p = 0.039 in the 2 x 3 comparison) turned out to be insignificant after Bonferroni correction. Haplotype analysis did not support the association between the patients and controls. The present study suggests that the DISC1/TRAX locus may not have a major role in Japanese schizophrenia.     

中国汉族人群磷酸酶与张力蛋白同源物基因多态性与早发性精神分裂症的关联研究

目的：探讨中国汉族人群磷酸酶与张力蛋白同源物（phosphataseandtensinhomolog,PTEN）基因多态性与早发性精神分裂症（EOS）的关系。方法：纳入270例EOS患者和447名健康对照,用SNaPshot技术对PTEN的标签SNP进行基因分型,比较其等位基因、基因型、单体型分布频率在两组间有无差异。结果：rs2299941的等位基因分布在两组间存在边缘统计学差异（X2=4．454,P：0．035,校正P=0．175）,GG基因型在隐性遗传模式下显著降低EOS的发生风险（OR=0．51,95％CI=0．31～0．85,P=0．007）。rs17562384的CC基因型在隐性遗传模式下显著增加EOS的发生风险（OR：2．23,95％CI=1．01～4．91,P=0．047）。单体型GTr（rs2299941、rsl7562384、rs532678）的分布频率在患者组与对照组间存在边缘统计学差异（O．308VS0．364;x2=4．677,P=0．031,校正P=0．057）。结论：中国汉族人群PTEN基因多态性与EOS易感性有关。     

An association study of tachykinin receptor 3 gene with schizophrenia in the Japanese population

The tachykinin receptor 3 (TACR3) gene encodes the neurokinin3 (NK3) receptor. Animal studies showed that agonist-induced stimulation of the NK3 receptor leads to the excessive release of dopamine in the ventral and dorsal striatal and prefrontal cortical regions. Data from clinical trials of selective NK3 receptor antagonists in schizophrenia have shown significant improvement in positive symptoms. We performed an association study of the TACR3 gene in the Japanese population of 384 schizophrenic patients and 384 controls. Nine single nucleotide polymorphisms were genotyped using TaqMan assays and polymerase chain reaction-restriction fragment length polymorphism method. No significant association between schizophrenia and these single nucleotide polymorphisms was observed in single-marker and haplotype analyses. Our results suggest that TACR3 is unlikely to be related to the development of schizophrenia in the Japanese population.     

Association study between glutathione S-transferase P1 polymorphism and schizophrenia in the Korean population

This study is aimed to test the association between the coding sequence functional polymorphism (Ile105Val) of glutathione S-transferase P gene (GSTP1) and schizophrenia in the Korean population. Two hundred fourteen patients with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria and 110 healthy controls were enrolled in this study. Patients and controls were biologically unrelated age and sex-matched native Koreans. Genotyping for GSTP1 polymorphism was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). Genotype and allele distributions of GSTP1 polymorphism in patients with schizophrenia were not significantly different from those of the controls. Comparisons of clinical variables including Positive and Negative Syndrome Scale (PANSS), change of Brief Psychiatric Rating Scale (BPRS), number of admission, and onset age also were not different according to genotype distribution. The present study suggests that GSTP1 polymorphism may not confer susceptibility to development of schizophrenia in the Korean population.     

Association study between reward dependence temperament and a polymorphism in the phenylethanolamine N-methyltransferase gene in a Japanese female population

Cloninger's theory is that specific dimensions of temperament are associated with single neurotransmitter systems, and it is based on neurophysiologic and genetic approaches to the human traits. It suggests that overexpression of temperament could cause psychiatric illness. Based on this theory, we examined the correlation between reward dependence (RD) trait, measured with the Temperament and Character Inventory, and 5 polymorphisms in genes of norepinephrine pathways, ADRB1, COMT, PNMT, SLC18A1, and SLC6A2, in 85 Japanese female nursing students. We found that rs3764351 in PNMT was significantly associated with RD on Fisher's exact test (P = .029, P_corr = .236). When haplotype analysis was performed for rs3764351 and rs876493 polymorphisms in the 5′ flanking region of PNMT, 3 haplotypes were identified. Rs3764351 itself appeared to be correlated with RD in the present study of a specific population, although we could not demonstrate an association between RD and any of the haplotypes. Our findings have implications for the understanding of temperament using neurophysiologic approaches.     

Association between dopamine D3 receptor gene polymorphisms and schizophrenia in an isolate population

There are several lines of evidence implicating the dopamine D3 receptor in the pathophysiology of schizophrenia. The Ser9Gly polymorphism of the dopamine D3 receptor gene (DRD3) has been the most extensively investigated DRD3 variant in connection with the disease but results have been inconclusive. Recent reports indicate that the Ser9Gly polymorphism is in linkage disequilibrium with other markers, but association studies between DRD3 haplotypes and schizophrenia have had mixed results. Genetic heterogeneity may be one of the causes of contradicting results. In order to clarify the role of DRD3 alterations in the aetiology of disease, we have investigated three D3 genetic variants (Ser9Gly, -205-G/A, -7685-G/C) in a sample of patients with schizophrenia or schizoaffective disorder (N=118) and controls (N=162) recruited from a human isolate from Navarra (Northern Spain) of Basque origin. Although no association was found between the Ser9Gly or the -205-A/G polymorphisms and disease, an excess of allele -7685-C was observed in patients (p=0.002 after correction for multiple analyses). Haplotype analysis shows the three markers to be in strong linkage disequilibrium (p<0.0001) and strongly associated with disease (p<1x 10(-5)). These results may suggest that these polymorphisms exert a combined or synergistic effect on susceptibility to schizophrenia, or are in linkage with an unknown causative factor. However, further replication in independent samples is required.     

No association between the tumor necrosis factor-alpha gene promoter polymorphisms and schizophrenia in a Japanese population

Tumor necrosis factor-alpha (TNF-alpha) is a pleiotrophic cytokine and exerts neuroprotective and neurodegenerative effects in brain. Several studies have indicated that TNF-alpha is likely related to the pathogenesis of schizophrenia. Recent genetic investigations have revealed that a TNF-alpha gene promoter polymorphism (-G308A) is associated with schizophrenia, although negative findings have also been reported. To assess whether the TNF-alpha gene promoter variants including -G308A could be implicated in vulnerability to schizophrenia, we conducted a case-control association analysis (265 cases and 424 controls) and the transmission disequilibrium test (TDT) analysis (83 trios) for four polymorphisms (-G238A, -G308A, -C857T and -T1031C) in Japanese subjects. In a case-control analysis, there was no significant association between the promoter polymorphisms or haplotypes in the TNF-alpha gene and schizophrenia. In the TDT analysis, we also did not observe transmission distortion. Our results suggest that the above four polymorphisms in the promoter region of the TNF-alpha gene appear not to confer increased susceptibility for schizophrenia in a Japanese population.