No association between the metabotropic glutamate receptor type 3 gene (GRM3) and schizophrenia in a Japanese population

Several lines of evidence have suggested that the metabotropic glutamate receptor 3 (GRM3) gene is a candidate susceptibility gene for schizophrenia. To our knowledge, six studies have investigated the genetic association between GRM3 and schizophrenia, although the results have been quite controversial. In the present study, we investigated the association between the GRM3 gene and schizophrenia in 402 Japanese people by analyzing 10 single nucleotide polymorphisms (SNPs), including all SNPs that showed significant results in previous studies. We observed no significant difference in allelic frequencies or genotypic distributions of the 10 SNPs between the controls and patients. A permutation test showed no significant global differences in estimated haplotype frequencies between the controls and patients. Thus, the present study provides no positive evidence of an association between the GRM3 gene and schizophrenia in the Japanese population.     

Genetic susceptibility to tardive dyskinesia in chronic schizophrenia subjects: III. Lack of association of CYP3A4 and CYP2D6 gene polymorphisms

Recent studies of the association between the metabotropic glutamate receptor 3 gene (GRM3) and schizophrenia have produced conflicting results, although GRM3 is a promising candidate gene. Fujii et al. found a single nuclear polymorphism (SNP) for within this gene, rs1468412 to have a positive association to schizophrenia in Japanese patients. To investigate this further, we genotyped 7 SNPs around GRM3 including rs1468412, in 752 Chinese patients with schizophrenia and 752 controls using Taqman technology. We did not detect any association between rs1468412 and schizophrenia, however we found differences in the allele frequency distribution of SNP rs2299225 (p=0.0297, odds ration [OR]=1.44, 95% confidence interval 1.05-1.99) between cases and controls. Moreover, the overall frequency of haplotypes constructed from three SNPs including rs2299225 showed significant differences between cases and controls (p=0.0017). Our results partially support the previous studies in other ethnic groups and indicate that the GRM3 gene may play an important role in the etiology of schizophrenia in the Han Chinese.     

No association between the ryanodine receptor 3 gene and autism in a Japanese population

Aim:  Autism is a neurodevelopmental disorder with a complex genetic etiology. Chromosome 15q11-q14 has been proposed to harbor a gene for autism susceptibility because deletion of the region leads to Prader-Willi syndrome or Angelman syndrome, having phenotypic overlap with autism. Here we studied the association between autism and the ryanodine receptor 3 (RyR3) gene, which is located in the region. This is the first study, to our knowledge, that has investigated the association.
Methods:  We genotyped 14 tag single nucleotide polymorphisms (SNPs) in 166 Japanese patients with autism and 375 controls.
Results:  No significant difference was observed between the patients and controls in allelic frequencies or genotypic distributions of the 14 SNPs. Analysis after confining the subjects to males showed similar results.
Conclusions:  The present study provides no positive evidence for the association between the RyR3 gene and autism in the Japanese population.     

No evidence for an association between the BDNF Val66Met polymorphism and schizophrenia or personality traits

Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family, which plays a critical role in neurodevelopment. Based on the neurodevelopmental hypothesis, the BDNF gene has been a candidate locus for schizophrenia. In Caucasians, recent studies identified an association with the Val66Met polymorphism, which has been suggested to affect episodic memory and hippocampal function in humans. However, in other populations, the association has not been replicated. In the present study, we investigated the association between the Val66Met polymorphism of the gene and schizophrenia in 401 Japanese patients with schizophrenia and 569 controls. As a result, we did not observe a significant difference in genotypic distribution or allele frequencies between the patients and controls (chi2=0.56, df=2, p=0.76 and chi2=0.39, df=1, p=0.53, respectively). We also investigated the association between the polymorphism and personality traits in the controls; however, no significant association was observed. Thus, the present study did not provide evidence for an association between the BDNF gene and schizophrenia or personality traits 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.     

Failure to confirm an association between <Emphasis Type="Italic">Epsin 4</Emphasis> and schizophrenia in a Japanese population

Previous studies suggested that genetic variations in the 5' region of Epsin 4, a gene encoding enthoprotin on chromosome 5q33, are associated with schizophrenia. However, conflicting results have also been reported. We examined the possible association in a Japanese sample of 354 patients and 365 controls. Seventeen polymorphisms of Epsin 4 [3 microsatellites and 14 single nucleotide polymorphisms (SNPs)] were selected. A microsatellite marker (D5S1403) demonstrated a significant difference in the allele frequency between patients and controls (uncorrected P = 0.04). However, there was no significant difference in the genotype or allele frequency between the two groups for the other microsatellites or SNPs. Haplotype-based analysis provided no evidence for an association. The positive result at D5S1403 no longer reached statistical significance when multiple testing was taken into consideration. Our results suggest that the examined region of Epsin 4 does not have a major influence on susceptibility to schizophrenia in Japanese.     

Association study of the frizzled-3 (FZD3) gene with schizophrenia and mood disorders

Summary. 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.     

代谢型谷氨酸受体3基因多态性与酒依赖的关联研究

目的探讨中国北方汉族人群代谢型谷氨酸受体3(GRM3)基因多态性与酒依赖的相关性。方法采用聚合酶链反应(Polymerase Chain Reaction,PCR)和连接酶检测反应(Ligase Detection Reaction,LDR)方法,检测100例酒依赖患者和100例正常对照的GRM3基因上3个位点rs1468412、rs917071和rs1989796的基因多态性。结果酒依赖组和对照组之间GRM3基因rs1468412、rs917071以及rs1989796位点的等位基因频率和基因型分布的差异均无统计学意义(P>0.05),但酒依赖组中rs1468412、rs917071和rs19897963个位点所构建的单倍型TTT的频率明显高于对照组(6%vs.1%,OR=5.17,P<0.05),TTT基因型携带者患酒依赖的可能性较高。结论在本样本中,中国北方汉族人群GRM3基因rs1468412、rs917071和rs1989796位点的多态性单独存在时与酒依赖无关联,而由此3个位点所构建的单倍型TTT可能为酒依赖的易感危险因素。     

No genetic association between SLC7A10 and Japanese patients with schizophrenia

Disrupted glutamatergic neurotransmission may be a pathophysiological feature in the brains from patients with schizophrenia, and glutamatergic amino acids including d-serine have been found to be involved in pathophysiology. Endogenous and exogenous d-serine have shown potential as biological markers for the pathophysiology of schizophrenia and especially as a therapeutic strategy in treatment-resistant schizophrenia (TRS). This is the first study investigating whether SLC7A10, a d-serine transporter gene, is associated with schizophrenia in Japanese patients.We investigated the association between schizophrenia in Japanese patients with SLC7A10 using six tag single nucleotide polymorphisms (SNPs). Results failed to show any association between Japanese schizophrenia and each individual SNP or with two-, three-, or four-window haplotype analyses. We also investigated whether SLC7A10 contributes to TRS in Japanese participants. Results showed no association.In conclusion, SLC7A10 had no apparent degree of association with schizophrenia as a candidate susceptibility gene in the disease per se.     

Association study of dopamine transporter gene and schizophrenia in Korean population using multiple single nucleotide polymorphism markers

Inherited or acquired dysfunction of the dopamine system is believed to underlie the core symptoms of schizophrenia, and there are some evidences that dopamine transporter activity may be altered in schizophrenic patients. Therefore, dopamine transporter gene (DAT1) has been traditionally considered a probable candidate gene for the association study of schizophrenia. Until now, association studies of the dopamine transporter gene (DAT1) with schizophrenia have yielded largely negative results. However, these results cannot be regarded as conclusive in that they were all obtained from just a single marker, that is, 3' untranslated region variable number of tandem repeat (VNTR). We have therefore tried to find other single nucleotide polymorphisms (SNPs) in DAT1 gene and to use them as additional markers for the association study of schizophrenia. Searching for the SNPs had been done with 50 Korean schizophrenic patients. DNA sequences encompassing the whole exon and flanking exon-intron junctions were amplified and searched for the presence of SNPs. Total of five SNPs were found. Among these, three SNPs (1215A>G, 1398C>T, IVS11+14G>A) as well as the 3' untranslated region VNTR were selected as the markers to be genotyped. The allelic and genotypic frequencies of these markers were determined in 252 schizophrenic patients and 271 controls and compared between them. The frequencies of algorithmically derived haplotypes were also compared. No evidence of association was found between any of these markers and schizophrenia. The result using haplotypes was also negative. However, when the patient subgroup with verified familial history and the subgroup with early age of onset were re-analyzed, weak trend of association between 1398C>T SNP marker with schizophrenia was found in both cases. In accordance with the previous literature, we could not find any evidence of association between DAT1 gene and schizophrenia. This result acquired more certainty because not only the VNTR but several SNPs present in DAT1 gene and newly constructed haplotypes were also used as additional markers. However, the finding of weak association between one of the SNP markers (1398C>T) and the specific subgroups of schizophrenia patients added further support to the importance of defining more homogenous subgroups in association studies.     

Association analysis of GRM2 and HTR2A with methamphetamine-induced psychosis and schizophrenia in the Japanese population

Background

Abnormalities in glutaminergic neural transmission have been suggested to be involved in the pathogenesis of schizophrenia. A recent study reported that alterations in the 5-HT2A–mGluR2 complex may be involved in neural transmission in the schizophrenic cortex. In addition, methamphetamine-induced psychosis is thought to be similar to schizophrenia. Therefore, we conducted a case-control study with Japanese samples (738 schizophrenia patients, 196 methamphetamine-induced psychosis patients, and 802 controls) to evaluate the association and interaction between GRM2, HTR2A and schizophrenia.

Methods

We selected three ‘tagging SNPs’ in GRM2, and two biologically functional SNPs in HTR2A (T102C and A1438G), for the association analysis.

Results

We detected a significant association between methamphetamine-induced psychosis and GRM2 in a haplotype-wise analysis, but not HTR2A. We did not detect an association between GRM2 or HTR2A and schizophrenia. In addition, no interactions of GRM2 and HTR2A were found in methamphetamine-induced psychosis or schizophrenia. We did not detect any novel polymorphisms in GRM2 when we performed a mutation search using methamphetamine-induced psychosis samples.

Conclusion

Our results suggested that GRM2 may play a role in the pathophysiology of methamphetamine-induced psychosis but not schizophrenia in the Japanese population. A replication study using larger samples or samples of other populations will be required for conclusive results.     

Association study of polymorphisms in the GluR7, KA1 and KA2 kainate receptor genes (GRIK3, GRIK4, GRIK5) with schizophrenia

On the basis of the glutamatergic dysfunction hypothesis of schizophrenia, we have been conducting a systematic study of the association of glutamate receptor genes with schizophrenia. Here we report association studies of schizophrenia with polymorphisms in three kainate receptor genes: GRIK3, GRIK4 and GRIK5. We selected 16, 24 and 5 common single nucleotide polymorphisms (SNPs) distributed in the entire gene regions of GRIK3 (>240 kb), GRIK4 (>430 kb) and GRIK5 (>90 kb), respectively. We tested associations of the polymorphisms with schizophrenia using 100 Japanese case-control pairs (the Kyushu set). We observed no significant "single marker" associations with the disease in any of the 45 SNPs tested except for one (rs3767092) in GRIK3 showing a nominal level of significance. The significant association, however, disappeared after the application of the Bonferroni correction. We also observed significant haplotype associations in seven SNP pairs in GRIK3 and in four SNP pairs in GRIK4. None, however, remained significant after Bonferroni correction. We also failed to replicate the nominally significant haplotype associations in a second sample set, the Aichi set (106 cases and 100 controls). We conclude that SNPs in the gene regions of GRIK3, GRIK4 or GRIK5 do not play a major role in schizophrenia pathogenesis in the Japanese population.     

No association between the PCM1 gene and schizophrenia: a multi-center case-control study and a meta-analysis

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.     

Association study between the transferrin gene and schizophrenia in the Japanese population

Several lines of evidence, including diffusion tensor imaging and microarray studies, indicate that abnormalities in myelination play an important role in the pathophysiology of schizophrenia. Of myelin and oligodendrocyte-related genes, a significant decrease in the mRNA levels of transferrin in schizophrenics has been reported by both microarray and quantitative polymerase chain reaction studies. We performed an association analysis of the transferrin gene in a Japanese population of 384 schizophrenic patients and 384 controls. Six single nucleotide polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism and a TaqMan assay. No significant differences in genotype, allele, or haplotype frequencies of the six single nucleotide polymorphisms were observed between schizophrenic patients and controls. The present results suggest that the transferrin gene is not related to the development of schizophrenia in the Japanese population.     

Failure to confirm an association between the PLXNA2 gene and schizophrenia in a Japanese population

Plexins are receptors for multiple classes of semaphorins, either alone or in combination with neuropilins. Plexins participate in many cellular events that include axonal repulsion, axonal attraction, cell migration, axon pruning, and synaptic plasticity. PLXNA2 maps to chromosome 1q32. Several linkage studies reported schizophrenia susceptibility loci in the 1q22-42 region. A recent study reported that intronic single nucleotide polymorphisms (SNPs) of PLXNA2 were associated with schizophrenia in a European American population. We attempted to replicate this finding in a Japanese sample of 336 patients with schizophrenia and 304 controls. In addition, we examined 3 non-synonymous SNPs (Arg5Gln, GLn57Arg, and Ala267Thr) in PLXNA2. Genotyping was performed by the TaqMan allelic discrimination assay. There was no significant difference in genotype or allele distribution of either the 4 intronic SNPs or the 3 non-synonymous SNPs between patients and controls. Furthermore, haplotype-based analyses did not provide evidence for an association. These results suggest that PLXNA2 may not play a major role in the development of schizophrenia in our Japanese sample.     

Polymorphism analysis of the upstream region of the human N-methyl-D-aspartate receptor subunit NR1 gene (GRIN1): implications for schizophrenia

Dysfunction of the gene for the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor (GRIN1) has been implicated in the pathogenesis of schizophrenia. In support of this hypothesis are behavioral abnormalities reminiscent of schizophrenia in mice with an attenuated expression of the NR1 subunit receptor and the reduced level of NR1 mRNA in postmortem brains of patients with schizophrenia. We screened single nucleotide polymorphisms (SNPs) in the upstream region between +51 and -941 from the translation initiation codon of GRIN1 and identified 17 SNPs, 10 of which were located within the region containing the Sp1 motif and the GSG motifs. As genotyping of 191-196 Japanese patients with schizophrenia and 202-216 controls revealed no significant association between schizophrenia and the SNPs in the upstream region of GRIN1, these SNPs apparently do not play a critical role in the pathogenesis of schizophrenia in the Japanese population.     

Further evidence for the association of genetic variants of ZNF804A with schizophrenia and a meta-analysis for genome-wide significance variant rs1344706

Recent accumulating evidence has indicated that ZNF804A (zinc finger protein 804A) may be one of the most robustly implicated genes in schizophrenia. In this report, we examined ZNF804A single nucleotide polymorphisms (SNPs) encompassing exon 4 by performing an association study that used a Han Chinese sample comprised of 492 schizophrenia patients and 516 healthy control subjects. A meta-analysis based on previous studies was also performed. For markers rs4667000 and rs1366842, significant differences in allele frequencies were found between cases and controls (Mantel-Haenszel corrected P=0.014 and P=0.025, respectively). Analysis of haplotype rs61739290-rs1366842 showed significant association with schizophrenia (global P=0.0018). Moreover, several other two-, three-, and four-SNP tests of haplotype association were also significant. A meta-analysis comprised of studies that utilized sample sets of either European and/or Han Chinese origin revealed statistically significant associations for two SNPs (rs1366842, P=0.002; and rs3731834, P=0.03) and schizophrenia. In addition, we observed a significant association between marker rsl344706 and schizophrenia (P<1.0×10(-5)) in combined populations. When we separately analyzed the studies by population, consistent and significant differences were found between cases and controls both in the European samples (P<1.0×10(-4)) and in the Chinese samples (P=0.03). In summary, we have added new evidence supporting the association between ZNF804A and schizophrenia in our Han Chinese sample. Further functional exploration of ZNF804A will greatly help us to elucidate the pathogenesis of schizophrenia and find promising new approaches for the treatment of this disorder.     

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.