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Several genome-wide linkage studies have suggested linkage between markers on the long arm of chromosome 22 and schizophrenia. It has also been reported that 22q11.2 deletions increase the risk of schizophrenia. Therefore, 22q is a candidate region for schizophrenia. To search for genetic susceptibility loci for schizophrenia on 22q, we conducted a three-stage case-control association study in Japanese individuals. In the first stage, we examined 13 microsatellite markers on 22q in 766 individuals (340 patients with schizophrenia and 426 control individuals) and found a potential association of AFM262VH5 (D22S283) with schizophrenia. In the second stage, we performed fine mapping of the myosin heavy chain 9, non-muscle (MYH9) gene, where AFM262VH5 is located, using 25 tagging single nucleotide polymorphisms (SNPs). We obtained potential associations between three SNPs in MYH9 and schizophrenia in 1193 individuals (595 patients and 598 controls), which included the individuals analyzed in the first stage. In the third stage, however, we could not replicate these associations in 4694 independent individuals (2288 patients and 2406 controls). Our results suggest that MYH9 does not confer increased susceptibility to schizophrenia in the Japanese population, although we could not exclude possible contributions of other genes on 22q to the pathogenesis of schizophrenia. [ABSTRACT FROM AUTHOR]

The dopamine D3 receptor (DRD3) has been suggested to be involved in the pathophysiology of schizophrenia. DRD3 has been tested for an association with schizophrenia, but with conflicting results. A recent meta-analysis suggested that the haplotype T-T-T-G for the SNPs rs7631540-rs1486012-rs2134655-rs963468 may confer protection against schizophrenia. However, almost all previous studies of the association between DRD3 and schizophrenia have been performed using a relatively small sample size and a limited number of markers. To assess whether DRD3 is implicated in vulnerability to schizophrenia, we conducted case-control association studies and performed an updated meta-analysis. In the first population (595 patients and 598 controls), we examined 16 genotyped single nucleotide polymorphisms (SNPs), including tagging SNPs selected from the HapMap database and SNPs detected through resequencing, as well as 58 imputed SNPs that are not directly genotyped. To confirm the results obtained, we genotyped the SNPs rs7631540-rs1486012-rs2134655-rs963468 in a second, independent population (2126 patients and 2228 controls). We also performed an updated meta-analysis of the haplotype, combining the results obtained in five populations, with a total sample size of 7551. No supportive evidence was obtained for an association between DRD3 and schizophrenia in our Japanese subjects. Our updated meta-analysis also failed to confirm the existence of a protective haplotype. To draw a definitive conclusion, further studies using larger samples and sufficient markers should be carried out in various ethnic populations. [ABSTRACT FROM AUTHOR]

Genetic studies have identified rare RELN variants as risk factors for psychiatric disorders. However, additional genetic factors appear to be necessary for disease onset. Detailed genetic information and the use of patient-derived neuronal cells may thus enable to discover these disease-related additional factors. Here, we performed whole-genome sequencing of a schizophrenia patient with a rare RELN deletion and his healthy mother, and examined the phenotypes of 3D-cultured neuronal cells derived from induced pluripotent stem cells of this patient. Our results revealed that, along with the RELN deletion, neuronal death was promoted in this patient; thus, neuronal death may be a vulnerable factor for schizophrenia., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

The ubiquitin ligase F-box protein 45 (FBXO45) is critical for synaptogenesis, neuronal migration, and synaptic transmission. FBXO45 is included in the 3q29 microdeletion region that confers a significant risk for schizophrenia, as shown by rare structural variant studies. Thus, FBXO45 is considered a prominent candidate for mediating schizophrenia pathogenesis. Here, we investigated rare, deleterious single nucleotide variants (SNVs) as well as small insertions and deletions (INDELs) in FBXO45 that may contribute to schizophrenia susceptibility. Using Sanger sequencing, we performed mutation screening in FBXO45 exon regions in 337 schizophrenia patients. Novel missense or nonsense variants were followed up with a genetic association study in an independent sample set of 601 schizophrenia patients and 916 controls, a case report for assessing the clinical consequence of the mutations, a pedigree study for measuring mutation inheritance in the proband's family, bioinformatics analyses for evaluating mutation effect on protein structure and function, and mRNA expression analysis for examining mutation transcriptional influence on FBXO45 expression. One heterozygous, novel, and rare missense mutation (R108C) was identified in a single schizophrenia patient and in his healthy mother. At age 20, this patient was diagnosed with paranoid schizophrenia and carried some clinical features of 3q29 deletion phenotypes, including premorbid IQ decline. With follow-up genotyping, this mutation was not found in either the schizophrenia group (0/601) or the healthy control group (0/916). Bioinformatics analyses predicted that R108C probably pathologically impacted the structure and function of the FBXO45 protein. The relative expression of FBXO45 in SCZ case with R108C mutation was relatively low when compared to 50 schizophrenia patients and 52 healthy controls. The R108C mutation in FBXO45 is a rare variant with a modest effect on schizophrenia risk that may disrupt the structure and function of the FBXO45 protein. Our findings also suggest that FBXO45 may be a new attractive candidate gene for schizophrenia., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The etiology of schizophrenia has been proposed to be neurodevelopmental based on neuroimaging and molecular biological studies. If there is neuronal vulnerability based on neurodevelopment failures in schizophrenic brains, then the impact of aging may have a greater effect on schizophrenic brains than on normal brains. To determine the impact of aging on schizophrenic brains, we investigated the age-related morphological changes of the cross-sectional area of the gray matter (GM) in the left Heschl's gyrus (HG) and the left superior gyrus (STG) in 22 schizophrenic and 24 age- and sex-matched normal control postmortem brains two-dimensionally. The subject groups were divided into younger groups (30-54years of age) and older groups (65-84years of age) on the basis of age at death. Both in schizophrenic and control subjects, the GM area in HG and the STG was significantly smaller in the older group than in the younger group, however, no significant differences were observed between the schizophrenic and control subjects. In the STG, the cross-sectional area of the white matter (WM) was also measured. In the older group, the ratio of the GM area to the WM area in the STG was significantly larger in schizophrenic subjects than controls, although there was no significant difference between the schizophrenic and control subjects in the younger group. These findings indicate that the impact of aging has a greater effect on the WM in the STG in schizophrenic subjects than in normal individuals, although the pathological basis is still unclear., (Copyright © 2011 Elsevier B.V. All rights reserved.)

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., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Methylenetetrahydrofolate reductase (MTHFR) is a critical molecule for single-carbon transfer reactions. Recent evidence suggests that polymorphisms of MTHFR are related to neural tube deficits and the pathogenesis of schizophrenia. While several studies have demonstrated associations between the gene encoding the MTHFR (MTHFR) polymorphisms and schizophrenia, these studies lack consistency. Therefore, we conducted a gene-wide association study (patients with schizophrenia = 696, control subjects = 747) and performed imputation analysis. Additionally, we performed meta-analysis on currently available data from 18 studies for two common functional polymorphisms (rs1801131 and rs1801133). There were no significant associations with schizophrenia in the single marker analysis for the seven tagging SNPs of MTHFR. In the haplotypic analysis, a nominally significant association was observed between the haplotypes, which included four SNPs (rs1801133, rs17421511, rs17037396, and rs9651118) and the schizophrenic patients. Additionally, the imputation analysis demonstrated there were several associated markers on the MTHFR chromosomal region. However, confirmatory analyses of three tagging SNPs (rs1801133, rs17037396, and rs9651118) and the top SNP (rs17421511) for the imputation results (patients with schizophrenia = 797, control subjects = 1025) failed to replicate the haplotypic analysis and the imputation results. These findings suggest that MTHFR polymorphisms are unlikely to be related to the development of schizophrenia in the Japanese population. However, since our meta-analysis results demonstrated strong support for association of rs1801133 with schizophrenia, further replication studies based on a gene-wide approach need to be considered., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Gene expression profiling with microarray technology suggests that peripheral blood cells might be a surrogate for postmortem brain tissue in studies of schizophrenia. The development of an accessible peripheral biomarker would substantially help in the diagnosis of this disease. We used a bioinformatics approach to examine whether the gene expression signature in whole blood contains enough information to make a specific diagnosis of schizophrenia. Unpaired t-tests of gene expression datasets from 52 antipsychotics-free schizophrenia patients and 49 normal controls identified 792 differentially expressed probes. Functional profiling with DAVID revealed that eleven of these genes were previously reported to be associated with schizophrenia, and 73 of them were expressed in the brain tissue. We analyzed the datasets with one of the supervised classifiers, artificial neural networks (ANNs). The samples were subdivided into training and testing sets. Quality filtering and stepwise forward selection identified 14 probes as predictors of the diagnosis. ANNs were then trained with the selected probes as the input and the training set for known diagnosis as the output. The constructed model achieved 91.2% diagnostic accuracy in the training set and 87.9% accuracy in the hold-out testing set. On the other hand, hierarchical clustering, a standard but unsupervised classifier, failed to separate patients and controls. These results suggest analysis of a blood-based gene expression signature with the supervised classifier, ANNs, might be a diagnostic tool for schizophrenia., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

The aim of the current study was to examine the association of KREMEN1 and DKK1, two wnt pathway-related genes with schizophrenia in Japanese subjects. We genotyped 16 common genetic variants within the aforementioned genes and examined their associations with schizophrenia. Results demonstrated that a common variant in the promoter region of KREMEN1 might modulate the risk of schizophrenia in the Japanese. However, further replication will be needed for conclusive interpretation of the effect of this locus on the pathogenesis of schizophrenia., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

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., (2009 Elsevier B.V. All rights reserved.)

A variety of evidence suggests brain-derived neurotrophic factor (BDNF) as a candidate gene for schizophrenia, and several genetic studies have shown a significant association between the disease and certain SNPs within BDNF (specifically, Val66Met and C270T). According to a recent study, the functional microsatellite marker BDNF-LCPR (BDNF-linked complex polymorphic region), which affects the expression level of BDNF, is associated with bipolar disorder. The goals of our current study were to 1) evaluate the quality of HapMap-based linkage disequilibrium (LD) tagging of BDNF-LCPR, 2) examine whether these tagging SNPs are associated with schizophrenia in a Japanese population, and 3) conduct a meta-analysis of the two most extensively studied polymorphisms: Val66Met and C270T. We genotyped eight tagging SNPs, including Val66Met and C270T. Our LD evaluation showed that BDNF-LCPR could be represented by these tagging SNPs in controls (with 73.5% allelic coverage). However, the functional A1 allele was not captured due to its low minor allele frequency (2.2%). In a case-control study (1117 schizophrenics and 1102 controls), no association was found in single-marker or multimarker analysis. Moreover, in a meta-analysis, the Val66Met polymorphism was not associated with schizophrenia, whereas C270T showed a trend for association in a fixed model (p=0.036), but not in a random model (p=0.053). From these findings, we conclude that if BDNF is indeed associated with schizophrenia, the A1 allele in BDNF-LCPR would be the most promising candidate. Further LD evaluation, as well as an association study in which BDNF-LCPR is genotyped directly, would be required for a more conclusive result.

A common functional polymorphism, Val108/158Met (rs4680), and haplotypes rs737865-rs4680-rs165599 in the Catechol-O-methyltransferase gene (COMT) have been extensively examined for association to schizophrenia; however, results of replication studies have been inconsistent. The aim of this study was to comprehensively evaluate the genetic risk of COMT for schizophrenia. First, we performed a mutation scan to detect the existence of potent functional variants in the 5'-flanking and exon regions. Second, we conducted a gene-based case-control study between tagging single nucleotide polymorphisms (SNPs) in COMT [19 SNPs including six possible functional SNPs (rs2075507, rs737865, rs4680, rs165599, rs165849)] and schizophrenia in large Japanese samples (schizophrenics 1118, controls 1100). Lastly, we carried out a meta-analysis of 5 functional SNPs and haplotypes (rs737865-rs4680-rs165599). No novel functional variant was detected in the mutation scan. There is no association between these tagging SNPs in COMT and Japanese schizophrenia. In this updated meta-analysis, no evidence was found for an association between Val108/158Met polymorphisms, rs6267, rs165599, and haplotypes (rs7378655-rs4680-rs165599) and schizophrenia, although rs2075507 and rs737865 showed trends for significance in allele-wise analyses (P=0.039 in a multiplicative model, P=0.025 in a recessive model for rs2075507, P=0.018 in a dominant model for rs737865, uncorrected). This significance did not remain, however, after correcting the P-values using a false discovery rate controlling procedure. Our results suggest that the COMT is unlikely to contribute to susceptibility to schizophrenia.

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.

Systematic linkage disequilibrium (LD) mapping of 8p12-21 in the Icelandic population identified neuregulin 1 (NRG1) as a prime candidate gene for schizophrenia. However, results of replication studies have been inconsistent, and no large sample analyses have been reported. Therefore, we designed this study with the aim of assessing this putative association between schizophrenia and NRG1 (especially HAP(ICE) region and exon region) using a gene-based association approach in the Japanese population. This study was a two-stage association analysis with a different panel of samples, in which the significant association found in the first-set screening samples (1126 cases and 1022 controls) was further assessed in the confirmation samples (1262 cases and 1172 controls, and 166 trio samples). In the first-set scan, 60 SNPs (49 tagging SNPs from HapMap database, four SNPs from other papers, and seven SNPs detected in the mutation scan) were examined. One haplotype showed a significant association in the first-set screening samples (Global P-value=0.0244, uncorrected). However, we could not replicate this association in the following independent confirmation samples. Moreover, we could not find sufficient evidence for association of the haplotype identified as being significant in the first-set samples by imputing ungenotyped SNPs from HapMap database. These results indicate that the positionally and functionally attractive regions of NRG1 are unlikely to contribute to susceptibility to schizophrenia in the Japanese population. Moreover, the nature of our results support that two-stage analysis with large sample size is appropriate to examine the susceptibility genes for common diseases.

Introduction: Glutamate dysfunction has been implicated in the pathophysiology of schizophrenia. The metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors. GRM7, the gene that encodes mGluR7, is expressed in many regions of the human central nervous system. The GRM7 gene is located on human chromosome 3p26, which has been suggested by linkage analysis to contain a susceptibility locus for schizophrenia., Methods: We screened for mutations in all exons, exon/intron junctions, and promoter regions of the GRM7 gene in Japanese patients with schizophrenia and evaluated associations between the detected polymorphisms and schizophrenia. We examined the influence of one polymorphism associated with schizophrenia on the expression of GRM7 by dual-luciferase assay in transfected cells., Results: Twenty-five polymorphisms/mutations were detected in GRM7. Case-control analysis revealed a potential association of a synonymous polymorphism (371T/C, rs3749380) in exon 1 with schizophrenia in our case-control study of 2293 Japanese patients with schizophrenia and 2382 Japanese control subjects (allelic p=0.009). Dual-luciferase assay revealed suppression of transcription activity by exon 1 containing this polymorphism and a statistically significant difference in the promoter activity between the T and C alleles., Conclusions: Our results support the possible association of a GRM7 gene polymorphism with genetic susceptibility to schizophrenia.

Several lines of evidence, including genome-wide linkage scans and postmortem brain studies of patients with schizophrenia or bipolar disorder, have suggested that DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32 kDa), a key regulatory molecule in the dopaminergic signaling pathway, is involved in these disorders. After evaluating the linkage disequilibrium pattern of the gene encoding DARPP-32 (PPP1R1B; located on 17q12), we conducted association analyses of this gene with schizophrenia and bipolar disorder. Single-marker and haplotypic analyses of four single nucleotide polymorphisms (SNPs; rs879606, rs12601930, rs907094, and rs3764352) in a sample set (subjects with schizophrenia=384, subjects with bipolar disorder=318, control subjects=384) showed that PPP1R1B polymorphisms were not significantly associated with schizophrenia, whereas, even after Bonferroni corrections, significant associations with bipolar disorder were observed for rs12601930 (corrected genotypic p=0.00059) and rs907094 (corrected allelic p=0.040). We, however, could not confirm these results in a second independent sample set (subjects with bipolar disorder=366, control subjects=370). We now believe that the significant association observed with the first sample set was a result of copy number aberrations in the region surrounding these SNPs. Our findings suggest that PPP1R1B SNPs are unlikely to be related to the development of schizophrenia and bipolar disorder in the Japanese population.

Postmortem studies regarding schizophrenia revealed altered expression of genes related to gamma-amino butyric acid neurotransmission system. One of the most consistent findings is the reduced level of 67 kDa glutamic acid decarboxylase isoform (GAD(67)). Moreover, several studies reported positive associations between the GAD(67) gene (GAD1) and schizophrenia. These reasons, motivated us to carry out replication study regarding association between GAD1 (fourteen tagging SNPs) and schizophrenia in Japanese population (562 schizophrenic patients and 470 controls). However we couldn't confirm significant association that had been previously reported. Considering size of our sample and strategy that corresponds well with the approaches used in gene-based association analysis, our conclusion is that GAD1 does not play a major role in schizophrenia in Japanese population.

Several lines of evidence suggest that disturbance of myelin-related genes is associated with the etiology of schizophrenia. Recently, the 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) gene and the oligodendrocyte lineage transcription factor 2 (OLIG2) gene were reported to be related to the development of schizophrenia, based on the results of genetic association and microarray studies. In the present study, no significant association with schizophrenia was observed by single-marker or haplotype analysis for 6 tag SNPs of these genes (759 cases, 757 controls). These findings suggest that CNP and OLIG2 are unlikely to be related to the development of 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.

Several investigations suggest that complexin may be a schizophrenia-susceptibility factor. We conducted a genetic association analysis between complexin genes (CPLX1 and CPLX2) and schizophrenia in Japanese patients (377 cases and 341 controls). Ten and eleven haplotype-tagging (ht)SNPs in CPLX1 and CPLX2, respectively, were selected. Only one htSNP (rs930047 in CPLX2) in allele-wise analysis showed significance, and even this disappeared with an increased sample size (563 cases and 519 controls: P = .757). Haplotype-wise analysis showed a weak association with a combination of htSNPs in CPLX2 (P = .0424), but this may be a result of type I error due to multiple testing. Our results suggest that complexin genes do not play a major role in schizophrenia in Japanese patients.

Recent study of linkage disequilibrium mapping showed one of the trace amine receptor (TRAR) genes, TRAR4, was associated with schizophrenia. We conducted a replication study of TRAR4 with schizophrenia in Japanese patients. We used two large independent sets of samples in a first-set analysis (cases=405, controls=401) and second-set analysis (cases=503, controls=440). In the first-set analysis, one Marker (Marker5) showed a significant association, but this significance was not seen in the second-set analysis. Our results indicate that TRAR4 may not play a major role in Japanese schizophrenia patients, and that it is important to examine the possibility of false positives in genetic association analysis.