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Cognitive impairments are a core feature in patients with schizophrenia. These deficits could serve as effective tools for understanding the genetic architecture of schizophrenia. This study investigated whether genetic variants associated with cognitive impairments aggregate in functional gene networks related to the pathogenesis of schizophrenia. Here, genome-wide association studies (GWAS) of a range of cognitive phenotypes relevant to schizophrenia were performed in 411 healthy subjects. We attempted to replicate the GWAS data using 257 patients with schizophrenia and performed a meta-analysis of the GWAS findings and the replicated results. Because gene networks, rather than a single gene or genetic variant, may be strongly associated with the susceptibility to schizophrenia and cognitive impairments, gene-network analysis for genes in close proximity to the replicated variants was performed. We observed nominal associations between 3054 variants and cognitive phenotypes at a threshold of P < 1.0 × 10(-) (4). Of the 3054 variants, the associations of 191 variants were replicated in the replication samples (P < .05). However, no variants achieved genome-wide significance in a meta-analysis (P > 5.0 × 10(-) (8)). Additionally, 115 of 191 replicated single nucleotide polymorphisms (SNPs) have genes located within 10 kb of the SNPs (60.2%). These variants were moderately associated with cognitive phenotypes that ranged from P = 2.50 × 10(-) (5) to P = 9.40 × 10(-) (8). The genes located within 10 kb from the replicated SNPs were significantly grouped in terms of glutamate receptor activity (false discovery rate (FDR) q = 4.49 × 10(-) (17)) and the immune system related to major histocompatibility complex class I (FDR q = 8.76 × 10(-) (11)) networks. Our findings demonstrate that genetic variants related to cognitive trait impairment in schizophrenia are involved in the N-methyl-d-aspartate glutamate network., (© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: Genome-wide significant associations of schizophrenia with eight SNPs in the CNNM2, MIR137, PCGEM1, TRIM26, CSMD1, MMP16, NT5C2 and CCDC68 genes have been identified in a recent mega-analysis of genome-wide association studies. To date, the role of these SNPs on gray matter (GM) volumes remains unclear., Methods: After performing quality control for minor-allele frequency > 5% using a JPT HapMap sample and our sample, a genotyping call rate > 95% and Hardy-Weinberg equilibrium testing (p > 0.01), five of eight SNPs were eligible for analysis. We used a comprehensive voxel-based morphometry (VBM) technique to investigate the effects of these five SNPs on GM volumes between major-allele homozygotes and minor-allele carriers in Japanese patients with schizophrenia (n = 173) and healthy subjects (n = 449)., Results: The rs7914558 risk variant at CNNM2 was associated with voxel-based GM volumes in the bilateral inferior frontal gyri (right T = 4.96, p = 0.0088, left T = 4.66, p = 0.031). These peak voxels, which were affected by the variant, existed in the orbital region of the inferior frontal gyri. Individuals with the risk G/G genotype of rs7914558 had smaller GM volumes in the bilateral inferior frontal gyri than carriers of the non-risk A-allele. Although several effects of the genotype and the genotype-diagnosis interaction of other SNPs on GM volumes were observed in the exploratory VBM analyses, these effects did not remain after the FWE-correction for multiple tests (p > 0.05)., Conclusions: Our findings suggest that the genetic variant in the CNNM2 gene could be implicated in the pathogenesis of schizophrenia through the GM volumetric vulnerability of the orbital regions in the inferior frontal gyri.

Genome-wide association studies have reported an association between schizophrenia and rs12807809 of the neurogranin (NRGN) gene. We have recently found that an rs12807809-rs12278912 haplotype of the gene is associated with schizophrenia in a Japanese population and that the NRGN expression of the high-risk TG haplotype is lower than that of the protective TA haplotype in immortalized lymphoblasts. In this study, we investigated the influences of neurogranin genotypes (rs12807809 and rs12278912), haplotypes and diplotypes and genetic variant-diagnosis interactions on intellectual ability in 414 Japanese patients with schizophrenia and healthy subjects. We detected possible effects of the genome-wide screen-supported rs12807809, haplotypes, diplotypes and their genetic variant-diagnosis interactions on intellectual abilities at the threshold level of P<0.05. After applying Bonferroni correction for 13 genotype measures and setting P-values for significance (P<0.0039; 0.05/13), three effects remained significant: the rs12807809-rs12278912 diplotype-diagnosis interactions on performance intelligence quotient (CG/CG: P=3.9 × 10(-13); TA/TA: P=1.1 × 10(-7)) and TA/TA diplotype on performance intelligence quotient in patients with schizophrenia (P=8.2 × 10(-8)) remained significant. The intellectual abilities of the high-risk TG/TG diplotype of the neurogranin gene were lower compared to those with the non-risk TA/TA diplotype. Our findings suggest that the genetic risk variant in the neurogranin gene may be related to reduced intellectual ability.

Objectives: A genetic variant (rs3800779; M30) in the KCNH2 gene has been associated with schizophrenia, a lower intelligence quotient (IQ) and processing speed scores, altered brain functions and increased KCNH2-3.1. mRNA levels in the hippocampus. The aims of this study were to investigate whether the KCNH2 polymorphism is associated with schizophrenia-related neurocognitive deficits and to confirm the association between the variant and schizophrenia., Methods: The effects of the risk genotype on IQ and seven neurocognitive batteries were examined by the analysis of covariance in 191 healthy subjects. We performed a meta-analysis of the association between M30 and schizophrenia using five independent ethnic groups (1,720 cases; 2,418 controls)., Results: Consistent with the previous study, we provided evidence that subjects with the risk T carriers had significantly lower IQ scores than those with the G/G genotype (P = 0.048). Of the seven neurocognitive batteries, subjects with the risk genotype demonstrated lower performances on attention/vigilance (P = 0.0079) and working memory (P = 0.0066) relative to subjects with the G/G genotype. Meta-analysis demonstrated evidence for an association between M30 and schizophrenia without showing heterogeneity across studies (odds ratio = 1.18; P = 0.0017)., Conclusions: These data suggest that the KCNH2 polymorphism could be associated with schizophrenia-related neuropsychological deficits and the risk of developing schizophrenia.

Objectives: A meta-analysis of the associations between genetic variants in the AKT1 gene and schizophrenia found that a single nucleotide polymorphism (SNP5; rs2494732) was associated with schizophrenia in Asian populations., Methods: In this study, we investigated the effects of this SNP on memory and attentional performance and brain structure using magnetic resonance imaging in a Japanese population (117 patients with schizophrenia and 189 healthy subjects)., Results: The memory performance, particularly attention/concentration score, measured by the Wechsler Memory Scale-Revised in A carriers of SNP5, which was found to be enriched in patients with schizophrenia, was lower than that in individuals with the G/G genotype. We confirmed the association of the SNP with attentional performance using the Continuous Performance Test, which assessed sustained attention and vigilance of attentional function. Patients with A allele demonstrated lower attentional performance than patients with the G/G genotype. Patients with the A allele had smaller gray matter volumes in the right inferior parietal lobule related to attentional processes and in the frontostriatal region related to different SNPs in AKT1 than patients with the G/G genotype., Conclusions: Our results suggest that a genetic variant of AKT1 might be associated with attentional deficits and brain morphological vulnerability in patients with schizophrenia.

Personality is considered to be an important aspect of schizophrenia, primarily because it may influence patients' symptoms and social functioning. Specific personality traits are related to schizophrenia. The Temperament and Character Inventory (TCI) measures four traits of temperament - novelty seeking (NS), harm avoidance (HA), reward dependence (RD) and persistence (PS) - and three traits of character - self-directedness (SD), cooperativeness (CO) and self-transcendence (ST). We investigated associations between schizophrenia and personality traits using the TCI in a Japanese case-control sample (99 patients and 179 controls). Patients with schizophrenia scored higher on HA and ST and lower on NS, RD, SD and CO compared with controls in our case-control sample. We then performed a meta-analysis of samples from the published literature and our sample (384 patients and 656 controls). We found no evidence of heterogeneity among studies, except for NS in the overall population. Possible associations between personality traits (HA, RD, PS, SD, CO and ST) and schizophrenia were revealed. The effect sizes (Hedges' g) of the temperament traits were 0.98 for HA, -0.43 for RD and -0.23 for PS, and those of the character traits were -0.96 for SD, -0.47 for CO and 0.61 for ST. These findings suggest that patients with schizophrenia have a unique temperament and character profile compared with the general population., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2012 Wiley Periodicals, Inc.)

The chitinase 3-like 1 (CHI3L1) gene, a cellular survival factor against several environmental and psychosocial stresses, has been sown to be more highly expressed in the hippocampus and prefrontal cortex of patients with schizophrenia than unaffected individuals. We recently reported a significant association between schizophrenia and SNP rs4950928, which is located in the promoter region of the CHI3L1 gene, in a Japanese population. The G-allele at this SNP in the gene has been associated with higher transcriptional activity in a luciferase reporter assay and with higher mRNA levels in the peripheral blood cells of patients with schizophrenia. We investigated the impact of the CHI3L1 polymorphism rs4950928 on serum YKL-40 levels, the protein product of CHI3L1. We found that individuals with the G-allele, who were more prevalent among patients with schizophrenia, had significantly higher serum YKL-40 levels (p=0.043). Personality traits are considered to be an important aspect of schizophrenia primarily because they may influence symptoms and social functioning. Personality trait analyses using the temperament and character inventory (TCI) indicated that schizophrenic patients have a unique personality profile that appears to be present across cultures. We hypothesized that higher serum YKL-40 levels are associated with personality trait in patients with schizophrenia. Thus, we next examined the impact of the risk CHI3L1 polymorphism on personality traits using the TCI. We found that individuals with the G-allele had significantly higher self-transcendence scores (p=0.0054). These findings suggest possible associations between the SNP in the CHI3L1 gene, the risk for schizophrenia, and higher serum YKL-40 levels and personality traits in a Japanese population., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: The rs12807809 single-nucleotide polymorphism in NRGN is a genetic risk variant with genome-wide significance for schizophrenia. The frequency of the T allele of rs12807809 is higher in individuals with schizophrenia than in those without the disorder. Reduced immunoreactivity of NRGN, which is expressed exclusively in the brain, has been observed in Brodmann areas (BA) 9 and 32 of the prefrontal cortex in postmortem brains from patients with schizophrenia compared with those in controls., Methods: Genotype effects of rs12807809 were investigated on gray matter (GM) and white matter (WM) volumes using magnetic resonance imaging (MRI) with a voxel-based morphometry (VBM) technique in a sample of 99 Japanese patients with schizophrenia and 263 healthy controls., Results: Although significant genotype-diagnosis interaction either on GM or WM volume was not observed, there was a trend of genotype-diagnosis interaction on GM volume in the left anterior cingulate cortex (ACC). Thus, the effects of NRGN genotype on GM volume of patients with schizophrenia and healthy controls were separately investigated. In patients with schizophrenia, carriers of the risk T allele had a smaller GM volume in the left ACC (BA32) than did carriers of the non-risk C allele. Significant genotype effect on other regions of the GM or WM was not observed for either the patients or controls., Conclusions: Our findings suggest that the genome-wide associated genetic risk variant in the NRGN gene may be related to a small GM volume in the ACC in the left hemisphere in patients with schizophrenia.

Background: Hypofunction of the glutamate N-Methyl-d-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. p250GAP is a brain-enriched NMDA receptor-interacting RhoGAP. p250GAP is involved in spine morphology, and spine morphology has been shown to be altered in the post-mortem brains of patients with schizophrenia. Schizotypal personality disorder has a strong familial relationship with schizophrenia. Several susceptibility genes for schizophrenia have been related to schizotypal traits., Methods: We first investigated the association of eight linkage disequilibrium-tagging single-nucleotide polymorphisms (SNPs) that cover the p250GAP gene with schizophrenia in a Japanese sample of 431 schizophrenia patients and 572 controls. We then investigated the impact of the risk genetic variant in the p250GAP gene on schizotypal personality traits in 180 healthy subjects using the Schizotypal Personality Questionnaire., Results: We found a significant difference in genotype frequency between the patients and the controls in rs2298599 (χ(2) = 17.6, p = 0.00015). The minor A/A genotype frequency of rs2298599 was higher in the patients (18%) than in the controls (9%) (χ(2) = 15.5, p = 0.000083). Moreover, we found that subjects with the rs2298599 risk A/A genotype, compared with G allele carriers, had higher scores of schizotypal traits (F(1,178) = 4.08, p = 0.045), particularly the interpersonal factor (F(1,178) = 5.85, p = 0.017)., Discussion: These results suggest that a genetic variation in the p250GAP gene might increase susceptibility not only for schizophrenia but also for schizotypal personality traits. We concluded that the p250GAP gene might be a new candidate gene for susceptibility to schizophrenia.

Alpha rhythm is one of the most prominent electromagnetic changes in the brain, and electroencephalography (EEG) alpha reactivity disturbance may sometimes represent an early sign of cerebral dysfunction. Although magnetoencephalography (MEG) has a better spatial resolution than EEG, it has not extensively been used to explore alpha-power change deficits in schizophrenia as a possible neurophysiological marker of the disease. The purpose of this study was to use MEG to identify abnormalities in alpha synchronization induced by eye-closing in schizophrenia patients compared to healthy controls, and to investigate whether alpha reactivity deficits correlate with clinical features of the disorder. MEG data were recorded in 22 schizophrenia patients and 20 age- and gender-matched controls during eyes-open/eyes-closed resting states. Cortical sources of event-related synchronization (ERS) were estimated using multiple source beamformer, and BrainVoyager was used for statistic group analysis. A significant decrease in ERS in the upper alpha band (10-13 Hz) was found in the left posterior temporal region in schizophrenia patients relative to controls, and this activity showed correlation with visual memory scores. This upper alpha ERS deficit may indicate left temporal dysfunction and visual-information processing impairment in schizophrenia, and upon further confirmation it might represent a neurophysiological state marker of the disorder., (Copyright © 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

The pathogenesis of schizophrenia is thought to involve aberrant immune and inflammatory responses. Nuclear factor kappa B (NF-κB) has important roles in the immune and inflammatory responses. The v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) gene encodes the major component of the NF-κB complex. We genotyped four single-nucleotide polymorphisms (SNPs) in the RELA gene and performed a gene-based association analysis using 1224 patients with schizophrenia and 1663 controls. We found significant associations of three SNPs (rs11820062: p=0.00011, rs2306365: p=0.0031, and rs7119750: p=0.0080) with schizophrenia and stronger evidence for association in a multi-marker sliding window haplotype analysis (the lowest p=0.00006). The association between this gene and schizophrenia was evident in male subjects but not in female subjects, when separately analyzed by gender. In silico genotype-gene expression analysis using web database and the WGAViewer software revealed that these three schizophrenia-associated SNPs might be related to RELA mRNA expression in immortalized B-lymphocytes. In silico analysis also suggested the putative promoter SNP, rs11820062, might disrupt the consensus transcription factor binding sequence of the androgen receptor. The impact of four RELA polymorphisms on pre-pulse inhibition (PPI) was investigated in 53 patients with schizophrenia. We provided evidence that at risk genotypes of three SNPs were associated with deficits in PPI; however, there was no effect of the one non-risk SNP on PPI. These findings suggest that variants of the RELA gene are associated with risk for schizophrenia and PPI deficits in a Japanese population.

Several studies have identified the possible involvement of sigma non-opioid intracellular receptor 1 (SIGMAR1) in the pathogenesis of schizophrenia. The Gln2Pro polymorphism in the SIGMAR1 gene has been extensively examined for an association with schizophrenia. However, findings across multiple studies have been inconsistent. We performed a meta-analysis of the association between the functional Gln2Pro polymorphism and schizophrenia using combined samples (1254 patients with schizophrenia and 1574 healthy controls) from previously published studies and our own additional samples (478 patients and 631 controls). We then used near-infrared spectroscopy to analyze the effects of the Gln2Pro genotype, a schizophrenia diagnosis and the interaction between genotype and diagnosis on activation of the prefrontal cortex (PFC) during a verbal fluency task (127 patients and 216 controls). The meta-analysis provided evidence of an association between Gln2Pro and schizophrenia without heterogeneity across studies (odds ratio=1.12, p=0.047). Consistent with previous studies, patients with schizophrenia showed lower bilateral activation of the PFC when compared to controls (p<0.05). We provide evidence that Pro carriers, who are more common among patients with schizophrenia, have significantly lower activation of the right PFC compared to subjects with the Gln/Gln genotype (p=0.013). These data suggest that the SIGMAR1 polymorphism is associated with an increased risk of schizophrenia and differential activation of the PFC., (Copyright © 2011 Elsevier Inc. 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.)

A recent genome-wide association study showed that a variant (rs1344706) in the ZNF804A gene was associated with schizophrenia and bipolar disorder. Replication studies supported the evidence for association between this variant in the ZNF804A gene and schizophrenia and that this variant is the most likely susceptibility variant. Subsequent functional magnetic resonance imaging studies in healthy subjects demonstrated the association of the high-risk ZNF804A variant with neural activation during a memory task and a theory of mind task. As these cognitive performances are disturbed in patients with schizophrenia, this gene may play a role in cognitive dysfunction in schizophrenia. The aim of the current study was to investigate the potential relationship between this ZNF804A polymorphism and memory function. The effects of the high-risk ZNF804A genotype, diagnosis, and genotype-diagnosis interaction on verbal memory, visual memory (VisM), attention/concentration, and delayed recall (measured by the Wechsler Memory Scale-Revised) were analyzed by two-way analysis of covariance in 113 patients with schizophrenia and 184 healthy subjects. Consistent with previous studies, patients with schizophrenia exhibited poorer performance on all indices as compared to healthy control subjects (P < 0.001). A significant ZNF804A genotype-diagnosis interaction was found for VisM performance (P = 0.0012). Patients with the high-risk T/T genotype scored significantly lower on VisM than G carriers did (P = 0.018). In contrast, there was no genotype effect for any index in the healthy control subjects (P > 0.05). Our data suggest that rs1344706 may be related to memory dysfunction in schizophrenia. © 2010 Wiley-Liss, Inc., (Copyright © 2010 Wiley-Liss, Inc.)

While psychiatric disorders such as schizophrenia are largely diagnosed on symptomatology, several studies have attempted to determine which biomarkers can discriminate schizophrenia patients from non-patients with schizophrenia. The objective of this study is to assess whether near-infrared spectroscopy (NIRS) measurement can distinguish schizophrenia patients from healthy subjects. Sixty patients with schizophrenia and sixty age- and gender-matched healthy controls were divided into two sequential groups. The concentration change in oxygenated hemoglobin (Delta[oxy-Hb]) was measured in the bilateral prefrontal areas (Fp1-F7 and Fp2-F8) during the Verbal Fluency Test (VFT) letter version and category version, Tower of Hanoi (TOH), Sternberg's (SBT) and Stroop Tasks. In the first group, schizophrenia patients showed poorer task performance on all tasks and less prefrontal cortex activation during all but the Stroop Task compared to healthy subjects. In the second group, schizophrenia patients showed poorer task performance and less prefrontal cortex activation during VFTs and TOH tasks than healthy subjects. We then performed discriminant analysis by a stepwise method using Delta[oxy-Hb] and task performance measures as independent variables. The discriminant analysis in the first group included task performance of TOH, VFT letter and VFT category and Delta[oxy-Hb] of VFT letter. As a result, 88.3% of the participants were correctly classified as being schizophrenic or healthy subjects in the first analysis. The discriminant function derived from the first group correctly assigned 75% of the subjects in the second group. Our findings suggest that NIRS measurement could be applied to differentiate patients with schizophrenia from healthy subjects., ((c) 2009 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.)

Schizophrenia is a common polygenic disease in distinct populations, while spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominant neurodegenerative disorder. Both diseases involve psychotic symptoms. SCA17 is caused by an expanded polyglutamine tract in the TATA box-binding protein (TBP) gene. In the present study, we investigated the association between schizophrenia and CAG repeat length in common TBP alleles with fewer than 42 CAG repeats in a Japanese population (326 patients with schizophrenia and 116 healthy controls). We found that higher frequency of alleles with greater than 35 CAG repeats in patients with schizophrenia compared with that in controls (p = 0.042). We also examined the correlation between CAG repeats length and age at onset of schizophrenia. We observed a negative correlation between the number of CAG repeats in the chromosome with longer CAG repeats out of two chromosomes and age at onset of schizophrenia (p = 0.020). We further provided evidence that TBP genotypes with greater than 35 CAG repeats, which were enriched in patients with schizophrenia, were significantly associated with hypoactivation of the prefrontal cortex measured by near-infrared spectroscopy during the tower of Hanoi, a task of executive function (right PFC; p = 0.015, left PFC; p = 0.010). These findings suggest possible associations of the genetic variations of the TBP gene with risk for schizophrenia, age at onset and prefrontal function.

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.

In schizophrenia, dysfunction of the prefrontal cortex (PFC), regarded as a core feature of the disease, has been investigated by different neuroimaging methods. Near infrared spectroscopy (NIRS), a novel neurophysiological method, is being increasingly used in the investigation of frontal dysfunction in schizophrenia. However, NIRS measurements during multiple frontal activation tasks have been rarely reported. The purpose of this study was to compare hemodynamic changes in the PFC between patients with schizophrenia and healthy controls during four different types of frontal lobe tasks using a 2-channel NIRS system. Thirty patients with schizophrenia and thirty age- and gender-matched healthy controls were enrolled in this study. In both groups, changes in oxygenated hemoglobin concentration (Delta[oxyHb]) at the bilateral forehead were measured during Verbal fluency test letter version (VFT-letter), VFT category version, Tower of Hanoi (TOH), the Sternberg and Stroop tasks. Regarding Delta[oxyHb] in PFC, a diagnosis group effect was found for VFT-letter and TOH. Significant negative correlation was found between left Delta[oxyHb] during TOH and negative and cognitive symptom scores in schizophrenia patients. Right Delta[oxyHb] during TOH also showed significant negative correlation with cognitive symptoms scores. No significant correlation between Delta[oxyHb] and clinical characteristics were observed during VFT-letter. These findings suggest that among a battery of frontal lobe tasks administered to schizophrenia patients, VFT-letter and TOH are more sensitive to detect PFC activation, as indicated by Delta[oxyHb] using a 2-channel NIRS. Taken together, these findings and those of previous neuroimaging studies suggest that VFT-letter and TOH might represent possible candidate physiological markers of prefrontal dysfunction in schizophrenia, though extensive testing in clinical settings will be necessary.