The regulation of soluble receptor for AGEs contributes to carbonyl stress in schizophrenia.

Our previous study showed that enhanced carbonyl stress is closely related to schizophrenia. The endogenous secretory receptor for advanced glycation end-products (esRAGE) is a splice variant of the AGER gene and is one of the soluble forms of RAGE. esRAGE is considered to be a key molecule for alleviating the burden of carbonyl stress by entrapping advanced glycation end-products (AGEs). In the current study, we conducted genetic association analyses focusing on AGER, in which we compared 212 schizophrenic patients to 214 control subjects. We also compared esRAGE levels among a subgroup of 104 patients and 89 controls and further carried out measurements of total circulating soluble RAGE (sRAGE) in 25 patients and 49 healthy subjects. Although the genetic association study yielded inconclusive results, multiple regression analysis indicated that a specific haplotype composed of rs17846798, rs2071288, and a 63 bp deletion, which were in perfect linkage disequilibrium (r2 = 1), and rs2070600 (Gly82Ser) were significantly associated with a marked decrease in serum esRAGE levels. Furthermore, compared to healthy subjects, schizophrenia showed significantly lower esRAGE (p = 0.007) and sRAGE (p = 0.03) levels, respectively. This is the first study to show that serum esRAGE levels are regulated by a newly identified specific haplotype in AGER and that a subpopulation of schizophrenic patients are more vulnerable to carbonyl stress.

Paliperidone Induced Hypoglycemia by Increasing Insulin Secretion.

We report the case of a 41-year-old woman with schizophrenia who developed persistent hypoglycemia following paliperidone administration. After discontinuing paliperidone, the hypoglycemia resolved, but symptoms of diabetes emerged. Therefore, it appears that the hypoglycemia induced by paliperidone may mask symptoms of diabetes. Paliperidone may induce hypoglycemia by increasing insulin secretion. This report could help elucidate the relationship between atypical antipsychotics and glucose metabolism.

Relation between remission status and attention in patients with schizophrenia.

AIM: Patients with schizophrenia in remission have shown significantly higher levels of neurocognitive function than patients not in remission. However, previous studies have mainly examined the association between neurocognitive function and the remission status of schizophrenia without considering the time component of the definition for remission using cross-sectional methods. The purpose of this study was to investigate the relations between remission status with considering time components and three cognitive functions of intellectual ability, memory and attention, which were examined before fulfilling the remission criteria, using longitudinal methods. METHODS: We assessed the remission status using the Positive and Negative Syndrome Scale (PANSS) on the same patients twice: at recruitment and at 6 months after the first PANSS assessment. Cognitive tests were performed within 3 months after recruitment. At recruitment, 337 patients were enrolled. Of the patients, 63 patients were followed up and completedthe first and second PANSS assessments and three cognitive tests at the end of study. RESULTS: Of the patients, 33 patients fulfilled the remission criteria, while 30 patients did not fulfill the criteria. Patients in remission showed significantly higher levels of 2-digit (P = 0.020) and 3-digit (P = 0.015) Continuous Performance Test scores, attention/concentration in the Wechsler Memory Scale-Revised (P = 0.034) and processing speeds in the Wechsler Adult Intelligence Scale-III (P = 0.047) than patients not in remission. Additionally, these cognitive scores were positively correlated with each other (P < 0.05). CONCLUSION: Our findings suggest that patients who achieve remission may demonstrate a pre-existing higher level of attention than patients who do not achieve remission.

Influence of the NRGN gene on intellectual ability in schizophrenia.

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.

The regulation of gene expression involved in TGF-ß signaling by ZNF804A, a risk gene for schizophrenia.

ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. However, the biological functions of ZNF804A are not entirely understood. To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). Furthermore, we confirmed that the expression of ANKRD1, PIK3AP1, INHBE and DDIT3 at the protein level was significantly increased by ZNF804A-overexpression. This is the first report to identify genes whose protein expressions are regulated by ZNF804A. ANKRD1, PIK3AP1, INHBE and DDIT3 are related to transforming growth factor-ß (TGF-ß) signaling, which plays a crucial role in cell growth and differentiation. On the other hand, recent studies have reported that TGF-ß signaling is associated with schizophrenia. These results provide basis for a more progressive investigation of ZNF804A contributions to the susceptibility or pathophysiology of schizophrenia.

Analysis of the VAV3 as candidate gene for schizophrenia: evidences from voxel-based morphometry and mutation screening.

In recently completed Japanese genome-wide association studies (GWAS) of schizophrenia (JPN_GWAS) one of the top association signals was detected in the region of VAV3, a gene that maps to the chromosome 1p13.3. In order to complement JPN_GWAS findings, we tested the association of rs1410403 with brain structure in healthy individuals and schizophrenic patients and performed exon resequencing of VAV3. We performed voxel-based morphometry (VBM) and mutation screening of VAV3. Four independent samples were used in the present study: (1) for VBM analysis, we used case-control sample comprising 100 patients with schizophrenia and 264 healthy controls, (2) mutation analysis was performed on a total of 321 patients suffering from schizophrenia, and 2 case-control samples (3) 729 unrelated patients with schizophrenia and 564 healthy comparison subjects, and (4) sample comprising 1511 cases and 1517 healthy comparison subjects and were used for genetic association analysis of novel coding variants with schizophrenia. The VBM analysis suggests that rs1410403 might affect the volume of the left superior and middle temporal gyri (P=.011 and P=.013, respectively), which were reduced in patients with schizophrenia compared with healthy subjects. Moreover, 4 rare novel missense variants were detected. The mutations were followed-up in large independent sample, and one of the novel variants (Glu741Gly) was associated with schizophrenia (P=.02). These findings demonstrate that VAV3 can be seen as novel candidate gene for schizophrenia in which both rare and common variants may be related to increased genetic risk for schizophrenia in Japanese population.

The AKT1 gene is associated with attention and brain morphology in 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.

The KCNH2 gene is associated with neurocognition and the risk of schizophrenia.

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.

[How far have biomarkers in psychiatry advanced?].

A biomarker is defined as a biological indicator of normal or pathological processes, and a pharmacological response to a therapeutic intervention, whose characteristics can be measured and evaluated objectively. In medicine and health, biomarkers can be paraphrased as diagnostic methods objectively conducive to treatment. Here, we discuss biomarkers of schizophrenia as a representative mental illness, whose research has advanced compared with that of other disorders. Schizophrenia is a syndrome with a typical course and symptoms. Its pathophysiology and pathogenesis have not been elucidated (medically however, its underlying biological mechanisms are assumed to be present. That is, in biomarker discovery, when the pathogenesis and cause are elucidated, the patient group would not consiste of schizophrenia but, it is a new disease of "x x disease." For example, neurosyphilis is exogenous psychosis, by finding a biomarker of syphilis spirochete, a new disease concept of neurosyphilis could be distinguished from the schizophrenia). In this way, it can be said that biomarker research is essential for the development of new diagnostic and treatment methods for mental illness. There are several biomarker research methods such as genetic analysis, biological sample analysis, cognitive analysis, neurophysiology, neuroimaging, animal models, and post-mortem brain analysis. Further, studies have been made, however, biomarkers that can explain all of schizophrenia has not been found yet. As schizophrenia is assumed to be a heterogenous syndrome, it is believed that the etiology varies. Thus, there is a possibility that targeting schizophrenia as a whole will make it difficulty to find biomarkers for patients with schizophrenia. It is considered that appropriate subgroup analysis is needed. In order to overcome it, amount-of-resources strategy to find patients by using large of samples has been made mainly in Europe and the United States. In Japan, we have used sub-group analysis strategy to elaborate this issue such as the use of an intermediate phenotype. It is not possible to research a similar strategy, because of the limited funds and manpower in Japan compared to U. S. and Europe. As nationwide research organizations in Japan, such as IGC (Imaging genetics consortium), combination analysis of genetics and neuroimaging and COCORO (Cognitive genetics collaborative research organization), combination analysis of genetics and cognitive function, have been established, the development of biomarkers for mental illnesses is expected in the near future.

The p250GAP gene is associated with risk for schizophrenia and schizotypal personality traits.

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.

Personality traits and schizophrenia: evidence from a case-control study and meta-analysis.

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.

Functional genetic variation at the NRGN gene and schizophrenia: evidence from a gene-based case-control study and gene expression analysis.

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.

A promoter variant in the chitinase 3-like 1 gene is associated with serum YKL-40 level and personality trait.

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.

Impact of the genome wide supported NRGN gene on anterior cingulate morphology in schizophrenia.

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.

Relationship of prepulse inhibition to temperament and character in healthy Japanese subjects.

Prepulse inhibition (PPI) of acoustic startle reflex (ASR) and personality, such as temperament and character, are considered candidate endophenotypes of schizophrenia. Gene polymorphism studies have provided evidence that both PPI and self-transcendence (ST) are polygenetic traits that involve several neurotransmitters, including the serotonin and dopamine signaling pathways. However, the relationship between PPI and temperament/character has not been properly addressed to date. Here, we investigated the link between PPI and temperament/character in 169 healthy Japanese subjects. A human startle response monitoring system was used to deliver acoustic startle stimuli and to record and score the electromyographic activity of the orbicularis oculi muscle. PPI was evaluated at signal-to-noise ratios (SnRs: intensity difference between background noise and prepulse) of +12, +16, and +20 dB. The lead interval (from prepulse onset to pulse onset) was 120 ms, and Temperament and Character Inventory was used in both groups. Significant correlations at SnR of +16 and +20 dB to ST were identified. Our results suggest that impaired sensorimotor gating, evaluated as lower PPI of ASR, of healthy subjects is correlated with self transcendence, the character which is closely related with schizophrenia and schizotypy.

Different characteristics of cognitive impairment in elderly schizophrenia and Alzheimer's disease in the mild cognitive impairment stage.

We compared indices of the revised version of the Wechsler Memory Scale (WMS-R) and scaled scores of the five subtests of the revised version of the Wechsler Adult Intelligence Scale (WAIS-R) in 30 elderly schizophrenia (ES) patients and 25 Alzheimer's disease (AD) patients in the amnestic mild cognitive impairment (aMCI) stage (AD-aMCI). In the WMS-R, attention/concentration was rated lower and delayed recall was rated higher in ES than in AD-aMCI, although general memory was comparable in the two groups. In WAIS-R, digit symbol substitution, similarity, picture completion, and block design scores were significantly lower in ES than in AD-aMCI, but the information scores were comparable between the two groups. Delayed recall and forgetfulness were less impaired, and attention, working memory and executive function were more impaired in ES than in AD-aMCI. These results should help clinicians to distinguish ES combined with AD-aMCI from ES alone.