PICK1 is not a susceptibility gene for schizophrenia in a Japanese population: Association study in a large case–control population

The protein interacting with C-kinase 1 (PICK1) has been implicated in thesusceptibility to schizophrenia. PICK1 interacts with enzymes and receptors that playroles in the pathogenesis of schizophrenia via glutamatergic dysfunction. Recently, twostudies reported associations between schizophrenia and two PICK1 genepolymorphisms, rs3952 in Chinese and Japanese populations and rs2076369 in aJapanese population. We attempted to confirm these associations in a case-control studyof 1765 Japanese patients with schizophrenia and 1851 Japanese control subjects.Neither polymorphism was associated with schizophrenia (rs3952, p = 0.755;rs2076369, p = 0.997). A haplotype block with these polymorphisms spanning the 5’region of the PICK1 gene showed high linkage disequilibrium in the Japanesepopulation (D’ = 0.98, r2 = 0.34); however, neither haplotype was significantlyassociated with schizophrenia. We conclude that the common haplotypes andpolymorphisms of the PICK1 gene identified thus far are unlikely to contribute togenetic susceptibility to schizophrenia in the Japanese population

No association between the sigma receptor type 1 gene and schizophrenia: results of analysis and meta-analysis of case-control studies

BACKGROUND: Several lines of evidence have supported possible roles of the sigma receptors in the etiology of schizophrenia and mechanisms of antipsychotic efficacy. An association study provided genetic evidence that the sigma receptor type 1 gene (SIGMAR1) was a possible susceptibility factor for schizophrenia, however, it was not replicated by a subsequent study. It is necessary to evaluate further the possibility that the SIGMAR1 gene is associated with susceptibility to schizophrenia. METHODS: A case-control association study between two polymorphisms of the SIGMAR1 gene, G-241T/C-240T and Gln2Pro, and schizophrenia in Japanese population, and meta-analysis including present and previous studies. RESULTS: There was no significant association of any allele or genotype of the polymorphisms with schizophrenia. Neither significant association was observed with hebephrenic or paranoid subtype of schizophrenia. Furthermore, a meta-analysis including the present and previous studies comprising 779 controls and 636 schizophrenics also revealed no significant association between the SIGMAR1 gene and schizophrenia. CONCLUSION: In view of this evidence, it is likely that the SIGMAR1 gene does not confer susceptibility to schizophrenia

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Association Study of Two Cannabinoid Receptor Genes, CNR1 and CNR2, with Methamphetamine Dependence

Several studies have suggested that the endocannabinoid system plays significant roles in the vulnerability to psychiatric disorders including drug abuse. To examine the possible association of the CNR1 and CNR2 genes, which encode cannabinoid receptors CB1 and CB2, with methamphetamine dependence, we investigated three single nucleotide polymorphisms (SNPs) (rs806379, rs1535255, rs2023239) in intron 2 of the CNR1 gene and a nonsynonymous SNP, Q63R, in the CNR2 gene. The study samples consisted of 223 patients with methamphetamine dependence and 292 age- and sex- matched controls. There were no significant differences between the patients and controls in genotypic or allelic distribution of any SNP of the CNR1 and CNR2 genes. We also analyzed the clinical features of methamphetamine dependence. Rs806379 of the CNR1 gene showed a significant association with the phenotype of latency of psychosis after the first consumption of methamphetamine. Patients with the T allele or T-positive genotypes (T/T or A/T) may develop a rapid onset of psychosis after methamphetamine abuse. The present study suggests a possibility that genetic variants of the CNR1 gene may produce a liability to the complication of psychotic state after abuse of methamphetamine; however, our findings need to be confirmed by future replications

The (CTG)n polymorphism in the NOTCH4 gene is not associated with schizophrenia in Japanese individuals

BACKGROUND: The human NOTCH4 gene is a candidate gene for schizophrenia due to its chromosomal location and neurobiological roles. In a British linkage study, NOTCH4 gene polymorphisms were highly associated with schizophrenia. In a Japanese case-control association study, however, these polymorphisms did not show significant associations with schizophrenia. We conducted a case-control study with Japanese subjects to explore an association between the triplet repeat polymorphism in the NOTCH4 gene and schizophrenia, including subtypes of schizophrenia, longitudinal disease course characteristics, and a positive family history for psychoses. METHODS: We examined the (CTG)n repeat polymorphism in the NOTCH4 gene among 100 healthy Japanese individuals and 102 patients with schizophrenia (22 paranoid, 38 disorganized, 29 residual, 64 episodic, 31 continuous, 42 with prominent negative symptoms, and 46 with positive family histories) using a polymerase chain reaction-based, single-strand conformational polymorphism analysis. RESULTS: Five different alleles consisting of 6, 9, 10, 11, and 13 repeats of CTG (Leu) in patients with schizophrenia, and 4 alleles consisting of 6, 9, 10, and 11 repeats in controls were found. No significant differences in genotype or allele frequencies of repeat numbers were found between controls and patients. In addition, there were no associations between the polymorphism and schizophrenia subtypes, longitudinal disease course characteristics, or positive family history of the patients. CONCLUSIONS: Our data suggest a lack of association between the NOTCH4 gene triplet repeat polymorphism and schizophrenia in Japanese individuals

Association Between 5HT1b Receptor Gene and Methamphetamine Dependence

Several lines of evidence implicate serotonergic dysfunction in diverse psychiatric disorders including anxiety, depression, and drug abuse. Mice with a knock-out of the 5HT1b receptor gene (HTR1B) displayed increased locomotor response to cocaine and elevated motivation to self-administer cocaine and alcohol. Previous genetic studies showed significant associations of HTR1B with alcohol dependence and substance abuse, but were followed by inconsistent results. We examined a case-control genetic association study of HTR1B with methamphetamine-dependence patients in a Japanese population. The subjects were 231 patients with methamphetamine dependence, 214 of whom had a co-morbidity of methamphetamine psychosis, and 248 age- and sex-matched healthy controls. The three single nucleotide polymorphisms (SNPs), rs130058 (A-165T), rs1228814 (A-700C) and rs1228814 (A+1180G) of HTR1B were genotyped. There was no significant difference in allelic and genotypic distributions of the SNPs between methamphetamine dependence and the control. Genetic associations of HTR1B were tested with several clinical phenotypes of methamphetamine dependence and/or psychosis, such as age at first abuse, duration of latency from the first abuse to onset of psychosis, prognosis of psychosis after therapy, and complication of spontaneous relapse of psychotic state. There was, however, no asscocation between any SNP and the clinical phenotypes. Haplotype analyses showed the three SNPs examined were within linkage disequilibrium, which implied that the three SNPs covered the whole HTR1B, and distribution of estimated haplotype frequency was not different between the groups. The present findings may indicate that HTR1B does not play a major role in individual susceptibility to methamphetamine dependence or development of methamphetamine-induced psychosis

Association of polymorphisms in the haplotype block spanning the alternatively spliced exons of the NTNG1 gene at 1p13.3 with schizophrenia in Japanese populations

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Role of Serine Racemase in Behavioral Sensitization in Mice after Repeated Administration of Methamphetamine

BACKGROUND: The N-methyl-D-aspartate (NMDA) receptors play a role in behavioral abnormalities observed after administration of the psychostimulant, methamphetamine (METH). Serine racemase (SRR) is an enzyme which synthesizes D-serine, an endogenous co-agonist of NMDA receptors. Using Srr knock-out (KO) mice, we investigated the role of SRR on METH-induced behavioral abnormalities in mice. METHODOLOGY/PRINCIPAL FINDINGS: Evaluations of behavior in acute hyperlocomotion, behavioral sensitization, and conditioned place preference (CPP) were performed. The role of SRR on the release of dopamine (DA) in the nucleus accumbens after administration of METH was examined using in vivo microdialysis technique. Additionally, phosphorylation levels of ERK1/2 proteins in the striatum, frontal cortex and hippocampus were examined using Western blot analysis. Acute hyperlocomotion after a single administration of METH (3 mg/kg) was comparable between wild-type (WT) and Srr-KO mice. However, repeated administration of METH (3 mg/kg/day, once daily for 5 days) resulted in behavioral sensitization in WT, but not Srr-KO mice. Pretreatment with D-serine (900 mg/kg, 30 min prior to each METH treatment) did not affect the development of behavioral sensitization after repeated METH administration. In the CPP paradigm, METH-induced rewarding effects were demonstrable in both WT and Srr-KO mice. In vivo microdialysis study showed that METH (1 mg/kg)-induced DA release in the nucleus accumbens of Srr-KO mice previously treated with METH was significantly lower than that of the WT mice previously treated with METH. Interestingly, a single administration of METH (3 mg/kg) significantly increased the phosphorylation status of ERK1/2 in the striatum of WT, but not Srr-KO mice. CONCLUSIONS/SIGNIFICANCE: These findings suggest first, that SRR plays a role in the development of behavioral sensitization in mice after repeated administration of METH, and second that phosphorylation of ERK1/2 by METH may contribute to the development of this sensitization as seen in WT but not Srr-KO mice

Common Variants in MAGI2 Gene Are Associated with Increased Risk for Cognitive Impairment in Schizophrenic Patients

Schizophrenia is a complex psychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive impairment. MAGI2, a relatively large gene (∼1.5 Mbps) that maps to chromosome 7q21, is involved in recruitment of neurotransmitter receptors such as AMPA- and NMDA-type glutamate receptors. A genetic association study designed to evaluate the association between MAGI2 and cognitive performance or schizophrenia has not been conducted. In this case-control study, we examined the relationship of single nucleotide polymorphism (SNP) variations in MAGI2 and risk for schizophrenia in a large Japanese sample and explored the potential relationships between variations in MAGI2 and aspects of human cognitive function related to glutamate activity. Based on the result of first schizophrenia genome-wide association study in a Japanese population (JGWAS), we selected four independent SNPs and performed an association study using a large independent Japanese sample set (cases 1624, controls 1621). Wisconsin Card Sorting Test (WCST) was used to evaluate executive function in 114 cases and 91 controls. We found suggestive evidence for genetic association of common SNPs within MAGI2 locus and schizophrenia in Japanese population. Furthermore in terms of association between MAGI2 and cognitive performance, we observed that genotype effect of rs2190665 on WCST score was significant (p = 0.034) and rs4729938 trended toward significance (p = 0.08). In conclusion, although we could not detect strong genetic evidence for association of common variants in MAGI2 and increased schizophrenia risk in a Japanese population, these SNPs may increase risk of cognitive impairment in schizophrenic patients