岩田 仲生

Chromosome 1p13 is linked with schizophrenia in Japanese families, and one of the candidate genes in this region is the netrinG1(NTNG1) gene at1p13.3. Associations of 56 tag single-nucleotide polymorphisms (SNPs) with schizophrenia were explored by transmission disequilibrium analysisin 160 Japanese trios and by case–control analysis in 2174 Japanese cases and 2054 Japanese controls. An association between SNP rs628117and schizophrenia was identified by case–control comparison (nominal allelic p = 0.0009; corrected p = 0.006). The associated polymorphism islocated in intron 9 and in the haplotype block encompassing the alternatively spliced exons of the gene. Allelic association of a different SNP in thesame haplotype block in Japanese families was previously reported. These findings support that the NTNG1 gene is associated with schizophreniain the Japanese.

Because methamphetamine (METH) is metabolized by CYP2D6 at the first step of hydroxylation and demethylation, it is possible that functional variants of CYP2D6 alter susceptibility to methamphetamine-induced dependence. We genotyped CYP2D6*1, *4, *5, *10, and *14 for 202 patients with METH dependence and 337 controls in a Japanese population and found a significant association of the CYP2D6 gene with METH dependence (p=0.0299). The patients had fewer *10 and *14 alleles, which are hypofunction alleles, than the controls. CYP2D6 genotypes were divided into three phenotypes: extensive metabolizers, intermediate metabolizers, and poor metabolizers. There was no poor metabolizer among our Japanese subjects, and intermediate metabolizers of CYP2D6 were significantly fewer in methamphetamine-dependent subjects than in controls (p=0.0212), with an odds ratio of 0.62 (95% confidence interval: 0.51-0.76). The present study demonstrated that reduced CYP2D6 activity was a negative risk factor for methamphetamine dependence.

Selective serotonin reuptake inhibitor (SSRI)-induced nausea can be severe enough to lead to early treatment discontinuation. However, it is currently not possible to predict the occurrence of nausea before the initiation of SSRI treatment. In this study, we investigated the effect of genetic polymorphisms in the 5-hydroxytryptamine type 2A, 3A, and 3B (5-HT3B) receptors, 5-HT transporter, and CYP2D6 genes on the incidence of paroxetine-induced nausea. A consecutive series of 72 Japanese patients with depressive or anxiety disorders were treated with paroxetine. Paroxetine-induced nausea was assessed by a pharmacist and was observed in 29.2% of the patients. A significant (nominal p=0.00286) association was found between the incidence of nausea and the -100_-102AAG insertion/deletion polymorphism of the 5-HT3B receptor gene. No significant associations were observed between the other genetic polymorphisms and the incidence of nausea. The -100_-102AAG deletion variant of the 5-HT3B receptor gene may affect paroxetine-induced nausea.

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.

CONTEXT: We can improve understanding of human methamphetamine dependence, and possibly our abilities to prevent and treat this devastating disorder, by identifying genes whose allelic variants predispose to methamphetamine dependence. OBJECTIVE: To find "methamphetamine dependence" genes identified by each of 2 genome-wide association (GWA) studies of independent samples of methamphetamine-dependent individuals and matched controls. DESIGN: Replicated GWA results in each of 2 case-control studies. SETTING: Japan and Taiwan. PARTICIPANTS: Individuals with methamphetamine dependence and matched control subjects free from psychiatric, substance abuse, or substance dependence diagnoses (N = 580). MAIN OUTCOME MEASURES: "Methamphetamine dependence" genes that were reproducibly identified by clusters of nominally positive single-nucleotide polymorphisms (SNPs) in both samples in ways that were unlikely to represent chance observations, based on Monte Carlo simulations that corrected for multiple comparisons, and subsets of "methamphetamine dependence" genes that were also identified by GWA studies of dependence on other addictive substances, success in quitting smoking, and memory. RESULTS: Genes identified by clustered nominally positive SNPs from both samples were unlikely to represent chance observations (Monte Carlo P < .00001). Variants in these "methamphetamine dependence" genes are likely to alter cell adhesion, enzymatic functions, transcription, cell structure, and DNA, RNA, and/or protein handling or modification. Cell adhesion genes CSMD1 and CDH13 displayed the largest numbers of clustered nominally positive SNPs. "Methamphetamine dependence" genes overlapped, to extents much greater than chance, with genes identified in GWA studies of dependence on other addictive substances, success in quitting smoking, and memory (Monte Carlo P range < .04 to < .00001). CONCLUSION: These data support polygenic contributions to methamphetamine dependence from genes that include those whose variants contribute to dependence on several addictive substances, success in quitting smoking, and mnemonic processes.

The aim of this study was to examine the effects of negative cognition on PBI score before and after treatment for depression. Forty major depressive disorder outpatients were assessed with the PBI scale and Structured Interview Guide for Hamilton Rating Scale for Depression (SIGH-D) at the time of the first medical examination (baseline) and 8 weeks later. The SIGH-D scores decreased by about 50% from baseline to 8 weeks, but there was no significant change in the PBI scores of the depressed outpatients from baseline to 8 weeks. Analysis of covariance with the SIGH-D scores as covariate was conducted for PBI scores between baseline and 8 weeks to remove effects of MDD. No significant differences were found on any of the PBI scales. Even though the therapeutic values on the SIGH-D of the depressed patients indicated that depressive symptoms were reduced by about 50%, depression level did not influence the PBI scores. This study provides evidence for the stability of parental representations throughout treatment, as measured by the PBI.

BACKGROUND: The dysbindin (DTNBP1 [dystrobrevin-binding protein 1]) gene has repeatedly been shown to be associated with schizophrenia across diverse populations. One study also showed that risk haplotypes were shared with a bipolar disorder subgroup with psychotic episodes, but not with all cases. DTNBP1 may confer susceptibility to psychotic symptoms in various psychiatric disorders besides schizophrenia. METHODS: Methamphetamine psychosis, the psychotic symptoms of which are close to those observed in schizophrenia, was investigated through a case (n = 197)-control (n = 243) association analyses of DTNBP1. RESULTS: DTNBP1 showed significant associations with methamphetamine psychosis at polymorphisms of P1635 (rs3213207, p = .00003) and SNPA (rs2619538, p = .049) and the three-locus haplotype of P1655 (rs2619539)-P1635-SNPA (permutation p = .0005). The C-A-A haplotype, which was identical to the protective haplotype previously reported for schizophrenia and psychotic bipolar disorders, was a protective factor (p = .0013, odds ratio [OR] = .62, 95% confidence interval [CI] .51-.77) for methamphetamine psychosis. The C-G-T haplotype was a risk for methamphetamine psychosis (p = .0012, OR = 14.9, 95% CI 3.5-64.2). CONCLUSIONS: Our genetic evidence suggests that DTNBP1 is involved in psychotic liability not only for schizophrenia but also for other psychotic disorders, including substance-induced psychosis.

Glycine transporter (GlyT)-1 plays a pivotal role in maintaining the glycine level at the glutamatergic synapse. Glycine is an allosteric agonist of N-methyl-D-aspartate (NMDA) receptors. Because activation of NMDA receptors is an essential step for induction of methamphetamine dependence and psychosis, differences in the functioning of GlyT-1 due to genetic variants of the GlyT-1 gene (GLYT1) may influence susceptibility. A case-control genetic association study of the GLYT1 gene examined 204 patients with methamphetamine-use disorder and 210 healthy controls. We examined three single nucleotide polymorphisms (SNPs), SNP1, IVS3 + 411C > T, rs2486001; SNP2, 1056G > A, rs2248829; and SNP3, IVS11 + 22G > A, rs2248632, of the GLYT1 gene and found that SNP1 showed a significant association in both genotype (P = 0.0086) and allele (P = 0.0019) with methamphetamine-use disorder. The T-G haplotype at SNP1 and SNP2 was a significant risk factor for the disorder (P = 0.000039, odds ratio: 2.04). The present findings indicate that genetic variation of the GLYT1 gene may contribute to individual vulnerability to methamphetamine dependence and psychosis.

Lithium is one of the most commonly used drugs for the treatment of bipolar disorder. To prescribe lithium appropriately to patients, predictors of response to this drug were explored, and several genetic markers are considered to be good candidates. We previously reported a significant association between genetic variations in the breakpoint cluster region (BCR) gene and bipolar disorder. In this study, we examined a possible relationship between response to maintenance treatment of lithium and Asn796Ser single-nucleotide polymorphism in the BCR gene. Genotyping was performed in 161 bipolar patients who had been taking lithium for at least 1 year, and they were classified into responders for lithium mono-therapy and non-responders. We found that the allele frequency of Ser796 was significantly higher in non-responders than in responders. Further investigation is warranted to confirm our findings.

PLP1 is one of the major myelin-related genes. A large body of expression-based studies showed significantly lower levels of the PLP1 messenger ribonucleic acid (mRNA) transcripts in schizophrenia. Moreover, one family-based study identified a weak association signal in a male subset using 487 Chinese family trios. We carried out a population-based association study between PLP1 and schizophrenia in 1,640 subjects. Our data does not support genetic variation in close vicinity or within PLP1 locus as a susceptibility factor.

UNLABELLED: We evaluated the diagnostic usefulness of combination studies with a statistical mapping method in N-isopropyl-p-(123)I-iodoamphetamine ((123)I-IMP) brain perfusion SPECT, cardiac sympathetic nerve function by (123)I-metaiodobenzylguanidine ((123)I-MIBG), and myocardial function by electrocardiographically gated (99m)Tc-sestamibi ((99m)Tc-MIBI) SPECT for patients with probable or possible dementia with Lewy bodies (DLB). METHODS: Twelve patients with probable DLB (7 male, 5 female; mean age +/- SD, 72.3 +/- 5.63 y; range, 65-82 y) and 9 patients with possible DLB (3 male, 6 female; mean age +/- SD, 73.1 +/- 9.23 y; range, 59-88 y) were enrolled in this study. (123)I-IMP SPECT images were analyzed with 3-dimensional stereotactic surface projections (3D-SSP) and the severity of ischemia was classified objectively using quantitatively analytic and display software; stereotactic extraction estimation (SEE) methods were compared with a normal database. In addition, we evaluated (123)I-MIBG heart-to-mediastinum (H/M) uptake ratios. Moreover, we performed (99m)Tc-MIBI SPECT to evaluate myocardial perfusion and the left ventricular ejection fraction (LVEF) compared with a normal database. RESULTS: 3D-SSP images of group comparison with healthy control subjects showed significantly decreased perfusion in the parietotemporal, occipital cortex, posterior cingulated, and precuneus regions in the probable DLB group but no significant reduction in the possible DLB group. Mean H/M ratios in the probable DLB group were significantly lower than those of the possible DLB group and the control group, respectively. Ten of 12 patients (83.3%) with probable DLB and 1 of 9 patients (11.1%) with possible DLB showed severe reduction in the bilateral occipital lobe and also a low (123)I-MIBG uptake. One patient (8.3%) with probable DLB and 2 patients (22.2%) with possible DLB showed no bilateral occipital hypoperfusion but showed low (123)I-MIBG uptake. One patient (8.3%) with probable DLB and 6 patients (66.7%) with possible DLB showed no occipital hypoperfusion and normal (123)I-MIBG uptake. (99m)Tc-MIBI gated SPECT did not indicate any wall motion abnormality in any subjects. CONCLUSION: These results suggest that combined examination of cerebral blood flow with 3D-SSP and SEE analysis, and cardiac sympathetic nerve function with (123)I-MIBG, would be a useful supporting diagnostic method in patients with DLB-particularly, in possible DLB and when cerebral blood flow does not indicate occipital hypoperfusion.

The Hamilton Rating Scale for Depression (HAMD) is the de facto international gold standard for the assessment of depression. There are some criticisms, however, especially with regard to its inter-rater reliability, due to the lack of standardized questions or explicit scoring procedures. The GRID-HAMD was developed to provide standardized explicit scoring conventions and a structured interview guide for administration and scoring of the HAMD. We developed the Japanese version of the GRID-HAMD and examined its inter-rater reliability among experienced and inexperienced clinicians (n=70), how rater characteristics may affect it, and how training can improve it in the course of a model training program using videotaped interviews. The results showed that the inter-rater reliability of the GRID-HAMD total score was excellent to almost perfect and those of most individual items were also satisfactory to excellent, both with experienced and inexperienced raters, and both before and after the training. With its standardized definitions, questions and detailed scoring conventions, the GRID-HAMD appears to be the best achievable set of interview guides for the HAMD and can provide a solid tool for highly reliable assessment of depression severity.

Lithium is an effective mood stabilizer for bipolar disorder patients and its therapeutic effect may involve inhibition of inositol monophosphatase activity. In humans, the enzyme is encoded by two genes, IMPA1 and IMPA2. IMPA2 maps to 18p11.2, a genomic interval for which evidence of linkage to bipolar disorder has been supported by several reports. We performed a genetic association study in Japanese cohorts (496 patients with bipolar disorder and 543 control subjects). Interestingly, we observed association of IMPA2 promoter single nucleotide polymorphisms (SNPs) (-461C and -207T) with bipolar disorder, the identical SNPs reported previously in a different population. In vitro promoter assay and genetic haplotype analysis showed that the combination of (-461C)-(-207T)-(-185A) drove enhanced transcription and the haplotypes containing (-461C)-(-207T)-(-185A) contributed to risk for bipolar disorder. Expression study on post-mortem brains revealed increased transcription from the IMPA2 allele that harbored (-461C)-(-207T)-(-185A) in the frontal cortex of bipolar disorder patients. The examination of allele-specific expressions in post-mortem brains did not support genomic imprinting of IMPA2, which was suggested nearby genomic locus. Contrasting to a prior report, therapeutic concentrations of lithium could not suppress the transcription of IMPA2 mRNA, and the mood-stabilizing effect of lithium is, if IMPA2 was one of the targets of lithium, deemed to be generated via inhibition of enzymatic reaction rather than transcriptional suppression. In conclusion, the present study suggests that a promoter haplotype of IMPA2 possibly contributes to risk for bipolar disorder by elevating IMPA2 levels in the brain, albeit the genetic effect varies among populations.

BACKGROUND: Microarray studies of schizophrenic brains revealed decreases in the expression of myelin and oligodendrocyte-related genes. Of these genes, sex-determining region Y-box 10 (SOX10) is a major transcription factor modulating the expression of proteins involved in neurogenesis and myelination. The SOX10 gene is located on chromosome 22q13.1, a region repeatedly reported to show positive signals in linkage studies on schizophrenia. OBJECTIVE: This study was conducted to clarify the exact role of SOX10 in the pathophysiology of schizophrenia. METHODS: We performed an association analysis of SOX10 in a Japanese population of 915 schizophrenic patients and 927 controls. Genotyping was carried out using polymerase chain reaction restriction fragment length polymorphism. MAIN RESULTS: One single nucleotide polymorphism of the SOX10 gene (rs139,887) was selected as a haplotype tag single nucleotide polymorphism using 96 controls. A significant association was observed in the genotype and allelic frequency of this single nucleotide polymorphism between schizophrenic patients and controls (P=0.025 and P=0.009, respectively). Especially, a significant association was found in male patients, but not female patients. We also performed a mutational search of the whole coding region, branch site, and promoter region of SOX10 in 96 schizophrenic patients, but no potential functional polymorphisms were detected. CONCLUSION: This study suggests that the SOX10 gene is related to the development of schizophrenia in the Japanese population.

AKT1 (V-akt murine thyoma viral oncogene homolog 1) is involved in intracellular signalling pathways postulated as of aetiological importance in schizophrenia. Markers in the AKT1 gene have also recently been associated with schizophrenia in two samples of European origin and in Japanese and Iranian samples. Aiming to replicate these findings, we examined ten SNPs spanning AKT1 in a UK case-control sample (schizophrenia cases n=673, controls n=716). These included all SNPs previously reported to be associated in European, Japanese and Iranian samples, alone or in haplotypes, as well as additional markers defined by the Haploview Tagger program (pair-wise tagging, minimum r(2)=0.8, minor allele frequency=0.02). We found no association with single markers (min p=0.17). We found weak evidence for association (p=0.04) with a four marker haplotype reported as significant in the original positive European sample of Emamian et al. [Emamian, E.S., Hall, D., Birnbaum, M.J., Karayiorgou, M., Gogos, J.A., 2004. Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat. Genet. 36, 131-137] and also an overlapping three marker haplotype (p=0.016) that had previously been reported as significant in a Japanese sample. Nominal p-values for these haplotypes did not survive correction for multiple testing. Our study provides at best weak support for the hypothesis that AKT1 is a susceptibility gene for schizophrenia. Examination of our own data and those of other groups leads us to conclude that overall, the evidence for association of AKT1 as a susceptibility gene for schizophrenia is weakly positive, but not yet convincing.

OBJECTIVE: Protein interacting with C-kinase-1 (PICK1) plays a role in the targeting and clustering of dopamine transporter, which is the primary target site for the abused drug methamphetamine. Based on the interaction of PICK1 with dopamine transporter, it is of particular interest to investigate the association between the PICK1 gene and methamphetamine abusers. METHOD: The authors studied the association between PICK1 gene polymorphisms and methamphetamine abusers in a Japanese group. Two hundred and eight methamphetamine abusers and 218 healthy comparison subjects were enrolled in the study. Furthermore, the authors also examined the effects of single nucleotide polymorphisms (SNPs) in the promoter and 5'-untranslated region on transcription levels of PICK1. RESULTS: The authors identified four highly frequent SNPs, rs737622 (-332 C/G) and rs3026682 (-205 G/A) in the promoter region and rs713729 (T/A) in intron3 and rs2076369 (T/G) in intron4. Of these SNPs, rs713729 was significantly associated with methamphetamine abusers in general, and rs713729 and rs2076369 were significantly associated with those with spontaneous relapse of psychosis. Furthermore, haplotype analysis revealed that specific haplotypes of these SNPs were associated with methamphetamine abusers. A gene reporter assay revealed that the two SNPs in the promoter region significantly altered transcriptional activity. CONCLUSIONS: Our findings suggest that the PICK1 gene may be implicated in the susceptibility to spontaneous relapse of methamphetamine psychosis and that, as an intracellular adapter protein, PICK1 may play a role in the pathophysiology of methamphetamine psychosis.

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.

Fasciculation and elongation of protein zeta-1 (FEZ1) is a binding partner of Disrupted-In-Schizophrenia 1 (DISC1). Because the DISC1 gene is shown to be a causative gene for psychosis in a Scottish family, the FEZ1 gene may well have importance in mental disease. A previous association study that analyzed polymorphisms of the FEZ1 gene in Japanese patients with schizophrenia and control subjects found significant association of the Asp123Glu polymorphism with schizophrenia. In the present study, we examined two polymorphic markers, rs559668 and rs597570 (Asp123Glu), in the FEZ1 gene to confirm the association in 1920 Japanese patients with schizophrenia and 1920 control subjects. The power to detect an association was more than 0.98. However, we did not detect genotypic associations of either of these two single nucleotide polymorphisms with schizophrenia (p=1 and 0.79, respectively). We concluded that the missense mutation Asp123Glu of the FEZ1 gene is unlikely to play a substantial role in the genetic susceptibility to schizophrenia.

Based on the glutamatergic dysfunction hypothesis for schizophrenia pathogenesis, we have been performing systematic association studies of schizophrenia with the glutamate receptor and transporter genes. We report here association studies of schizophrenia with three glutamate transporter genes SLC1A1, SLC1A3, and SLC1A6 encoding the glutamate transporters EAAT3, EAAT1, and EAAT4, respectively. We initially performed the screening of the total 25 single nucleotide polymorphisms (SNPs) distributed in the three gene regions using 100 out of 400 Japanese cases and 100 out of 420 Japanese controls. After controlling the false discovery rate (FDR) at level 0.05, we observed significant associations of schizophrenia with a genotype of SNP4 (rs2097837, P = 0.007) and with haplotypes of SNP2-SNP5 (P = 7.5 x 10(-5)) and SNP3-SNP5 (P = 9.0 x 10(-4)) in the SLC1A6 region. The haplotype of SNP2-SNP5 of SLC1A6 even showed marginally significant association with the disease in the full-size sample (400 cases and 420 controls, P = 0.031). We concluded that at least one susceptibility locus for schizophrenia may be located within or nearby SLC1A6, whereas SLC1A1 and SLC1A3 are unlikely to be major susceptibility genes for schizophrenia in the Japanese population.

Several single marker association and haplotypic analyses have been performed to identify susceptible genes for various common diseases, but these approaches using candidate genes did not provide accurate and consistent evidence in each analysis. This inconsistency is partly due to the fact that the common diseases are caused by complex interactions among various genetic factors. Therefore, in this study, to evaluate exhaustive genotype or allele combinations, we applied the binomial and random permutation test (BRP) proposed by Tomita et al. [IPSJ Digital Courier, 2, 691-709 (2006)] for the association analysis between an Apolipoprotein L gene cluster and schizophrenia. Using the seven selected representative single nucleotide polymorphisms (SNPs) based on the results of linkage disequilibrium evaluation, we analyzed 845 schizophrenic patients and 707 healthy controls, and investigated the validation of risk and protective factors with two randomly divided data sets. A comparative study of a method for analyzing the interactions was performed by conventional methods. Even if all the tested methods were used for analysis, the risk factor with a high significance was not commonly selected from both independent data sets. However, the significant interactions for the protective factor against disease development were commonly obtained from both data sets by BRP analysis. In conclusion, although it is considered that the causality of schizophrenia is too complex to identify a susceptible interaction using a small sample size, it was suggested that the healthy controls tend to have the same combination of certain alleles or genotypes for protection from disease development when BRP as a new exhaustive combination analytical method was used.

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.

Recent investigations suggest that the AKT/glycogen synthase kinase 3 (GSK3) signaling cascade may be associated with the pathophysiology of schizophrenia and methamphetamine (METH) use disorder. One important molecule related to this cascade is β-arrestin 2 (ARRB2). We therefore conducted a genetic case-control association analysis of the gene for ARRB2 with schizophrenia and METH use disorder in a Japanese population (547 people with schizophrenia, 177 with METH use disorder and 546 controls). A possible association of &#039;tag single nucleotide polymorphisms (SNPs)&#039; was found in METH use disorder (rs1045280: P genotype = 0.0118, P allele = 0.003 51; rs2036657: P allele = 0.0431; rs4790694: P genotype = 0.0167, P allele = 0.0202), but no association was found with schizophrenia. We also evaluated the gene-gene interactions among ARRB2, AKT1, and GSK3B, which we previously reported for each of these diseases. However, no interaction was seen in our samples. This is the first association analysis of ARRB2, and our results indicate that ARRB2 may play a role in the pathophysiology of METH use disorder. © 2006 Blackwell Publishing Ltd.

© 2007 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business. All rights reserved. The neurodevelopmental model of schizophrenia (1,2) is now a widely accepted hypothesis, and several investigations based on this model have been conducted. The actual pathophysiology of this disorder, however, is still not fully understood. The neurodevelopmental model suggests that schizophrenia is a behavioral phenotype, resulting from neurodevelopmental processes that start long before the onset of clinical manifestations and are due to a combination of environmental and genetic factors (Fig. 1). Clinical studies have provided the following support for this hypothesis (3).

We investigated the relationship between temperamental predisposition and brain structure by using a standard questionnaire and high-resolution T1-weighted magnetic resonance image (MRI) in normal young volunteers. Fifty-six subjects completed the Japanese version of the Temperament and Character Inventory (TCI, 125 items) and underwent an MRI acquisition of the brain. The gray matter (GM) was extracted from the whole brain image of the subjects and normalized to the standard brain template using statistical parametric mapping and the optimized voxel-based morphometry (VBM) method. When the score on the harm avoidance (HA) subscale was used as a dependent variable, the multiple regression analysis revealed that the HA score positively correlated with the volume of the part of left amygdala. The region-of-interest analysis showed that the correlation was significant in the female subjects but not in the male subjects. The correlation was significant even after the effects of age, depression score, and total GM volume were taken into account. The differential correlation between the sexes may be caused by differences in hormonal condition and the vulnerability of women to socio-psychological stress. In addition, the novelty seeking (NS) score positively correlated with the GM of the left middle frontal gyrus. The volume of the tail of the right caudate nucleus positively correlated with the reward dependence (RD) score. With regard to the NS and RD scores, no significant sex difference was observed in the correlation. These results indicate that the temperamental traits measured using the questionnaire may have a morphological basis in the human brain.

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.

Disrupted-in-schizophrenia 1 (DISC1), identified in a pedigree with a familial psychosis with the chromosome translocation (1:11), is a putative susceptibility gene for psychoses such as schizophrenia and bipolar disorder. Although there are a number of patients with major depressive disorder (MDD) in the family members with the chromosome translocation, the possible association with MDD has not yet been studied. We therefore performed an association study of the DISC1 gene with MDD and schizophrenia. We found that Cys704 allele of the Ser704Cys single-nucleotide polymorphism (SNP) was associated with an increased risk of developing MDD (P=0.005, odds ratio=1.46) and stronger evidence for association in a multi-marker haplotype analysis containing this SNP (P=0.002). We also explored possible impact of Ser704Cys on brain morphology in healthy volunteers using MR imaging. We found a reduction in gray matter volume in cingulate cortex and a decreased fractional anisotropy in prefrontal white matter of individuals carrying the Cys704 allele compared with Ser/Ser704 subjects. In primary neuronal culture, knockdown of endogenous DISC1 protein by small interfering RNA resulted in the suppression of phosphorylation of ERK and Akt, whose signaling pathways are implicated in MDD. When effects of sDISC1 (Ser704) and cDISC1 (Cys704) proteins were examined separately, phosphorylation of ERK was greater in sDISC1 compared with cDISC1. A possible biological mechanism of MDD might be implicated by these convergent data that Cys704 DISC1 is associated with the lower biological activity on ERK signaling, reduced brain gray matter volume and an increased risk for MDD.

BACKGROUND: Methamphetamine (MAP) is one of the most frequently used illegal substances in Japan, and family and twin studies have suggested that genetic factors contribute to psychostimulant dependence, including MAP dependence. Organic cation transporter 3 (OCT3) has been reported to be involved in the disposition of MAP as well as MAP-induced behavioral changes in animals. Moreover, SLC22A3 (which encodes OCT3) is a candidate gene for MAP dependence because it is located within a chromosomal region associated with substance dependence. METHODS: Using 96 healthy control subjects, linkage disequilibrium (LD) within the SLC22A3 was investigated, and 5 single-nucleotide polymorphisms (SNPs) were selected as haplotype tag SNPs to search for an association with MAP dependence. Single-marker analyses and haplotype analyses of these SNPs were performed in 213 subjects with MAP dependence and 443 healthy controls. RESULTS: SLC22A3 polymorphisms were not significantly associated with MAP dependence in any of the single-marker and haplotype analyses. When subjects with MAP dependence were divided into polysubstance and single-MAP users, genotype and allele frequency of SNP2 (p=0.024, p=0.011, respectively), allele frequency of SNP3 (p=0.037), and haplotypic frequencies for these 2 SNPs (p=0.0438) differed significantly between groups. CONCLUSIONS: These results suggest that polymorphisms of SLC22A3 are related to the development of polysubstance use in Japanese patients with MAP dependence.

SOD2 (superoxide dismutase 2) plays a crucial role in protecting the cells against damage caused by free radicals, by catalyzing their detoxification. On the other hand, cell damage caused by free radical generation following methamphetamine administration has been postulated as one of the possible pathophysiological mechanisms for methamphetamine psychosis. Hence, we investigated the association of SOD2 polymorphisms with the development of methamphetamine psychosis, in two independent populations of Japan and Taiwan. We recruited 116 patients with methamphetamine psychosis and 189 controls in Japan, and 135 patients with methamphetamine psychosis and 204 controls in Taiwan. The methamphetamine group was divided into two clinical subtypes: a transient type of psychosis (i.e., good prognosis) and a prolonged type of psychosis (i.e., poor prognosis), according to the course of the manifestation of psychosis. With reference to the genotypic and allelic frequencies of Ala/Val functional polymorphism in exon 2, we found significant differences between individuals with prolonged methamphetamine psychosis and control samples from Japan and Taiwan in the genotypic (P value 0.014 and 0.016, respectively) and in the allelic (P value 0.004 and 0.047, respectively) frequencies. Our results suggest that Ala/Val polymorphism of the SOD2 gene could be associated with the risk of developing methamphetamine psychosis.

OBJECTIVE: A series of methamphetamine psychosis reveals two kinds of clinical courses of methamphetamine psychosis: transient type and prolonged type. Furthermore, paranoid psychosis sometimes recurs without methamphetamine reuse, referred to as spontaneous relapse. Dysfunction of central dopaminergic neurotransmission has been implicated in the pathogenesis of these psychiatric states. Catechol-O-methyl transferase appears to play a unique role in regulating synaptic dopaminergic activity. This study aimed to investigate whether a functional polymorphism of the catechol-O-methyl transferase gene would be involved in the development of these psychiatric states. BASIC METHODS: We examined the functional polymorphism of val 158 met (catechol-O-methyl transferase) in 143 patients with methamphetamine psychosis and 200 healthy controls in Japan. The patients were divided into subgroups by several characteristic clinical features. MAIN RESULTS: We found a significant difference in the catechol-O-methyl transferase allele frequency between patients with spontaneous relapse and the controls (P=0.018, odds ratio=1.67). Odds ratio implied that the patients with spontaneous relapse had a nearly 1.7-fold higher rate of the low activity alleles (met) than the controls. CONCLUSIONS: Our results indicate that the met allele frequency of the catechol-O-methyl transferase is associated with patients who experienced methamphetamine psychosis and spontaneous relapse, suggesting that patients with a met allele appear to be at increased risk of an adverse response to methamphetamine.

Recent preclinical findings that repeated treatment with methamphetamine (METH) induced an increase in tumor necrosis factor-α (TNF-α) mRNA in some brain regions and that TNF-α blocked METH neurotoxicity and rewarding effects suggest TNF-α, a multifunctional pro-inflammatory cytokine, may be involved in METH dependence. We hypothesized that genetic polymorphisms of the TNF-α gene and its receptor genes may be associated with vulnerability to METH dependence. Genetic association of -308G &gt; A and -857C &gt; T in the promotor region of the TNF-α gene, and 36A &gt; G in exon 1 of the TNF receptor 1A gene (TNFR-SF1A), were analyzed in patients with METH dependence (n = 185) and healthy controls (n = 221) in a Japanese population. No significant association of alleles or haplotypes of the TNF-α or TNFR-SF1A genes with METH dependence was found. Neither was any significant association of clinical phenotype with METH dependence found. These results suggest that genetic variations in the TNF-α gene and its receptor genes may not be involved in individual vulnerability to METH dependence. © 2006 New York Academy of Sciences.

The role of the delta-opioid receptor (OPRD1) in methamphetamine (MAP) addiction was investigated using association analysis between OPRD1 gene polymorphisms and MAP dependence/psychosis. DNA samples from Japanese patients with MAP dependence/psychosis were analyzed to find polymorphisms in OPRD1 gene exons and exon-intron boundaries. One novel single nucleotide polymorphism (SNP) in intron 1 and two SNPs in exon 3 were identified. The two SNPs in exon 3 were in linkage disequilibrium. No significant difference was observed in either genotypic or allelic frequencies of these SNPs between controls (n = 260) and MAP dependent/psychotic patients (n = 170). Global analyses using the three SNPs and subcategory analyses on clinical parameters also showed no significant differences. These results suggest that the OPRD1 gene variants may not be a factor in vulnerability to MAP dependence/psychosis.