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Casein kinase 1 epsilon (CKIℇ) is a component of the DARPP-32 in second-messenger pathway. CKIℇ phosphorylates and activates DARPP-32, a key molecule in various complex signaling pathways, including dopamine and glutamine signaling, which have both been demonstrated to be main pathways in substance dependence. A recent clinical study showed that rs135745, a noncoding single nucleotide polymorphism of the 3′-untranslated region of the CSNK1E gene, was associated with the intensity of the subjective response to an oral amphetamine dose in normal volunteers. Differences in sensitivity to the drug should affect development of dependence to it. Hence, we genotyped rs135745 of the CSNK1E (MIM 600863) gene in 215 patients with methamphetamine dependence and 274 age- and gender-matched normal controls. No significant differences in genotype and allele frequencies were observed between the patients with methamphetamine dependence and controls. There was also no significant association between rs135745 and the clinical characteristics of methamphetamine dependence and co-morbid methamphetamine psychosis (e.g., age of first consumption, latency of psychosis, prognosis of psychosis after therapy, spontaneous relapse of psychotic symptoms, and poly-substance abuse status). The present findings suggest that having a genetic variant of the CSNK1E gene did not affect susceptibility to methamphetamine dependence or psychosis, at least in a Japanese population. [ABSTRACT FROM AUTHOR]

Several lines of evidence from animal and genetic analyses showed that the calcineurin A gamma subunit gene (PPP3CC) plays an important role in the pathogenesis of schizophrenia. Moreover, a recent large Japanese case-control study confirmed the genetic association of PPP3CC with schizophrenia. The symptoms of methamphetamine (MAP)-induced psychosis are similar to those of schizophrenia, suggesting that PPP3CC is an attractive candidate gene not only for schizophrenia, but also for METH-related disorders. In this study, we carried out a genetic association study of PPP3CC with MAP-use disorder in a Japanese population. We selected five haplotype-tagging SNPs from the aforementioned replication study and genotyped 393 samples (MAP abuse, 128; control, 265). We could not detect a significant association of all tagging SNPs with each condition. In conclusion, our data suggest that PPP3CC does not elevate the risk of MAP-use disorder in the Japanese population. [ABSTRACT FROM AUTHOR]

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 ‘tag single nucleotide polymorphisms (SNPs)’ was found in METH use disorder (rs1045280: Pgenotype = 0.0118, Pallele = 0.00351; rs2036657: Pallele = 0.0431; rs4790694: Pgenotype = 0.0167, Pallele = 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. [ABSTRACT FROM AUTHOR]

Dihydropyrimidinase-related protein 2 (DRP-2 or DPYSL-2)mediates the intracellular response to collapsin, a repulsive extracellular guidance cue or axonal outgrowth. DRP-2 is also referred to as collapsin response mediator protein 2 (CRMP-2). We have previously demonstrated that the DRP-2 gene is associated with susceptibility to schizophrenia, but not to bipolar disorders. In addition, a genetic association was observed with paranoid-type schizophrenia, but not with hebephrenic-type schizophrenia. It has been well documented that repeated abuse of methamphetamine (METH) for a long period frequently produces psychotic symptoms, such as auditory hallucinations and delusions that are hardly distinguishable from those of paranoid-type schizophrenia. Therefore, we hypothesized that a certain genetic variant of the DRP-2 gene may affect individual vulnerability to the development of METH-induced psychosis. We examined the genetic association by a case–control method. The polymorphism *2236T>C in the 3′ untranslated region of the DRP-2 gene, which has been shown to be a negative genetic risk factor for paranoid-type schizophrenia, was analyzed in 198 patients with METH psychosis and 221 corresponding healthy controls in a Japanese population. No significant association of the DRP-2 gene with METH psychosis was found. Neither did we find an association with the clinical phenotype of METH psychosis, such as the age of first consumption of METH, latency to development of psychosis after METH abuse, prognosis of psychosis after detoxification from METH use, complication of spontaneous relapse of psychosis without reconsumption of the drug, or multisubstance abuse status. These findings indicate that a genetic variant of the DRP-2 gene may not affect the risk of METH psychosis or any clinical phenotype of the disorder. [ABSTRACT FROM AUTHOR]

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>A and -857C>T in the promotor region of the TNF-α gene, and 36A>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. [ABSTRACT FROM AUTHOR]

Cocaine- and amphetamine-regulated transcript (CART) was originally discovered as a peptide that increased in the rat striatum after injection of a psychostimulant drug, such as cocaine or amphetamine, and is suggested to play potential roles in drug dependence. We tested the genetic association between the CART gene and methamphetamine (METH) dependence and/or psychosis. The subjects were 203 patients with METH dependence and 239 age- and gender-matched healthy controls. Two single nucleotide polymorphisms (SNPs) of the CART gene, −156A>G and IVS1 + 224G>A, were examined . There were no significant differences in genotype and allele distributions of the polymorphisms between patients with METH dependence and/or psychosis and controls. Neither were significant differences in subgroups of clinical phenotypes, for example, age at first consumption of METH, latency to onset of psychotic symptoms after the first consumption of METH, prognosis of psychosis after therapy, complication of spontaneous relapse to a psychotic state, or multisubstance abuse status, observed. The present findings suggest that the CART gene may not play a pivotal role in the development of METH dependence and psychosis, at least in a Japanese population. [ABSTRACT FROM AUTHOR]

Our group, Ujike et al., recently reported that the A1 allele of TaqI A polymorphism of the dopamine receptor D2 (DRD2) gene, associated with transient psychosis, significantly differs from that of patients with prolonged psychosis in methamphetamine psychosis. Therefore, we examined the association between the TaqI A polymorphism of the DRD2 gene and the brain MRI view for patients with methamphetamine psychosis. The subjects underwent brain MRI scans using the FLAIR method. Genotyping was performed by PCR-RFLP methods using genomic DNA extracted from peripheral blood by the phenol method. Ten subjects had the A1/A2 genotype, eleven subjects had the A2/A2 genotype, and no subject had the A1/A1 genotype. The domain size, including the thalamus and basal ganglia that were inside each side of the putamens, did not differ between the three groups (the A1/A2-group, the A2/A2- group, and the young healthy person group). In the comparison based on this domain, the temporal lobe tended to narrow in the A2/A2-group compared to the A1/A2-group (P = .06). The other domain (cerebrum, corpus callosum, etc.) showed no difference between the A1/A2-group and the A2/A2-group. It is suggested that in methamphetamine psychosis the TaqI A polymorphism not only regulates prolongation of psychosis symptoms but also influences the form of the temporal lobe. [ABSTRACT FROM AUTHOR]

In the central nervous system, tissue-plasminogen activator (t-PA)/ plasmin system is involved in long-term synaptic plasticity and remodeling, and participates in rewarding effects of methamphetamine (MAP), by acutely regulating MAP-induced dopamine release in the nucleus accumbens. The aim of this study was to examine the relationships between the patients with MAP abusers/psychosis and the t-PA/plasminogen system genes. Subjects comprised 185 MAP abusers and 288 healthy controls. Four polymorphisms in the t-PA, plasminogen activator inhibitor, and plasminogen genes were examined in the present study. No significant differences were observed in each polymorphism between healthy controls and MAP abusers/psychosis. This study suggests that t-PA/plasminogen system is unlikely to be a major contributor to the substance abuse liability and/or the development of MAP psychosis. [ABSTRACT FROM AUTHOR]

Two functionally different MAP kinase phosphatases (MKPs) were investigated to clarify their roles in behavioral sensitization to methamphetamine (METH). MKP-1 mRNA levels increased substantially by about 60–300% in a range of brain regions, including several cortices, the striatum and thalamus 0.5–1 h after acute METH administration. After chronic METH administration its increase was less pronounced, but a more than 50% increase was still seen in the frontal cortex. MKP-1 protein levels also increased 3 h after acute or chronic METH administration. MKP-3 mRNA levels increased by about 30–50% in several cortices, the striatum and hippocampus 1 h after acute METH administration, but only in the hippocampus CA1 after chronic METH administration. Pre-treatment with the D[sub 1] dopamine receptor antagonist, SCH23390, attenuated the METH-induced increase of MKP-1 and MKP-3 mRNA in every brain region, while pre-treatment with the NMDA receptor antagonist, MK-801, attenuated it in some regions. These findings suggest that in METH-induced sensitization, MKP-1 and MKP-3 play important roles in the neural plastic modification in widespread brain regions in the earlier induction process, but in the later maintenance process, they do so only in restricted brain regions such as MKP-1 in the frontal cortices and MKP-3 in the hippocampus. [ABSTRACT FROM AUTHOR]

Recent genome-wide association studies (GWASs) of schizophrenia (SCZ) identified several susceptibility genes and suggested shared genetic components between SCZ and bipolar disorder (BD). We conducted a genetic association study of single nucleotide polymorphisms (SNPs) selected according to previous SCZ GWAS targeting psychotic disorders (SCZ and BD) in the Japanese population. Fifty-one SNPs were analyzed in a two-stage design using first-set screening samples (all SNPs: 1,032 SCZ, 1,012 BD, and 993 controls) and second-set replication samples ("significant" SNPs in the first-set screening analysis: 1,808 SCZ, 821 BD, and 2,321 controls). We assessed allelic associations between the selected SNPs and the three phenotypes (SCZ, BD, and "psychosis" [SCZ + BD]). Nine SNPs revealed nominal association signals for all comparisons (P(uncorrected) < 0.05), of which two SNPs located in the major histocompatibility complex region (rs7759855 in zinc finger and SCAN domain containing 31 [ZSCAN31] and rs1736913 in HLA-F antisense RNA1 [HLA-F-AS1]) were further assessed in the second-set replication samples. The associations were confirmed for rs7759855 (P(corrected) = 0.026 for psychosis; P(corrected) = 0.032 for SCZ), although the direction of effect was opposite to that in the original GWAS of the Chinese population. Finally, a meta-analysis was conducted using our two samples and using our data and data from Psychiatric GWAS Consortium (PGC), which have shown the same direction of effect. SNP in ZSCAN31 (rs7759855) had the strongest association with the phenotypes (best P = 6.8 × 10(-5) for psychosis: present plus PGC results). These data support shared risk SNPs between SCZ and BD in the Japanese population and association between MHC and psychosis., (© 2014 Wiley Periodicals, Inc.)

Glutamate is one of the key molecules involved in signal transduction in the brain, and dysfunction of glutamate signaling could be linked to schizophrenia. The SLC1A1 gene located at 9p24 encodes the glutamate transporter EAAT3/EAAC1. To investigate the association between the SLC1A1 gene and schizophrenia in the Japanese population, we genotyped 19 tagging single nucleotide polymorphisms (tagSNPs) in the SLC1A1 gene in 576 unrelated individuals with schizophrenia and 576 control subjects followed by replication in an independent case-control study of 1,344 individuals with schizophrenia and 1,344 control subjects. In addition, we determined the boundaries of the copy number variation (CNV) region in the first intron (Database of Genomic Variants, chr9:4516796-4520549) and directly genotyped the CNV because of significant deviation from the Hardy-Weinberg equilibrium. The CNV was not associated with schizophrenia. Four SNPs showed a possible association with schizophrenia in the screening subjects and the associations were replicated in the same direction (nominal allelic P < 0.05), and, among them, an association with rs7022369 was replicated even after Bonferroni correction (allelic nominal P = 5 × 10(-5) , allelic corrected P = 2.5 × 10(-4) , allelic odds ratio, 1.30; 95% CI: 1.14-1.47 in the combined subjects). Expression analysis quantified by the real-time quantitative polymerase chain reaction in the postmortem prefrontal cortex of 43 Japanese individuals with schizophrenia and 11 Japanese control subjects revealed increased SLC1A1 expression levels in individuals homozygous for the rs7022369 risk allele (P = 0.003). Our findings suggest the involvement of SLC1A1 in the pathogenesis of schizophrenia., (Copyright © 2011 Wiley Periodicals, Inc.)

As schizophrenia-like symptoms are produced by administration of phencyclidine (PCP), a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, PCP-responsive genes could be involved in the pathophysiology of schizophrenia. We injected PCP to Wistar rats and isolated five different parts of the brain in 1 and 4 hr after the injection. We analyzed the gene expression induced by the PCP treatment of these tissues using the AGILENT rat cDNA microarray system. We observed changes in expression level in 90 genes and 21 ESTs after the treatment. Out of the 10 genes showing >2-fold expressional change evaluated by qRT-PCR, we selected 7 genes as subjects for the locus-wide association study to identify susceptibility genes for schizophrenia in the Japanese population. In haplotype analysis, significant associations were detected in combinations of two SNPs of BTG2 (P = 1.4 × 10(-6) ), PDE4A (P = 1.4 × 10(-6) ), and PLAT (P = 1 × 10(-3) ), after false discovery rate (FDR) correction. Additionally, we not only successfully replicated the haplotype associations in PDE4A (P = 6.8 × 10(-12) ) and PLAT (P = 0.015), but also detected single-point associations of one SNP in PDE4A (P = 0.0068) and two SNPs in PLAT (P = 0.0260 and 0.0104) in another larger sample set consisting of 2,224 cases and 2,250 controls. These results indicate that PDE4A and PLAT may be susceptibility genes for schizophrenia in the Japanese population., (Copyright © 2011 Wiley-Liss, Inc.)

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene that encodes chorein. It is characterized by adult-onset chorea, peripheral acanthocytes, and neuropsychiatric symptoms. In the present study, we performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis, of the VPS13A gene in ChAc patients. All 73 exons and flanking regions of VPS13A were sequenced in 35 patients diagnosed with ChAc. To detect CNVs, we also performed real-time quantitative PCR and long-range PCR analyses for the VPS13A gene on patients in whom only a single heterozygous mutation was detected. We identified 36 pathogenic mutations, 20 of which were previously unreported, including two novel CNVs. In addition, we investigated the expression of chorein in 16 patients by Western blotting of erythrocyte ghosts. This demonstrated the complete absence of chorein in patients with pathogenic mutations. This comprehensive screen provides an accurate and useful method for the molecular diagnosis of ChAc., (Copyright © 2011 Wiley-Liss, Inc.)

Results of genome-wide association studies (GWASs) for bipolar disorder (BD) have indicated ANK3 as one of the most promising candidates for a susceptibility gene. In this study, we performed genetic association analysis of two single-nucleotide polymorphisms (SNPs) in ANK3 (rs1938526 and rs10994336), whose genome-wide significant associations were reported in a previous meta-analysis of GWASs, using genotyping data of Korean and Japanese case-control samples and a part of data from a GWAS in Han-Chinese from Taiwan. The total number of participants was 2,212 cases (352 from Korea, 860 from Japan, and 1,000 from Taiwan) and 2,244 controls (349 from Korea, 895 from Japan, and 1,000 from Taiwan). We could not detect any significant difference of allele frequency in individual analyses using each of the three populations. However, when we combined the three data sets and performed a meta-analysis, rs1938526 showed nominally significant association (P = 0.048, odds ratio = 1.09). The over-represented allele in BD was same as that reported in Caucasian GWASs. On the other hand, any significant association was not detected in rs10994336. This discrepancy between two SNPs may be explained by the different degree of linkage disequilibrium between Asian and Caucasian. These findings further supported the association between ANK3 and BD, and also suggested the genomic region around rs1938526 as a common risk locus across ethnicities., (Copyright © 2011 Wiley-Liss, Inc.)

Recent progress in genotyping technology and the development of public databases has enabled large-scale genome-wide association tests with diseases. We performed a two-stage genome-wide association study (GWAS) of bipolar disorder (BD) in Japanese cohorts. First we used Affymetrix 100K GeneChip arrays in the analysis of 107 cases with bipolar I disorder and 107 controls, and selected markers that were nominally significant (P < 0.01) in at least one of the three models (1,577 markers in total). In the follow-up stage, we analyzed these markers using an Illumina platform (1,526 markers; 51 markers were not designable for the platform) and an independent sample set, which consisted of 395 cases (bipolar I + II) and 409 controls. We also assessed the population stratification of current samples using principal components analysis. After the two-stage analysis, 89 markers remained nominally significant (allelic P < 0.05) with the same allele being consistently over-represented in both the first and the follow-up stages. However, none of these were significant after correction for multiple-testing by false discovery rates. Sample stratification was virtually negligible. Collectively, this is the first GWAS of BD in the Japanese population. But given the small sample size and the limited genomic coverage, these results should be taken as preliminary., (2009 Wiley-Liss, Inc.)

Accumulating evidence suggests that phosphatidylinositol (PI) pathways have been involved in the secretion of dopamine (DA) and the regulation of DA transporter, which is a target of methamphetamine (METH). A recent large-scale gene-association study in a Dutch population demonstrated that the PIK4CA gene was closely linked to schizophrenia [Jungerius et al. (2007); Mol Psychiatry]. Here, we conducted a case (N = 232)-control (N = 233) study of the PIK4CA gene on Japanese METH abusers, which can manifest severe psychosis similar to schizophrenia. The genotype and allelic distributions of all four single nucleotide polymorphisms (SNPs) did not differ significantly between the METH abusers and the controls. The comparisons based on the classification of the psychosis as transient or prolonged and on the presence or absence of spontaneous relapse revealed no significant distribution of the four SNPs compared to the controls. Furthermore, haplotype analyses showed almost the same frequencies between the METH abusers and the controls. The present study suggests that the PIK4CA gene does not play a significant role in the vulnerability to METH use disorder in the Japanese population., (2008 Wiley-Liss, Inc.)

Accumulating evidence suggests that oxidative stress plays a role in the mechanisms of action of methamphetamine (METH) in the brain. In the present study, we investigated the association between the genetic polymorphisms among glutathione (GSH)-related enzymes; glutathione S-transferases (GSTs) such as GSTT1 (Non-deletion/Null), GSTT2 (Met139Ile), GSTA1 (-69C/T), and GSTO1 (Ala140Asp); glutathione peroxidase 1 (GPX1) (Pro198Leu); and glutamate-cysteine ligase modifier (GCLM) subunit and METH use disorder in a Japanese population. Two hundred eighteen METH abusers and 233 healthy controls were enrolled in the study. There was a significant difference in GSTT1 genotype frequency between patients with METH psychosis and controls (P = 0.039, odds ratio: 1.52, 95% CI 1.03-2.24). Furthermore, the frequency (66.0%) of the GSTT1 null genotype among prolonged-type METH psychotic patients with spontaneous relapse was significantly higher (P = 0.025, odds ratio: 2.43, 95% CI 1.13-5.23) than that (44.4%) of transient-type METH psychotic patients without spontaneous relapse. However, there were no associations between the polymorphisms of other genes and METH abuse. The present study suggests that the polymorphism of the GSTT1 gene might be a genetic risk factor of the development of METH psychosis in a Japanese population.

The GRM3 gene, which encodes a metabotropic glutamate receptor, is an important candidate gene for susceptibility to schizophrenia. Two single nucleotide polymorphisms (SNPs), rs1468412 and rs2299225 in intron 3, were reported to be associated with schizophrenia in Japanese and Chinese populations, respectively. Haplotypes with these SNPs were also reported to be associated with schizophrenia. In the present study, we attempted to replicate these single marker and haplotype associations in a case-control study of 1,916 Japanese patients with schizophrenia and 1,915 Japanese control subjects. In addition to these two SNPs, we genotyped rs274622 in the promoter region of GRM3. In the present study, none of these polymorphisms were associated with schizophrenia (rs274622, allelic P = 0.68; rs1468412, allelic P = 0.74; rs2299225, allelic P = 0.20). Haplotypes constructed with these SNPs also were not associated with schizophrenia (P = 0.18-0.84). Meta-analysis of five case-control studies of more than 3,000 patients with schizophrenia and more than 3,000 control subjects did not support the associations of rs1468412 and rs2299225 with schizophrenia. Our data indicate that SNPs previously reported to be associated with schizophrenia do not contribute to genetic susceptibility to schizophrenia., (Copyright 2007 Wiley-Liss, Inc.)

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., ((c) 2007 Wiley-Liss, Inc.)

We examined the hypothesis that -485 T, a novel polymorphism in the promoter region of the neuropeptide Y gene which was shown to be associated with schizophrenia in our previous paper, confers susceptibility to the disease. For a case-control association study, 331 unrelated Japanese schizophrenics (S(1): milder cases in the previous study, n = 212; and S(2): additional severer cases, n = 119) and 199 unrelated normal controls were recruited. Contribution of -485 T to the risk and the severity of the illness was examined by (1) comparing the risk in each genotype in the general population, (2) testing correlations between the gene-dose of -485 T, and the severity of chronic outcome in S(2) assessed with the Positive and Negative Symptom Scale, and (3) comparing the distribution of age at onset in S(1) + S(2) among the three genotypes. -485 T was significantly associated with schizophrenia in S(1) + S(2). Significant negative correlations were observed between the gene-dose and the symptom assessment scores in all items. The homozygote of -485 T showed a second peak frequency in the late-onset group both in males and females, while the homozygote of the alternative allele showed a single peak in the early-onset group. The higher risk of schizophrenia in the heterozygote than in the homozygote of -485 T in the general population did not support the possibility of linkage disequilibrium with a susceptibility gene. -485 T most likely confers resistance but not susceptibility to schizophrenia. An interaction between a nuclear resistance gene and a presumptive pathogenic gene in the mitochondrial DNA was suggested., ((c) 2007 Wiley-Liss, Inc.)

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.

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., ((c) 2006 Wiley-Liss, Inc.)

Several lines of evidence suggest that genetic factors contribute to the vulnerability of drug abuse such as methamphetamine (MAP), and that dopamine-quinones produced by administration of MAP may be involved in the mechanism of MAP-related symptoms. The detoxification of quinones is catalyzed by a family of proteins designated as quinone oxidoreductases (NQOs). We analysed the polymorphisms of NQO1 and NQO2 genes to elucidate the association with genetic vulnerability to MAP abuse in Japan. The genotype and allele frequencies for the polymorphism (Pro187Ser) of the NQO1 gene did not differ between each subgroup of patients and controls. In contrast, the genotype frequency for the insertion/deletion (I/D) polymorphism in the promoter region of the NQO2 gene was a significant (p = 0.038) difference between patients with prolonged-type MAP psychosis and controls. This study suggests that the NQO2 gene polymorphism contributes to the aetiology of MAP-related psychosis in Japanese.

Several lines of evidence suggest that oxidative stress plays a role in the mechanisms of action of methamphetamine (MAP) in the human brain. Given the role of glutathione S-transferases (GSTs) in the protection against oxidative stress, genes encoding the GSTs have been considered as candidates for association studies of MAP abuse. This study was undertaken to investigate the role of the functional polymorphism of GSTP1 gene exon 5 (Ile105Val) in the pathogenesis of MAP abuse. Genotyping for GSTP1 gene polymorphism exon 5 (Ile105Val) in 189 MAP abusers and 199 normal controls was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). Association between GSTP1 gene polymorphism and clinical features (prognosis of psychosis (transient-type and prolonged-type), spontaneous relapse (positive and negative), and poly-substance abuse) of MAP abusers was evaluated. Significant differences in the frequency of both alleles (P = 0.026, odds ratio: 1.70, 95% confidence intervals (CI) 1.06-2.72) and genotypes (P = 0.029) between MAP abusers and controls were detected. In particular, a significant difference in both genotype frequency (P = 0.013) and allele frequency (P = 0.014, odds ratio: 1.84, 95% CI 1.13-2.97) between MAP abusers with psychosis (transient-type and prolonged-type) and controls was detected. Our findings suggest that the polymorphism (Ile105Val) on exon 5 of the GSTP1 gene may contribute to a vulnerability to psychosis associated with MAP abuse in Japanese population., (Copyright 2005 Wiley-Liss, Inc.)

Several lines of evidence suggest that genetic factors might contribute to drug abuse vulnerability. Recent genomic scans for association demonstrated that the brain-derived neurotrophic factor (BDNF) gene was associated with drug abuse vulnerability. In this study, we analyzed association of two BDNF gene single nucleotide polymorphisms (SNPs), 132C > T (C270T named formerly) in the noncoding region of exon V and 196G > A (val66met) in the coding region of exon XIIIA, with methamphetamine (MAP) abuse in Japan. No significant differences were found in the frequency of the genotype or allele in these two SNPs between MAP abusers and controls (132C > T in exon V: genotype, P = 0.586, allele, P = 0.594; 196G > A (val66met) in exon XIIIA: genotype, P = 0.889, allele, P = 0.713). Furthermore, there was no difference between clinical parameters (e.g., prognosis psychosis, spontaneous relapse, or poly-substance abuse) and the two SNPs of BDNF gene. These results suggest that the two SNPs (132C > T in exon V and 196G > A (val66met) in exon XIIIA) of the BDNF gene may not be associated with Japanese MAP abusers. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299:1/suppmat/index.html., (Copyright 2004 Wiley-Liss, Inc.)

Several lines of evidence suggest that increased generation of auto-oxidized dopamine (DA) o-quinone is associated with the neurotoxicity of methamphetamine (MAP) in the brain, and that, as a cellular defenses against DA-derived quinines, glutathione S-transferase (GST) detoxifies auto-oxidized DA o-quinone in the brain. Glutathione S-transferase M1 (GSTM1) of the mu-class of GSTs catalyzes reaction between glutathione and catecholamine o-quinones under physiological conditions. This study was undertaken to investigate the role of the GSTM1 gene deletion polymorphism in the neuropathology of MAP abuse. One hundred fifty-seven MAP abusers and 200 healthy comparison subjects were tested for a genetic polymorphism of GSTM1. The difference in the frequency of deletion (D)/non-deletion (N) alleles between the female abusers and female controls was close to statistical significance (P = 0.071), although there was no statistical difference (P = 0.651) between male abusers and male controls. Furthermore, the number of female abusers with deletion alleles was significantly (P = 0.007, odds ratio: 2.77, 95% CI 1.30-5.89) higher than that of male abusers with deletion alleles. These findings suggest that GSTM1 gene deletion may contribute to a vulnerability to MAP abuse in female subjects, but not in male subjects., (Copyright 2003 Wiley-Liss, Inc.)

Susceptibility to Alzheimer's disease (AD) is thought to be regulated by multiple genetic factors. Recently, three independent studies have reported that loci on chromosome 10q are linked with AD, and the insulin degrading enzyme (IDE; MIM 146680) gene located on chromosome 10q23-q25; IDE is located close to the maker D10S583, which exhibits a maximum LOD score for late-onset AD. We examined seven polymorphisms in the IDE gene, the marker D10S583 in the 5' flanking region, and SNPs in introns 1, 3, 11, 20, 21, and 22 (rs#1999764, 1855915, 1970244, 538469, 551266, and 489517, respectively). Four SNPs in introns 3, 11, 20, and 22 did not exhibit any polymorphisms in the Japanese population that was studied. D10S583 and two SNPs in introns 1 and 21 did not exhibit a significant association with early- or late-onset AD. In addition, no associations were observed for subgroups of AD grouped according to APOE status. The present study indicates that the IDE gene polymorphisms do not confer susceptibility to early- or late-onset AD at least in a Japanese population., (Copyright 2003 Wiley-Liss, Inc.)

Fibronectin is one of the cell adhesion proteins. Adhesion molecules play an important role in neural and synaptic genesis, and their dysfunction may result in neurodevelopmental abnormalities, which have been assumed to be a factor in the pathogenesis of schizophrenia. To examine the possible involvement of fibronectin in the etiology of schizophrenia, we analyzed six polymorphisms, located in introns 2, 21, 24, and 26, and exons 20 and 28, in the human fibronectin gene (FN1) of schizophrenic patients in the Japanese population (n = 104) and age-and gender-matched controls (n = 104). No significant positive association was observed between either of the polymorphisms and schizophrenia, nor was an association found between either of the polymorphisms and any subtypes of schizophrenia. These data did not provide evidence for a contribution of the FN1 gene to susceptibility to schizophrenia., (Copyright 2002 Wiley-Liss, Inc.)