Tokutaro Komiyama

Association between severity of alcoholism and the A1 allele of the dopamine D2 receptor gene TaqI A RFLP in Japanese

The allelic association of TaqI A restriction fragment length polymorphism (RFLP) of the dopamine D2 receptor gene with alcoholism was examined in 78 Japanese alcoholics and compared with Japanese controls. A significantly higher frequency of the A1 allele (0.42) was found in 100 Japanese unscreened controls compared with those reported in white populations. Among 70 alcoholics whose severities were determined, the A1 allele was present in 77% of 43 more severe alcoholics and in 59% of 27 less severe alcoholics. The A1 allele was present significantly less frequently in the alcoholics at the age of 60 or older (42%), compared with those under the age of 60 (74%). In the subjects under the age of 60, the A1 allele was present in 83% of the 35 more severe alcoholics, being significantly more frequent than in 60% of the 35 nonalcoholic controls. All of the 7 alcoholics homozygous for the A1 allele were classified as severe. The average severity of alcoholism increased in the order A2/A2, A1/A2, and A1/A1 genotypes. These data suggest that the A1 allele is associated with severe alcoholism in the Japanese population and that the effect is related to or has a linkage disequilibrium with a genetic factor that has a small but not negligible additive effect on alcoholism.

Nine- or fewer repeat alleles in VNTR polymorphism of the dopamine transporter gene is a strong risk factor for prolonged methamphetamine psychosis.

ABSTRACTSusceptibility to drug dependence and drug-induced psychoses is influenced not only by the pharmacological effects of the drug but also by the genetic factors of the individual. To clarify the latter, we investigated the association between methamphetamine (METH) dependence/psychosis and the hDAT1 gene (SLC6A3) encoding the dopamine transporter, which is the primary site of METH activity in the brain. Four exonic polymorphisms of the hDAT1 gene, 242C/T (exon 2), 1342A/G (exon 9), 2319G/A (3′UTR), and VNTR (3′UTR) were examined. Although there was no significant difference in genotypic and allelic distribution of the four polymorphisms between all METH dependence/psychosis patients (N=124) and controls (N=160), the patients with METH psychosis lasting for 1 month or more after discontinuance of METH consumption showed a significant excess of nine- or fewer repeat alleles of the VNTR in 3′UTR of the hDAT1 gene (P=0.0054, OR=4.24, 95% CI=2.46–7.31). The present study demonstrated that the presence of nine- or fewer repeat alleles of hDAT1 is a strong risk factor for a worse prognosis of METH psychosis.

The Dysbindin Gene (DTNBP1) Is Associated with Methamphetamine Psychosis

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.

Gene Polymorphisms of the Mu Opioid Receptor in Methamphetamine Abusers

Abstract: In drug addiction, the opioid system is thought to mediate motivational effects through dopamine‐independent mechanisms. We have investigated associations of the μ‐opioid receptor gene (OPRM) variations with methamphetamine (MAP) dependence/psychosis. The allelic frequency of A118G (Asn40Asp) in exon 1 of ORPM was 45.3% in our control subjects, but only 7.5‐25.8% in the Caucasian or African‐American population of previous studies. We have identified several novel polymorphisms in intron 1 and the 5′ untranslated region (5′UTR) of OPRM. Polymorphisms in the functionally relevant 5′ regulatory region of OPRM were different in our Japanese population from Caucasian or African‐American populations. No significant differences between controls and MAP abusers were found in either genotype or allele frequency at any single nucleotide polymorphism (SNP) or (AC)n dinucleotide repeat in intron 1. A subdivision of our MAP group revealed that A118G of OPRM shows a significant association with MAP psychosis having latency less than three years. Further analysis should be capable of identifying associations between the OPRM variations and MAP dependence/psychosis.

Association study between brain-derived neurotrophic factor gene polymorphisms and methamphetamine abusers in Japan.

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.

A nonsynonymous polymorphism in the human fatty acid amide hydrolase gene did not associate with either methamphetamine dependence or schizophrenia.

Genetic contributions to the etiology of substance abuse and dependence are topics of major interest. Acute and chronic cannabis use can produce drug-induced psychosis resembling schizophrenia and worsen positive symptoms of schizophrenia. The endocannabinoid system is one of the most important neural signaling pathways implicated in substance abuse and dependence. The fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme of endocannabinoids. To clarify a possible involvement of FAAH in the etiology of methamphetamine dependence/psychosis or schizophrenia, we examined the genetic association of a nonsynonymous polymorphism of the FAAH gene (Pro129Thr) by a case-control study. We found no significant association in allele and genotype frequencies of the polymorphism with either disorder. Because the Pro129Thr polymorphism reduces enzyme instability, it is unlikely that dysfunction of FAAH and enhanced endocannabinoid system induce susceptibility to either methamphetamine dependence/psychosis or schizophrenia.

A functional glutathione S‐transferase P1 gene polymorphism is associated with methamphetamine‐induced psychosis in Japanese population

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.

Haplotype association between GABAA receptor gamma2 subunit gene (GABRG2) and methamphetamine use disorder

Psychostimulant use disorder and schizophrenia have a substantial genetic basis. Evidence from human and animal studies on the involvement of the γ-aminobutyric acid (GABA) system in methamphetamine (METH) use disorder and schizophrenia is mounting. As we tested for the association of the human GABAA receptor gamma 2 subunit gene (GABRG2) with each diagnostic group, we used a case–control design with a set of 178 subjects with METH use disorder, 288 schizophrenics and 288 controls. First, we screened 96 controls and identified six SNPs in GABRG2, three of whom we newly reported. Next, we selected two SNPs, 315C>T and 1128+99C>A, as representatives of the linkage disequilibrium blocks for further case–control association analysis. Although no associations were found in either allelic or genotypic frequencies, we detected a haplotypic association in GABRG2 with METH use disorder, but not with schizophrenia. This finding partly replicates a recent case–control study of GABRG2 in METH use disorder, and thus indicates that GABRG2 may be one of the susceptibility genes of METH use disorder.

Linkage disequilibrium and association with methamphetamine dependence/psychosis of μ -opioid receptor gene polymorphisms

Several studies indicate that the μ-opioid receptor plays a role in addiction not only to opiate drugs but also to alcohol and non-opiate addictive drugs. Our studies aim to reveal the associations between gene polymorphisms and methamphetamine (MAP) dependence/psychosis. We newly identified several polymorphisms and four substantial linkage disequilibrium (LD) blocks in the μ-opioid receptor (OPRM1) gene. We found significant differences in both genotype and allele frequencies of the single-nucleotide polymorphism (SNP) IVS2+G691C between control (n=232) and MAP-dependent/psychotic patients (n=128). There was also a significant association between IVS2+G691C and patients with transient psychosis. These results suggest that the OPRM1 gene variations may be a factor in development and prognosis of MAP psychosis.

Study of Association between α-Synuclein Gene Polymorphism and Methamphetamine Psychosis/Dependence

Abstract: Methamphetamine (MAP) dissipates proton gradients across the membranes of synaptic vesicles, enhances cytoplasmic dopamine (DA) concentrations, and causes calcium‐independent, nonvesicular DA release into synapses. MAP is taken into the cytosol by the dopamine transporter (DAT) on the synaptic terminals of DA neurons, and endogenous DA is concurrently released through the transporter by carrier exchange mechanisms, resulting in a robust increase in DA concentration in the synaptic clefts. The enhanced DA release through DAT by MAP is the main mechanism for the reinforcing effects of MAP. The complexes of α‐synuclein and DAT facilitate membrane clustering of the DAT, thereby accelerating DA uptake in vitro. α‐Synuclein has been shown to be overexpressed in the midbrain DA neurons of chronic cocaine abusers. The present study was performed to study the association between the α‐synuclein gene polymorphisms and MAP psychosis/dependence in Japanese population. Since the T10A7 polymorphic site at the 5′ end of the noncoding exon 1′ in the α‐synuclein gene is highly polymorphic, we analyzed the noncoding exon 1′ and intron 1, including this polymorphic site by sequencing. We confirmed four single nucleotide polymorphisms (SNPs) within 1.38 kbp of the T10A7 polymorphic site. No significant difference was found in genotype or allele frequencies in the T10A7 polymorphic site between MAP psychotic/dependent and control subjects. We found significant association between three SNPs in the vicinity of this polymorphic site in intron 1 and MAP psychosis/dependence in female subjects, but not in males. These results suggest an association of the α‐synuclein gene polymorphisms with MAP psychosis/dependence in our female subjects. Further analyses are necessary to clarify the gender difference, by using a larger sample size and/or different ethnic groups, as well as functional variations in the α‐synuclein gene.