Toru Hori

A Missense Variation in Human Casein Kinase I Epsilon Gene that Induces Functional Alteration and Shows an Inverse Association with Circadian Rhythm Sleep Disorders

Recent studies have shown that functional variations in clock genes, which generate circadian rhythms through interactive positive/negative feedback loops, contribute to the development of circadian rhythm sleep disorders in humans. Another potential candidate for rhythm disorder susceptibility is casein kinase I epsilon (CKIɛ), which phosphorylates clock proteins and plays a pivotal role in the circadian clock. To determine whether variations in CKIɛ induce vulnerability to human circadian rhythm sleep disorders, such as delayed sleep phase syndrome (DSPS) and non-24-h sleep–wake syndrome (N-24), we analyzed all of the coding exons of the human CKIɛ gene. One of the variants identified encoded an amino-acid substitution S408N, eliminating one of the putative autophosphorylation sites in the carboxyl-terminal extension of CKIɛ. The N408 allele was less common in both DSPS (p=0.028) and N-24 patients (p=0.035) compared to controls. When DSPS and N-24 subjects were combined, based on an a priori prediction of a common mechanism underlying both DSPS and N-24, the inverse association between the N408 allele and rhythm disorders was highly significant (p=0.0067, odds ratio=0.42, 95% confidence interval: 0.22–0.79). In vitro kinase assay revealed that CKIɛ with the S408N variation was ∼1.8-fold more active than wild-type CKIɛ. These results indicate that the N408 allele in CKIɛ plays a protective role in the development of DSPS and N-24 through alteration of the enzyme activity.

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.

The glycine transporter 1 gene (GLYT1) is associated with methamphetamine‐use disorder

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.

Glutamate Cysteine Ligase Modifier (GCLM) Subunit Gene Is Not Associated with Methamphetamine-Use Disorder or Schizophrenia in the Japanese Population

A recent study showed a significant association between schizophrenia in European samples and the glutamate cysteine ligase modifier (GCLM) subunit gene, which is the key glutathione (GSH)‐synthesizing enzyme. Since the symptoms of methamphetamine (METH)‐induced psychosis are similar to those of schizophrenia, the GCLM gene is thought to be a good candidate gene for METH‐use disorder or related disorders. To evaluate the association between the GCLM gene and METH‐use disorder and schizophrenia, we conducted a case‐control study of Japanese subjects (METH‐use disorder, 185 cases; schizophrenia, 742 cases; and controls, 819). Four SNPs (2 SNPs from an original report and JSNP database, and 2 “tagging SNPs” from HapMap database) in the GCLM gene were examined in this association analysis; one SNP showed an association with both METH‐use disorder and METH‐induced psychosis. After Bonferronis correction for multiple testing, however, this significance disappeared. No significant association was found with schizophrenia. Our findings suggest that a common genetic variation in the GCLM gene might not contribute to the risk of METH‐use disorder and schizophrenia in the Japanese population.

Association Study of the Dihydropyrimidinase‐Related Protein 2 Gene and Methamphetamine Psychosis

Abstract:  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.

Alpha4 and Beta2 Subunits of Neuronal Nicotinic Acetylcholine Receptor Genes Are Not Associated with Methamphetamine-Use Disorder in the Japanese Population

The mesolimbic system is thought to be involved in the reinforcing action of many addictive drugs and the release of dopamine modulated by neuronal nicotine cholinergic receptors (nAChRs). Several investigations suggested that nAChRs on dopaminergic terminals play an important role in the development of some long‐lasting adaptations associated with drug abuse. A majority of high‐affinity nicotine binding sites in the brain have been showed in heteropentameric alpha4 (alpha4) and beta2 subunit (beta2) of nAChRs. Therefore, we conducted a genetic association analysis of the alpha4 gene (CHRNA4) and beta2 gene (CHRNB2) with methamphetamine (METH)‐use disorder (191 cases and 753 controls). We first evaluated the linkage disequilibrium (LD) structure of these genes and selected 7 and 5 tagging SNPs (tag SNPs) on CHRNA4 and CHRNB2, respectively. Some tag SNPs were significantly associated with total METH‐use disorder and METH‐induced psychosis; however, these associations were no longer statistically significant after Bonferronis correction for multiple testing. In conclusion, our results suggest that neither CHRNA4 nor CHRNB2 plays a major role in Japanese METH‐use disorder.

Reduced CYP2D6 activity is a negative risk factor for methamphetamine dependence

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.

Association Study between Casein Kinase 1 Epsilon Gene and Methamphetamine Dependence

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.

Association Study of the Calcineurin A Gamma Subunit Gene (PPP3CC) and Methamphetamine‐Use Disorder in a Japanese Population

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.

Physical symptoms under forced-phase advance treatment in a patient with delayed sleep phase syndrome: A case report

Abstract The physical symptoms that are observed with forced waking in patients with delayed sleep phase syndrome (DSPS) often prevent the successful treatment of patients. Better understanding of these symptoms will assist in providing appropriate treatment in such patients. Herein, a 19‐year‐old female patient with DSPS is described, in whom headache, fatigue, and dizziness were observed under forced‐phase advance treatment. Statistical analysis showed that her headache was dependent on the therapeutic week, and her fatigue was dependent on the period of the day. There was no association between dizziness and either factor. Experience with this patient indicates that the fatigue observed with forced waking is related to the circadian system. This relationship should be explored for other physical symptoms as well.