Elsevier

Neuropharmacology

Volume 58, Issue 2, February 2010, Pages 452-456
Neuropharmacology

Serotonin 1A receptor gene is associated with Japanese methamphetamine-induced psychosis patients

https://doi.org/10.1016/j.neuropharm.2009.09.006Get rights and content

Abstract

Background

Several investigations have reported associations the serotonin 1A (5-HT1A) receptor to schizophrenia and psychotic disorders, making 5-HT1A receptor gene (HTR1A) an adequate candidate gene for the pathophysiology of schizophrenia and methamphetamine (METH)-induced psychosis. Huang and colleagues reported that rs6295 in HTR1A was associated with schizophrenia. The symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia. It may indicate that METH-induced psychosis and schizophrenia have common susceptibility genes. In support of this hypothesis, we reported that the V-act murine thymoma viral oncogene homologue 1 (AKT1) gene was associated with METH-induced psychosis and schizophrenia in the Japanese population. Furthermore, we conducted an analysis of the association of HTR1A with METH-induced psychosis.

Method

Using one functional SNP (rs6295) and one tagging SNP (rs878567), we conducted a genetic association analysis of case-control samples (197 METH-induced psychosis patients and 337 controls) in the Japanese population. The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients.

Results

Rs878567 was associated with METH-induced psychosis patients in the allele/genotype-wise analysis. Moreover, this significance remained after Bonferroni correction. In addition, we detected an association between rs6295 and rs878567 in HTR1A and METH-induced psychosis patients in the haplotype-wise analysis. Although we detected an association between rs6295 and METH-induced psychosis patients, this significance disappeared after Bonferroni correction.

Conclusion

HTR1A may play an important role in the pathophysiology of METH-induced psychosis in the Japanese population. However, because we did not perform a mutation scan of HTR1A, a replication study using a larger sample may be required for conclusive results.

Introduction

Altered serotonergic neural transmission is hypothesized to be a susceptibility factor for schizophrenia (Geyer and Vollenweider, 2008, Meltzer et al., 2003). Several postmortem studies reported increased serotonin 1A (5-HT1A) receptor in the prefrontal cortex of schizophrenic patients (Burnet et al., 1996, Hashimoto et al., 1993, Hashimoto et al., 1991, Simpson et al., 1996, Sumiyoshi et al., 1996). Huang and colleagues reported that rs6295 in an SNP (C-1019G: rs6295) in the promoter region of the 5-HT1A receptor gene (HTR1A), which regulate HTR1A transcription (Le Francois et al., 2008, Lemonde et al., 2003), was associated with schizophrenia (Huang et al., 2004). These facts suggest a crucial relationship between the 5-HT1A receptor and schizophrenia, and that HTR1A is an adequate candidate for the etiology of schizophrenia. HTR1A (OMIM*109 760, 1 exon in this genomic region spanning 2.069 kb) is located on 5q11.

The symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia (Sato et al., 1992). It may indicate that METH-induced psychosis and schizophrenia have common susceptibility genes (Bousman et al., 2009). In support of this hypothesis, we reported that the V-act murine thymoma viral oncogene homologue 1 (AKT1) gene was associated with METH-induced psychosis (Ikeda et al., 2006) and schizophrenia (Ikeda et al., 2004) in the Japanese population. Furthermore, we conducted an analysis of the association of these genes with METH-induced psychosis, using the recently recommended strategy of ‘gene-based’ association analysis (Neale and Sham, 2004).

Section snippets

Subjects

The subjects in the association analysis were 197 METH-induced psychosis patients (164 males: 83.2% and 33 females; mean age ± standard deviation (SD) 37.6 ± 12.2 years) and 337 healthy controls (271 males: 80.4% and 66 females; 37.6 ± 14.3 years). The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients. All subjects were unrelated to each other, ethnically Japanese, and lived in the central area of Japan. The patients were diagnosed

Results

The LD from rs6449693, rs878567 and rs1423691 was tight in from the HapMap database samples (r2 = 1.00). However, the LD structure of rs6295 (functional SNP) and rs878567 (tagging SNP) in our control samples was not tight (r2 = 0.160). Genotype frequencies of all SNPs were in HWE (Table 1). Rs878567 was associated with METH-induced psychosis patients in the allele/genotype-wise analysis (P allele = 0.000122 and P genotype = 0.00103) (Table 1). Moreover, these significances remained after

Discussion

We found associations between HTR1A and Japanese METH-induced psychosis patients. Therefore, we reasoned that HTR1A may play an important role in the pathophysiology of METH-induced psychosis in the Japanese population. However, our samples are small. Although Bonferroni's correction was used to control inflation of the type I error rate, we considered that there is a possibility of type I error in these results.

The 5-HT1A receptor is present in various regions of the brain, including the

Acknowledgements

We thank Ms. M. Miyata and Ms. S. Ishihara for their technical support. This work was supported in part by research grants from the Japan Ministry of Education, Culture, Sports, Science and Technology, the Ministry of Health, Labor and Welfare, and the Health Sciences Foundation (Research on Health Sciences focusing on Drug Innovation).

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