Elsevier

Psychiatry Research

Volume 185, Issues 1–2, 30 January 2011, Pages 16-19
Psychiatry Research

Association of calcineurin A gamma subunit (PPP3CC) and early growth response 3 (EGR3) gene polymorphisms with susceptibility to schizophrenia in a Japanese population

https://doi.org/10.1016/j.psychres.2009.11.003Get rights and content

Abstract

To examine the association of PPP3CC (rs10108011 and rs2461491) and EGR3 (rs3750192) single-nucleotide polymorphisms (SNPs) with Japanese schizophrenia, we performed a case–control association study using 337 patients and 369 healthy controls. As a result, by our moderated cohort-size study, PPP3CC and EGR3 are not genetic risk factors for schizophrenia, whereas meta-analysis showed weak association of rs10108011 with schizophrenia in the Japanese population (odds ratio (OR) = 1.12, P = 0.01).

Introduction

The pathogenesis of schizophrenia is complex and involves multiple genetic and environmental factors, each contributing a modest increase in risk. So far, no single gene variation has been consistently associated (Tandon et al., 2008). However, a large body of pharmacological studies has suggested that alteration in the regulation of dopamine and glutamate neurotransmitter systems may be an important contributing factor in the pathogenesis of schizophrenia (Collier and Li, 2003).

Calcineurin (CaN), a calcium-dependent serine/threonine protein phosphatase, has been reported to be a downstream molecule of dopaminergic signaling (Greengard, 2001) and be involved in N-methyl d-aspartate (NMDA) receptor-mediated glutamatergic signal transduction (Zeng et al., 2001). Calcineurin consists of a heterodimer composed of a regulatory subunit, CNB, and a catalytic subunit, CNA (Klee et al., 1998). There are three different CNA isoforms encoded by distinct genes; CNAα(PPP3CA), CNAβ(PPP3CB), and CNAγPPP3CC. The expression of calcineurin is particularly enriched in the central nervous system (CNS), where it plays a crucial role in the various neural functions (Groth et al., 2003), suggesting that calcineurin could be a candidate gene for schizophrenia.

First insight that observed the relationship between calcineurin and schizophrenia was reported by Miyakawa et al. (2003). Their forebrain-specific CNB knockout mice displayed similar behavioral abnormalities to patients with schizophrenia. Following that study, genetic association of PPP3CC gene with schizophrenia in a Caucasian population was reported (Gerber et al., 2003). Since then, positive associations of PPP3CC with schizophrenia have been reported in Japanese (Yamada et al., 2007, Horiuchi et al., 2007) and in Taiwanese (Liu et al., 2007) as well as by meta-analysis in Asian populations (Shi et al., 2008). On the other hand, negative associations also have been reported in Japanese (Kinoshita et al., 2005), in Chinese (Xi et al., 2007), and in European population (Sanders et al., 2008).

Recently, Yamada et al. (2007) reported additional susceptibility gene to schizophrenia on 8p21.3 chromosomal region, early growth response 3 (EGR3). The study showed that although PPP3CC and EGR3 are located within close genomic interval, their contribution to genetic risk for schizophrenia is independent. EGR3 is known to be a downstream transcription factor of calcineurin signaling pathway, and its messenger RNA (mRNA) level in the schizophrenia brain was shown to be down-regulated (Yamada et al. 2007). Yamada et al. also demonstrated that other CNA isoforms such as PPP3CA, PPP3CB, and CNB genes are not genetic risk factors for schizophrenia in Japanese.

The current study aimed to examine the association of PPP3CC and EGR3 with susceptibility for schizophrenia in a Japanese population. A case–control association study of PPP3CC single-nucleotide polymorphisms (SNPs); rs10108011 (CC21) and rs2461491 (CCS3), and EGR3 SNP; rs3750192 (M227) was performed using Japanese subjects. We also conducted a meta-analysis by adding our PPP3CC SNP data to previously reported association studies in Asian populations.

Section snippets

Study subjects

The primary subjects consist of 296 patients with schizophrenia and 240 healthy controls. Additional 41 patients and 129 controls were collected, summing up to the total sample set of 337 patients with schizophrenia (171 males and 166 females, average age 52.7 ± 12.9 years) and 369 healthy controls (157 males and 212 females, average age 43.0 ± 16.9 years). The patients were recruited from Kobe University Hospital and diagnosed by International Classification of Diseases, 10th Revision

Association of PPP3CC and EGR3 with schizophrenia in Japanese

First, PPP3CC rs10108011, rs2461491, and EGR3 rs3750192 were genotyped in 296 Japanese patients with schizophrenia and 240 healthy controls using TaqMan® SNP Genotyping Assays. Sequencing data confirmed the accuracy of the assays. We found no significant difference in the distribution of both genotype and allele frequencies between the patients and the controls for any of the SNPs examined (Table 1). The results did not change with adjustment of the age and sex differences between the patients

Discussion

According to the original report on association between PPP3CC and schizophrenia (Gerber et al., 2003), rs10108011 (CC21) and rs2461491 (CCS3) showed significant evidence for association in Caucasian. Both rs10108011 and rs2461491 are intronic SNPs locating within intron 1 and intron 4 of PPP3CC, respectively, and ∼ 40 kb apart from each other. In Caucasian population, disease risk was conferred by one of the four haplotypes at the PPP3CC locus, and notably, rs10108011 tagged its risk haplotype.

Acknowledgments

We thank all the patients and healthy donors, as well as the lab workers who were devoted to collecting and analyzing the samples, especially Mr. Kazuhisa Kishimoto and Ms. Yasuko Nagashima (Kobe University Graduate School of Medicine). The work was supported by 21st Century COE Program and research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The authors declare no conflicts of interest.

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