Schizophrenia Research 141 (2012) 279–280

Contents lists available at SciVerse ScienceDirect

Schizophrenia Research

j ourna l homepage: www.e lsev ie r .com/ locate /schres

Letter to the Editor

Supportive evidence for the association between the Gln2Propolymorphism in the SIGMAR1 gene and schizophrenia in theJapanese population: A case–control study and anupdated meta-analysis

Dear Editors,

Sigma non-opioid intracellular receptor 1 (SIGMAR1) is aligand-operated chaperone regulating neuronal survival, synaptogenesisand neuronal plasticity (for a review see Hayashi et al., 2011).Postmortem studies reported contradictory results of sigma receptorsbinding in brains from patients with schizophrenia (for a review seeHayashi et al., 2011). Clinical studies suggest that SIGMAR1 ligandsmay not possess antipsychotic-like effects against positive symptoms,but possibly ameliorate negative symptoms (for a review see Hayashiet al., 2011). Nevertheless, SIGMAR1 is likely to play a role in the patho-physiology of schizophrenia, enabling SIGMAR1 to serve as a potentialcandidate gene for schizophrenia.

To date, all studies on the association between SIGMAR1 andschizophrenia have been performed in the Japanese population. Themost extensively investigated SIGMAR1 polymorphism is Gln2Pro(rs1800866). The first reported study found an association betweenthe Pro allele and schizophrenia (Ishiguro et al., 1998), however sub-sequent studies failed to replicate the association (Ohmori et al.,2000; Uchida et al., 2003; Satoh et al., 2004; Takizawa et al., 2009;Ohi et al., 2011). Recently, a meta-analysis reported a marginally sig-nificant association between the Pro allele and schizophrenia (Ohi etal., 2011), although the significance of the association may have beeninfluenced by an overestimation of the effect size in the first study. In-deed, the association did not remain significant after omission of thestudy by Ishiguro et al. (1998), although Ohi et al. (2011) did not per-form a sensitivity analysis. Thus, the association between Gln2Pro andschizophrenia remains to be determined. To assess whether theSIGMAR1 Gln2Pro polymorphism confers increased susceptibility toschizophrenia, we conducted a case–control study and an updatedmeta-analysis.

The present study was approved by the Ethics Committee ofGenetics at the Niigata University School of Medicine, and written in-formed consent was obtained from all participants. All participantswere unrelated and of Japanese descent. The study population com-prised 644 patients with schizophrenia (348 men and 296 women;mean age 39.7±13.8 years), diagnosed according to the Diagnosticand Statistical Manual of Mental Disorders Fourth Edition criteria,and 671 mentally healthy individuals (338 men and 333 women;mean age 38.3±10.8 years), with no personal or family history(within first-degree relatives) of psychiatric disorders. Patient andcontrol groups were matched for sex, but not for age (p=0.048,t-test). However, differences in mean age between the groupswere relatively small (1.4 years). A psychiatric assessment of eachparticipant was conducted, as previously described (Watanabe et al.,2006).

0920-9964/$ – see front matter © 2012 Elsevier B.V. All rights reserved.doi:10.1016/j.schres.2012.06.043

We genotyped Gln2Pro using the TaqMan 5′-exonuclease assay(assay ID, C_8342715_10; Applied Biosystems, Foster City, CA), as previ-ously described (Watanabe et al., 2006). Deviations from the Hardy–Weinberg equilibrium (HWE) were tested using the χ2 test forgoodness of fit. Genotypic and allelic associations were tested usingthe Cochran–Armitage test for trends and the χ2 test, respectively. Afixed effect model meta-analysis was performed using catmap (http://cran.r-project.org/src/contrib/Archive/catmap/), as previously described(Watanabe et al., 2007). A probability level of pb0.05 indicated statisti-cal significance. A power calculation was performed using the GeneticPower Calculator (http://pngu.mgh.harvard.edu/~purcell/gpc/).

The genotype distributions of Gln2Pro did not deviate significantlyfrom the HWE in either group (Supplementary Table 1). There was amarginally significant association between the Pro allele andschizophrenia (p=0.049). Next, we performed a meta-analysis using atotal sample size of 4143 individuals, from seven independent Japanesepopulations (Table 1). The Pro allele was found to be significantly associ-ated with schizophrenia (odds ratio [OR]=1.14, 95% confidenceinterval=1.04–1.25, p=0.006), without heterogeneity among ORs.Sensitivity analysis showed that the combined ORs remained significantafter the sequential omission of individual studies (Supplementary Fig.1). Linear regression analysis showed no significant funnel plot asym-metry (Supplementary Fig. 2), suggesting no existence of publicationbias.

In the present study, we have replicated the association betweenthe SIGMAR1 Gln2Pro polymorphism and schizophrenia in our Japa-nese population, thereby confirming the study of Ishiguro et al.(1998). In contrast, other published studies have failed to find a signif-icant association, but this may be due to the insufficient statisticalpower of individual studies. The sample size of our population (n=1315) was one of the largest sample sizes examined. Nevertheless,under the multiplicative model of inheritance, our sample size hadonly a statistical power of 0.60 for detecting the association with anα of 0.05, assuming a disease prevalence of 0.01, a risk allele frequencyof 0.30 and a genotypic relative risk of 1.44 for homozygous risk allelecarriers. We also performed a meta-analysis to assess the collectiveevidence across individual studies and confirmed the association be-tween the Pro allele and schizophrenia. In conclusion, our case–con-trol study and updated meta-analysis provide supportive evidencefor the contribution of the SIGMAR1 Gln2Pro polymorphism to schizo-phrenia susceptibility in the Japanese population.

Supplementary data related to this article can be found online athttp://dx.doi.org/10.1016/j.schres.2012.06.043.

ContributorsAuthor Watanabe designed the study, performed laboratory assays, undertook

statistical analysis, and wrote the first draft of the manuscript. Authors Nunokawa,Kaneko, Shibuya and Egawa recruited the participants. Author Someya supervisedthe study. All authors contributed to and have approved the final manuscript.

Conflict of interestNone of the authors has a conflict of interest to declare.

Table 1Meta-analysis of case–control association studies between the SIGMAR1 Gln2Propolymorphism and schizophrenia in the Japanese population.

Study Patients Controls OR 95% CI

n Gln Pro n Gln Pro

Ishiguro et al.(1998)

308 414 202 433 624 242 1.26 1.01–1.57

Ohmori et al.(2000)

129 177 81 140 205 75 1.25 0.86–1.82

Uchida et al.(2003)

199 271 127 206 278 134 0.97 0.72–1.31

Satoh et al.(2004)

100 142 58 104 146 62 0.96 0.63–1.47

Takizawa et al.(2009)

40 53 27 60 86 34 1.29 0.70–2.37

Ohi et al.(2011)

478 626 330 631 850 412 1.09 0.91–1.30

Current study 644 875 413 671 959 383 1.18 1.00–1.40Pooled a 1898 2245 1.14 1.04–1.25

Abbreviations: CI, confidence interval; OR, odds ratio; SIGMAR1, sigma non-opioidintracellular receptor 1.

a χ2=7.55, df=1, p=0.006 for the association; Q=3.31, df=6, p=0.768 for theheterogeneity; t=−0.23, df=5, p=0.285 for the publication bias.

280 Letter to the Editor

AcknowledgmentsThe authors thank the patients, their families and the healthy volunteers for par-

ticipation; Drs. Inoue, Nemoto and Houya for cooperation in recruiting participants;Mr. Kusano and Ms. Yamazaki for excellent technical assistance.

References

Hayashi, T., Tsai, S.Y., Mori, T., Fujimoto, M., Su, T.P., 2011. Targeting ligand-operatedchaperone sigma-1 receptors in the treatment of neuropsychiatric disorders.Expert Opin. Ther. Targets 15 (5), 557–577.

Ishiguro, H., Ohtsuki, T., Toru, M., Itokawa, M., Aoki, J., Shibuya, H., Kurumaji, A., Okubo,Y., Iwawaki, A., Ota, K., Shimizu, H., Hamaguchi, H., Arinami, T., 1998. Associationbetween polymorphisms in the type 1 sigma receptor gene and schizophrenia.Neurosci. Lett. 257 (1), 45–48.

Ohi, K., Hashimoto, R., Yasuda, Y., Fukumoto, M., Yamamori, H., Umeda-Yano, S., Kamino,K., Ikezawa, K., Azechi, M., Iwase, M., Kazui, H., Kasai, K., Takeda, M., 2011. TheSIGMAR1 gene is associated with a risk of schizophrenia and activation of the prefron-tal cortex. Prog. Neuropsychopharmacol. Biol. Psychiatry 35 (5), 1309–1315.

Ohmori, O., Shinkai, T., Suzuki, T., Okano, C., Kojima, H., Terao, T., Nakamura, J., 2000.Polymorphisms of the σ1 receptor gene in schizophrenia: an association study.Am. J. Med. Genet. 96 (1), 118–122.

Satoh, F., Miyatake, R., Furukawa, A., Suwaki, H., 2004. Lack of association betweensigma1 receptor gene variants and schizophrenia. Psychiatry Clin. Neurosci. 58(4), 359–363.

Takizawa, R., Hashimoto, K., Tochigi, M., Kawakubo, Y., Marumo, K., Sasaki, T., Fukuda, M.,Kasai, K., 2009. Association between sigma-1 receptor gene polymorphism and pre-frontal hemodynamic response induced by cognitive activation in schizophrenia.Prog. Neuropsychopharmacol. Biol. Psychiatry 33 (3), 491–498.

Uchida, N., Ujike, H., Nakata, K., Takaki, M., Nomura, A., Katsu, T., Tanaka, Y., Imamura,T., Sakai, A., Kuroda, S., 2003. No association between the sigma receptor type 1

gene and schizophrenia: results of analysis andmeta-analysis of case–control studies.BMC Psychiatry 3, 13.

Watanabe, Y., Muratake, T., Kaneko, N., Nunokawa, A., Someya, T., 2006. No associationbetween the brain-derived neurotrophic factor gene and schizophrenia in a Japanesepopulation. Schizophr. Res. 84 (1), 29–35.

Watanabe, Y., Nunokawa, A., Kaneko, N., Someya, T., 2007. Meta-analysis of case–control association studies between the C270T polymorphism of the brain-derivedneurotrophic factor gene and schizophrenia. Schizophr. Res. 95 (1–3), 250–252.

Yuichiro WatanabeDepartment of Psychiatry, Niigata University Graduate School of Medical

and Dental Sciences, Niigata, JapanDivision of Medical Education, Comprehensive Medical Education Center,

School of Medicine, Faculty of Medicine, Niigata University,Niigata, Japan

Corresponding author at: Department of Psychiatry,Niigata University Graduate School of Medical and Dental Sciences,757 Asahimachidori-ichibancho, Chuo-ku, Niigata 951‐8510, Japan.

Tel.: +81 25 227 2213; fax: +81 25 227 0777.E-mail address: yuichiro@med.niigata-u.ac.jp

Ayako NunokawaDepartment of Psychiatry, Niigata University Graduate School of Medical

and Dental Sciences, Niigata, JapanNiigata Psychiatric Center, Nagaoka, Japan

Naoshi KanekoDepartment of Psychiatry, Niigata University Graduate School of Medical

and Dental Sciences, Niigata, JapanOojima Hospital, Sanjo, Japan

Masako ShibuyaDepartment of Psychiatry, Niigata University Graduate School of Medical

and Dental Sciences, Niigata, JapanHealth Administration Center, Headquarters for Health Administration,

Niigata University, Niigata, Japan

Jun EgawaDepartment of Psychiatry, Niigata University Graduate School of Medical

and Dental Sciences, Niigata, JapanDepartment of Psychiatry, National Hospital Organization,

Saigata National Hospital, Joetsu, Japan

Toshiyuki SomeyaDepartment of Psychiatry, Niigata University Graduate School of Medical

and Dental Sciences, Niigata, Japan

1 January 2012