Genetic analysis of the gene coding for DARPP-32 (PPP1R1B) in Japanese patients with schizophrenia or bipolar disorder

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Abstract

Several lines of evidence, including genome-wide linkage scans and postmortem brain studies of patients with schizophrenia or bipolar disorder, have suggested that DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32Ā kDa), a key regulatory molecule in the dopaminergic signaling pathway, is involved in these disorders. After evaluating the linkage disequilibrium pattern of the gene encoding DARPP-32 (PPP1R1B; located on 17q12), we conducted association analyses of this gene with schizophrenia and bipolar disorder. Single-marker and haplotypic analyses of four single nucleotide polymorphisms (SNPs; rs879606, rs12601930, rs907094, and rs3764352) in a sample set (subjects with schizophreniaĀ =Ā 384, subjects with bipolar disorderĀ =Ā 318, control subjectsĀ =Ā 384) showed that PPP1R1B polymorphisms were not significantly associated with schizophrenia, whereas, even after Bonferroni corrections, significant associations with bipolar disorder were observed for rs12601930 (corrected genotypic pĀ =Ā 0.00059) and rs907094 (corrected allelic pĀ =Ā 0.040). We, however, could not confirm these results in a second independent sample set (subjects with bipolar disorderĀ =Ā 366, control subjectsĀ =Ā 370). We now believe that the significant association observed with the first sample set was a result of copy number aberrations in the region surrounding these SNPs. Our findings suggest that PPP1R1B SNPs are unlikely to be related to the development of schizophrenia and bipolar disorder in the Japanese population.

Introduction

A number of studies have proposed that disruption of monoaminergic pathways, and in particular the dopaminergic pathway, contributes to both schizophrenia and bipolar disorder (Catapano and Manji, 2007, Murray et al., 2004). DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32Ā kDa), a critical molecule in the striatal neurons, regulates the dopaminergic signaling pathway through phosphorylation of protein phosphatase-1 and protein kinase A (Fienberg et al., 1998). Recently, it has been revealed that DARPP-32 also plays an important role in the regulation of glutamatergic signaling pathway (Nishi et al., 2005), which is also thought to contribute to the development of these disorders (Beneyto et al., 2007, Svenningsson et al., 2003).

DARPP-32 knockout mice have been shown to have abnormal responses to psychoactive drugs, such as the decrease of cage climbing behavior induced by dopamine agonists (Fienberg et al., 1998) and the decrease of attenuating effect of antidepressants on immobility (Svenningsson et al., 2002).

Moreover, reduced expression of DARPP-32 has been observed in the postmortem brain of schizophrenic patients (Albert et al., 2002). This is suggested to be related to neostriatal volume, activation, and functional connectivity in the prefrontal cortex, all of which are thought to be abnormal in patients with schizophrenia (Meyer-Lindenberg et al., 2007).

Additionally, several lines of evidence have demonstrated that genetic factors contribute to the development of schizophrenia and bipolar disorder, and genome-wide linkage scans have shown that several chromosomal regions are simultaneously linked to the development of these disorders. Namely, a chromosomal region within 17q, which includes the gene encoding DARPP-32 (PPP1R1B; located on 17q12), has been demonstrated to have high logarithm of the odds scores for schizophrenia (Cardno et al., 2001) and bipolar disorder (Dick et al., 2003), i.e. 2.54 and 3.63, respectively.

Therefore, PPP1R1B is considered to be one of the candidate genes that contribute to these disorders. In the present study, we performed linkage disequilibrium analysis of PPP1R1B, and investigated the association of polymorphisms in this gene with schizophrenia and bipolar disorder in Japanese patients. We employed a two-stage analysis using two independent sets of samples as a previous report (Ikeda et al., 2005). Additionally, copy number variations (CNVs), which have been observed for many genes (Lee and Lupski, 2006, Redon et al., 2006) can affect the accuracy of genotyping with single nucleotide polymorphisms (SNPs). Therefore, we also explored copy number differences of this gene to test the accuracy of genotyping with the SNPs, which deviated from the Hardyā€“Weinberg equilibrium (HWE).

Section snippets

Subjects

The subjects for the case-control analysis consisted of 384 patients with schizophrenia (226 males and 158 females; 52.1Ā Ā±Ā 15.3Ā years old), 318 patients with bipolar disorder (162 males and 156 females; 44.0Ā Ā±Ā 20.7Ā years old), and 384 control subjects (159 males and 225 females; 43.9Ā Ā±Ā 15.9Ā years old). To confirm a significant association with bipolar disorder, a second sample set was used, which consisted of 366 patients with bipolar disorder (181 males and 185 females; 50.1Ā Ā±Ā 13.4Ā years old), and 370

Results

The genotype and allele frequency of each SNP in schizophrenic patients, bipolar disorder patients, and control subjects are summarized in Table 1 and Table 2-1, respectively. The observed genotype frequencies of the tagging SNPs were within the distribution expected from the HWE except for rs12601930.

Neither the genotype nor the allele frequency of any of the examined PPP1R1B SNPs in the schizophrenic patients differed significantly from those observed for the control subjects (Table 1).

Discussion

According to the common disease-common variants hypothesis (Chakravarti, 1999), the present study showed that PPP1R1B was unlikely to be related to be the development of schizophrenia and bipolar disorder in Japanese patients. These results were consistent with a recently published study that examined Chinese patients (Li et al., 2006).

The SNPs used in the association analysis, which covered the entire gene, included all of the common SNPs (more than 5% frequency) listed in the dbSNP database;

Role of funding source

Funding for this study was provided by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Ministry of Health, Labour and Welfare of Japan; and the Japanese Health Sciences Foundation (Research on Health Sciences Focusing on Drug Innovation). These institutions had no further role in the study design; the collection, analysis, and interpretation of the data; the writing of this report; or the decision to submit the paper for publication.

Contributors

Author Akira Yoshimi, Nagahide Takahashi, and Shinichi Saito designed the study and wrote the protocol. Author Norio Ozaki and Yukihiro Noda performed the literature searches and analyses. Author Akira Yoshimi wrote the first draft of the manuscript and Nagahide Takahashi and Shinichi Saito revised it. All of the authors contributed to and have approved the final version of the manuscript.

Conflict of interest

All authors declare that they have no conflicts of interests.

Acknowledgements

We sincerely thank the patients and healthy volunteers for their participation in our study; Dr. H Hori for helpful discussions; and Dr. R. Ishihara and Ms. Y. Nakamura for their technical assistance. This work was supported in part by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Ministry of Health, Labour and Welfare of Japan; and the Japanese Health Sciences Foundation (Research on Health Sciences Focusing on Drug Innovation).

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