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Glycogen synthase kinase 3β gene polymorphisms may be associated with bipolar I disorder and the therapeutic response to lithium

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Abstract

Background

Glycogen Synthase Kinase 3β (GSK-3β) is thought to be a key feature in the therapeutic mechanism of mood stabilizers (e.g., lithium). Overexpression of GSK-3β might play a role in the pathogenesis of bipolar I disorder. Within the GSK-3β gene, a promoter single nucleotide polymorphism (SNP) rs334558 was identified associated with transcriptional strength, and an intronic SNP rs6438552 was found to regulate selection of splice acceptor sites. The aim of this study is to test the association between the two polymorphisms and bipolar I disorder.

Methods

We genotyped the two SNPs in 138 Taiwanese bipolar I disorder patients and 131 controls. Lithium treatment efficacy was evaluated for 83 patients who had been treated with lithium carbonate for at least 24 months.

Results

We found no association between each of the two SNPs and the risk of bipolar I disorder. Following correction for multiple testing, CT genotype at rs6438552 was associated with an older age of onset than other genotypes (P=0.042) in female patients. Patients with genotype TT at rs334558 (P=0.044) had poorer response to lithium treatment. There was a trend that haplotype C-T increased the risk for bipolar I disorder (adjusted OR=4.22, corrected P=0.084), and patients with haplotype T-T had poorer treatment response to lithium than those with haplotype C-C.

Limitations

Limitations included small sample size, retrospective data collection, and a potential sampling bias.

Conclusions

Despite the several limitations of the study, our results suggested GSK-3β genetic variants may be associated with the risk of bipolar I disorder, age of disease onset in females, and the therapeutic response to lithium.

Introduction

Bipolar I disorder is a chronic, severe and recurrent mood disorder characterized by mood swings between manic and depressive state. This multifactorial disease can interfere with behavior and cognition, leading to a severe impact on patients and families. According to the estimates of the World Health Organization and the World Bank, bipolar disorder is one of the leading causes of handicap throughout the world (World Health Organization, 2011).

Bipolar I disorder is an etiologically complex syndrome but is clearly heritable in a polygene inheritance manner (Sklar et al., 2008). We could decipher the polygenetic disorders by investigating the known treatment target molecules to untangle the disease puzzle. Lithium and valproate are well known effective mood-stabilizing agents in the treatment of bipolar I disorder. Animal experiments provided evidence that lithium inhibits brain GSK-3 activity at a therapeutic dose and suggested GSK-3 as a critical target of lithium in affecting mammalian behaviors (Gould and Manji, 2005, Kozikowski et al., 2007, O'Brien et al., 2011). Valproate has also been proved to have inhibitory effects on GSK-3-regulated pathways (Gould and Manji, 2005). GSK-3 is a serine/threonine kinase. It was first shown to modulate glucose homeostasis by phosphorylating and inactivating glycogen synthase. Moreover, GSK-3 has been shown to be coupled to signaling cascades of many receptors, such as neurotransmitters, neurotrophins, and growth factors (Doble and Woodgett, 2003, Frame and Cohen, 2001, Grimes and Jope, 2001). The GSK-3 downstream substrates are also complicated. Therefore, it is now believed that GSK-3 acts as a multifunctional downstream switch determining the output of several signaling pathways involving in various cellular functions such as cell fate determination, cytoskeleton stability, neurodevelopment, and apoptosis (Kozlovsky et al., 2002). The dysregulation of multifunctional GSK-3 might result in behavioral disturbances. Transgenic mice with over-expressed GSK-3β were shown to have behaviors resembled mania (Prickaerts et al., 2006). Taken together, these data suggested that GSK-3β might play a role in the pathogenesis of bipolar I disorder. Therefore, we designed this study to investigate the genetic variations of GSK-3β in bipolar I disorder patients.

Several single nucleotide polymorphisms of GSK-3β have been studied in bipolar disorders. SNP rs334558 (−50C/T), is located in the effective promoter region (nt −171 to +29) of GSK-3β gene (Russ et al., 2001). This common promoter SNP rs334558 is related to transcriptional strength in vitro, in which the T allele has a stronger activity. It has been reported to be associated with response to lithium treatment and age of disease onset for Italian bipolar I patients (Benedetti et al., 2004a, Benedetti et al., 2004b, Benedetti et al., 2005). These observations suggest carriers of genotype TT at rs334558 had poorer response to lithium than either the TC or CC groups, and the T allele was associated with earlier disease onset. Another association study in Poland found significant differences of genotype distribution and allele frequencies of the rs334558 polymorphism in female bipolar II patients (Szczepankiewicz et al., 2006b). However, the relationship between rs334558 polymorphism and the potential prophylactic lithium response suggested by the Italian group could not be demonstrated in a subsequent study by the Polish group (Szczepankiewicz et al., 2006a). In a Korean study for the association of bipolar disorder with SNPs at rs334558 (−50C/T) and rs3755557 (−1727A/T), the results showed no difference in genotype and haplotype distributions between bipolar cases and healthy controls (Lee et al., 2006).

Another functional intronic SNP rs6438552 (−157C/T) in intron 5, was identified by Kwok et al. in a study of Parkinson's disease (Kwok et al., 2005). rs6438552 regulates the selection of splice acceptor sites, in which the T allele correlates with altered splicing to increase the transcript of lacking exon 9 and 11, moreover, this transcript is shown to increase its phosphorylation activity. A significant association was found between rs6438552 and brain structural changes in recurrent major depressive patients (Inkster et al., 2009).

In this case-control study, we selected the two potentially functional SNPs (rs334558 and rs648552) as markers to investigate the pathological role for GSK-3β in bipolar I disorder. Since there is a great variability among patients in terms of their response to lithium treatment and there is evidence suggesting that genetic factors might play an integral role in lithium treatment response (Serretti and Artioli, 2003), lithium therapeutic efficacy was also examined.

Section snippets

Subjects

We enrolled 138 bipolar I disorder patients (71 male and 67 female patients; 39.6±10.7 years of age) from Taipei City Psychiatric Center, Taipei City Hospital, Taiwan. The patients were diagnosed according to DSM-IV criteria with consensus of at least two experienced psychiatrists on the basis of a SCID interview (First, 1996) and a review of medical records. Exclusion criteria were additional DSM-IV Axis I diagnoses (including schizophrenia, schizoaffective disorder, major depressive disorder,

Results

The mean age and sex distributions of the bipolar I patients and the controls were similar. The genotypes and allele distribution of the two GSK-3β SNPs for the bipolar I patients group and the control group are shown in Table 1. The results showed no association between the two investigated SNPs and the development of bipolar I disorder. The distributions of the genotypes for bipolar I cases and controls were not deviated from Hardy–Weinberg equilibrium (Table 1).

Table 1 also provides the

Discussion

In this study, we investigated whether the two functional SNPs of GSK-3β (rs334558 and rs648552) were associated with bipolar I disorder and the response to lithium treatment. Regarding the genetic risk for bipolar I disorder, no association was shown in the alleles and genotypes of single loci. However, in the subsequent haplotype analyses, we found the C-T haplotype (established by rs334558 and rs648552) may carry a genetic risk for bipolar I disorder. Our results suggested that subjects with

Role of funding source

The funding sponsors did not participate in the design, methods, subject recruitment, data collections, analysis or preparation of paper. The corresponding author had full access to all data in the study and final responsibility for the decision to submit this publication.

Conflict of interest

All authors declare no conflict of interest.

Acknowledgments

We thank the Department of Health, Taipei City Government (Grant 96001-62-037) for their support of this project.

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