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

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