GSK-3b 50 T/C Polymorphism And Lithium Maintenance Treatment In Bipolar Disorder

Background Bipolar Disorder is a chronic debilitating mental illness requiring long term medications. Bipolar disorder also has heritability of 80%, thus probably indicating an underlying genetic etiology. Glycogen Synthase Kinase (GSK) is a serine/threonine kinase. GSK3-b is an essential element of the Wnt/beta-catenin pathway. GSK-3B gene has been mapped to chromosome 3q13.3, a potential susceptibility locus for bipolar disorder. GSK-3B 50 T/C single nucleotide polymorphism (SNP) falls into the effective promoter region (nt − 171 to + 29) of the GSK-3B gene and the presence of T allele is noted to increase the transcriptional activity. GSK-3B is also directly inhibited by Lithium which is widely used in the prophylaxis of Bipolar Disorder. Earlier Studies have also found a positive correlation between Mutant C allele carriers of 50 T/C SNP and better response to Lithium. Methods 441 patients with Diagnosis of Bipolar Disorder according to DSM-IV were recruited from all patients attending Outpatient Services of National Institute of Mental Health and Neurological Sciences (NIMHANS). The diagnosis was confirmed using Clinical Interview and MINI 5.0.0. Genotype analysis for 189 patients selected was done for GSK-3B -50 T/C using PCR-RFLP method. Treatment response has been assessed using “Retrospective Criteria of Long Term Treatment Response in Research Subjects with Bipolar Disorder” for 95 patients for whom NIMH life charts were available Results Of all the 441 patients who were selected for the study, demographic analysis was done with the mean age at onset being 21.40 years (SD- 6.940). Lifetime psychotic symptoms were noted among 377 subjects. The genotype Frequencies for the GSK-3B 50 T/C polymorphism CC-25.9%, TC-47.6%, TT-26.5% for 189 patients, did not deviate significantly from Hardy-Weinberg equilibrium. Of the patients who were C allele carriers (N=78) there were 14 subjects who were poor responders (score less than or equal 3) and 64 subjects who were good responders (score >3).However this difference was not significant(p>0.05,Spearman’s correlation p>0.05). No statistically significant correlation was found between GSK-3B 50 T/C SNP and the clinical parameters that were studied including age at onset(n=186), and presence of psychotic symptoms(n=186) (all p>0.05) Discussion The study did not duplicate the favorable response to Lithium among patients who carry C allele in GSK-3B 50T/C SNP using a well validated scale to assess lithium response like “Retrospective Criteria of Long Term Treatment Response in Research Subjects with Bipolar Disorder” scale probably owing to difference in the allelic frequencies in the studied population. In a previous study by Benedetti et al,2008 among 60 Caucasian subjects had CC- 5%, TC-40%, TT-55% which significantly varies with the frequencies noted in the studied population. The limitation being that study was under-powered to assess the allelic association and a larger study is being completed currently. The study though did not find any positive association of GSK-3B 50 T/C with other clinical parameters that were studied. No other previous studies have looked into the association between the studied SNP and clinical parameters of Bipolar Disorder in this population. We are also in the process of doing gene expression analysis from cell lines (lymphoblastoid, induced pluripotent) derived from patients with this SNP to obtain further insights into the mechanism of Lithium in bipolar disorder.