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Rs6454674, Rs806368 and Rs1049353 CNR1 Gene Polymorphisms in Turkish Bipolar Disorder Patients: A Preliminary Study

Gökay Alpak, Sertan Çöpoğlu, Esra Geyik, Ahmet Ünal, Mehri İğci, Yusuf Ziya İğci, İbrahim Bozgeyik, Feridun Bülbül, Haluk A. Savaş.

Abstract
Bipolar disorder (BD) is one of the most prevalent psychiatric disorders in clinical practice. The etiology of the BD is not thoroughly understood. Endocannabinoid system, which is involved in regulation of emotion, stress, memory, and cognition, may have an important role in the pathophysiology of BD. Mutations on the cannabinoid-1 receptor (CNR1) gene are associated with several psychiatric disorders. The main cannabinoid (CB) receptor is CB1 and its activation inhibits neuronal depolarization. One previous study showed rs1049353 polymorphism of CNR1 gene is associated with major depression but not with BD. In this study, we aimed to investigate the rs6454674, rs806368 and rs1049353 CNR1 gene polymorphisms in Turkish BD patients. A total of 96 patients and 58 healthy controls were included in the current case-control study. Blood samples of study participants were collected into sterile tubes and processed to obtain genomic DNA. Restriction Fragment Length Polymorphism analysis were done by digesting the PCR products with HpyCH4III and BseGI enzymes for the rs6454674 and rs806368 restriction sites, respectively. Single-Strand Conformation Polymorphism (SSCP) analysis was also performed. Among three polymorphisms investigated in this study, only rs6454674 polymorphism was significantly different between BD patients and controls (rs6454674 T/G; p=0.042, rs806368 T/C; p>0.05, rs1049353 A/G; p>0.05). Furthermore, we found that the mean of the yearly manic attacks was statistically higher in patients who have heterozygote (0.91±0.67) rs6454674 T/G polymorphisms compared to those with homozygote (p=0.043) polymorphism. The post-hoc analysis showed that the main differences were between the heterozygotes genotype and non-mutant (GG) homozygotes (0.42±0.31; p=0.037) but not in homozygote mutant genotype (0.74±0.74; p=0.149). When patients were compared with the other clinical parameters, and mutated alleles and genotypes for each polymorphism, we did not find any significant difference. These results suggest that a heterozygote advantage exists for the CNR1 gene rs6454674 polymorphism in manic episode frequency in Turkish BD patients. The results of our study should be confirmed in future studies with larger sample size.

Key words: CNR1 gene, polymorphisms, bipolar disorder



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