The genetic association of DUSP6 with bipolar disorder and its effect on ERK activity

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• 作者：Se Hyun Kim^a ; Soon Young Shin^b ; Kyu Young Lee^c ; Eun Jeong Joo^c ; Joo Youn Song^a ; ^d ; Yong Min Ahn^a ; ^e ; Young Han Lee^b ; Yong Sik Kim^a ; ^d ; ^e ; ^{kys@snu.ac.kr}
• 关键词：BD ; bipolar disorder ; COMT ; catechol-O-methyltransferase ; DIGS ; Diagnostic Interview for Genetic Studies ; DISC1 ; disrupted in schizophrenia 1 ; DMEM ; Dulbecco's modified Eagle's medium ; DNA ; deoxyribonucleic acid ; DUSP ; dual-specificity phosphatase ; ERK ; e
• 刊名：Progress in Neuro-Psychopharmacology and Biological Psychiatry
• 出版年：2012
• 期刊代码：222_02785846
• 类别：med
• 出版时间：27 April, 2012
• 卷：37
• 期：1
• 页码：41-49
• 文件大小：502 K

摘要

The dual-specificity phosphatase 6 (DUSP6) gene resides at chromosome location 12q22-23, which is one of the candidate loci for susceptibility to bipolar disorder and which encodes a phosphatase selective for extracellular signal-regulated kinase (ERK). Previously, we reported a positive association between the functional Leu114Val polymorphism (rs2279574) in DUSP6 and bipolar disorder. Given that the association between DUSP6 and the reported down-regulation of DUSP6 transcript in bipolar postmortem brains were sex-dimorphic, showing significance in women but not men, we performed two independent analyses in homogenous samples of male and female Korean patients with bipolar disorder or schizophrenia using samples enlarged from our previous report. Among the examined DUSP6 SNPs, five (rs769700, rs704076, rs770087, rs808820, and rs2279574) showed positive allelic associations, with the frequency of minor alleles (C, T, G, G, and G) in each SNP significantly increased in women with BD. Consequently, the 鈥淐-T-G-G-G鈥?haplotype was significantly over-represented (P = 0.016; OR = 3.242), whereas the 鈥淭-G-T-A-T鈥?haplotype was significantly under-represented (P = 0.014; OR = 0.697). We found no significant associations with DUSP6 SNPs in men with bipolar disorder or schizophrenia. We also investigated the functions of the functional SNPs' positive associations and found that Leu114Val (rs2279574; T/G) and Ser144Ala (rs770087; T/G) mutations in DUSP6 proteins reduced lithium-induced ERK1/2 phosphorylation in vitro, implicating the dominant active functions. Thus, DUSP6 may not only play important roles in the pathogenesis of bipolar disorder, particularly in women, but also affect the therapeutic response to lithium through modulating lithium's effects on intracellular signaling.