title: The genetic association of DUSP6 with bipolar disorder and its effect on ERK activity.
abstract: 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 "C-T-G-G-G" haplotype was significantly over-represented (P=0.016; OR=3.242), whereas the "T-G-T-A-T" 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.
authors.affiliation: Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Se Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Shin
authors.forename: Kyu Young
authors.initials: KY
authors.lastname: Lee
authors.forename: Eun Jeong
authors.initials: EJ
authors.lastname: Joo
authors.forename: Joo Youn
authors.initials: JY
authors.lastname: Song
authors.forename: Yong Min
authors.initials: YM
authors.lastname: Ahn
authors.forename: Young Han
authors.initials: YH
authors.lastname: Lee
authors.forename: Yong Sik
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000328:Adult; D000483:Alleles; D001714:Bipolar Disorder / Q000201:enzymology* / Q000235:genetics*; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics*; D004789:Enzyme Activation / Q000235:genetics / Q000502:physiology; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055815:Young Adult
chemical_list: C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6