title: Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling.
abstract: Disrupted-in-schizophrenia 1 (DISC1), identified in a pedigree with a familial psychosis with the chromosome translocation (1:11), is a putative susceptibility gene for psychoses such as schizophrenia and bipolar disorder. Although there are a number of patients with major depressive disorder (MDD) in the family members with the chromosome translocation, the possible association with MDD has not yet been studied. We therefore performed an association study of the DISC1 gene with MDD and schizophrenia. We found that Cys704 allele of the Ser704Cys single-nucleotide polymorphism (SNP) was associated with an increased risk of developing MDD (P=0.005, odds ratio=1.46) and stronger evidence for association in a multi-marker haplotype analysis containing this SNP (P=0.002). We also explored possible impact of Ser704Cys on brain morphology in healthy volunteers using MR imaging. We found a reduction in gray matter volume in cingulate cortex and a decreased fractional anisotropy in prefrontal white matter of individuals carrying the Cys704 allele compared with Ser/Ser704 subjects. In primary neuronal culture, knockdown of endogenous DISC1 protein by small interfering RNA resulted in the suppression of phosphorylation of ERK and Akt, whose signaling pathways are implicated in MDD. When effects of sDISC1 (Ser704) and cDISC1 (Cys704) proteins were examined separately, phosphorylation of ERK was greater in sDISC1 compared with cDISC1. A possible biological mechanism of MDD might be implicated by these convergent data that Cys704 DISC1 is associated with the lower biological activity on ERK signaling, reduced brain gray matter volume and an increased risk for MDD.
authors.affiliation: Osaka-Hamamatsu Joint Research Center for Child Mental Development, Osaka University Graduate School of Medicine, D3, 2-2 Yamadaoka, 4-1-1 Suita, Osaka 565-0871, Japan. hashimor@psy.med.osaka-u.ac.jp
authors.forename: Ryota
authors.initials: R
authors.lastname: Hashimoto
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Numakawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohnishi
authors.forename: Emi
authors.initials: E
authors.lastname: Kumamaru
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yagasaki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ishimoto
authors.forename: Takeyuki
authors.initials: T
authors.lastname: Mori
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Nemoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Adachi
authors.forename: Aiko
authors.initials: A
authors.lastname: Izumi
authors.forename: Sachie
authors.initials: S
authors.lastname: Chiba
authors.forename: Hiroko
authors.initials: H
authors.lastname: Noguchi
authors.forename: Tatsuyo
authors.initials: T
authors.lastname: Suzuki
authors.forename: Nakao
authors.initials: N
authors.lastname: Iwata
authors.forename: Norio
authors.initials: N
authors.lastname: Ozaki
authors.forename: Takahisa
authors.initials: T
authors.lastname: Taguchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kamiya
authors.forename: Asako
authors.initials: A
authors.lastname: Kosuga
authors.forename: Masahiko
authors.initials: M
authors.lastname: Tatsumi
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Kamijima
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.forename: Akira
authors.initials: A
authors.lastname: Sawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kunugi
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D001921:Brain / Q000473:pathology*; D016022:Case-Control Studies; D003865:Major Depressive Disorder / Q000097:blood / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D049452:Green Fluorescent Proteins; D006801:Humans; D020935:MAP Kinase Signaling System; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D014162:Transfection
chemical_list: C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D048049:Extracellular Signal-Regulated MAP Kinases