TY - JOUR
T1 - Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling
AU - Hashimoto, Ryota
AU - Numakawa, Tadahiro
AU - Ohnishi, Takashi
AU - Kumamaru, Emi
AU - Yagasaki, Yuki
AU - Ishimoto, Tetsuya
AU - Mori, Takeyuki
AU - Nemoto, Kiyotaka
AU - Adachi, Naoki
AU - Izumi, Aiko
AU - Chiba, Sachie
AU - Noguchi, Hiroko
AU - Suzuki, Tatsuyo
AU - Iwata, Nakao
AU - Ozaki, Norio
AU - Taguchi, Takahisa
AU - Kamiya, Atsushi
AU - Kosuga, Asako
AU - Tatsumi, Masahiko
AU - Kamijima, Kunitoshi
AU - Weinberger, Daniel R.
AU - Sawa, Akira
AU - Kunugi, Hiroshi
PY - 2006/10/15
Y1 - 2006/10/15
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddl244
DO - 10.1093/hmg/ddl244
M3 - Article
C2 - 16959794
AN - SCOPUS:33749576292
SN - 0964-6906
VL - 15
SP - 3024
EP - 3033
JO - Human molecular genetics
JF - Human molecular genetics
IS - 20
ER -