Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling.
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.
Hashimoto
Ryota
R
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
Numakawa
Tadahiro
T
Ohnishi
Takashi
T
Kumamaru
Emi
E
Yagasaki
Yuki
Y
Ishimoto
Tetsuya
T
Mori
Takeyuki
T
Nemoto
Kiyotaka
K
Adachi
Naoki
N
Izumi
Aiko
A
Chiba
Sachie
S
Noguchi
Hiroko
H
Suzuki
Tatsuyo
T
Iwata
Nakao
N
Ozaki
Norio
N
Taguchi
Takahisa
T
Kamiya
Atsushi
A
Kosuga
Asako
A
Tatsumi
Masahiko
M
Kamijima
Kunitoshi
K
Weinberger
Daniel R
DR
Sawa
Akira
A
Kunugi
Hiroshi
H
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
C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D048049:Extracellular Signal-Regulated MAP Kinases