Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling

Ryota Hashimoto, Tadahiro Numakawa, Takashi Ohnishi, Emi Kumamaru, Yuki Yagasaki, Tetsuya Ishimoto, Takeyuki Mori, Kiyotaka Nemoto, Naoki Adachi, Aiko Izumi, Sachie Chiba, Hiroko Noguchi, Tatsuyo Suzuki, Nakao Iwata, Norio Ozaki, Takahisa Taguchi, Atsushi Kamiya, Asako Kosuga, Masahiko Tatsumi, Kunitoshi KamijimaDaniel R. Weinberger, Akira Sawa, Hiroshi Kunugi

Research output: Contribution to journalArticle

209 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3024-3033
Number of pages10
JournalHuman molecular genetics
Volume15
Issue number20
DOIs
Publication statusPublished - 15-10-2006

Fingerprint

Major Depressive Disorder
Schizophrenia
Depression
Brain
Psychotic Disorders
Single Nucleotide Polymorphism
Alleles
Phosphorylation
Chromosomes, Human, Pair 1
Gyrus Cinguli
Anisotropy
Pedigree
Bipolar Disorder
Haplotypes
Small Interfering RNA
Genes
Healthy Volunteers
Proteins
Chromosomes
Odds Ratio

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Hashimoto, R., Numakawa, T., Ohnishi, T., Kumamaru, E., Yagasaki, Y., Ishimoto, T., ... Kunugi, H. (2006). Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling. Human molecular genetics, 15(20), 3024-3033. https://doi.org/10.1093/hmg/ddl244
Hashimoto, Ryota ; Numakawa, Tadahiro ; Ohnishi, Takashi ; Kumamaru, Emi ; Yagasaki, Yuki ; Ishimoto, Tetsuya ; Mori, Takeyuki ; Nemoto, Kiyotaka ; Adachi, Naoki ; Izumi, Aiko ; Chiba, Sachie ; Noguchi, Hiroko ; Suzuki, Tatsuyo ; Iwata, Nakao ; Ozaki, Norio ; Taguchi, Takahisa ; Kamiya, Atsushi ; Kosuga, Asako ; Tatsumi, Masahiko ; Kamijima, Kunitoshi ; Weinberger, Daniel R. ; Sawa, Akira ; Kunugi, Hiroshi. / Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling. In: Human molecular genetics. 2006 ; Vol. 15, No. 20. pp. 3024-3033.
@article{9949be3820194732849eb7b006d5af0f,
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.",
author = "Ryota Hashimoto and Tadahiro Numakawa and Takashi Ohnishi and Emi Kumamaru and Yuki Yagasaki and Tetsuya Ishimoto and Takeyuki Mori and Kiyotaka Nemoto and Naoki Adachi and Aiko Izumi and Sachie Chiba and Hiroko Noguchi and Tatsuyo Suzuki and Nakao Iwata and Norio Ozaki and Takahisa Taguchi and Atsushi Kamiya and Asako Kosuga and Masahiko Tatsumi and Kunitoshi Kamijima and Weinberger, {Daniel R.} and Akira Sawa and Hiroshi Kunugi",
year = "2006",
month = "10",
day = "15",
doi = "10.1093/hmg/ddl244",
language = "English",
volume = "15",
pages = "3024--3033",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "20",

}

Hashimoto, R, Numakawa, T, Ohnishi, T, Kumamaru, E, Yagasaki, Y, Ishimoto, T, Mori, T, Nemoto, K, Adachi, N, Izumi, A, Chiba, S, Noguchi, H, Suzuki, T, Iwata, N, Ozaki, N, Taguchi, T, Kamiya, A, Kosuga, A, Tatsumi, M, Kamijima, K, Weinberger, DR, Sawa, A & Kunugi, H 2006, 'Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling', Human molecular genetics, vol. 15, no. 20, pp. 3024-3033. https://doi.org/10.1093/hmg/ddl244

Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling. / Hashimoto, Ryota; Numakawa, Tadahiro; Ohnishi, Takashi; Kumamaru, Emi; Yagasaki, Yuki; Ishimoto, Tetsuya; Mori, Takeyuki; Nemoto, Kiyotaka; Adachi, Naoki; Izumi, Aiko; Chiba, Sachie; Noguchi, Hiroko; Suzuki, Tatsuyo; Iwata, Nakao; Ozaki, Norio; Taguchi, Takahisa; Kamiya, Atsushi; Kosuga, Asako; Tatsumi, Masahiko; Kamijima, Kunitoshi; Weinberger, Daniel R.; Sawa, Akira; Kunugi, Hiroshi.

In: Human molecular genetics, Vol. 15, No. 20, 15.10.2006, p. 3024-3033.

Research output: Contribution to journalArticle

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.

UR - http://www.scopus.com/inward/record.url?scp=33749576292&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33749576292&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddl244

DO - 10.1093/hmg/ddl244

M3 - Article

C2 - 16959794

AN - SCOPUS:33749576292

VL - 15

SP - 3024

EP - 3033

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 20

ER -

Hashimoto R, Numakawa T, Ohnishi T, Kumamaru E, Yagasaki Y, Ishimoto T et al. Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling. Human molecular genetics. 2006 Oct 15;15(20):3024-3033. https://doi.org/10.1093/hmg/ddl244