Human Molecular Genetics Advance Access published online on September 7, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl244
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 The Osaka-Hamamatsu Joint Research Center For Child Mental Development, Osaka University Graduate School of Medicine, D3, 2-2, Yamadaoka, Suita, Osaka, 4-1-1, Suita, Osaka 565-0871, Japan; Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
* To whom correspondence should be addressed. DISC1 (Disrupted in schizophrenia 1), identified in a pedigree with familial psychosis with 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 of gray matter volume in cingulate cortex and 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 (siRNA) 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 lower biological activity on ERK signaling, reduced brain gray matter volume and an increased risk for MDD.
Received May 22, 2006
Revised August 8, 2006
Accepted September 4, 2006
Article
Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology, and ERK signaling
Ryota Hashimoto 1 *, Tadahiro Numakawa 2, Takashi Ohnishi 3, Emi Kumamaru 2, Yuki Yagasaki 2, Tetsuya Ishimoto 4, Takeyuki Mori 3, Kiyotaka Nemoto 5, Naoki Adachi 2, Aiko Izumi 2, Sachie Chiba 6, Hiroko Noguchi 2, Tatsuyo Suzuki 7, Nakao Iwata 7, Norio Ozaki 8, Takahisa Taguchi 4, Atsushi Kamiya 9, Asako Kosuga 10, Masahiko Tatsumi 10, Kunitoshi Kamijima 10, Daniel R. Weinberger 11, Akira Sawa 12, and Hiroshi Kunugi 2
2 Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
3 Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan; Department of Radiology, National Center Hospital of Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
4 Neuronics R. G. Special Division for Human Life Technology, National Institute of Advanced Industrial Science and Technology, Ikeda, Osaka, Japan
5 Department of Radiology, National Center Hospital of Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
6 Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, Koganei, Tokyo, Japan
7 Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
8 Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
9 Department Psychiatry, Johns Hopkins University, Baltimore, MD, USA
10 Department of Psychiatry, Showa University School of Medicine, Tokyo, Japan
11 Genes, Cognition, and Psychosis Program, Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA
12 Department of Psychiatry, Department of Neuroscience, Program in Cellular Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Ryota Hashimoto, E-mail: hashimor{at}psy.med.osaka-u.ac.jp
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. Nakata, B. K. Lipska, T. M. Hyde, T. Ye, E. N. Newburn, Y. Morita, R. Vakkalanka, M. Barenboim, Y. Sei, D. R. Weinberger, et al. DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms PNAS, September 15, 2009; 106(37): 15873 - 15878. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Schumacher, G. Laje, R. A. Jamra, T. Becker, T. W. Muhleisen, C. Vasilescu, M. Mattheisen, S. Herms, P. Hoffmann, A. M. Hillmer, et al. The DISC locus and schizophrenia: evidence from an association study in a central European sample and from a meta-analysis across different European populations Hum. Mol. Genet., July 15, 2009; 18(14): 2719 - 2727. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Tomppo, W. Hennah, J. Miettunen, M.-R. Jarvelin, J. Veijola, S. Ripatti, P. Lahermo, D. Lichtermann, L. Peltonen, and J. Ekelund Association of Variants in DISC1 With Psychosis-Related Traits in a Large Population Cohort Arch Gen Psychiatry, February 1, 2009; 66(2): 134 - 141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. E. Burdick, A. Kamiya, C. A. Hodgkinson, T. Lencz, P. DeRosse, K. Ishizuka, S. Elashvili, H. Arai, D. Goldman, A. Sawa, et al. Elucidating the relationship between DISC1, NDEL1 and NDE1 and the risk for schizophrenia: Evidence of epistasis and competitive binding Hum. Mol. Genet., August 15, 2008; 17(16): 2462 - 2473. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Prasad and M. S. Keshavan Structural Cerebral Variations as Useful Endophenotypes in Schizophrenia: Do They Help Construct "Extended Endophenotypes"? Schizophr Bull, July 1, 2008; 34(4): 774 - 790. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. M. Palo, M. Antila, K. Silander, W. Hennah, H. Kilpinen, P. Soronen, A. Tuulio-Henriksson, T. Kieseppa, T. Partonen, J. Lonnqvist, et al. Association of distinct allelic haplotypes of DISC1 with psychotic and bipolar spectrum disorders and with underlying cognitive impairments Hum. Mol. Genet., October 15, 2007; 16(20): 2517 - 2528. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Murdoch, S. Mackie, D. M. Collins, E. V. Hill, G. B. Bolger, E. Klussmann, D. J. Porteous, J. K. Millar, and M. D. Houslay Isoform-Selective Susceptibility of DISC1/Phosphodiesterase-4 Complexes to Dissociation by Elevated Intracellular cAMP Levels J. Neurosci., August 29, 2007; 27(35): 9513 - 9524. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kamiya, T. Tomoda, J. Chang, M. Takaki, C. Zhan, M. Morita, M. B. Cascio, S. Elashvili, H. Koizumi, Y. Takanezawa, et al. DISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1 Hum. Mol. Genet., November 15, 2006; 15(22): 3313 - 3323. [Abstract] [Full Text] [PDF]
|
|