Human Molecular Genetics Advance Access originally published online on September 7, 2006
Human Molecular Genetics 2006 15(20):3024-3033; doi:10.1093/hmg/ddl244
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Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling
1 The Osaka-Hamamatsu Joint Research Center For Child Mental Development and 2 Department of Psychiatry, Osaka University Graduate School of Medicine, D3, 2-2 Yamadaoka, 4-1-1 Suita, Osaka 565-0871, Japan, 3 Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan, 4 Department of Radiology, National Center Hospital of Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan, 5 Neuronics R.G. Special Division for Human Life Technology, National Institute of Advanced Industrial Science and Technology, Ikeda, Osaka, Japan, 6 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, MD, USA and 12 Department of Psychiatry and 13 Department of Neuroscience, Program in Cellular Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
* To whom correspondence should be addressed. Tel: +81 668793074; Fax: +81 668793059; Email: hashimor{at}psy.med.osaka-u.ac.jp
Received May 22, 2006; Revised August 8, 2006; Accepted September 4, 2006
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.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.
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