Journal Article

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 Kamijima, Daniel R. Weinberger, Akira Sawa and Hiroshi Kunugi

in Human Molecular Genetics

Volume 15, issue 20, pages 3024-3033
Published in print October 2006 | ISSN: 0964-6906
Published online September 2006 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddl244
Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling

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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.

Journal Article.  5259 words.  Illustrated.

Subjects: Genetics and Genomics

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