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.

The DISC locus in psychiatric illness

“…25 A similar trend towards decreased hippocampal volume has also been reported in the Finnish population for the DISC1-associated haplotype HEP1. 36 In contrast to these studies, Hashimoto et al 27 did not find decreases in hippocampal volume associated with the Ser704Cys polymorphism in their Japanese control sample; however, they did report decreases in the grey matter of the cingulate cortex, cingulate gyrus and the posterior gyrus, and abnormalities in prefrontal white matter, in carriers of the Cys704 allele. Therefore, while this study supports the idea that the Ser704Cys polymorphism is associated with reductions in brain tissue volume, the regions of volume reduction differ and the allele associated with the reductions differs also.…”

“…43 This evidence favours a haploinsufficiency model of causation, and is supported by RNA interference experiments for DISC1, as outlined in subsequent sections. 27,66,75,87,88 DISC1 mRNA was also shown to be decreased in lymphoblastoid cells derived from bipolar subjects in comparison to control unaffected family members. 93 This decreased expression was associated with a 12 marker DISC1 risk haplotype spanning the full-length of the DISC1 gene; 93 however, this broad haplotype is most likely a surrogate for an as yet unidentified risk variant.…”

“…This Ser704Cys SNP has also recently been associated with schizophrenia in a Han-Chinese population 26 and with risk for developing major depression in a Japanese population. 27 Thomson et al 28 reported the first comprehensive linkage disequilibrium map of the DISC locus and performed an association study using tagging SNPs in a Scottish population sample diagnosed with schizophrenia and bipolar disorder. Consistent with the linkage results from this population, 17 the strongest association was seen with bipolar disorder (four-SNP haplotype spanning intron 4-intron 6 of DISC1), although some evidence for association was also seen for schizophrenia (two-SNP haplotype within intron 6 of DISC1).…”

“…28 Additional sex-specific associations for DISC1 have been reported within the Han-Chinese and Japanese populations, making this a common finding for the DISC locus in relation to its involvement in psychiatric illness. 27,29 A recent association study of Finnish autism and Asperger families detected sex-specific associations of DISC1 with autism spectrum disorders and Asperger syndrome in affected male subjects. 30 This study implicated a microsatellite within DISC1 intron 9, and a three-SNP haplotype, encompassing HEP3, both of which have previously displayed linkage or association to schizophrenia in the Finnish population.…”

“…43 However, this simple model is complicated by our recent observations that the dynamic association is DISC1 and PDE4 isoform-specific (Murdoch et al, in press) and it is clear that there is potential for complex compartmentalized regulation of cAMP signalling through this interaction. Further potential intricacy is added by observations that reduction of DISC1 expression using RNA interference results in reduced levels of active extracellular signal-related kinase (ERK) in cultured rat cortical neurons 27 and at axonal growth cones of neurotrophin-treated cultured rat hippocampal neurons, 87 which may in turn influence PDE4 activity, because ERK phosphorylates, and regulates the activity of, the PDE4 catalytic domain. 137 It is clear that the function of DISC1/PDE4 complexes is likely to be elaborately regulated at many levels and, since both DISC1 and PDE4B have been independently identified as risk factors for major mental illness, it is possible that disturbance of any aspect of this interaction may be an important factor in the aetiology of disorders such as schizophrenia.…”