Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling
Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling
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DOI：
10.1093/hmg/ddl244
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发表时间：
2006-10-15
影响因子：
3.5
通讯作者：
Kunugi, Hiroshi
中科院分区：
文献类型：
--
作者：
Hashimoto, Ryota;Numakawa, Tadahiro;Kunugi, Hiroshi
DISC1基因是一家系中发现的具有染色体易位(1：11)的家族性精神病患者，可能是精神分裂症和双相情感障碍等精神病的易感基因。虽然有染色体易位的家族成员中有一些患有严重抑郁障碍(MDD)的患者，但与MDD的可能联系尚未被研究。因此，我们进行了一项DISC1基因与MDD和精神分裂症的相关性研究。我们发现Ser704Cys单核苷酸多态的Cys704等位基因与患MDD的风险增加相关(P=0.005，优势比=1.46)，并且在包含该SNP的多标记单倍型分析中有更强的相关性(P=0.002)。我们还利用磁共振成像技术研究了Ser704Cys对健康志愿者脑形态的可能影响。我们发现携带Cys704等位基因的受试者与Ser704受试者相比，扣带皮质灰质体积减少，前额叶白质各向异性分数降低。在原代培养的神经元中，小干扰RNA下调内源性DISC1蛋白导致ERK和Akt的磷酸化受到抑制，其信号通路参与了MDD的发生。当分别检测sDISC1(Ser704)和cDISC1(Cys704)蛋白的作用时，sDISC1的ERK磷酸化程度高于cDISC1。结果提示，Cys704 DISC1与ERK信号转导活性降低、脑灰质体积减少、MDD发病风险增加有关。
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.