A putative cis-acting polymorphism in the NOS1 gene is associated with schizophrenia and NOS1 immunoreactivity in the postmortem brain
A putative cis-acting polymorphism in the NOS1 gene is associated with schizophrenia and NOS1 immunoreactivity in the postmortem brain
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DOI：
10.1016/j.schres.2010.05.003
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发表时间：
2010-08-01
影响因子：
4.5
通讯作者：
Hishimoto, Akitoyo
中科院分区：
文献类型：
--
作者：
Cui, Huxing;Nishiguchi, Naoki;Hishimoto, Akitoyo
精神分裂症是一种破坏性的神经发育障碍，其遗传影响仍然难以捉摸。最近的全基因组扫描显示，罕见的结构变异破坏了神经发育通路中的多个基因，这强烈暗示了精神分裂症中的一氧化氮（NO）信号传导。NO作为N-甲基-D天冬氨酸受体激活的第二信使，其进一步与多巴胺能和多巴胺能途径相互作用。脑内NO主要由神经元型一氧化氮合酶1（neuronalnitricoxidesynthase，NOS 1）合成，其基因位点12q24.2作为精神分裂症的一个主要连锁区域而备受关注。NOS 1的遗传变异也与精神分裂症有关，并且在精神分裂症患者的死后脑中观察到NOS 1的差异表达。在这里，我们探讨了一个假定的顺式作用的G-84 A单核苷酸多态性（SNP; rs 41279104）的NOS 1基因的外显子1c启动子区与水平的NOS 1免疫反应性在死后的前额皮质标本，无论疾病表型。具有该SNP的A等位基因的个体显示出显著低于GG纯合子的NOS 1免疫反应性水平（p=0.002）。此外，在日本人群中使用720个个体的病例对照研究揭示了SNP与精神分裂症之间的显著关联（基因型p=0.0013和等位基因p=0.0011）。此外，A等位基因的精神分裂症患者的平均发病年龄显着早于GG纯合子（p=0.018）。当分析考虑到性别时，这种意义对女性来说更显着。这些发现为NOS 1与精神分裂症的生物易感基因相关提供了进一步的证据。(C)2010爱思唯尔有限公司版权所有。
Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. Recent genome-wide scans revealed that rare structural variants disrupted multiple genes in neurodevelopmental pathways, which strongly implicate nitric oxide (NO) signaling in schizophrenia. NO acts as a second messenger of N-methyl-D aspartate receptor activation, which further interacts with both dopaminergic and serotonergic pathways. NO is mainly synthesized by neuronal nitric oxide synthase (NOS1) in the brain, and its gene locus, 12q24.2, has attracted much attention as a major linkage region for schizophrenia. Genetic variations of NOS1 have also been associated with schizophrenia, and differential expression of NOS1 was observed in the postmortem brain of schizophrenic patients. Here, we explored the hypothesis that a putative cis-acting G-84A single nucleotide polymorphism (SNP; rs41279104) in the exon 1c promoter region of the NOS1 gene is associated with the levels of NOS1 immunoreactivity in postmortem prefrontal cortex specimens regardless of disease phenotype. Individuals with the A-allele of this SNP showed significantly lower levels of NOS1 immunoreactivity than did GG homozygotes (p=0.002). Furthermore, a case-control study using 720 individuals in a Japanese population revealed a significant association between the SNP and schizophrenia (genotypic p=0.0013 and allelic p=0.0011). Additionally, the average of onset age in schizophrenic patients with the A-allele was significantly earlier than GG homozygotes (p=0.018). When the analyses took gender into account, this significance was more significant for female. These findings provide further evidences that NOS1 is associated with a biological susceptibility gene to schizophrenia. (C) 2010 Elsevier B.V. All rights reserved.