Zhang Yanxia, Fan Mei, Wang Qingzhong, He Guang, Fu Yingmei, Li Huafang, Yu Shunying
Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, 600 Wan Ping Nan Road, Shanghai 200030, China.
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, 600 Wan Ping Nan Road, Shanghai 200030, China.
Sci Rep. 2015 Aug 10;5:12984. doi: 10.1038/srep12984.
Disturbances in glutamate signaling caused by disruption of N-methyl-D-aspartate-type glutamate receptor (NMDAR) have been implicated in schizophrenia. Findings suggested that miR-219, miR-132 and miR-107 could involve in NMDAR signaling by influencing the expression of pathway genes or the signaling transmission and single nucleotide polymorphisms (SNPs) within miRNA genes or miRNA target sites could result in their functional changes. Therefore, we hypothesized that SNPs in miRNAs and/or their target sites were associated with schizophrenia. 3 SNPs in hsa-pri-miR-219/132/107 and 6 SNPs in 3'UTRs of GRIN2A/2B/3A and CAMK2G were selected and genotyped in a case-control study of 1041 schizophrenia cases and 953 healthy controls in Chinese Han population. In the present study, GRIN2B rs890 showed significant associations with schizophrenia. Further functional analyses showed that the rs890 variant C allele led to significantly lower luciferase activity, compared with the A allele. MDR analysis showed that a 4-locus model including rs107822, rs2306327, rs890 and rs12342026 was the best model. These findings suggest that GRIN2B may be associated with schizophrenia and interaction effects of the polymorphisms in hsa-miR-219, CAKM2G, GRIN2B and GRIN3A may confer susceptibility to schizophrenia in the Chinese Han population.
由N-甲基-D-天冬氨酸型谷氨酸受体（NMDAR）破坏引起的谷氨酸信号传导紊乱与精神分裂症有关。研究结果表明，miR-219、miR-132和miR-107可能通过影响通路基因的表达或信号传导参与NMDAR信号传导，并且miRNA基因或miRNA靶位点内的单核苷酸多态性（SNP）可能导致其功能改变。因此，我们假设miRNA及其靶位点中的SNP与精神分裂症有关。在一项针对1041例精神分裂症患者和953名中国汉族健康对照的病例对照研究中，对hsa-pri-miR-219/132/107中的3个SNP以及GRIN2A/2B/3A和CAMK2G的3'UTR中的6个SNP进行了基因分型。在本研究中，GRIN2B rs890与精神分裂症显示出显著关联。进一步的功能分析表明，与A等位基因相比，rs890变异体C等位基因导致荧光素酶活性显著降低。多因素降维分析表明，包含rs107822、rs2306327、rs890和rs12342026的四基因座模型是最佳模型。这些发现表明，GRIN2B可能与精神分裂症有关，并且hsa-miR-219、CAKM2G、GRIN2B和GRIN3A中多态性的相互作用可能使中国汉族人群易患精神分裂症。
