NOS1AP基因非编码区位点多态性与精神分裂症的关联研究

Association study of non-coding variant of NOS1AP gene with schizophrenia

目的·明确一氧化氮合成酶1接头蛋白(nitric oxide synthase 1 adaptor protein,NOS1AP)基因与中国汉族人群精神分裂症患者的相关性,并对NOS1AP基因阳性多态性位点变异引起的RNA和蛋白质的二级结构改变进行预测。方法·选择2012年10月至2015年12月期间上海交通大学医学院附属精神卫生中心收治的333例早发性精神分裂症(early onset schizophrenia,EOS)患者和491例非早发性精神分裂症(non-early onset schizophrenia,non-EOS)患者,通过招募方式在上海交通大学医学院附属精神卫生中心的职工和复旦大学附属中山医院青浦分院体检中心的受检人群中筛选901名健康对照(health control,HC),用TaqMan探针检测3组人群NOS1AP基因rs12742393、rs4145621和rs1415263位点多态性。使用SHEsis在线软件进行各位点Hardy-Weinberg(H-W)平衡检验,分析等位基因和基因型频率的分布。通过SNPstats在线网站进行最优遗传模型的分析。利用RNAfold软件和DNAstar软件对阳性多态性位点变异引起的RNA和蛋白质的二级结构改变进行预测。结果·3个多态性位点基因型频率在各组中均符合H-W遗传平衡(P>0.05)。经Bonferroni校正后,EOS组与HC组相比,NOS1AP基因rs12742393位点等位基因和基因型频率分布差异均具有统计学意义(P=0.012,P=0.039)。遗传模型分析发现rs12742393位点最优基因型分布符合显性遗传模式(P=0.004)。软件预测发现,rs12742393位点A等位基因变异成C等位基因后,NOS1AP基因编码RNA和蛋白质的二级结构发生重要改变,导致空间稳定性下降。结论·NOS1AP基因非编码区rs12742393位点对EOS易感性存在重要影响。

Objective·To clarify the correlation between nitric oxide synthase 1 adaptor protein(NOS1AP)gene and Han Chinese schizophrenia patients,and predict the changes in the secondary structure of RNA and protein caused by variation of NOS1AP gene positive polymorphism.Methods·From October 2012 to December 2015,333 patients with early onset schizophrenia(EOS)and 491 patients with non-early onset schizophrenia(non-EOS)were included from Shanghai Mental Health Center,Shanghai Jiao Tong University School of Medicine,and 901 healthy controls(HC)were selected from the staff of Shanghai Mental Health Center,Shanghai Jiao Tong University School of Medicine and the people receiving physical examination in the Physical Examination Center of Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University through recruitment.The rs12742393,rs4145621 and rs1415263 polymorphisms of NOS1AP gene were detected by TaqMan probe.The Hardy-Weinberg(H-W)equilibrium of the three polymorphism loci and the allele and genotype frequencies were analyzed by the SHEsis online software.The optimal genetic model analysis was carried out by the SNPstats online website.RNAfold and DNAstar softwares were used to predict the secondary structures of RNA and protein encoded by the significantly different polymorphism locus.Results·The distribution of genotypes fit H-W equilibrium(P>0.05).There were significant difference in allele and genotype frequencies between EOS patients and HC subjects for rs12742393 after Bonferroni correction(P=0.012,P=0.039).Genetic model analysis found that the distribution of genotypes best fit the dominant genetic pattern(P=0.004).After the mutation of the A allele into the C allele for rs12742393,the secondary structures of RNA and protein encoded by the NOS1AP gene underwent important changes,resulting in the decrease in spatial stability.Conclusion·The NOS1AP rs12742393 polymorphism has a major influence on susceptibility to EOS.