整合全基因组关联研究和大脑表达数量性状位点探究精神分裂症重要风险基因  

Integrate genome-wide association studies and expression quantitative trait loci to explore novel susceptibility genes for schizophrenia

作　　者：贾婷婷 张程程[1] Jia Tingting;Zhang Chengcheng(Mental Health Center,West China Hospital of Sichuan University,Chengdu 610041,China)

机构地区：[1]四川大学华西医院心理卫生中心,成都610041

出　　处：《中华精神科杂志》2022年第5期399-407,共9页Chinese Journal of Psychiatry

基　　金：中国博士后科学基金(2020M673247);四川省科技厅重点研发项目(2021YFS0248);大学生创新创业训练计划项目(C2022121154)。

摘　　要：目的探究精神分裂症表达异常的致病风险基因。方法选取56418例精神分裂症患者与78818名健康对照者的全基因组关联研究(genome-wide association study,GWAS)数据和大脑表达数量性状位点(expression quantitative trait loci,eQTLs),采用基于汇总数据的孟德尔随机化(summary data-based mendelian randomization analysis,SMR)整合分析精神分裂症的重要风险致病基因,并采用精神分裂症患者尸脑背外侧前额叶皮质第3层和第5层锥体神经元、人诱导多能干细胞(human induced pluripotent stem cell,hiPSC)和全血表达数据集进行差异表达分析,以验证风险基因表达失调情况。结果基于SMR共发现16个精神分裂症风险基因(P_(SMR)<5×10^(-6)),分别为C4A、HLA-C、EMB、SLC9B1、PCDHA7、BTN3A2、KRT8P46、PCDHA8、SFMBT1、PCCB、WBP1L、BTN3A3、MUSTN1、PPM1M、TYW5和SF3B1。差异表达分析结果进一步验证显示,SF3B1在大脑背外侧前额叶皮质第3层和第5层锥体神经元(P_(adjust)=5.22×10^(-3))和hiPSC(P_(adjust)=1.41×10^(-4))中表达水平均显著下调。WBP1L在hiPSC(P_(adjust)=1.28×10^(-8))和全血(P_(adjust)=1.17×10^(-4))中表达水平均显著上调。TYW5(P_(adjust)=3.06×10^(-6))在hiPSC中表达水平显著上调,PCCB(P_(adjust)=1.34×10^(-4))、BTN3A2(P_(adjust)=1.48×10^(-3))、PPM1M(P_(adjust)=5.13×10^(-6))和PCDHA8(P_(adjust)=4.31×10^(-2))在hiPSC中表达水平显著下调。BTN3A3(P_(adjust)=2.18×10^(-2))在全血中表达水平显著下调。结论精神分裂症风险基因SF3B1、TYW5、PCCB、BTN3A2、PPM1M、PCDHA8、WBP1L和BTN3A3异常表达可增加发病风险。Objective To explore novel susceptibility genes for schizophrenia with aberrant expression.Methods The expression quantitative trait loci(eQTLs)dataset was combined with the genome-wide association study(GWAS)results from 56418 patients with schizophrenia and 78818 healthy controls using summary data-based mendelian randomization(SMR)methodology.Datasets from dorsolateral prefrontal cortex layer 3 and 5 pyramidal cells,human induced pluripotent stem cells and whole blood were used to identify differential expression of novel genes discovered using SMR.Results A total of 16 novel schizophrenia susceptibility genes were identified based on SMR,that is,C4A,HLA-C,EMB,SLC9B1,PCDHA7,BTN3A2,KRT8P46,PCDHA8,SFMBT1,PCCB,WBP1L,BTN3A3,MUSTN1,PPM1M,TYW5 and SF3B1.In dorsolateral prefrontal cortex layer 3 and 5 pyramidal cells,differential expression analysis revealed that SF3B1(P_(adjust)=5.22×10^(-3))was down-regulated.In induced pluripotent stem cells,SF3B1(P_(adjust)=1.41×10^(-4)),PCCB(P_(adjust)=1.34×10^(-4)),BTN3A2(P_(adjust)=1.48×10^(-3)),PPM1M(P_(adjust)=5.13×10^(-6))and PCDHA8(P_(adjust)=4.31×10^(-2))were considerably down-regulated,whereas WBP1L(P_(adjust)=1.28×10^(-8))and TYW5(P_(adjust)=3.06×10^(-6))were dramatically up-regulated.In whole blood,WBP1L(P_(adjust)=1.17×10^(-4))was considerably up-regulated,while BTN3A3(P_(adjust)=2.18×10^(-2))was down-regulated.Conclusion The abnormal expression of schizophrenia risk genes SF3B1,TYW5,PCCB,BTN3A2,PPM1M,PCDHA8,WBP1L and BTN3A3 could increase the risk of the development of schizophrenia.

关 键 词：精神分裂症 数量性状基因座位 全基因组关联研究 易感基因 

分 类 号：R749.3[医药卫生—神经病学与精神病学]