精神分裂症和抗结核药物所致肝损伤共同致病基因的筛选与验证

目的筛选并验证抗结核药物所致肝损伤(anti-tuberculosis drug-induced hepatotoxicity,ATDH)与精神分裂症(schizophrenia,SCZ)之间可能的共同致病基因。方法通过查询基因数据库及文献,分别确定ATDH和SCZ的致病基因,利用重启动随机游走(integrating network random walk with restart,RWR)、基因富集分析(gene set enrichment analysis,GSEA)和超几何检验等生物信息学分析技术筛选出两种疾病的可能共同致病基因,建立定期更新的两种疾病共同致病基因在线数据库(www.bio-x.cn/atdh-sczgenes.html),查阅文献以进一步筛选与ATDH和SCZ都有关的基因;利用meta分析等方法验证候选基因,以最终确定共同致病基因。结果经信息学分析技术筛选,共获得500个候选共同致病基因。进一步经文献检索,得到GSTM1和GSTT1基因为候选共同致病基因并纳入meta分析。Meta分析显示,GSTM1基因同ATDH(P=0.01)和SCZ(P0.01)相关均有统计学意义;而GSTT1基因同ATDH和SCZ的发病风险关系均无统计学意义(P0.05)。结论 GSTM1基因为ATDH和SCZ的共同致病基因。

Identification and validation of common susceptible genes for ATDH and schizophrenia

Objective To identify and validate the common susceptible genes for schizophrenia (SCZ) and anti-tuberculosis drug-induced hepatotoxicity (ATDH).Methods ATDH-related genes and SCZ-related genes were identified through seeking GenBank and were confirmed through literature review.A new network-based pipeline was proposed to identify potential common key causal genes that influence the development of these two diseases by integrating network random walk with restart (RWR) algorithm,gene set enrichment analysis (GSEA) and hypergeometric test.Then,a field synopsis or systemic meta-analysis of published studies was conducted to assess these candidate causal genes.Results Five hundred candidate genes were identified as potential common causal genes for both ATDH and SCZ after screening by our proposed method.During validation of these 500 candidate genes,only GSTM1 and GSTT1 were found to be widely studied with a plenty of multi-center study data.Meta-analysis results indicated that the GSTM1 present genotype was significantly associated with a decreased risk of ATDH (P=0.01) and SCZ (P＜0.01).Conclusion GSTM1 may be a causal gene for both ATDH and SCZ.