利用孟德尔随机化分析探索治疗重度抑郁症的药物

Exploring medications for treating major depression disorder using Mendelian randomization analysis

本文通过双样本孟德尔随机化分析(two-sample Mendelian randomization,2SMR)开展对重度抑郁症(major depression disorder,MDD)潜在的药物靶点挖掘。从全基因组关联研究(genome-wide association studies,GWAS)中获取关于MDD与注意力缺陷多动症(attention deficit hyperactivity disorder,ADHD)单核苷酸多态性(single nucleotide polymorphism,SNP)的相关数据,在DrugBank数据库中获取关于治疗ADHD的药物及药物靶点的数据,共发现17种不同药物与136个药物靶点。主要分析方法为逆方差加权法,加权中位数法、加权中值法和MR-Egger回归法作为辅助方法,并对显著性结果进行敏感性分析。通过2SMR计算得到CHRNA3(IVW,OR:0.95,95%CI:0.92~0.98,P=0.003)和HTR3A(IVW,OR:0.96,95%CI:0.92~1.00,P=0.04)的高表达会抑制MDD的发生;而SLC6A4、ADRB1、GRIN2A和GRIN2C的高表达会增加MDD的患病风险。本文通过利用2SMR方法揭示了CHRNA3和HTR3A会成为治疗MDD的潜在药物靶点,进而为治疗和预防MDD的研究提供新的思路。

In this paper,we explored the potential drug targets for major depression disorder(MDD)through two-sample Mendelian randomization(2SMR).Data on single nucleotide polymorphism(SNP)in MDD and attention deficit hyperactivity disorder(ADHD)were obtained from genome-wide association studies(GWAS).Additionally,data on drugs and drug targets for treating ADHD are obtained from the DrugBank database,including 17 different drugs and 136 drug targets.The main analysis methods are inverse varianceweighted method(IVW).Weighted median method,weighted mode method,and mendelian randomization-Egger was used as auxiliary methads,with sensitivity analysis performed on significant results.2SMR calculates that high expression of CHRNA3(IVW,OR:0.95,95%CI:0.92-0.98,P=0.003)and HTR3A(IVW,OR:0.96,95%CI:0.92-1.00,P=0.04)inhibits the occurrence of MDD.High expression of SLC6A4,ADRB1,GRIN2A,and GRIN2C increases the risk of MDD.The findings suggest that CHRNA3 and HTR3A will be potential drug targets for the treatment of MDD,which provides new directions for exploring therapeutic options of MDD.