Data_Sheet_1_Mendelian randomization analysis suggests no associations of human herpes viruses with amyotrophic lateral sclerosis.doc

BackgroundThe causal associations between infections with human herpes viruses (HHVs) and amyotrophic lateral sclerosis (ALS) has been disputed. This study investigated the causal associations between herpes simplex virus (HSV), varicella-zoster virus (VZV), Epstein–Barr virus (EBV), cytomegalovirus (CMV), HHV-6, and HHV-7 infections and ALS through a bidirectional Mendelian randomization (MR) method.MethodsThe genome-wide association studies (GWAS) database were analyzed by inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods. MR-Egger intercept test, MR-PRESSO test, Cochran’s Q test, funnel plots, and leaveone-out analysis were used to verify the validity and robustness of the MR results.ResultsIn the forward MR analysis of the IVW, genetically predicted HSV infections [odds ratio (OR) = 0.9917; 95% confidence interval (CI): 0.9685–1.0154; p = 0.4886], HSV keratitis and keratoconjunctivitis (OR = 0.9897; 95% CI: 0.9739–1.0059; p = 0.2107), anogenital HSV infection (OR = 1.0062; 95% CI: 0.9826–1.0304; p = 0.6081), VZV IgG (OR = 1.0003; 95% CI: 0.9849–1.0160; p = 0.9659), EBV IgG (OR = 0.9509; 95% CI: 0.8879–1.0183; p = 0.1497), CMV (OR = 0.9481; 95% CI: 0.8680–1.0357; p = 0.2374), HHV-6 IgG (OR = 0.9884; 95% CI: 0.9486–1.0298; p = 0.5765) and HHV-7 IgG (OR = 0.9991; 95% CI: 0.9693–1.0299; p = 0.9557) were not causally associated with ALS. The reverse MR analysis of the IVW revealed comparable findings, indicating no link between HHVs infections and ALS. The reliability and validity of the findings were verified by the sensitivity analysis.ConclusionAccording to the MR study, there is no evidence of causal associations between genetically predicted HHVs (HSV, VZV, EBV, CMV, HHV-6, and HHV-7) and ALS.

背景：人类疱疹病毒（HHV）感染与肌萎缩侧索硬化症（ALS）之间的因果关联尚存争议。本研究通过双向孟德尔随机化（MR）方法，探究了单纯疱疹病毒（HSV）、水痘-带状疱疹病毒（VZV）、EB病毒（EBV）、巨细胞病毒（CMV）、HHV-6和HHV-7感染与ALS之间的因果关联。方法：通过全基因组关联研究（GWAS）数据库，采用逆方差加权（IVW）、MR-Egger、加权中位数、简单模态和加权模态方法进行分析。运用MR-Egger截距检验、MR-PRESSO检验、Cochran's Q检验、漏斗图和单次移除分析等方法，验证了MR结果的可靠性和稳健性。结果：在IVW的向前MR分析中，遗传预测的HSV感染[比值比（OR）=0.9917；95%置信区间（CI）：0.9685–1.0154；p=0.4886]、HSV角膜炎和结膜炎（OR=0.9897；95% CI：0.9739–1.0059；p=0.2107）、生殖器HSV感染（OR=1.0062；95% CI：0.9826–1.0304；p=0.6081）、VZV IgG（OR=1.0003；95% CI：0.9849–1.0160；p=0.9659）、EBV IgG（OR=0.9509；95% CI：0.8879–1.0183；p=0.1497）、CMV（OR=0.9481；95% CI：0.8680–1.0357；p=0.2374）、HHV-6 IgG（OR=0.9884；95% CI：0.9486–1.0298；p=0.5765）和HHV-7 IgG（OR=0.9991；95% CI：0.9693–1.0299；p=0.9557）与ALS之间无因果关联。IVW的逆向MR分析揭示了相似的发现，表明HHV感染与ALS之间无关联。通过敏感性分析验证了研究结果的可靠性。结论：根据MR研究，遗传预测的HHV（HSV、VZV、EBV、CMV、HHV-6和HHV-7）与ALS之间无因果关联的证据。