目的 探讨巨细胞病毒(CMV)感染与儿童神经发育障碍(NDDs)之间的因果关系,为制定针对性干预措施提供循证依据。方法 基于全基因组关联研究(GWAS)数据,采用两样本孟德尔随机化(TSMR)方法, 分析4种CMV抗体与孤独症谱系障碍(ASD)、注意缺陷多动障碍(ADHD)、智力发育障碍(DID)、抽动障碍(TD)之间的因果关联。因果效应评估主要采用逆方差加权法(IVW),通过Bonferroni校正确定显著性阈值。运用Cochran′s Q检验、MR-Egger回归截距、MR-PRESSO及留一法验证结果的稳健性,并通过反向孟德尔随机化(MR)排除反向因果干扰。结果 TSMR分析结果显示,结合Bonferroni校正后,抗CMV-IgG与ASD风险存在显著正相关(OR=1.333,95%CI:1.103~1.611,P=0.003),提示CMV感染显著增加ASD的发病风险。未发现CMV抗体与ADHD、DID、TD存在因果关系。Cochran′s Q检验显示不存在异质性,MR-Egger回归提示不存在水平多效性,MR-PRESSO检验未发现离群值,留一法支持结果的可靠性。通过反向MR排除反向因果干扰。结论 MR研究证实CMV感染与ASD发病存在遗传预测的正向因果关联,提示围生期CMV防控可能对降低ASD风险具有潜在价值。
Abstract
Objective To investigate the causal relationship between cytomegalovirus (CMV) infection and neurodevelopmental disorders (NDDs) in children,in order to provide evidence for targeted intervention. Methods Using genome-wide association study (GWAS) data, a two-sample Mendelian randomization (TSMR) approach was employed to analyze causal associations between four CMV antibodies and autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), developmental intellectual disability (DID), and tic disorder (TD). The inverse variance weighted (IVW) method was primarily used for causal effect estimation, with Bonferroni correction applied to determine significance thresholds. Robustness of Results was validated via Cochran′s Q test, MR-Egger regression intercept, MR-PRESSO, and leave-one-out analysis. Reverse MR was conducted to exclude reverse causality. Results TSMR analysis under Bonferroni correction revealed a significant positive causal relationship between anti-CMV IgG and ASD risk (OR=1.333, 95%CI:1.103 - 1.611, P=0.003), indicating that CMV infection significantly increased ASD risk. No causal associations were found between CMV antibodies and ADHD, DID, or TD. Cochran′s Q test confirmed no heterogeneity, MR-Egger regression indicated no horizontal pleiotropy, MR-PRESSO detected no outliers, and leave-one-out analysis supported result reliability. Reverse MR excluded reverse causality. Conclusion This Mendelian randomization study confirms a genetically predicted positive causal link between CMV infection and ASD risk, suggesting that perinatal CMV prevention may hold potential value for reducing ASD risk.
关键词
巨细胞病毒 /
神经发育障碍 /
孤独症谱系障碍 /
孟德尔随机化
Key words
cytomegalovirus /
neurodevelopmental disorders /
autism spectrum disorder /
Mendelian randomization
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基金
福建省科技创新联合资金项目(2024Y9547)
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