基于全基因组关联研究数据分析空气污染物与神经发育障碍的因果关系

Causal relationships between common ambient air pollutants and neurodevelopmental disorders based on genome-wide association study data

摘要

目的 探讨主要空气污染物与常见神经发育障碍之间的因果关系,从遗传学角度分析环境暴露在神经发育障碍发生机制中的作用。方法 本研究采用双样本孟德尔随机化(MR)方法,基于大样本欧洲人群的公开全基因组关联研究(GWAS)数据进行分析。暴露变量为5类空气污染物(PM_2.5、PM_2.5-10、PM₁₀、NO₂、NO_X),结局变量为孤独症谱系障碍(ASD)、注意缺陷多动障碍(ADHD)和抽动秽语综合征(TS)3种神经发育障碍,以逆方差加权法(IVW)为主分析方法,并采用加权中位数法、MR-Egger回归、简单模式法和加权模式法等方法进行质量控制,使用异质性检验、水平多效性检验、MR-PRESSO和留一法方法进行敏感性检验,验证结果的稳定性和可靠性。结果 MR分析结果显示,PM_2.5(OR=2.63,95%CI: 1.73~4.01,P<0.01)、NO₂(OR=1.56,95%CI: 1.13~2.16,P<0.01)和NO_x(OR=1.69,95%CI: 1.23~2.34,P<0.01)暴露与ADHD的发病风险存在显著正向因果关联,且在多种补充分析方法中结果方向一致。其余路径(包括PM_2.5-10和PM₁₀与ADHD,所有污染物与ASD和TS)未观察到显著因果关系(P>0.05)。敏感性分析中,MR-Egger截距检验表明结果不存在水平多效性,留一法分析支持结果的稳健性,MR-PRESSO方法提示部分路径存在异质性和潜在异常SNP,但失真检验均未提示显著估计偏移(P>0.05),支持原始估计结果的稳健性。结论 空气污染物PM_2.5、NO₂及NO_X是ADHD危险因素,提示加强对空气污染的控制,对于神经发育障碍的预防与干预具有重要的公共卫生意义。

Abstract

Objective To investigate the potential causal relationships between major ambient air pollutants and common neurodevelopmental disorders (NDDs), so as to explore the role of environmental exposure in the pathogenesis of NDDs from a genetic perspective. Methods A two-sample Mendelian randomization(MR) design was adopted, drawing on large-scale genome-wide association study (GWAS) summary data from individuals of European ancestry.Five common air pollutants (PM_2.5,PM_2.5-10, PM₁₀, NO₂, NO_X) served as exposures and three major NDDs including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD) and Tourette syndrome (TS) were considered as outcomes.The inverse-variance weighted (IVW) method was employed as the primary analytical approach, complemented by weighted median, MR-Egger regression, simple mode, and weighted mode estimators to ensure robustness.Sensitivity analysis included heterogeneity testing (Cochran's Q), horizontal pleiotropy assessment (MR-Egger intercept), MR-PRESSO analysis (global test, outlier detection, and distortion test), and leave-one-out analysis to evaluate the stability and reliability of the causal estimates. Results The MR analysis showed that exposure to PM_2.5 (OR=2.63, 95%CI: 1.73 - 4.01, P<0.01), NO₂(OR=1.56, 95%CI:1.13 - 2.16, P<0.01) and NO_x(OR=1.69, 95%CI: 1.23 - 2.34, P<0.01) was significantly associated with an increased risk of ADHD, and these associations remained consistent across multiple complementary analytical methods.No significant causal effects were observed for PM_2.5-10 or PM₁₀ on ADHD, nor for any air pollutants on ASD or TS (P>0.05).Sensitivity analysis indicated no evidence of directional pleiotropy based on the MR-Egger intercepts,and the robustness of the causl estimate was further supported by leave-one-out analysis.While some heterogeneity and potential outlier SNPs were detected, MR-PRESSO distortion tests showed no significant bias in causal estimates (P>0.05), reinforcing the robustness of the original findings. Conclusion Air pollutants PM_2.5,NO₂ and NO_X are confirmed as environmental risk factors contributing to the development of ADHD, indicating the critical public health importance of enhancing air pollution control measures for the prevention and intervention of NDDs.

关键词

空气污染 / 神经发育障碍 / 全基因组关联研究 / 孟德尔随机化

Key words

air pollution / neurodevelopmental disorders / genome-wide association study / Mendelian randomization

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基金资助

江苏省科教能力提升工程(JSDW202219)