Multi-omics causal inference of childhood asthma triggered by ambient particulate matter

Background The causal impact of PM 2.5 , an established environmental risk factor, on childhood asthma and its biological mechanisms remain to be elucidated. Objective To evaluate the causal association between PM 2.5 and childhood asthma and to dissect the mediating role of plasma proteins through a multi-omics integrated Mendelian randomization (MR) framework. Methods Two-sample MR was performed on large-scale genome-wide association data to estimate the causal effect of PM 2.5 on childhood asthma. Genes commonly associated with PM 2.5 and childhood asthma were screened by transcriptome-wide association study (TWAS) and subjected to enrichment analyses and MR. Mediator proteins were identified by two-step MR. Potential adverse effects were scanned by phenome-wide MR (Phe-MR). Results MR revealed a significant positive causal effect of PM 2.5 on childhood asthma (OR=1.897, 95% CI: 1.063–3.388, p=0.030). TWAS highlighted 70 genes co-expressed in PM 2.5 and childhood asthma that were enriched in inflammatory pathways such as lysosome- and leukocyte-mediated immunity. MEAF6 was validated as a protective gene and RNF40 as a risk gene for childhood asthma. Two-step MR identified FUT10 as a positive mediator mediating 19.3% of the causal effect, and CD200 and MANBA as negative mediator proteins. Phe-MR indicated the association of these genes and proteins with multiple other diseases, implying possible adverse effects from therapeutic intervention. Conclusion Long-term PM 2.5 exposure is causally linked to childhood asthma with MEAF6 , RNF40 , CD200, MANBA and FUT10 identified as key molecules. The study provides new evidence for the biological mechanisms linking PM 2.5 to childhood asthma.