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

The causal impact of fine particulate matter (PM_2.5), an established environmental risk factor, on childhood asthma and its biological mechanisms remain to be elucidated. The objective of the present study was 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 randomisation (MR) framework.

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).

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.

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.