Observational and MR mediation analyses
According to both observational and MR analyses, the two mediators with the highest ranking of mediation proportions were FEV1/FVC and physical fitness (Figure 4). For all the mediators, the mediation proportions of the MR analysis (Figure 4, right) were higher than that of the observational analysis (Figure 4, left). FeNO did not appear to mediate the influence of obesity on asthma, because the mediation coefficient was in the opposite direction from obesity to FeNO (negative in Figure 2) and from FeNO to active asthma (positive in Figure 3), making the indirect pathway coefficient negative; hence, the mediation proportion was unable to be calculated. Furthermore, SDB was not considered a strong mediator because the MR analysis showed that obesity-induced SDB was insignificant (Figure 2). The mediators presented as consistent causal relationships from obesity to the mediators and then from the mediators to asthma were FEV1/FVC, physical fitness, and early puberty in mediation proportions of 61.57%, 91.42%, and 28.28%, respectively, based on the MR methods; and 24.88%, 21.05%, and 10.32% based on the observational analysis. The mediation proportion implies the proportion of the mediating pathway compared with the total effect from obesity to asthma, considering one mediator at a time. Therefore, the mediation proportion from all five mediators does not necessarily have to sum to 100%. The more substantial mediation proportion indicates that the mediator might play a more critical role.
The mediation analysis assumes that the exposure and mediators had no interaction effects on the outcome.14 We did not observe an obvious interaction effect of BMI or BMI-GRS and the mediators on predicting active asthma after correction for multiple comparisons (Table E17).