Observational, MR, and longitudinal association: obesity and the mediators
Figure 2 depicts the associations between BMI z-scores and mediators in both observational and MR 2SLS analyses. According to the MR analysis, a one-unit increase in the BMI z-score was associated with a decrease in FEV1/FVC ratio (β, −2.17; 95% CI, −3.92 to −0.42), physical fitness index (β, −0.71; 95% CI, −1.30 to −0.13), and an increased risk of early puberty (OR, 1.09; 95% CI, 1.02 to 1.17). Both observational and MR 2SLS analyses consistently supported the causal association of obesity with FEV1/FVC, physical fitness, and early puberty, with a similar causality direction. Although the observational association between obesity and SDB was significant (β, 0.21; 95% CI, 0.06–0.35), the MR 2SLS analysis did not support causal relationships. Furthermore, most of the results of the MR sensitivity analysis (IVW and weighted median method) confirmed the direction of causal relationships (Figure E2). No evidence supported the association of individual BMI-SNPs with the mediators (Tables E5 and E6). The GRSs of the 28 BMI-SNPs showed strong evidence of an association of obesity with low FEV1/FVC, low physical fitness, high SDB scores, and high early puberty risk (Table E1). Prospective cohort analyses supported the finding of Figure 2 that obesity was associated with a decline in FEV1/FVC, physical fitness, and increased risk of early puberty (Table 2).