Maternal origin of children-onset asthma: evidence from observational study and instrumental variable analysis

Background: An inverse association was observed between birthweight and children-onset asthma (COA), the origin of the connection however remains elusive. Instrumental variable causal inference analysis can be used to reveal the origin of such associationbut requires resolving the mixed genetic effect of birthweight into fetal/maternal-specific components. Methods: We first performed a meta-analysis to study the relation between birthweight and COA using updated literature published from 2014 to 2020. Using maternal-specific instruments of birthweight, we next performed a genetic risk score (GRS) based Mendelian randomization (MR) to estimate the causal effect of low birthweight on COA in mother-offspring pairs ( n =3,634) and father-offspring pairs ( n =1,334) of the UK Biobank. Two sensitivity analyses of MR were applied to assess the robustness of our causal inference and another method called iMAP was conducted to offer complementary result regarding the direction of referred causality. Results: The updated meta-analysis indicated individuals born with lower birthweight would be more vulnerable to asthma in childhood. The GRS-based MR analysis demonstrated a significantly negative maternal impact of birthweight on COA ( β =-0.162, P =0.037) after adjusting for offspring’s genetic effect in mother-offspring pairs, but failed to repeat this relation in father-offspring pairs. Our sensitivity analyses showed such inverse association was robust against horizontal pleiotropy of used instruments ( β =-0.169, P =0.030) and was not likely affected by preterm birth ( β =-0.165, P =0.035). The iMAPresult also provided additional evidence supporting the causal influence of low birthweight on COA. Conclusions: This study provides supportive evidence for the maternal origin of COA and helps guide early prevention for COA via improving intrauterine environments during pregnancy.