Genetic predisposition to high BMI increases risk of early life respiratory infections and episodes of severe wheeze and asthma

Background High body mass index (BMI) is an established risk factor for asthma, but the underlying mechanisms remain unclear. Objective To increase understanding of the BMI–asthma relationship by studying the association between genetic predisposition to higher BMI and asthma, infections and other asthma traits during childhood. Methods Data were obtained from the two ongoing Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) mother–child cohorts. Polygenic risk scores for adult BMI were calculated for each child. Replication was done in the large-scale register-based Integrative Psychiatric Research (iPSYCH) cohort using data on hospitalisation for asthma and infections. Results In the COPSAC cohorts (n=974), the adult BMI polygenic risk score was significantly associated with lower respiratory tract infections (incidence rate ratio (IRR) 1.20, 95% CI 1.08–1.33, false discovery rate p-value (pFDR)=0.005) at age 0–3 years and episodes of severe wheeze (IRR 1.30, 95% CI 1.06–1.60, pFDR=0.04) at age 0–6 years. Lower respiratory tract infections partly mediated the association between the adult BMI polygenic risk score and severe wheeze (proportion mediated: 0.59, 95% CI 0.28–2.24, p-value associated with the average causal mediation effect (pACME)=2e −16 ). In contrast, these associations were not mediated through the child's current BMI and the polygenic risk score was not associated with an asthma diagnosis or reduced lung function up to age 18 years. The associations were replicated in iPSYCH (n=114 283), where the adult BMI polygenic risk score significantly increased the risk of hospitalisations for lower respiratory tract infections and wheeze or asthma throughout childhood to age 18 years. Conclusion Children with genetic predisposition to higher BMI had increased risk of lower respiratory tract infections and severe wheeze, independent of the child's current BMI. These results shed further light on the complex relationship between body mass BMI and asthma.