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

Background: High 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 body mass index (BMI) and asthma, infections, and other asthma-traits during childhood. Methods: Data was obtained from the two ongoing COPSAC mother-child cohorts. Polygenic risk score (PRS) for adult BMI were calculated for each child. Replication was done in the large-scale iPSYCH cohort using data on hospitalization for asthma and infections. Results: In the COPSAC cohorts (n=974), the adult BMI PRS was significantly associated with lower respiratory tract infections (LRTI) (IRR 1.20 95% CI 1.08–1.33, FDR=0.005) age 0-3 years and episodes of severe wheeze (IRR 1.30, 1.06–1.60, FDR=0.04) age 0-6 years. LRTI partly mediated the association between the adult BMI PRS and severe wheeze (proportion mediated: 0.59, 0.28–2.24, pACME 2E-16). In contrast, these associations were not mediated through the child’s current BMI and the PRS was not associated with an asthma diagnosis or reduced lung function up to age 18. The associations were replicated in iPSYCH (n=114,283), where the adult BMI PRS significantly increased the risk of hospitalizations for LRTI and wheeze or asthma during childhood to age 18 years. Conclusion: Children with genetic predisposition to higher BMI had increased risk of LRTI and severe wheeze, independent of the child’s current BMI. These results shed further light on the complex relationship between BMI and asthma.