Infant respiratory syncytial virus and childhood asthma: a nationwide phenotyping, sibling-controlled, and genome-wide association study

Background Early-life respiratory syncytial virus (RSV) infection is associated with childhood recurrent wheeze or asthma (RW/A), but causality and shared genetic liability remain unclear. Methods We combined Finnish nationwide registries and Nordic genetic cohorts. First, in 965 312 Finnish children born between 1998 and 2014, we defined severe RSV as RSV hospitalisation before age 1 year, and recurrent wheezing or asthma (RW/A) as inhaled medication reimbursement between ages 1 and 7 years, and compared medication and eosinophil trajectories by RSV history. Second, we assessed familial confounding in 527 776 full siblings and 15 667 RW/A-discordant pairs. Third, we performed a genome-wide association study (GWAS) of RSV susceptibility with meta-analysis across six Nordic cohorts (3 107 cases, 92 031 controls) and two-sample Mendelian randomisation (2SMR) using 155 asthma-associated variants. Findings RSV-associated RW/A showed higher inhaled medication use at ages 1-2 years but lower use after age 4, and lower mean blood eosinophils (0.34 vs 0.39*10e9/L; p=0.003) than RW/A without RSV hospitalisation. In RW/A-discordant sibling pairs, RSV hospitalisation was associated with RW/A (OR 2.8; 95% CI 2.4-3.2), while unaffected siblings also had elevated RW/A prevalence. GWAS identified an RSV association at APBB1IP (rs787036; beta=0.209; p=8.80*10e-9). 2SMR provided no evidence that asthma genetic liability influenced RSV susceptibility. Interpretation The RSV-asthma association is unlikely to be explained by shared genetic or environmental factors, and RSV-associated RW/A shows a distinct trajectory. These findings help prioritise long-term outcomes for RSV prevention trials and monitoring. Funding: Paivikki and Sakari Sohlberg Foundation, Foundation for Pediatric Research, Sigrid Juselius Foundation, Orion Research Foundation, the Research Council of Norway.