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

Abstract

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 (3107 cases, 92,091 controls) and two-sample Mendelian randomisation (MR) 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 5, and lower mean blood eosinophils (0.341 vs. 0.398 × 109/L; p = 0.008) 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; β = 0.209; p = 8.80 × 10−9). Two-sample MR 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: Päivikki and Sakari Sohlberg Foundation, Foundation for Pediatric Research, Sigrid Jusélius Foundation, Orion Research Foundation, the Research Council of Norway.