BackgroundMany genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of “doctor-diagnosed asthma”, thereby diluting genetic signals by not considering asthma heterogeneity. The objective of our study was to identify genetic associates of childhood wheezing phenotypes.MethodsWe conducted a novel multivariate GWAS meta-analysis of wheezing phenotypes jointly derived using unbiased analysis of data collected from birth to 18 years in 9,568 individuals from five UK birth-cohorts.Results44 independent SNPs were associated with early-onset persistent, 25 with preschool remitting, 33 with mid-childhood remitting and 32 with late onset wheeze. We identified a novel locus on chr9q21.13 (close to annexin 1 (ANXA1), p<6.7×10−9), associated exclusively with early-onset persistent wheeze. We identified rs75260654 as the most likely causative single nucleotide polymorphism (SNP) using Promoter Capture Hi-C loops, and then showed that the risk allele (T) confers a reduction inANXA1expression. Finally, in a murine model of house dust mite (HDM)-induced allergic airway disease, we demonstrated that anxa1 protein expression increased and anxa1 mRNA was significantly induced in lung tissue following HDM exposure. Using anxa1−/−deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge.ConclusionsWe discovered a novel locus uniquely associated with early-onset persistent wheeze, identified the most likely causative variant, and showed thatANXA1may play a role in regulating the pulmonary immune response to allergens. Targeting this pathway in persistent disease may represent an exciting therapeutic prospect.