A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing

Background Many 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. Methods We 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. Results 44 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 in ANXA1 expression. 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. Conclusions We discovered a novel locus uniquely associated with early-onset persistent wheeze, identified the most likely causative variant, and showed that ANXA1 may play a role in regulating the pulmonary immune response to allergens. Targeting this pathway in persistent disease may represent an exciting therapeutic prospect. ### Competing Interest Statement Graham Roberts: MRC grant to my institution President of the British Society of Allergy and Clinical Immunology. Gerard Koppelman: Dutch Lung Foundation, Ubbo Emmius Foundation (Money to insititution) Dutch Lung Foundation, Vertex, TEVA the Netherlands, GSK, ZON-MW (VICI grant), European Union (Money to institution) Astra Zeneca, Pure IMS, GSK (Money to institution) Sanofi, Boehringer Ingelheim (Money to institution). Angela Simpson: Medical research council Research grant JP Moulton Charitable Foundation Research grant Asthma UK Research grant. Clare Murray: Asthma Uk National Institute for Health Research Moulton Charitable Foundation North West Lung Centre Charity GSK (Lecture fees) Novartis (Lecture fees). Clare Lloyd: Wellcome Trust 107059/Z/15/Z. John Holloway: Medial Research Council grant MR/S025340/1 (to institution) American Academy of Allergy Asthma and Immunology (AAAI) (Support for speaker travel to AAAAI annual congress). Adnan Custovic: MRC (research grants) EPSRC (research grant) Wellcome Trust (research grant) Worg Pharmaceoticals (Personal payment