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- Title
A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing.
- Authors
Granell, Raquel; Curtin, John A.; Haider, Sadia; Kitaba, Negusse Tadesse; Mathie, Sara A.; Gregory, Lisa G.; Yates, Laura L.; Tutino, Mauro; Hankinson, Jenny; Perretti, Mauro; Vonk, Judith M.; Arshad, Hasan S.; Cullinan, Paul; Fontanella, Sara; Roberts, Graham C.; Koppelman, Gerard H.; Simpson, Angela; Turner, Steve W.; Murray, Clare S.; Lloyd, Clare M.
- Abstract
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 9568 individuals from five UK birth cohorts. Results: Forty-four independent SNPs were associated with early-onset persistent, 25 with pre-school 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: Targeting this pathway in persistent disease may represent an exciting therapeutic prospect.
- Subjects
UNITED Kingdom; GENOME-wide association studies; PHENOTYPES; WHEEZE; PROTEIN expression; HOUSE dust mites; SINGLE nucleotide polymorphisms
- Publication
eLife, 2023, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.84315