dc.contributor.author | Granell, R | en_US |
dc.contributor.author | Curtin, JA | en_US |
dc.contributor.author | Haider, S | en_US |
dc.contributor.author | Kitaba, NT | en_US |
dc.contributor.author | Mathie, SA | en_US |
dc.contributor.author | Gregory, LG | en_US |
dc.contributor.author | Yates, LL | en_US |
dc.contributor.author | Tutino, M | en_US |
dc.contributor.author | Hankinson, J | en_US |
dc.contributor.author | Perretti, M | en_US |
dc.contributor.author | Vonk, JM | en_US |
dc.contributor.author | Arshad, HS | en_US |
dc.contributor.author | Cullinan, P | en_US |
dc.contributor.author | Fontanella, S | en_US |
dc.contributor.author | Roberts, GC | en_US |
dc.contributor.author | Koppelman, GH | en_US |
dc.contributor.author | Simpson, A | en_US |
dc.contributor.author | Turner, SW | en_US |
dc.contributor.author | Murray, CS | en_US |
dc.contributor.author | Lloyd, CM | en_US |
dc.contributor.author | Holloway, JW | en_US |
dc.contributor.author | Custovic, A | en_US |
dc.contributor.author | UNICORN and Breathing Together investigators | en_US |
dc.date.accessioned | 2023-12-04T12:14:35Z | |
dc.date.available | 2023-05-22 | en_US |
dc.date.issued | 2023-05-25 | en_US |
dc.identifier.uri | https://qmro.qmul.ac.uk/xmlui/handle/123456789/92576 | |
dc.description.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. FUNDING: UK Medical Research Council Programme Grant MR/S025340/1 and the Wellcome Trust Strategic Award (108818/15/Z) provided most of the funding for this study. | en_US |
dc.language | eng | en_US |
dc.relation.ispartof | Elife | en_US |
dc.rights | Attribution 3.0 United States | * |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/us/ | * |
dc.subject | ALSPAC | en_US |
dc.subject | ANXA1 | en_US |
dc.subject | GWAS | en_US |
dc.subject | MAAS | en_US |
dc.subject | epidemiology | en_US |
dc.subject | genetics | en_US |
dc.subject | genomics | en_US |
dc.subject | global health | en_US |
dc.subject | human | en_US |
dc.subject | meta-analysis | en_US |
dc.subject | wheezing phenotypes | en_US |
dc.subject | Animals | en_US |
dc.subject | Mice | en_US |
dc.subject | Asthma | en_US |
dc.subject | Genome-Wide Association Study | en_US |
dc.subject | Hypersensitivity | en_US |
dc.subject | Phenotype | en_US |
dc.subject | Respiratory Sounds | en_US |
dc.subject | Annexins | en_US |
dc.title | A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing. | en_US |
dc.type | Article | |
dc.identifier.doi | 10.7554/eLife.84315 | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/37227431 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published online | en_US |
pubs.volume | 12 | en_US |
dcterms.dateAccepted | 2023-05-22 | en_US |