{"doi":"10.7554/elife.84315","title":"A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing","abstract":"<jats:sec id=\"abs1\">\n                    <jats:title>Background:</jats:title>\n                    <jats:p>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.</jats:p>\n                  </jats:sec>\n                  <jats:sec id=\"abs2\">\n                    <jats:title>Methods:</jats:title>\n                    <jats:p>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.</jats:p>\n                  </jats:sec>\n                  <jats:sec id=\"abs3\">\n                    <jats:title>Results:</jats:title>\n                    <jats:p>\n                      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 [\n                      <jats:italic>ANXA1</jats:italic>\n                      ], p&lt;6.7 × 10\n                      <jats:sup>-9</jats:sup>\n                      ), 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\n                      <jats:italic>ANXA1</jats:italic>\n                      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\n                      <jats:sup>-/-</jats:sup>\n                      deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge.\n                    </jats:p>\n                  </jats:sec>\n                  <jats:sec id=\"abs4\">\n                    <jats:title>Conclusions:</jats:title>\n                    <jats:p>Targeting this pathway in persistent disease may represent an exciting therapeutic prospect.</jats:p>\n                  </jats:sec>\n                  <jats:sec id=\"abs5\">\n                    <jats:title>Funding:</jats:title>\n                    <jats:p>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.</jats:p>\n                  </jats:sec>","journal":"eLife","year":2023,"id":602044,"datarank":0.5101796072493234,"base_score":3.4011973816621555,"endowment":3.4011973816621555,"self_citation_contribution":0.5101796072493234,"citation_network_contribution":0.0,"self_endowment_contribution":0.5101796072493234,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1543872,"name":"John A Curtin","orcid":null,"position":1,"is_corresponding":false},{"id":696972,"name":"Sadia Haider","orcid":"0000-0003-4411-0618","position":2,"is_corresponding":false},{"id":1464017,"name":"Negusse Kitaba","orcid":"0000-0001-7518-9096","position":3,"is_corresponding":false},{"id":1543874,"name":"Sara A Mathie","orcid":null,"position":4,"is_corresponding":false},{"id":1543875,"name":"Lisa G Gregory","orcid":null,"position":5,"is_corresponding":false},{"id":1543876,"name":"Laura L Yates","orcid":null,"position":6,"is_corresponding":false},{"id":58677,"name":"Mauro Tutino","orcid":"0000-0003-2222-3128","position":7,"is_corresponding":false},{"id":334222,"name":"Jenny Hankinson","orcid":"0000-0002-9021-4031","position":8,"is_corresponding":false},{"id":251813,"name":"Mauro Perretti","orcid":"0000-0003-2068-3331","position":9,"is_corresponding":false},{"id":1543877,"name":"Judith M Vonk","orcid":null,"position":10,"is_corresponding":false},{"id":1543878,"name":"Hasan S Arshad","orcid":null,"position":11,"is_corresponding":false},{"id":862791,"name":"Paul Cullinan","orcid":"0000-0002-9314-6468","position":12,"is_corresponding":false},{"id":862789,"name":"Sara Fontanella","orcid":"0000-0003-1681-9873","position":13,"is_corresponding":false},{"id":1543879,"name":"Graham C Roberts","orcid":null,"position":14,"is_corresponding":false},{"id":1543880,"name":"Gerard H Koppelman","orcid":null,"position":15,"is_corresponding":false},{"id":241501,"name":"Angela Simpson","orcid":"0000-0003-2733-6666","position":16,"is_corresponding":false},{"id":1543881,"name":"Steve W Turner","orcid":null,"position":17,"is_corresponding":false},{"id":1543883,"name":"Clare S Murray","orcid":null,"position":18,"is_corresponding":false},{"id":1543885,"name":"Clare M Lloyd","orcid":null,"position":19,"is_corresponding":false},{"id":282188,"name":"John W. Holloway","orcid":"0000-0001-9998-0464","position":20,"is_corresponding":false},{"id":234872,"name":"Adnan Ćustović","orcid":"0000-0001-5218-7071","position":21,"is_corresponding":false},{"id":347013,"name":"Raquel Granell","orcid":"0000-0002-4890-4012","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing","abstract":"<jats:sec id=\"abs1\">\n                    <jats:title>Background:</jats:title>\n                    <jats:p>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.</jats:p>\n                  </jats:sec>\n                  <jats:sec id=\"abs2\">\n                    <jats:title>Methods:</jats:title>\n                    <jats:p>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.</jats:p>\n                  </jats:sec>\n                  <jats:sec id=\"abs3\">\n                    <jats:title>Results:</jats:title>\n                    <jats:p>\n                      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 [\n                      <jats:italic>ANXA1</jats:italic>\n                      ], p&lt;6.7 × 10\n                      <jats:sup>-9</jats:sup>\n                      ), 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\n                      <jats:italic>ANXA1</jats:italic>\n                      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\n                      <jats:sup>-/-</jats:sup>\n                      deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge.\n                    </jats:p>\n                  </jats:sec>\n                  <jats:sec id=\"abs4\">\n                    <jats:title>Conclusions:</jats:title>\n                    <jats:p>Targeting this pathway in persistent disease may represent an exciting therapeutic prospect.</jats:p>\n                  </jats:sec>\n                  <jats:sec id=\"abs5\">\n                    <jats:title>Funding:</jats:title>\n                    <jats:p>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.</jats:p>\n                  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