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Though previous studies have identified several quantitative trait loci (QTL) and candidate genes underlying responses to O3 exposure, precise mechanisms of susceptibility remain incompletely described. We sought to update our understanding of the genetic architecture of O3 responsiveness using the Collaborative Cross (CC) recombinant inbred mouse panel. We evaluated hallmark O3-induced inflammation and injury phenotypes in 56 CC strains after exposure to filtered air or 2 ppm O3, and performed focused genetic analysis of variation in lung injury, as reflected by protein in lung lavage fluid. Strain-dependent responses to O3 were clear, and QTL mapping revealed two novel loci on Chr (Chromosomes) 10 (peak, 26.2 Mb; 80% confidence interval [CI], 24.6\u201343.6 Mb) and 15 (peak, 47.1 Mb; 80% CI, 40.2\u201354.9 Mb), the latter surpassing the 95% significance threshold. At the Chr 15 locus, C57BL\/6J and CAST\/EiJ founder haplotypes were associated with higher lung injury responses compared with all other CC founder haplotypes. With further statistical analysis and a weight of evidence approach, we delimited the Chr 15 QTL to an \u223c2 Mb region containing 21 genes (10 protein coding) and nominated three candidate genes, namely Oxr1, Rspo2, and Angpt1. Gene and protein expression data further supported Oxr1 and Angpt1 as priority candidate genes. In summary, we have shown that O3-induced lung injury is modulated by genetic variation, identified two high priority candidate genes, and demonstrated the value of the CC for detecting GxE.<\/jats:p>","DOI":"10.1165\/rcmb.2021-0326oc","type":"journal-article","created":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T14:13:04Z","timestamp":1657548784000},"page":"528-538","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":10,"title":["A Locus on Chromosome 15 Contributes to Acute Ozone-induced Lung Injury in Collaborative Cross Mice"],"prefix":"10.1093","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1699-7231","authenticated-orcid":false,"given":"Adelaide","family":"Tovar","sequence":"first","affiliation":[{"name":"Department of Genetics"},{"name":"Curriculum in Genetics and Molecular Biology, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5305-0445","authenticated-orcid":false,"given":"Gregory J.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Genetics"},{"name":"Curriculum in Toxicology and Environmental Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morgan B.","family":"Nalesnik","sequence":"additional","affiliation":[{"name":"Curriculum in Toxicology and Environmental Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph M.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Genetics"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathryn M.","family":"McFadden","sequence":"additional","affiliation":[{"name":"Department of Genetics"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jack R.","family":"Harkema","sequence":"additional","affiliation":[{"name":"Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2676-9232","authenticated-orcid":false,"given":"Samir N. 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