{"doi":"10.1101/2021.05.20.445039","title":"A novel gene-by-environment quantitative trait locus on mouse chromosome 15 underlies susceptibility to acute ozone-induced lung injury","abstract":"Abstract Respiratory toxicity caused by the common urban air pollutant ozone (O 3 ) varies considerably within the human population and across inbred mouse strains, suggestive of gene-environment interactions (GxE). Though previous studies genetic mapping studies using classical inbred strains have identified several and quantitative trait locus (QTL) and candidate genes underlying responses to O 3 exposure, precise mechanisms of susceptibility remain incompletely described. We sought to expand our understanding of the genetic architecture of O 3 responsiveness using the Collaborative Cross (CC) recombinant inbred mouse panel, which contains more genetic diversity than previous inbred strain panels. We evaluated hallmark O 3 -induced respiratory phenotypes in 56 CC strains after exposure to filtered air or 2 ppm O 3 , and performed focused genetic analysis of variation in lung injury as measured by the total bronchoalveolar lavage protein concentration. Because animals were exposed in sex- and batch-matched pairs, we defined a protein response phenotype as the difference in lavage protein between the O 3 - and FA-exposed animal within a pair. The protein response phenotype was heritable, and QTL mapping revealed two novel loci on Chromosomes 10 (peak: 26.2 Mb; 80% CI: 24.6-43.6 Mb) and 15 (peak: 47.1 Mb; 80% CI: 40.2-54.9 Mb), the latter surpassing the 95% significance threshold. At the Chr. 15 locus, C57BL/6J and CAST/EiJ founder haplotypes were associated with higher protein responses compared to all other CC founder strain haplotypes. Using additional statistical analysis and high-density SNP data, we delimited the Chr. 15 QTL to a ∼2 Mb region containing 21 genes (10 protein coding). Using a weight of evidence approach that incorporated candidate variant analysis, functional annotations, and publicly available lung gene expression data, we nominated three candidate genes ( Oxr1, Rspo2 , and Angpt1 ). In summary, we have shown that O 3 -induced lung injury is modulated by genetic variation and demonstrated the value of the CC for uncovering and dissecting gene-environment interactions.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":224222,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9487,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":535476,"name":"Gregory J. Smith","orcid":"0000-0002-5305-0445","position":1,"is_corresponding":false},{"id":440813,"name":"Joseph M. Thomas","orcid":null,"position":2,"is_corresponding":false},{"id":571725,"name":"Kathryn M. McFadden","orcid":null,"position":3,"is_corresponding":false},{"id":570717,"name":"Samir N. P. Kelada","orcid":"0000-0003-2676-9232","position":4,"is_corresponding":false},{"id":582406,"name":"Adelaide Tovar","orcid":"0000-0003-1699-7231","position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":null,"created_at":"2026-07-18T23:54:18.470602Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}