PT - JOURNAL ARTICLE AU - Alexandra Schäfer AU - Sarah R. Leist AU - Lisa E. Gralinski AU - David R. Martinez AU - Emma S. Winkler AU - Kenichi Okuda AU - Padraig E. Hawkins AU - Kendra L Gully AU - Rachel L. Graham AU - D. Trevor Scobey AU - Timothy A. Bell AU - Pablo Hock AU - Ginger D. Shaw AU - Jennifer F. Loome AU - Emily A. Madden AU - Elizabeth Anderson AU - Victoria K. Baxter AU - Sharon A. Taft-Benz AU - Mark R. Zweigart AU - Samantha R. May AU - Stephanie Dong AU - Matthew Clark AU - Darla R. Miller AU - Rachel M Lynch AU - Mark T. Heise AU - Roland Tisch AU - Richard C. Boucher AU - Fernando Pardo Manuel de Villena AU - Stephanie A. Montgomery AU - Michael S. Diamond AU - Martin T. Ferris AU - Ralph S. Baric TI - A Multitrait Locus Regulates Sarbecovirus Pathogenesis AID - 10.1101/2022.06.01.494461 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.06.01.494461 4099 - http://biorxiv.org/content/early/2022/06/02/2022.06.01.494461.short 4100 - http://biorxiv.org/content/early/2022/06/02/2022.06.01.494461.full AB - Infectious diseases have shaped the human population genetic structure, and genetic variation influences the susceptibility to many viral diseases. However, a variety of challenges have made the implementation of traditional human Genome-wide Association Studies (GWAS) approaches to study these infectious outcomes challenging. In contrast, mouse models of infectious diseases provide an experimental control and precision, which facilitates analyses and mechanistic studies of the role of genetic variation on infection. Here we use a genetic mapping cross between two distinct Collaborative Cross mouse strains with respect to SARS-CoV disease outcomes. We find several loci control differential disease outcome for a variety of traits in the context of SARS-CoV infection. Importantly, we identify a locus on mouse Chromosome 9 that shows conserved synteny with a human GWAS locus for SARS-CoV-2 severe disease. We follow-up and confirm a role for this locus, and identify two candidate genes, CCR9 and CXCR6 that both play a key role in regulating the severity of SARS-CoV, SARS-CoV-2 and a distantly related bat sarbecovirus disease outcomes. As such we provide a template for using experimental mouse crosses to identify and characterize multitrait loci that regulate pathogenic infectious outcomes across species.