1. Genetic regulation ofOAS1nonsense-mediated decay underlies association with risk of severe COVID-19
- Author
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Jordan J. Feld, Pyoeng Gyun Choe, Rex L Chrisholm, Joselin M Vargas, Vibha Vij, Nathan Erdmann, Mary Carrington, A Rouf Banday, Sharon A. Savage, Michael G. Ison, Duane R. Wesemann, Anurag Verma, Leslie G. Biesecker, Euijin Chang, Chia-Han Lee, Gary S. Firestein, Adam J. Gehring, Lisa Mirabello, Robert J. Kreitman, Timothy J Ring, Michael J Peluso, Bruce R. Korf, Hogune Im, Yu Zhang, Daniel J. Rader, Megan L. Stanifer, Marylyn D. Ritchie, Jennifer A. Pacheco, Muhammad Atif Zahoor, Hanaisa P Sant Anna, Greg Barsh, Steeve Boulant, Meredith Yeager, Brooke Rosenbloom, Ludmila Prokunina-Olsson, David T. Redden, David L. Boyle, Olusegun O Onabajo, Evangelos Andreakos, Michelle Ho, Oscar Florez-Vargas, Heather Spencer Feigelson, Eleni Siouti, Amy Hutchinson, Xu G. Yu, Vasiliki Triantafyllia, Brenen W Papenberg, Andrea N. Burnett-Hartman, Jeffrey C. Edberg, Clifton L. Dalgard, Steven M. Holland, Evgeny Arons, Stephen J. Chanock, and Hong Bin Kim
- Subjects
Genetics ,Coronavirus disease 2019 (COVID-19) ,SARS-CoV-2 ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Nonsense-mediated decay ,Haplotype ,COVID-19 ,Locus (genetics) ,Biology ,Article ,Hospitalization ,Clinical trial ,RNA splicing ,2',5'-Oligoadenylate Synthetase ,Humans ,Risk haplotype ,Alleles - Abstract
Genomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76OAS1variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The risk haplotype was also associated with impaired spontaneous but not treatment-induced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1. We demonstrate that two exonic variants, rs10774671 and rs1131454, affect splicing and nonsense-mediated decay ofOAS1. We suggest that genetically-regulated loss ofOAS1expression contributes to impaired spontaneous clearance of SARS-CoV-2 and elevated risk of hospitalization for COVID-19. Our results provide the rationale for further clinical studies using interferons to compensate for impaired spontaneous SARS-CoV-2 clearance, particularly in carriers of theOAS1risk haplotypes.
- Published
- 2021
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