Genetic regulation of OAS1 nonsense-mediated decay underlies association with risk of severe COVID-19

A Rouf Banday, Megan L Stanifer, Oscar Florez-Vargas, Olusegun O Onabajo, Muhammad A Zahoor, Brenen W Papenberg, Timothy J Ring, Chia-Han Lee, Evangelos Andreakos, Evgeny Arons, Greg Barsh, Leslie G Biesecker, David L Boyle, Andrea Burnett-Hartman, Mary Carrington, Euijin Chang, Pyoeng Gyun Choe, Rex L Chrisholm, Clifton Dalgard, Jeff Edberg, Nathan Erdmann, Heather S Feigelson, Gary S Firestein, Adam J Gehring, Michelle Ho, Steven Holland, Amy A Hutchinson, Hogune Im, Michael G Ison, Hong Bin Kim, Robert J Kreitman, Bruce R Korf, Lisa Mirabello, Jennifer A Pacheco, Michael J Peluso, Daniel J Rader, David T Redden, Marylyn D Ritchie, Brooke Rosenbloom, Hanaisa P Sant Anna, Sharon Savage, Eleni Siouti, Vasiliki Triantafyllia, Joselin M Vargas, Anurag Verma, Vibha Vij, Duane R Wesemann, Meredith Yeager, Xu Yu, Yu Zhang, Steeve Boulant, Stephen J Chanock, Jordan J Feld, Ludmila Prokunina-Olsson

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 76 OAS1 variants 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 of OAS1 . We suggest that genetically-regulated loss of OAS1 expression 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 the OAS1 risk haplotypes.