Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries

A Rouf Banday # 1, Megan L Stanifer # 2 3, Oscar Florez-Vargas # 1, Olusegun O Onabajo 1, Brenen W Papenberg 1, Muhammad A Zahoor 4, Lisa Mirabello 5, Timothy J Ring 1, Chia-Han Lee 1, Paul S Albert 6, Evangelos Andreakos 7, Evgeny Arons 8, Greg Barsh 9, Leslie G Biesecker 10, David L Boyle 11, Mark S Brahier 12, Andrea Burnett-Hartman 13, Mary Carrington 14 15 16, Euijin Chang 17, Pyoeng Gyun Choe 17, Rex L Chisholm 18, Leandro M Colli 19, Clifton L Dalgard 20, Carolynn M Dude 21, Jeff Edberg 22, Nathan Erdmann 23, Heather S Feigelson 13, Benedito A Fonseca 24, Gary S Firestein 11, Adam J Gehring 4 25, Cuncai Guo 26, Michelle Ho 1, Steven Holland 27, Amy A Hutchinson 28, Hogune Im 29, Les'Shon Irby 21, Michael G Ison 30, Naima T Joseph 31, Hong Bin Kim 17 32, Robert J Kreitman 8, Bruce R Korf 33, Steven M Lipkin 34, Siham M Mahgoub 35, Iman Mohammed 36, Guilherme L Paschoalini 19, Jennifer A Pacheco 18, Michael J Peluso 37, Daniel J Rader 38, David T Redden 39, Marylyn D Ritchie 38, Brooke Rosenblum 10, M Elizabeth Ross 36, Hanaisa P Sant Anna 40, Sharon A Savage 5, Sudha Sharma 41, Eleni Siouti 7, Alicia K Smith 21, Vasiliki Triantafyllia 7, Joselin M Vargas 1, Jose D Vargas 42, Anurag Verma 38, Vibha Vij 43, Duane R Wesemann 44, Meredith Yeager 28, Xu Yu 16, Yu Zhang 27, Steeve Boulant 3 26 45, Stephen J Chanock 40, Jordan J Feld 4 25, Ludmila Prokunina-Olsson 46

The chr12q24.13 locus encoding OAS1-OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European (n = 2,249) and African (n = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-λ1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454 -A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19.