1. Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries
- Author
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A. Rouf Banday, Megan L. Stanifer, Oscar Florez-Vargas, Olusegun O. Onabajo, Brenen W. Papenberg, Muhammad A. Zahoor, Lisa Mirabello, Timothy J. Ring, Chia-Han Lee, Paul S. Albert, Evangelos Andreakos, Evgeny Arons, Greg Barsh, Leslie G. Biesecker, David L. Boyle, Mark S. Brahier, Andrea Burnett-Hartman, Mary Carrington, Euijin Chang, Pyoeng Gyun Choe, Rex L. Chisholm, Leandro M. Colli, Clifton L. Dalgard, Carolynn M. Dude, Jeff Edberg, Nathan Erdmann, Heather S. Feigelson, Benedito A. Fonseca, Gary S. Firestein, Adam J. Gehring, Cuncai Guo, Michelle Ho, Steven Holland, Amy A. Hutchinson, Hogune Im, Les’Shon Irby, Michael G. Ison, Naima T. Joseph, Hong Bin Kim, Robert J. Kreitman, Bruce R. Korf, Steven M. Lipkin, Siham M. Mahgoub, Iman Mohammed, Guilherme L. Paschoalini, Jennifer A. Pacheco, Michael J. Peluso, Daniel J. Rader, David T. Redden, Marylyn D. Ritchie, Brooke Rosenblum, M. Elizabeth Ross, Hanaisa P. Sant Anna, Sharon A. Savage, Sudha Sharma, Eleni Siouti, Alicia K. Smith, Vasiliki Triantafyllia, Joselin M. Vargas, Jose D. Vargas, Anurag Verma, Vibha Vij, Duane R. Wesemann, Meredith Yeager, Xu Yu, Yu Zhang, Steeve Boulant, Stephen J. Chanock, Jordan J. Feld, and Ludmila Prokunina-Olsson
- Subjects
Genetics - Abstract
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.
- Published
- 2022
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