Genetic regulation ofOAS1nonsense-mediated decay underlies association with risk of severe COVID-19

  1. A Rouf Banday
  2. Megan L Stanifer
  3. Oscar Florez-Vargas
  4. Olusegun O Onabajo
  5. Muhammad A Zahoor
  6. Brenen W Papenberg
  7. Timothy J Ring
  8. Chia-Han Lee
  9. Evangelos Andreakos
  10. Evgeny Arons
  11. Greg Barsh
  12. Leslie G Biesecker
  13. David L Boyle
  14. Andrea Burnett-Hartman
  15. Mary Carrington
  16. Euijin Chang
  17. Pyoeng Gyun Choe
  18. Rex L Chrisholm
  19. Clifton Dalgard
  20. Jeff Edberg
  21. Nathan Erdmann
  22. Heather S Feigelson
  23. Gary S Firestein
  24. Adam J Gehring
  25. Michelle Ho
  26. Steven Holland
  27. Amy A Hutchinson
  28. Hogune Im
  29. Michael G Ison
  30. Hong Bin Kim
  31. Robert J Kreitman
  32. Bruce R Korf
  33. Lisa Mirabello
  34. Jennifer A Pacheco
  35. Michael J Peluso
  36. Daniel J Rader
  37. David T Redden
  38. Marylyn D Ritchie
  39. Brooke Rosenbloom
  40. Hanaisa P Sant Anna
  41. Sharon Savage
  42. Eleni Siouti
  43. Vasiliki Triantafyllia
  44. Joselin M Vargas
  45. Anurag Verma
  46. Vibha Vij
  47. Duane R Wesemann
  48. Meredith Yeager
  49. Xu Yu
  50. Yu Zhang
  51. Steeve Boulant
  52. Stephen J Chanock
  53. Jordan J Feld
  54. Ludmila Prokunina-Olsson
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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.

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