Genome-wide analysis in 756,646 individuals provides first genetic evidence that ACE2 expression influences COVID-19 risk and yields genetic risk scores predictive of severe disease

  1. J. E. Horowitz
  2. J. A. Kosmicki
  3. A. Damask
  4. D. Sharma
  5. G. H. L. Roberts
  6. A. E. Justice
  7. N. Banerjee
  8. M. V. Coignet
  9. A. Yadav
  10. J. B. Leader
  11. A. Marcketta
  12. D. S. Park
  13. R. Lanche
  14. E. Maxwell
  15. S. C. Knight
  16. X. Bai
  17. H. Guturu
  18. D. Sun
  19. A. Baltzell
  20. F. S. P. Kury
  21. J. D. Backman
  22. A. R. Girshick
  23. C. O’Dushlaine
  24. S. R. McCurdy
  25. R. Partha
  26. A. J. Mansfield
  27. D. A. Turissini
  28. A. H. Li
  29. M. Zhang
  30. J. Mbatchou
  31. K. Watanabe
  32. L. Gurski
  33. S. E. McCarthy
  34. H. M. Kang
  35. L. Dobbyn
  36. E. Stahl
  37. A. Verma
  38. G. Sirugo
  39. Regeneron Genetics Center
  40. M. D. Ritchie
  41. M. Jones
  42. S. Balasubramanian
  43. K. Siminovitch
  44. W. J. Salerno
  45. A. R. Shuldiner
  46. D. J. Rader
  47. T. Mirshahi
  48. A. E. Locke
  49. J. Marchini
  50. J. D. Overton
  51. D. J. Carey
  52. L. Habegger
  53. M. N. Cantor
  54. K. A. Rand
  55. E. L. Hong
  56. J. G. Reid
  57. C. A. Ball
  58. A. Baras
  59. G. R. Abecasis
  60. M. A. Ferreira
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Abstract

SARS-CoV-2 enters host cells by binding angiotensin-converting enzyme 2 (ACE2). Through a genome-wide association study, we show that a rare variant (MAF = 0.3%, odds ratio 0.60, P=4.5x10-13) that down-regulates ACE2 expression reduces risk of COVID-19 disease, providing human genetics support for the hypothesis that ACE2 levels influence COVID-19 risk. Further, we show that common genetic variants define a risk score that predicts severe disease among COVID-19 cases.

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