GWAS and meta-analysis identifies multiple new genetic mechanisms underlying severe Covid-19

  1. Erola Pairo-Castineira
  2. Konrad Rawlik
  3. Lucija Klaric
  4. Athanasios Kousathanas
  5. Anne Richmond
  6. Jonathan Millar
  7. Clark D Russell
  8. Tomas Malinauskas
  9. Ryan Thwaites
  10. Alex Stuckey
  11. Christopher A Odhams
  12. Susan Walker
  13. Fiona Griffiths
  14. Wilna Oosthuyzen
  15. Kirstie Morrice
  16. Sean Keating
  17. Alistair Nichol
  18. Malcolm G Semple
  19. Julian Knight
  20. Manu Shankar-Hari
  21. Charlotte Summers
  22. Charles Hinds
  23. Peter Horby
  24. Lowell Ling
  25. Danny McAuley
  26. Hugh Montgomery
  27. Peter J.M. Openshaw
  28. Timothy Walsh
  29. Albert Tenesa
  30. GenOMICC Investigators
  31. SCOURGE Consortium
  32. ISARIC4C Investigators
  33. 23andMe
  34. Richard H Scott
  35. Mark J Caulfield
  36. Loukas Moutsianas
  37. Chris P Ponting
  38. James F Wilson
  39. Veronique Vitart
  40. Alexandre C Pereira
  41. Andre Luchessi
  42. Esteban Parra
  43. Raquel Cruz-Guerrero
  44. Angel Carracedo
  45. Angie Fawkes
  46. Lee Murphy
  47. Kathy Rowan
  48. Andy Law
  49. Sara Clohisey Hendry
  50. J. Kenneth Baillie

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Abstract

Pulmonary inflammation drives critical illness in Covid-19, 1;2 creating a clinically homogeneous extreme phenotype, which we have previously shown to be highly efficient for discovery of genetic associations. 3;4 Despite the advanced stage of illness, we have found that immunomodulatory therapies have strong beneficial effects in this group. 1;5 Further genetic discoveries may identify additional therapeutic targets to modulate severe disease. 6 In this new data release from the GenOMICC (Genetics Of Mortality in Critical Care) study we include new microarray genotyping data from additional critically-ill cases in the UK and Brazil, together with cohorts of severe Covid-19 from the ISARIC4C 7 and SCOURGE 8 studies, and meta-analysis with previously-reported data. We find an additional 14 new genetic associations. Many are in potentially druggable targets, in inflammatory signalling (JAK1, PDE4A), monocyte-macrophage differentiation (CSF2), immunometabolism (SLC2A5, AK5), and host factors required for viral entry and replication (TMPRSS2, RAB2A). As with our previous work, these results provide tractable therapeutic targets for modulation of harmful host-mediated inflammation in Covid-19.

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    SciScore for 10.1101/2022.03.07.22271833: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Meta-analysis: All meta-analysis across studies were performed using an inverse-variance weighting method and control for population stratification in the METAL software 30.
    METAL
    suggested: (METAL, RRID:SCR_002013)
    Transcriptome-wide Association Studies: We performed TWAS in the MetaXcan framework and the GTExv8 eQTL and sQTL MASHR-M models available for download in http://predictdb.org/.
    MetaXcan
    suggested: None

    Results from OddPub: Thank you for sharing your code and data.

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

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  2. Version published to 10.1101/2022.03.07.22271833v1 on medRxiv