A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program

  1. Anurag Verma
  2. Noah Tsao
  3. Lauren Thomann
  4. Yuk-Lam Ho
  5. Sudha Iyengar
  6. Shiuh-Wen Luoh
  7. Rotonya Carr
  8. Dana Crawford
  9. Jimmy T. Efird
  10. Jennifer Huffman
  11. Adriana Hung
  12. Kerry Ivey
  13. Michael Levin
  14. Julie Lynch
  15. Pradeep Natarajan
  16. Saiju Pyarajan
  17. Alexander Bick
  18. Lauren Costa
  19. Giulio Genovese
  20. Richard Hauger
  21. Ravi Madduri
  22. Gita Pathak
  23. Renato Polimanti
  24. Benjamin Voight
  25. Marijana Vujkovic
  26. Maryam Zekavat
  27. Hongyu Zhao
  28. Marylyn D Ritchie
  29. VA Million Veteran Program COVID-19 Science Initiative
  30. Kyong-Mi Chang
  31. Kelly Cho
  32. Juan P. Casas
  33. Philip S. Tsao
  34. J. Michael Gaziano
  35. Christopher O’Donnell
  36. Scott Damrauer
  37. Katherine Liao
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Abstract

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n=35) or hospitalization (n=42) due to severe COVID-19 using genome-wide association summary from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (nrs495828= 53 and nrs505922=59); strongest association with venous embolism, odds ratio (ORrs495828 1.33 (p=1.32 × 10−199), and thrombosis ORrs505922 1.33, p=2.2 ×10−265. Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p=4.12 × 10−191; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p=2.26× 10−12. The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p=6.48 ×10−23, lupus OR 0.84, p=3.97 × 10−06. PheWAS stratified by genetic ancestry demonstrated differences in genotype-phenotype associations across ancestry. LMNA (rs581342) associated with neutropenia OR 1.29 p=4.1 × 10−13 among Veterans of African ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.

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