Multi-ancestry Mendelian randomization of omics traits revealing drug targets of COVID-19 severity

Jie Zheng*, Yuemiao Zhang, Huiling Zhao, Yi Liu, Denis Baird, Mohd Anisul Karim, Maya Ghoussaini, Jeremy Schwartzentruber, Ian Dunham, Benjamin Elsworth, Katherine Roberts, Hannah Compton, Felix Miller-Molloy, Xingzi Liu, Lin Wang, Hong Zhang, George Davey Smith, Tom R Gaunt*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

BACKGROUND: Recent omic studies prioritised several drug targets associated with coronavirus disease 2019 (COVID-19) severity. However, little evidence was provided to systematically estimate the effect of drug targets on COVID-19 severity in multiple ancestries.

METHODS: In this study, we applied Mendelian randomization (MR) and colocalization approaches to understand the putative causal effects of 16,059 transcripts and 1608 proteins on COVID-19 severity in European and effects of 610 proteins on COVID-19 severity in African ancestry. We further integrated genetics, clinical and literature evidence to prioritise drug targets. Additional sensitivity analyses including multi-trait colocalization and phenome-wide MR were conducted to test for MR assumptions.

FINDINGS: MR and colocalization prioritized four protein targets, FCRL3, ICAM5, ENTPD5 and OAS1 that showed effect on COVID-19 severity in European ancestry. One protein target, SERPINA1 showed a stronger effect in African ancestry but much weaker effect in European ancestry (odds ratio [OR] in Africans=0.369, 95%CI=0.203 to 0.668, P = 9.96 × 10-4; OR in Europeans=1.021, 95%CI=0.901 to 1.157, P = 0.745), which suggested that increased level of SERPINA1 will reduce COVID-19 risk in African ancestry. One protein, ICAM1 showed suggestive effect on COVID-19 severity in both ancestries (OR in Europeans=1.152, 95%CI=1.063 to 1.249, P = 5.94 × 10-4; OR in Africans=1.481, 95%CI=1.008 to 2.176; P = 0.045). The OAS1, SERPINA1 and ICAM1 effects were replicated using updated COVID-19 severity data in the two ancestries respectively, where alternative splicing events in OAS1 and ICAM1 also showed marginal effects on COVID-19 severity in Europeans. The phenome-wide MR of the prioritised targets on 622 complex traits provided information on potential beneficial effects on other diseases and suggested little evidence of adverse effects on major complications.

INTERPRETATION: Our study identified six proteins as showing putative causal effects on COVID-19 severity. OAS1 and SERPINA1 were targets of existing drugs in trials as potential COVID-19 treatments. ICAM1, ICAM5 and FCRL3 are related to the immune system. Across the six targets, OAS1 has no reliable instrument in African ancestry; SERPINA1, FCRL3, ICAM5 and ENTPD5 showed a different level of putative causal evidence in European and African ancestries, which highlights the importance of more powerful ancestry-specific GWAS and value of multi-ancestry MR in informing the effects of drug targets on COVID-19 across different populations. This study provides a first step towards clinical investigation of beneficial and adverse effects of COVID-19 drug targets.

FUNDING: No.

Original languageEnglish
Article number104112
Number of pages13
JournalEBioMedicine
Volume81
DOIs
Publication statusPublished - 27 Jun 2022

Bibliographical note

Funding Information:
JZ is funded by a Vice-Chancellor Fellowship from the University of Bristol. J.Z. is supported by the Academy of Medical Sciences (AMS) Springboard Award, the Wellcome Trust, the Government Department of Business, Energy and Industrial Strategy (BEIS), the British Heart Foundation and Diabetes UK (SBF006\1117). This work has been supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol (G.D.S. and T.R.G.). This research was also funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/1, MC_UU_00011/4). This study was funded/supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol (TRG). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care. YMZ is supported by National Natural Science Foundation of China (82170711). HZ is supported by National Natural Science Foundation of China (82070733). This work was supported by a Wellcome Trust Institutional Translational Partnership Award (209739/Z/17/Z). We acknowledge Jun Zhang, Jiayan Wang and Xiaofei Liu for kindly supporting the design the cover photo of this manuscript.

Publisher Copyright:
© 2022 The Author(s)

Structured keywords

  • Bristol Population Health Science Institute

Keywords

  • COVID-19/drug therapy
  • Genome-Wide Association Study
  • Humans
  • Mendelian Randomization Analysis
  • Odds Ratio
  • Phenotype
  • Polymorphism, Single Nucleotide

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