A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance
- Wellcome Sanger Institute, United Kingdom
- EBI-EMBL, United Kingdom
- Bristol-Myers Squibb, United States
- University of Bristol, United Kingdom
- University of Oxford, United Kingdom
- Icelandic Heart Association, Iceland
- Wellcome Trust Sanger Institute, United Kingdom
- EMBL-European Bioinformatics Institute, United Kingdom
Abstract
Background:
The virus SARS-CoV-2 can exploit biological vulnerabilities (e.g. host proteins) in susceptible hosts that predispose to the development of severe COVID-19.
Methods:
To identify host proteins that may contribute to the risk of severe COVID-19, we undertook proteome-wide genetic colocalisation tests, and polygenic (pan) and cis-Mendelian randomisation analyses leveraging publicly available protein and COVID-19 datasets.
Results:
Our analytic approach identified several known targets (e.g. ABO, OAS1), but also nominated new proteins such as soluble Fas (colocalisation probability > 0.9, p = 1 x 10-4), implicating Fas-mediated apoptosis as a potential target for COVID-19 risk. The polygenic (pan) and cis-Mendelian randomisation analyses showed consistent associations of genetically predicted ABO protein with several COVID-19 phenotypes. The ABO signal is highly pleiotropic and a look-up of proteins associated with the ABO signal revealed that the strongest association was with soluble CD209. We demonstrated experimentally that CD209 directly interacts with the spike protein of SARS-CoV-2, suggesting a mechanism that could explain the ABO association with COVID-19.
Conclusions:
Our work provides a prioritised list of host targets potentially exploited by SARS-CoV-2 and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for COVID-19.
Funding:
MAK, JSc, JH, AB, DO, MC, EMM, MG, ID were funded by Open Targets. J.Z. and T.R.G were funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/4). JSh and GJW were funded by the Wellcome Trust Grant 206194. This research was funded in part by the Wellcome Trust [Grant 206194]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Data availability
Summary data used for genetic analyses are publicly available (Sun et al can be downloaded from GWAS catalog https://www.ebi.ac.uk/gwas/downloads/summary-statistics and COVID-19 HGI summary statistics can be downloaded from their website https://www.covid19hg.org/results/). Data generated from our study are provided in the supplementary tables (pan-MR and cis-MR association results filtered at p < 0.05 and no filters applied to colocalisation results).
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Genomic atlas of the human plasma proteomeGWAS Catalog, GCST005806.
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Mapping the human genetic architecture of COVID-19 by worldwide meta-analysisCOVID GWAS meta-analysis results, release 4.
Article and author information
Author details
Vilmundur Gudnason
Funding
Wellcome Trust (Grant 206194)
- Mohd Anisul
- Jarrod Shilts
- Jeremy Schwartzentruber
- Gavin J Wright
- Maya Ghoussaini
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: All institutions contributing cohorts to the COVID-19 Host Genetics Initiative and INTERVAL (Sun et al) study for proteomics received ethics approval from their respective research ethics review boards. All participants in the INTERVAL study provided informed consent before joining the INTERVAL study with approval from the National Research Ethics (11/EE/0538). Ethics statements of studies that contributed participant data to the COVID-19 Host Genetics Initiative are provided in Supplementary Table 1 of their recently published paper (https://www.nature.com/articles/s41586-021-03767-x).
Copyright
© 2021, Anisul et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance
eLife 10:e69719.
https://doi.org/10.7554/eLife.69719
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