A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance

  1. Mohd Anisul  Is a corresponding author
  2. Jarrod Shilts
  3. Jeremy Schwartzentruber
  4. James Hayhurst
  5. Annalisa Buniello
  6. Elmutaz Shaikho
  7. Jie Zheng
  8. Michael Holmes
  9. David Ochoa
  10. Miguel Carmona
  11. Joseph Maranville
  12. Tom R Gaunt
  13. Valur Emilsson
  14. Vilmundur Gudnason
  15. Ellen M McDonagh
  16. Gavin J Wright
  17. Maya Ghoussaini  Is a corresponding author
  18. Ian Dunham  Is a corresponding author
  1. Wellcome Sanger Institute, United Kingdom
  2. EBI-EMBL, United Kingdom
  3. Bristol-Myers Squibb, United States
  4. University of Bristol, United Kingdom
  5. University of Oxford, United Kingdom
  6. Icelandic Heart Association, Iceland
  7. Wellcome Trust Sanger Institute, United Kingdom
  8. 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).

The following previously published data sets were used

Article and author information

Author details

  1. Mohd Anisul

    Wellcome Sanger Institute, Cambridge, United Kingdom
    For correspondence
    mk31@sanger.ac.uk
    Competing interests
    Mohd Anisul, Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2960-6017
  2. Jarrod Shilts

    Wellcome Sanger Institute, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  3. Jeremy Schwartzentruber

    Wellcome Sanger Institute, Cambridge, United Kingdom
    Competing interests
    Jeremy Schwartzentruber, Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners..
  4. James Hayhurst

    EBI-EMBL, Cambridge, United Kingdom
    Competing interests
    James Hayhurst, Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners..
  5. Annalisa Buniello

    EBI-EMBL, Cambridge, United Kingdom
    Competing interests
    Annalisa Buniello, Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners..
  6. Elmutaz Shaikho

    Bristol-Myers Squibb, Cambridge, United States
    Competing interests
    Elmutaz Shaikho, Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners.. ES is also a full-time employee of Bristol-Myers Squibb..
  7. Jie Zheng

    Medical Research Council (MRC) Integrative Epidemiology Unit, Department of Population Health Sciences, University of Bristol, Bristol, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6623-6839
  8. Michael Holmes

    University of Oxford, Oxford, United Kingdom
    Competing interests
    Michael Holmes, Dr Holmes has consulted for Boehringer Ingelheim, and in adherence to the University of Oxford's Clinical Trial Service Unit & Epidemiological Studies Unit (CSTU) staff policy, did not accept personal honoraria or other payments from pharmaceutical companies..
  9. David Ochoa

    EBI-EMBL, Cambridge, United Kingdom
    Competing interests
    David Ochoa, Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners..
  10. Miguel Carmona

    EBI-EMBL, Cambridge, United Kingdom
    Competing interests
    Miguel Carmona, Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners..
  11. Joseph Maranville

    Bristol-Myers Squibb, Cambridge, United States
    Competing interests
    Joseph Maranville, JM is a full-time employee of Bristol-Myers Squibb and retains stock or stock options in Bristol-Myers Squibb. The author has no other competing interests to declare..
  12. Tom R Gaunt

    MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
    Competing interests
    Tom R Gaunt, TG received grants from Biogen and GlaxoSmithKline. The author has no other competing interests to declare..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0924-3247
  13. Valur Emilsson

    Icelandic Heart Association, Kopavogur, Iceland
    Competing interests
    No competing interests declared.
  14. Vilmundur Gudnason

    Icelandic Heart Association, Kopavogur, Iceland
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5696-0084
  15. Ellen M McDonagh

    EBI-EMBL, Cambridge, United Kingdom
    Competing interests
    Ellen M McDonagh, Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners..
  16. Gavin J Wright

    Cell Surface Signalling Laboratory, Wellcome Trust Sanger Institute, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0537-0863
  17. Maya Ghoussaini

    Wellcome Sanger Institute, Cambridge, United Kingdom
    For correspondence
    mg29@sanger.ac.uk
    Competing interests
    Maya Ghoussaini, Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners..
  18. Ian Dunham

    Open Targets, EMBL-European Bioinformatics Institute, Hinxton, United Kingdom
    For correspondence
    dunham@ebi.ac.uk
    Competing interests
    Ian Dunham, Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners. ID also received travel costs within the last 36 months from Takeda for speaking at their Reverse Translation Symposium. The author has no other competing interests to declare..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2525-5598

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.

Reviewing Editor

  1. John W Schoggins, University of Texas Southwestern Medical Center, United States

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).

Version history

  1. Preprint posted: March 17, 2021 (view preprint)
  2. Received: April 23, 2021
  3. Accepted: August 7, 2021
  4. Accepted Manuscript published: August 17, 2021 (version 1)
  5. Version of Record published: September 22, 2021 (version 2)

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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  1. Mohd Anisul
  2. Jarrod Shilts
  3. Jeremy Schwartzentruber
  4. James Hayhurst
  5. Annalisa Buniello
  6. Elmutaz Shaikho
  7. Jie Zheng
  8. Michael Holmes
  9. David Ochoa
  10. Miguel Carmona
  11. Joseph Maranville
  12. Tom R Gaunt
  13. Valur Emilsson
  14. Vilmundur Gudnason
  15. Ellen M McDonagh
  16. Gavin J Wright
  17. Maya Ghoussaini
  18. Ian Dunham
(2021)
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

Share this article

https://doi.org/10.7554/eLife.69719

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