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.

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).

Reviewing Editor

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

Publication 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
  1. Further reading

Further reading

    1. Epidemiology and Global Health
    Ceereena Ubaida-Mohien et al.
    Research Article Updated

    Background:

    Master athletes (MAs) prove that preserving a high level of physical function up to very late in life is possible, but the mechanisms responsible for their high function remain unclear.

    Methods:

    We performed muscle biopsies in 15 octogenarian world-class track and field MAs and 14 non-athlete age/sex-matched controls (NA) to provide insights into mechanisms for preserving function in advanced age. Muscle samples were assessed for respiratory compromised fibers, mitochondrial DNA (mtDNA) copy number, and proteomics by liquid-chromatography mass spectrometry.

    Results:

    MA exhibited markedly better performance on clinical function tests and greater cross-sectional area of the vastus lateralis muscle. Proteomics analysis revealed marked differences, where most of the ~800 differentially represented proteins in MA versus NA pertained to mitochondria structure/function such as electron transport capacity (ETC), cristae formation, mitochondrial biogenesis, and mtDNA-encoded proteins. In contrast, proteins from the spliceosome complex and nuclear pore were downregulated in MA. Consistent with proteomics data, MA had fewer respiratory compromised fibers, higher mtDNA copy number, and an increased protein ratio of the cristae-bound ETC subunits relative to the outer mitochondrial membrane protein voltage-dependent anion channel. There was a substantial overlap of proteins overrepresented in MA versus NA with proteins that decline with aging and that are higher in physically active than sedentary individuals. However, we also found 176 proteins related to mitochondria that are uniquely differentially expressed in MA.

    Conclusions:

    We conclude that high function in advanced age is associated with preserving mitochondrial structure/function proteins, with underrepresentation of proteins involved in the spliceosome and nuclear pore complex. Whereas many of these differences in MA appear related to their physical activity habits, others may reflect unique biological (e.g., gene, environment) mechanisms that preserve muscle integrity and function with aging.

    Funding:

    Funding for this study was provided by operating grants from the Canadian Institutes of Health Research (MOP 84408 to TT and MOP 125986 to RTH). This work was supported in part by the Intramural Research Program of the National Institute on Aging, NIH, Baltimore, MD, USA.

    1. Epidemiology and Global Health
    Toby Mansell et al.
    Research Article

    Background:

    The risk of adult onset cardiovascular and metabolic (cardiometabolic) disease accrues from early life. Infection is ubiquitous in infancy and induces inflammation, a key cardiometabolic risk factor, but the relationship between infection, inflammation, and metabolic profiles in early childhood remains unexplored. We investigated relationships between infection and plasma metabolomic and lipidomic profiles at age 6 and 12 months, and mediation of these associations by inflammation.

    Methods:

    Matched infection, metabolomics, and lipidomics data were generated from 555 infants in a pre-birth longitudinal cohort. Infection data from birth to 12 months were parent-reported (total infections at age 1, 3, 6, 9, and 12 months), inflammation markers (high-sensitivity C-reactive protein [hsCRP]; glycoprotein acetyls [GlycA]) were quantified at 12 months. Metabolic profiles were 12-month plasma nuclear magnetic resonance metabolomics (228 metabolites) and liquid chromatography/mass spectrometry lipidomics (776 lipids). Associations were evaluated with multivariable linear regression models. In secondary analyses, corresponding inflammation and metabolic data from birth (serum) and 6-month (plasma) time points were used.

    Results:

    At 12 months, more frequent infant infections were associated with adverse metabolomic (elevated inflammation markers, triglycerides and phenylalanine, and lower high-density lipoprotein [HDL] cholesterol and apolipoprotein A1) and lipidomic profiles (elevated phosphatidylethanolamines and lower trihexosylceramides, dehydrocholesteryl esters, and plasmalogens). Similar, more marked, profiles were observed with higher GlycA, but not hsCRP. GlycA mediated a substantial proportion of the relationship between infection and metabolome/lipidome, with hsCRP generally mediating a lower proportion. Analogous relationships were observed between infection and 6-month inflammation, HDL cholesterol, and apolipoprotein A1.

    Conclusions:

    Infants with a greater infection burden in the first year of life had proinflammatory and proatherogenic plasma metabolomic/lipidomic profiles at 12 months of age that in adults are indicative of heightened risk of cardiovascular disease, obesity, and type 2 diabetes. These findings suggest potentially modifiable pathways linking early life infection and inflammation with subsequent cardiometabolic risk.

    Funding:

    The establishment work and infrastructure for the BIS was provided by the Murdoch Children’s Research Institute (MCRI), Deakin University, and Barwon Health. Subsequent funding was secured from National Health and Medical Research Council of Australia (NHMRC), The Shepherd Foundation, The Jack Brockhoff Foundation, the Scobie & Claire McKinnon Trust, the Shane O’Brien Memorial Asthma Foundation, the Our Women’s Our Children’s Fund Raising Committee Barwon Health, the Rotary Club of Geelong, the Minderoo Foundation, the Ilhan Food Allergy Foundation, GMHBA, Vanguard Investments Australia Ltd, and the Percy Baxter Charitable Trust, Perpetual Trustees. In-kind support was provided by the Cotton On Foundation and CreativeForce. The study sponsors were not involved in the collection, analysis, and interpretation of data; writing of the report; or the decision to submit the report for publication. Research at MCRI is supported by the Victorian Government’s Operational Infrastructure Support Program. This work was also supported by NHMRC Senior Research Fellowships to ALP (1008396); DB (1064629); and RS (1045161) , NHMRC Investigator Grants to ALP (1110200) and DB (1175744), NHMRC-A*STAR project grant (1149047). TM is supported by an MCRI ECR Fellowship. SB is supported by the Dutch Research Council (452173113).