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

  1. Mohd Anisul
  2. Jarrod Shilts
  3. Jeremy Schwartzentruber
  4. James Hayhurst
  5. Annalisa Buniello
  6. Elmutaz Shaikho Elhaj Mohammed
  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

  • Curated by eLife

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    Evaluation Summary:

    This study analyzes publicly available genomic and proteomic data to identify host proteins that may be involved in regulation of COVID-19 susceptibility and severity. Several known and new targets are identified, further revealing the complexity of host genetic variation in COVID-19 disease.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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Abstract

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 × 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.

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  1. Version published to 10.7554/elife.69719 on eLife
  2. eLife

    Evaluation Summary:

    This study analyzes publicly available genomic and proteomic data to identify host proteins that may be involved in regulation of COVID-19 susceptibility and severity. Several known and new targets are identified, further revealing the complexity of host genetic variation in COVID-19 disease.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

  3. eLife

    Reviewer #1 (Public Review):

    The paper by Karim et al aims to explore the overlap (co-localization) of genetic variants associated with COVID-19 outcomes in COVID-19 Host Genetics Initiative (HGI) and protein expression in the blood of uninfected population controls reported by several studies. They use an approach of mendelian randomization (MR), considering both cis- and trans-effects of these genetic variants. In addition to several previously reported results, they report three relatively new results.

    The strengths of this paper, compared to a previous report (PMID: 33633408) that uses the same public datasets is a more detailed analysis of both cis- and trans-eQTLs and co-localization-first approach. Having identified an association between rs8176719 within the ABO gene on chromosome 9 and CD209 encoded on chromosome 19, the authors experimentally tested the interaction between recombinant CD209 and SARS-CoV-2 spike protein, suggesting it as a potential viral receptor.

    The limitations of this paper include significant overlap with already reported results, limited additional analyses and functional inferences.

    Overall, this paper, together with previously reported results, indicates that genetic variants associated with several COVID-19 outcomes may have functional effects on proteins already in uninfected population controls. This knowledge can help identify relevant therapeutic approaches targeting proteins and pathways affected by the associated genetic variants.

  4. eLife

    Reviewer #2 (Public Review):

    Karim et al. take an analytical approach using data from previously published proteomic GWAS along with publicly available COVID-19 GWAS data to identify host proteins that may influence COVID-19 outcomes. The findings suggest that the mechanism underlying the previously identified association of the ABO gene with COVID-19 susceptibility and severity might involve regulation of another gene, CD209. Additional proteins that may regulate COVID-19 outcomes are also reported (e.g. OAS1, THBS3 and FAS).

    Although I cannot fully evaluate analytical methods used, the study seems to be well-designed and comprehensive.

  5. ScreenIT

    SciScore for 10.1101/2021.03.15.21253625: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Cell-based receptor binding assay: HEK293 cells were transiently transfected as described previously35 with expression plasmids encoding full-length cDNA of CD209 (Origene SC304915), or a mock transfection lacking the expression plasmid.
    HEK293
    suggested: None

    Results from OddPub: Thank you for sharing your code.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    As noted by Bovign and colleagues66, with some caveats, the phenotypic consistency of associations between the IL-6R genetic instrument and pharmacological effect of tocilizumab enable potential use of the IL-6R instrument to investigate therapeutic or adverse effects of tocilizumab. Although a previous report showed largely neutral effects of tocilizumab compared to placebo in hospitalised COVID-19 patients67, two recent trials (REMAP-CAP68 and RECOVERY69) with a longer follow-up period showed beneficial effects on survival at 90 days, consistent with the prediction of a protective effect using the tocilizumab-mimicking IL-6R genetic instrument in the present study and the previous report. Major strengths of our study include use of both genome-wide and local genetic instruments for MR analysis, the proteome-wide genetic colocalisation tests to nominate additional proteins of therapeutic relevance, and the expanded list of COVID-19 phenotypes analysed. We showed consistency of the association of ABO with the different COVID-19 phenotypes for both instrument selection strategies. Proteome-wide colocalisation tests implicated additional proteins that likely lacked sufficient genetic instruments to be detected by the multi-instrument GSMR method. For our top-ranked association with the CD209 protein, we provide experimental evidence for a mechanism that implicates CD209 as having a potential causal role in disease pathology. Our experiments provide both direct evidence of bioch...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04505774RecruitingAnti-thrombotics for Adults Hospitalized With COVID-19 (ACTI…

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  6. Version published to 10.1101/2021.03.15.21253625v1 on medRxiv