ELF5 is a potential respiratory epithelial cell-specific risk gene for severe COVID-19

  1. Maik Pietzner
  2. Robert Lorenz Chua
  3. Eleanor Wheeler
  4. Katharina Jechow
  5. Julian D. S. Willett
  6. Helena Radbruch
  7. Saskia Trump
  8. Bettina Heidecker
  9. Hugo Zeberg
  10. Frank L. Heppner
  11. Roland Eils
  12. Marcus A. Mall
  13. J. Brent Richards
  14. Leif-Erik Sander
  15. Irina Lehmann
  16. Sören Lukassen
  17. Nicholas J. Wareham
  18. Christian Conrad
  19. Claudia Langenberg

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Abstract

Despite two years of intense global research activity, host genetic factors that predispose to a poorer prognosis of COVID-19 infection remain poorly understood. Here, we prioritise eight robust (e.g., ELF5) or suggestive but unreported (e.g., RAB2A) candidate protein mediators of COVID-19 outcomes by integrating results from the COVID-19 Host Genetics Initiative with population-based plasma proteomics using statistical colocalisation. The transcription factor ELF5 ( ELF5 ) shows robust and directionally consistent associations across different outcome definitions, including a >4-fold higher risk (odds ratio: 4.88; 95%-CI: 2.47–9.63; p-value < 5.0 × 10 −6 ) for severe COVID-19 per 1 s.d. higher genetically predicted plasma ELF5. We show that ELF5 is specifically expressed in epithelial cells of the respiratory system, such as secretory and alveolar type 2 cells, using single-cell RNA sequencing and immunohistochemistry. These cells are also likely targets of SARS-CoV-2 by colocalisation with key host factors, including ACE2 and TMPRSS2 . In summary, large-scale human genetic studies together with gene expression at single-cell resolution highlight ELF5 as a risk gene for severe COVID-19, supporting a role of epithelial cells of the respiratory system in the adverse host response to SARS-CoV-2.

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  1. Version published to 10.1038/s41467-022-31999-6
  2. ScreenIT

    SciScore for 10.1101/2022.01.17.22269283: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: This study was approved by the local ethics committees (EA1/144/13, EA2/066/20 and EA1/075/19) as well as by the Charité–BIH COVID-19 research board and was in compliance with the Declaration of Helsinki; autopsies were performed on the legal basis of §1 of the Autopsy Act of the state Berlin and §25(4) of the German Infection Protection Act.
    Sex as a biological variablenot detected.
    RandomizationMendelian randomization: To derive effect directions and estimate possible effects of life-long higher/lower protein abundances on COVID-19 susceptibility and severeness, we performed single-instrument Mendelian randomization (MR) analysis using cis protein quantitative trait loci (cis-pQTLs) as instruments.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Collation of target genes of ELF5: We collated a list of genes with possible direction association with ELF5 by querying the Molecular Signatures Data Base79, the Enricr tool80, the Harmonizome81, including ChIP-Seq experiments82, and a curated gene co-expression network83 (Supplementary Table 3).
    ChIP-Seq
    suggested: (ChIP-seq, RRID:SCR_001237)
    Analysis was performed with Seurat v3.1.487,88.
    Seurat
    suggested: (SEURAT, RRID:SCR_007322)
    Gene set enrichment analysis79 (GSEA; v4.1.0) was used to test for enrichment of the collated ELF5 target genes against all detected genes where the weights used were the Pearson’s correlation values.
    GSEA
    suggested: (SeqGSEA, RRID:SCR_005724)

    Results from OddPub: Thank you for sharing your code.

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    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.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  3. Version published to 10.1101/2022.01.17.22269283v1 on medRxiv