Genetic variants of PIEZO1 associate with COVID-19 fatality

  1. C.W. Cheng
  2. V. Deivasikamani
  3. M.J. Ludlow
  4. D. De Vecchis
  5. A.C. Kalli
  6. D.J. Beech
  7. P. Sukumar

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Abstract

Fatality from coronavirus disease 19 (COVID-19) is a major problem globally and so identification of its underlying molecular mechanisms would be helpful. The combination of COVID-19 clinical data and genome sequence information is providing a potential route to such mechanisms. Here we took a candidate gene approach to UK Biobank data based on the suggested roles of endothelium and membrane proteins in COVID-19. We focussed on the PIEZO1 gene, which encodes a non-selective cation channel that mediates endothelial responses to blood flow. The analysis suggests 3 missense PIEZO1 single nucleotide polymorphisms (SNPs) associated with COVID-19 fatality independently of risk factors. All of them affect amino acids in the proximal N-terminus of PIEZO1, which is an unexplored region of the protein. By using molecular modelling we predict location of all 3 amino acids to a common outward-facing structure of unknown functional significance at the tips of the PIEZO1 propeller blades. Through genome sequence analysis we show that these SNPs vary in prevalence with ethnicity and that the most significant SNP (rs7184427) varies between 65 to 90% even though the reference amino acid is evolutionarily conserved. The data suggest PIEZO1 as a contributor to COVID-19 fatality and factor in ethnic susceptibility.

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    SciScore for 10.1101/2020.06.01.20119651: (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

    Software and Algorithms
    SentencesResources
    The association analysis was performed using logistic regression implemented in PLINK v2.0 (whole genome data analysis toolset) 58.
    PLINK
    suggested: (PLINK, RRID:SCR_001757)
    Phylogenetic analysis: Protein sequences encoded by the PIEZO1 gene were obtained from the Ensembl database 60
    Ensembl
    suggested: (Ensembl, RRID:SCR_002344)
    The resulting alignments were manually curated and trimmed using alignment editor in MEGA 762.
    MEGA
    suggested: (Mega BLAST, RRID:SCR_011920)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    We recognise that a potential limitation of our study is the relatively small size of the COVID-19 data set on which we could base the analysis. Analysis of additional data as they become available will be important for deeper understanding and exploration of PIEZO1 in all groups and specifically in non-White ethnic groups. In an initial preprint released on 3 June 2020 based on UK Biobank data available on 16 April 2020 we suggested association of rs7184427 with SARS-CoV-2 infectivity (doi: https://doi.org/10.1101/2020.06.01.20119651; http://dx.doi.org/10.2139/ssrn.3618312). Subsequent to the 16 April release, changes were made to the underlying data by UK Biobank, we presume to improve accuracy. These changes caused the P-value for rs7184427 to become slightly greater than the threshold value for significance in regard to infection rates. Therefore, as reported in this article, we no longer suggest significant association of this variant with infectivity. It is intriguing that this same variant is the one that is most significantly associated with COVID-19 fatality. It may be that larger data sets will again suggest a link to infectivity and that rs7184427 has a role in susceptibility to infection as well as fatality. In summary, our study suggests genetic association that is relevant to COVID-19 fatality and ethnic variation in susceptibility to fatality and a previously unrecognised relationship between COVID-19 and PIEZO1, a gene that encodes an important mechanically-ac...

    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.

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  2. Version published to 10.1101/2020.06.01.20119651 on medRxiv