Severe COVID-19-associated variants linked to chemokine receptor gene control in monocytes and macrophages

  1. Bernard S. Stikker
  2. Grégoire Stik
  3. Antoinette F. van Ouwerkerk
  4. Lianne Trap
  5. Salvatore Spicuglia
  6. Rudi W. Hendriks
  7. Ralph Stadhouders

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Abstract

Genome-wide association studies have identified 3p21.31 as the main risk locus for severe COVID-19, although underlying mechanisms remain elusive. We perform an epigenomic dissection of 3p21.31, identifying a CTCF-dependent tissue-specific 3D regulatory chromatin hub that controls the activity of several chemokine receptor genes. Risk SNPs colocalize with regulatory elements and are linked to increased expression of CCR1 , CCR2 and CCR5 in monocytes and macrophages. As excessive organ infiltration of inflammatory monocytes and macrophages is a hallmark of severe COVID-19, our findings provide a rationale for the genetic association of 3p21.31 variants with elevated risk of hospitalization upon SARS-CoV-2 infection.

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  1. Version published to 10.1186/s13059-022-02669-z
  2. Version published to 10.1101/2021.01.22.427813v3 on bioRxiv
  3. Version published to 10.1101/2021.01.22.427813v2 on bioRxiv
  4. ScreenIT

    SciScore for 10.1101/2021.01.22.427813: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Experimental Models: Organisms/Strains
    SentencesResources
    GWAS data (GRCh37/hg38 genome build) was obtained from two studies: B1_ALL (Hospitalized COVID-19 vs. non-hospitalized COVID-19; 2430 cases versus 8478 controls) and B2_ALL (Hospitalized COVID-19 vs. population; 8638 cases versus 1736547
    B1_ALL
    suggested: None
    Software and Algorithms
    SentencesResources
    GWAS summary statistics files were used to generate input files for FUMA using standard data table processing functions in Rstudio v.1.3.1093.
    Rstudio
    suggested: (RStudio, RRID:SCR_000432)
    ENCODE and BLUEPRINT data were visualized in the UCSC Genome Browser (
    UCSC Genome Browser
    suggested: (UCSC Genome Browser, RRID:SCR_005780)
    Significant FUMA SNPs were converted to GRCh38/hg38 using UCSC LiftOver (https://genome.ucsc.edu/cgi-bin/hgLiftOver) to allow aligning variants to the epigenomic profiles.
    UCSC LiftOver
    suggested: None
    Circos plots visualizing promoter-capture HiC data from the BLUEPRINT consortium were generated using https://www.chicp.org/chicp/, with a threshold normalized interaction value of 7.
    Circos
    suggested: (Circos, RRID:SCR_011798)
    Immune cell-specific gene expression data was obtained using the DICE online platform (https://dice-database.org/) and visualized as averaged values (from n=81-91 individuals) using Morpheus (https://software.broadinstitute.org/morpheus/).
    Morpheus
    suggested: (Morpheus, RRID:SCR_014975)
    https://software.broadinstitute.org/morpheus/
    suggested: (Morpheus by Broad Institute, RRID:SCR_017386)

    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: 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 found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    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

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  5. Version published to 10.1101/2021.01.22.427813v1 on bioRxiv