Altered Blood Cell Traits Underlie a Major Genetic Locus of Severe COVID-19

  1. Jingqi Zhou
  2. Yitang Sun
  3. Weishan Huang
  4. Kaixiong Ye

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Abstract

Background

The genetic locus 3p21.31 has been associated with severe coronavirus disease 2019 (COVID-19), but the underlying pathophysiological mechanism is unknown.

Methods

To identify intermediate traits associated with the 3p21.31 locus, we first performed a phenome-wide association study (PheWAS) with 923 phenotypes in 310 999 European individuals from the UK Biobank. For genes potentially regulated by the COVID-19 risk variant, we examined associations between their expression and the polygenic score (PGS) of 1263 complex traits in a meta-analysis of 31 684 blood samples. For the prioritized blood cell traits, we tested their associations with age and sex in the same UK Biobank sample.

Results

Our PheWAS highlighted multiple blood cell traits to be associated with the COVID-19 risk variant, including monocyte count and percentage (p = 1.07 × 10–8, 4.09 × 10–13), eosinophil count and percentage (p = 5.73 × 10–3, 2.20 × 10–3), and neutrophil percentage (p = 3.23 × 10–3). The PGS analysis revealed positive associations between the expression of candidate genes and genetically predicted counts of specific blood cells: CCR3 with eosinophil and basophil (p = 5.73 × 10–21, 5.08 × 10–19); CCR2 with monocytes (p = 2.40 × 10–10); and CCR1 with monocytes and neutrophil (p = 1.78 × 10–6, 7.17 × 10–5). Additionally, we found that almost all examined white blood cell traits are significantly different across age and sex groups.

Conclusions

Our findings suggest that altered blood cell traits, especially those of monocyte, eosinophil, and neutrophil, may represent the mechanistic links between the genetic locus 3p21.31 and severe COVID-19. They may also underlie the increased risk of severe COVID-19 in older adults and men.

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  1. ScreenIT

    SciScore for 10.1101/2020.09.09.20191700: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: It was approved by the North West Multi-Centre Research Ethics Committee and proper informed consent was obtained.
    Consent: It was approved by the North West Multi-Centre Research Ethics Committee and proper informed consent was obtained.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Resources: eQTLGen: https://www.eqtlgen.org/index.htmlGene ATLAS: http://geneatlas.roslin.ed.ac.uk/GTEx: https://www.gtexportal.org/home/The COVID-19 GWAS Results Browser: https://ikmb.shinyapps.io/COVID-19_GWAS_Browser/The COVID-19 Host Genetics Initiative: https://www.covid19hg.org/The IEU OpenGWAS database: https://gwas.mrcieu.ac.uk/
    ATLAS
    suggested: (CATlas, RRID:SCR_018690)

    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:
    This study also has some weaknesses. First, there are still phenotypes not covered in our analyses, such as monocyte subsets, T cells and B cells. It is possible that the severe COVID-19 risk variant affects other unexplored intermediate traits. Moreover, future fine-mapping studies are needed to identify causal variants at locus 3p21.31 for both severe COVID-19 and blood cell traits. The possibility could not be ruled out at present that they are different variants in strong LD40. Our analyses were restricted to population samples and may not reflect patterns in COVID-19 patients. Additionally, the associations between gene expression and genetically predicted blood cell counts should be further confirmed with direct analysis of their measured counts. In conclusion, our phenome-wide association study for the severe COVID-19 risk variant at locus 3p21.31 and its candidate target genes identified altered blood cell traits, especially counts of monocyte, eosinophil, and neutrophil, as the probable mechanistic links between the genetic locus and severe COVID-19. These blood cell traits, together with their candidate acting genes, CCR1, CCR2 and CCR3, represent compelling and testable hypotheses that call for follow-up studies into their roles in COVID-19 pathogenesis.

    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 10.1093/gerona/glab035
  3. Version published to 10.1101/2020.09.09.20191700v1 on medRxiv