Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19

  1. Alish B. Palmos
  2. Vincent Millischer
  3. David K. Menon
  4. Timothy R. Nicholson
  5. Leonie S. Taams
  6. Benedict Michael
  7. Geraint Sunderland
  8. Michael J. Griffiths
  9. COVID Clinical Neuroscience Study Consortium
  10. Christopher Hübel
  11. Gerome Breen

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Abstract

In November 2021, the COVID-19 pandemic death toll surpassed five million individuals. We applied Mendelian randomization including >3,000 blood proteins as exposures to identify potential biomarkers that may indicate risk for hospitalization or need for respiratory support or death due to COVID-19, respectively. After multiple testing correction, using genetic instruments and under the assumptions of Mendelian Randomization, our results were consistent with higher blood levels of five proteins GCNT4, CD207, RAB14, C1GALT1C1, and ABO being causally associated with an increased risk of hospitalization or respiratory support/death due to COVID-19 (ORs = 1.12–1.35). Higher levels of FAAH2 were solely associated with an increased risk of hospitalization (OR = 1.19). On the contrary, higher levels of SELL, SELE, and PECAM-1 decrease risk of hospitalization or need for respiratory support/death (ORs = 0.80–0.91). Higher levels of LCTL, SFTPD, KEL, and ATP2A3 were solely associated with a decreased risk of hospitalization (ORs = 0.86–0.93), whilst higher levels of ICAM-1 were solely associated with a decreased risk of respiratory support/death of COVID-19 (OR = 0.84). Our findings implicate blood group markers and binding proteins in both hospitalization and need for respiratory support/death. They, additionally, suggest that higher levels of endocannabinoid enzymes may increase the risk of hospitalization. Our research replicates findings of blood markers previously associated with COVID-19 and prioritises additional blood markers for risk prediction of severe forms of COVID-19. Furthermore, we pinpoint druggable targets potentially implicated in disease pathology.

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  1. Version published to 10.1371/journal.pgen.1010042
  2. ScreenIT

    SciScore for 10.1101/2021.03.09.21253206: (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

    No key resources detected.

    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:
    The LDL receptor-related protein associated protein 1 (LRPAP1; OR = 1.73, 95% CI: 1.49-1.97) is involved as an escort protein in trafficking members of the LDL receptor family through the endoplasmic reticulum and Golgi apparatus preventing premature binding of ligands with these receptors.(78) In COVID-19, LDL cholesterol below or equal to 69 mg/dl has been associated with poor clinical outcomes.(79) Regarding a potential involvement in the development of neurological and cardiovascular symptoms, genomic variants in LRPAP1 have been associated with late-onset Alzheimer’s and Parkinson’s disease while serum anti-LRPAP1 is commonly used as a biomarker for atherosclerotic diseases.(80–82) Our study has several limitations. Firstly, although we required confirmation of our findings by several Mendelian randomization methods, the p-value threshold for selecting genetic variants as instruments for our analyses was set at suggestive significance (p < 5 × 10−6) to allow enough to be identified for each protein, meaning that some of the genetic variants may not have true associations with protein levels. Secondly, some blood marker GWASs were excluded from our analyses due to unavailability, therefore, we may have missed associations with these markers. Thirdly, the severe COVID-19 GWAS used is of small sample size, reducing power to detect associations. However, it was a GWAS of the extreme phenotype of COVID-19 mortality or ventilator support, which may compensate for this.(83) Fin...

    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.

    About SciScore

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  3. Version published to 10.1101/2021.03.09.21253206v1 on medRxiv