Leveraging Genetic Data to Elucidate the Relationship Between COVID‐19 and Ischemic Stroke

  1. Verena Zuber
  2. Alan Cameron
  3. Evangelos P. Myserlis
  4. Leonardo Bottolo
  5. Israel Fernandez‐Cadenas
  6. Stephen Burgess
  7. Christopher D. Anderson
  8. Jesse Dawson
  9. Dipender Gill

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Abstract

The relationship between COVID‐19 and ischemic stroke is poorly understood due to potential unmeasured confounding and reverse causation. We aimed to leverage genetic data to triangulate reported associations.

Methods and Results

Analyses primarily focused on critical COVID‐19, defined as hospitalization with COVID‐19 requiring respiratory support or resulting in death. Cross‐trait linkage disequilibrium score regression was used to estimate genetic correlations of critical COVID‐19 with ischemic stroke, other related cardiovascular outcomes, and risk factors common to both COVID‐19 and cardiovascular disease (body mass index, smoking and chronic inflammation, estimated using C‐reactive protein). Mendelian randomization analysis was performed to investigate whether liability to critical COVID‐19 was associated with increased risk of any cardiovascular outcome for which genetic correlation was identified. There was evidence of genetic correlation between critical COVID‐19 and ischemic stroke (r g =0.29, false discovery rate [FDR]=0.012), body mass index (r g =0.21, FDR=0.00002), and C‐reactive protein (r g =0.20, FDR=0.00035), but no other trait investigated. In Mendelian randomization, liability to critical COVID‐19 was associated with increased risk of ischemic stroke (odds ratio [OR] per logOR increase in genetically predicted critical COVID‐19 liability 1.03, 95% CI 1.00–1.06, P ‐value=0.03). Similar estimates were obtained for ischemic stroke subtypes. Consistent estimates were also obtained when performing statistical sensitivity analyses more robust to the inclusion of pleiotropic variants, including multivariable Mendelian randomization analyses adjusting for potential genetic confounding through body mass index, smoking, and chronic inflammation. There was no evidence to suggest that genetic liability to ischemic stroke increased the risk of critical COVID‐19.

Conclusions

These data support that liability to critical COVID‐19 is associated with an increased risk of ischemic stroke. The host response predisposing to severe COVID‐19 is likely to increase the risk of ischemic stroke, independent of other potentially mitigating risk factors.

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  1. Version published to 10.1161/jaha.121.022433
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    SciScore for 10.1101/2021.02.25.21252441: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementConsent: Appropriate patient consent and ethical approval had been obtained in the original studies from which they were obtained (Supplementary Table 1).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: Thank you for sharing your code.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    This has helped to overcome some of the limitations of previous observational studies (either retrospective or cross-sectional) assessing the relationship between Covid-19 and ischemic stroke.3–6 Our work also has limitations. A series of modelling assumptions are made when using MR, in particular, that the genetic variants do not affect the considered outcomes through pathways independent of the exposure. While this can never be completely excluded, we employed methods that are robust to genetic confounding (pleiotropy) in a series of sensitivity analyses (including pleiotropy-robust MR methods and accounting for measured pleiotropy using multivariable MR) and the estimates were consistent with our main analyses. We cannot be certain that genetic associations with liability to critical Covid-19 accurately reflect the pathophysiological process that actually occurs during critical Covid-19. For example, while genetic predisposition may place an individual at increased liability to critical Covid-19, it is not possible to determine from our analyses whether that factor is involved in the pathophysiological response to Covid-19. In conclusion, we have found genetic evidence that liability to critical Covid-19 is associated with increased risk of ischemic stroke. Our results are consistent with the host response in critical Covid-19 underlying this relationship, and support the evaluation of strategies to mitigate this.

    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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  3. Version published to 10.1101/2021.02.25.21252441v1 on medRxiv