Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study

  1. Guillaume Butler-Laporte
  2. Tomoko Nakanishi
  3. Vincent Mooser
  4. David R. Morrison
  5. Tala Abdullah
  6. Olumide Adeleye
  7. Noor Mamlouk
  8. Nofar Kimchi
  9. Zaman Afrasiabi
  10. Nardin Rezk
  11. Annarita Giliberti
  12. Alessandra Renieri
  13. Yiheng Chen
  14. Sirui Zhou
  15. Vincenzo Forgetta
  16. J. Brent Richards

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Abstract

Increased vitamin D levels, as reflected by 25-hydroxy vitamin D (25OHD) measurements, have been proposed to protect against COVID-19 based on in vitro, observational, and ecological studies. However, vitamin D levels are associated with many confounding variables, and thus associations described to date may not be causal. Vitamin D Mendelian randomization (MR) studies have provided results that are concordant with large-scale vitamin D randomized trials. Here, we used 2-sample MR to assess evidence supporting a causal effect of circulating 25OHD levels on COVID-19 susceptibility and severity.

Methods and findings

Genetic variants strongly associated with 25OHD levels in a genome-wide association study (GWAS) of 443,734 participants of European ancestry (including 401,460 from the UK Biobank) were used as instrumental variables. GWASs of COVID-19 susceptibility, hospitalization, and severe disease from the COVID-19 Host Genetics Initiative were used as outcome GWASs. These included up to 14,134 individuals with COVID-19, and up to 1,284,876 without COVID-19, from up to 11 countries. SARS-CoV-2 positivity was determined by laboratory testing or medical chart review. Population controls without COVID-19 were also included in the control groups for all outcomes, including hospitalization and severe disease. Analyses were restricted to individuals of European descent when possible. Using inverse-weighted MR, genetically increased 25OHD levels by 1 standard deviation on the logarithmic scale had no significant association with COVID-19 susceptibility (odds ratio [OR] = 0.95; 95% CI 0.84, 1.08; p = 0.44), hospitalization (OR = 1.09; 95% CI: 0.89, 1.33; p = 0.41), and severe disease (OR = 0.97; 95% CI: 0.77, 1.22; p = 0.77). We used an additional 6 meta-analytic methods, as well as conducting sensitivity analyses after removal of variants at risk of horizontal pleiotropy, and obtained similar results. These results may be limited by weak instrument bias in some analyses. Further, our results do not apply to individuals with vitamin D deficiency.

Conclusions

In this 2-sample MR study, we did not observe evidence to support an association between 25OHD levels and COVID-19 susceptibility, severity, or hospitalization. Hence, vitamin D supplementation as a means of protecting against worsened COVID-19 outcomes is not supported by genetic evidence. Other therapeutic or preventative avenues should be given higher priority for COVID-19 randomized controlled trials.

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  3. Version published to 10.1371/journal.pmed.1003605
  4. Version published to 10.1101/2020.09.08.20190975v5 on medRxiv
  5. ScreenIT

    SciScore for 10.1101/2020.09.08.20190975: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: Research Ethics: Each cohort included in this study received their respective institutional research ethics board approval to enroll patients.
    Randomizationnot detected.
    Blindingnot detected.
    Power AnalysisThis allows for increased statistical power by increasing the sample size in both the exposure and outcome cohorts.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    For SNPs that were not available in the outcome GWAS or with palindromic alleles of intermediate frequency (between 42% and 58%), we used the LDlink tool[31] to find genetic proxies in the European 1000 Genomes dataset (excluding Finnish populations) using linkage disequilibrium r2 of 90% or more.
    LDlink
    suggested: None
    Allele harmonization and computations were performed using the TwoSampleMR package[34].
    TwoSampleMR
    suggested: (TwoSampleMR, RRID:SCR_019010)

    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:
    Our study still has limitations. First, our results do not take true vitamin D deficiency into account, and it remains possible that truly deficient patients may benefit from supplementation for COVID-19 related purposes. However, when comparing previous results from MR studies and RCTs, we do not expect a large impact even in this population. Second, our study may suffer from weak instrument bias, especially the sensitivity analyses restricted to smaller sets of genetic instruments. In two-sample MR, this bias would tend to make estimates closer to the null. Nonetheless, similar studies have been able to use MR to establish an association between 25OHD levels and other diseases (most notably multiple sclerosis[25]), suggesting that these instruments are strong enough to find associations. Further, given the large percentage of shared individuals from the UKB between the vitamin D exposure GWAS[28] and the severe COVID-19 phenotype, this analysis is close to a one-sample MR, which would show bias towards the observational study association. Given that this analysis also shows largely null effects, we do not suspect that weak instruments bias is a significant issue in our results. Third, given that vitamin D levels are affected by season (with higher levels after sunlight exposure), even if our SNP-instruments were obtained from a GWAS that controlled for season of blood draw, there is still a chance for effect attenuation by averaging the effect of 25OHD levels on COVID-19 ov...

    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

    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.

  6. Version published to 10.1101/2020.09.08.20190975v4 on medRxiv
  7. Version published to 10.1101/2020.09.08.20190975v3 on medRxiv
  8. Version published to 10.1101/2020.09.08.20190975v1 on medRxiv
  9. Version published to 10.1101/2020.09.08.20190975v2 on medRxiv