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Review 1: "Vitamin D and COVID-19 Susceptibility and Severity in the COVID-19 Host Genetics Initiative: a Mendelian Random Study"

Published onApr 14, 2022
Review 1: "Vitamin D and COVID-19 Susceptibility and Severity in the COVID-19 Host Genetics Initiative: a Mendelian Random Study"
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key-enterThis Pub is a Review of
Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study

AbstractBackgroundIncreased vitamin D levels, as reflected by 25OHD measurements, have been proposed to protect against COVID-19 disease 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 two-sample MR to assess evidence supporting a causal effect of circulating 25OHD levels on COVID-19 susceptibility and severity.Methods and findingsGenetic 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 1,284,876 without COVID-19, from 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 one standard deviation on the logarithmic scale had no significant association with COVID-19 susceptibility (OR = 0.97; 95% CI: 0.95, 1.10; P=0.61), hospitalization (OR = 1.11; 95% CI: 0.91, 1.35; P=0.30), and severe disease (OR = 0.93; 95% CI: 0.73, 1.17; P=0.53). We used an additional 6 meta-analytic methods, as well as 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.ConclusionIn this two-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.Author SummaryWhy was this study done?-Vitamin D levels have been associated with COVID-19 outcomes in multiple observational studies, though confounders are likely to bias these associations.-By using genetic instruments which limit such confounding, Mendelian randomization studies have consistently obtained results concordant with vitamin D supplementation randomized trials. This provides rationale to undertake vitamin D Mendelian randomization studies for COVID-19 outcomes.What did the researchers do and find?-We used the genetic variants obtained from the largest consortium of COVID-19 cases and controls, and the largest study on genetic determinants of vitamin D levels.-We used Mendelian randomization to estimate the effect of increased vitamin D on COVID-19 outcomes, while limiting confounding.-In multiple analyses, our results consistently showed no evidence for an association between genetically predicted vitamin D levels and COVID-19 susceptibility, hospitalization, or severe disease.What do these findings mean?-Using Mendelian randomization to reduce confounding that has traditionally biased vitamin D observational studies, we did not find evidence that vitamin D supplementation in the general population would improve COVID-19 outcomes-These findings, together with recent randomized controlled trial data, suggest that other therapies should be prioritized for COVID-19 trials.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.



The manuscript investigates the effect of genetic determinants of 25OHD levels in COVID-19 susceptibility and severity using Mendelian randomization in the COVID-19 Host Genetics Initiative.

The study is robust, a total of 81 SNP (conditionally independent, allele freq >1% and linkage disequilibrium coefficient < 5%), from a previous previously published GWAS on circulating 25OHD levels in 401,460 white British participants in the UK Biobank (UKB), are assessed in relation to COVID-19 Host Genetics Initiative defined outcomes (susceptibility, hospitalization and severity) using results restricted to cohorts of European ancestry (total of 14,134 cases and 1,284,876 controls to define COVID-19 susceptibility, 6,406 cases and 902,088 controls to define COVID-19 hospitalization, and 4,336 cases and 623,902 controls to define COVID-19 severe disease).

Following the RR:C19 strength of evidence scale, I will consider the study is reliable.  The study presents a different approach from most of the studies published to date, to explore the association between vitamin D levels and COVID-19 disease and the data indicates that for genetic determinants of 25OHD levels there is no association observed with COVID-19 susceptibility or severity.

Various comments to consider in the manuscript are listed below:

  • The manuscript is not up to date on the published literature investigating the direct evidence of the interaction of vitamin D and COVID-19 susceptibility and severity. The study cited only two studies exploring direct evidence (Entrenas Castillo M et al. and Murai IH et al.). A large body of literature on the topic has been published during the COVID-19 pandemic (, including a recent meta-analysis including 39 studies that indicated a significant association between 25(OH)D concentration and SARS-CoV-2 infection, COVID-19 composite severity, and mortality ( These studies and new evidence should be acknowledged in the manuscript, in the introduction and the discussion, and more importantly to consider the impact of the study. Moreover, Amin et al.  recently published a study using mendelian randomization exploring this association (

  • It is important to highlight that many of the studies published to date, investigate vitamin D deficiency groups and this manuscript does not apply for that subgroup of population. This might have an impact on the external validity of the study if the authors aim to generalise the results in line with the published literature in the topic. This also needs to be considered when assessing the impact of the study. 

  • As the authors mentioned and explored in the methods, there is a potential problem with the second assumption in the MR analysis. MR studies are not my area of expertise so I will kindly request a review of the statistical approach by an expert on the field. This issue has been raised previously in MR studies exploring this association ( Moreover, the MR study does not account for potential confounders such as high solar UVB exposure or high- dose of vitamin D supplement in the analysis.

  • The authors suggest that the results can inform on the role of vitamin D supplementation in COVID-19 susceptibility and severity when comparing the study with the other two studies cited (Entrenas Castillo M et al. and Murai IH et al.). I will suggest to the authors to reconsider this interpretation of the data once they have included all the literature available in the topic. Moreover, I think it is important to highlight that the study explore only the genetic determinants of 25OHD levels in the discussion.

I will suggest the publication of the study after revisions considering the points raised above together with a review of the statistical pipeline conducted in the study.



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