Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study
Bibliographic record
Abstract
Abstract Background Increased 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 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 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. Conclusion In 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 Summary Why 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.005 | 0.018 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".