Genetically predicted serum vitamin D and COVID-19: a Mendelian randomisation study
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Abstract
To investigate causality of the association of serum vitamin D with the risk and severity of COVID-19 infection.
Design
Two-sample Mendelian randomisation study.
Setting
Summary data from genome-wide analyses in the population-based UK Biobank and SUNLIGHT Consortium, applied to meta-analysed results of genome-wide analyses in the COVID-19 Host Genetics Initiative.
Participants
17 965 COVID-19 cases including 11 085 laboratory or physician-confirmed cases, 7885 hospitalised cases and 4336 severe respiratory cases, and 1 370 547 controls, primarily of European ancestry.
Exposures
Genetically predicted variation in serum vitamin D status, instrumented by genome-wide significant single nucleotide polymorphisms (SNPs) associated with serum vitamin D or risk of vitamin D deficiency/insufficiency.
Main outcome measures
Susceptibility to and severity of COVID-19 infection, including severe respiratory infection and hospitalisation.
Results
Mendelian randomisation analysis, sufficiently powered to detect effects comparable to those seen in observational studies, provided little to no evidence for an effect of genetically predicted serum vitamin D on susceptibility to or severity of COVID-19 infection. Using SNPs in loci related to vitamin D metabolism as genetic instruments for serum vitamin D concentrations, the OR per SD higher serum vitamin D was 1.04 (95% CI 0.92 to 1.18) for any COVID-19 infection versus population controls, 1.05 (0.84 to 1.31) for hospitalised COVID-19 versus population controls, 0.96 (0.64 to 1.43) for severe respiratory COVID-19 versus population controls, 1.15 (0.99 to 1.35) for COVID-19 positive versus COVID-19 negative and 1.44 (0.75 to 2.78) for hospitalised COVID-19 versus non-hospitalised COVID-19. Results were similar in analyses using SNPs with genome-wide significant associations with serum vitamin D (ie, including SNPs in loci with no known relationship to vitamin D metabolism) and in analyses using SNPs with genome-wide significant associations with risk of vitamin D deficiency or insufficiency.
Conclusions
These findings suggest that genetically predicted differences in long-term vitamin D nutritional status do not causally affect susceptibility to and severity of COVID-19 infection, and that associations observed in previous studies may have been driven by confounding. These results do not exclude the possibility of low-magnitude causal effects or causal effects of acute responses to therapeutic doses of vitamin D.
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SciScore for 10.1101/2021.01.29.21250759: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The Institutional Review Board at RTI International approved the UK Biobank data use and analysis. Randomization Statistical Analysis for Two-Sample MR: We performed two-sample MR using the inverse variance weighted (IVW) method, which assumes that pleiotropy is either non-existent or balanced (i.e., any associations of genetic instrument SNPs with phenotypes other than vitamin D are randomly positive and negative such that the mean pleiotropic effect is zero). Blinding not detected. Power Analysis We calculated the minimum odds ratio detectable at 80% power for each COVID-19 outcome using the “mRnd” tool (https://shiny.cnsgenomics.com/mRnd/).60 Based on … SciScore for 10.1101/2021.01.29.21250759: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The Institutional Review Board at RTI International approved the UK Biobank data use and analysis. Randomization Statistical Analysis for Two-Sample MR: We performed two-sample MR using the inverse variance weighted (IVW) method, which assumes that pleiotropy is either non-existent or balanced (i.e., any associations of genetic instrument SNPs with phenotypes other than vitamin D are randomly positive and negative such that the mean pleiotropic effect is zero). Blinding not detected. Power Analysis We calculated the minimum odds ratio detectable at 80% power for each COVID-19 outcome using the “mRnd” tool (https://shiny.cnsgenomics.com/mRnd/).60 Based on heritability estimates from the UK Biobank and SUNLIGHT Consortium vitamin D GWA studies,23,61 we assumed the genetic instruments accounted for 3% of the variance in serum vitamin D for all power calculations. Sex as a biological variable The SNP–vitamin D associations were estimated stratified by sex (male vs. female), age group (40-50 vs. 50-60 vs. 60-70), BMI category (18.5-25 vs. 25-30 vs. 30-40 vs. >40), and smoking status (never vs. former vs. current smokers). Table 2: Resources
Software and Algorithms Sentences Resources Analyses were performed using the GENESIS R/ Bioconductor package,52 separately for European ancestry (N = 421,407) and African ancestry (N = 7,859) participants, as classified via analysis with STRUCTURE53 in comparison to the CEU, YRI, and CHB 1000 Genomes populations. GENESISsuggested: (Genesis, RRID:SCR_015775)Bioconductorsuggested: (Bioconductor, RRID:SCR_006442)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 MR approach addresses key limitations of these studies, including confounding and reverse causality, and is recognized as a method for improving causal inference in epidemiology. This study has many strengths. We used summary data from the largest GWA studies of serum vitamin D to maximize the strength and validity of the genetic instruments for vitamin D and leveraged publicly available data on nearly 1.4 million participants, including 17,965 COVID-19 cases, from 38 study cohorts in the COVID-19 Host Genetics Initiative. We addressed potential pleiotropy of the genetic instruments, which if present would limit the interpretation of the MR results, by comparing results across the biologically plausible and expanded instruments, testing for evidence of pleiotropy with the MR-Egger intercept test, and performing sensitivity analysis with alternative MR methods that address pleiotropy. We explored potential threshold effects using genetic instruments for vitamin D deficiency and insufficiency. Our findings were robust across all exploration, and, in triangulation with results of the largest to date observational study of vitamin D and COVID-19, the findings help to clarify the nature of the association of vitamin D with COVID-19 outcomes. As in any MR study, the valid interpretation of our results rests on the MR assumptions of adequate strength of the genetic instruments for vitamin D and absence of direct effects of the instruments on COVID-19 outcomes and potential confo...
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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