Genetically predicted serum vitamin D and COVID-19: a Mendelian randomisation study
Bonnie K Patchen, Andrew G Clark, Nathan Gaddis, Dana B Hancock, Dr Patricia A Cassano
BMJ Nutrition, Prevention & Health, doi:10.1136/bmjnph-2021-000255
Objectives 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 genomewide 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 genomewide 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.
BMJ Nutrition, Prevention & Health Provenance and peer review Not commissioned; externally peer reviewed by Xia Jiang, Karolinska Institute, Sweden and Dr Emmanuel Baah, University of North Carolina System. Data availability statement All data used for this analysis are publicly available. UK Biobank and COVID-19 Host Genetics Initiative data used for the main analysis are available in a public, open access repository. UK Biobank data used for stratified anayses of SNP-vitamin D associations are available on reasonable request from the UK Biobank. Code implementing the MR analysis is available on request from the corresponding author. Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0)..
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'abstract': '<jats:sec><jats:title>Objectives</jats:title><jats:p>To investigate causality of the '
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'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.</jats:p></jats:sec><jats:sec><jats:title>Main outcome '
'measures</jats:title><jats:p>Susceptibility to and severity of COVID-19 infection, including '
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'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 '
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'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 '
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'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 '
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