Vitamin D and Covid-19 Susceptibility and Severity: a Mendelian Randomization Study

Butler-Laporte, Guillaume; Nakanishi, Tomoko; Mooser, Vincent; Morrison, David R; Abdullah, Tala; Adeleye, Olumide; Mamlook, Noor; Kimchi, Nofar; Afrasiabi, Zaman; Rezk, Nardin; Giliberti, Annarita; Renieri, Alessandra; Chen, Yiheng; Zhou, Sirui; Forgetta, Vincenzo; Richards, J Brent

INTRODUCTION: Increased vitamin D levels, as reflected by 25OHD measurements, has 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 MR studies have provided results that are concordant with large-scale vitamin D randomized trials. Here, we used two-sample MR to assess the effect of circulating 25OHD levels on Covid-19 susceptibility. METHODS: Genetic variants strongly associated with 25OHD levels in a 443,734-participant genome-wide association study (GWAS) were used as instrumental variables. GWASs of Covid-19 susceptibility and severity from the Covid-19 Host Genetics Initiative were used to test the effect of 25OHD levels on these outcomes. Cohorts from the Covid-19 Host Genetics Initiative GWAS included up to 966,395 individuals of European ancestry. RESULTS: Genetically increased 25OHD levels by one standard deviation on the logarithmic scale had no clear effect on susceptibility but tended to increase the odds ratio of hospitalization (OR = 2.34; 95% CI: 1.33, 4.11) and severe disease (OR = 2.21; 95% CI: 0.87, 5.55). Extensive sensitivity analyses probing the assumptions of MR provided consistent estimates. CONCLUSION: These findings do not support a protective role of increased 25OHD levels on Covid-19 outcomes and may suggest harm. At present, individuals should not use vitamin D supplements to protect against Covid-19 outcomes, and on-going supplementation trials should closely monitor for signals of harm.