Genetically Predicted Circulating Concentrations of Micronutrients and COVID-19 Susceptibility and Severity: A Mendelian Randomization Study

Abstract

Background: Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which since 2019 has caused over 5 million deaths to date. The pathogenicity of the virus is highly variable ranging from asymptomatic to fatal. Evidence from experimental and observational studies suggests that circulating micronutrients may affect COVID-19 outcomes.

Objectives: To complement and inform observational studies, we investigated the associations of genetically predicted concentrations of 12 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, vitamin D, and zinc) with SARS-CoV-2 infection risk and COVID-19 severity using Mendelian randomization (MR).

Methods: Two-sample MR was conducted using 87,870 individuals of European descent with a COVID-19 diagnosis and 2,210,804 controls from the COVID-19 host genetics initiative. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions.

Results: Compared to the general population, nominally significant associations were noted for higher genetically predicted vitamin B-6 (Odds ratio per standard deviation [OR _SD]: 1.06; 95% confidence interval [CI]: 1.00, 1.13; p-value = 0.036) and lower magnesium concentrations (OR _SD: 0.33; 95%CI: 0.11, 0.96; P = 0.042) with COVID-19 infection risk. However, the association for magnesium was not consistent in some sensitivity analyses, and sensitivity analyses could not be performed for vitamin B-6 as only two genetic instruments were available. Genetically predicted levels of calcium, folate, β-carotene, copper, iron, vitamin B-12, vitamin D, selenium, phosphorus, or zinc were not associated with the outcomes from COVID-19 disease.

Conclusion: These results, though based only on genetically predicated circulating micronutrient concentrations, provide scant evidence for possible associations of micronutrients with COVID-19 outcomes.

Keywords: COVID-19; GWAS; Mendelian randomization; SARS CoV-2; micronutrients; supplements.

Figure 1

Schematic representation of the Mendelian randomization assumptions and study design. Genetic instruments are selected based on their association with the concentration of a specific micronutrient (assumption 1), but do not directly impact the assessed outcomes (assumption 2), or any confounders of micronutrient concentrations and the assessed outcomes (assumption 3). IVW, inverse variance weighted; SNP, single nucleotide polymorphism; GWAS, genome-wide association study; MR, Mendelian randomization; MR-PRESSO, Mendelian randomization pleiotropy residual sum and outlier.

Figure 2

Summary of the Mendelian randomization results for the associations between genetically predicted micronutrient concentrations and COVID-19 outcomes. IVW, inverse variance weighted; conMIX, contamination mixture.