Extensive Mendelian randomization study identifies potential causal risk factors for severe COVID-19

Abstract

Background: Identifying causal risk factors for severe coronavirus disease 2019 (COVID-19) is critical for its prevention and treatment. Many associated pre-existing conditions and biomarkers have been reported, but these observational associations suffer from confounding and reverse causation.

Methods: Here, we perform a large-scale two-sample Mendelian randomization (MR) analysis to evaluate the causal roles of many traits in severe COVID-19.

Results: Our results highlight multiple body mass index (BMI)-related traits as risk-increasing: BMI (OR: 1.89, 95% CI: 1.51-2.37), hip circumference (OR: 1.46, 1.15-1.85), and waist circumference (OR: 1.82, 1.36-2.43). Our multivariable MR analysis further suggests that the BMI-related effect might be driven by fat mass (OR: 1.63, 1.03-2.58), but not fat-free mass (OR: 1.00, 0.61-1.66). Several white blood cell counts are negatively associated with severe COVID-19, including those of neutrophils (OR: 0.76, 0.61-0.94), granulocytes (OR: 0.75, 0.601-0.93), and myeloid white blood cells (OR: 0.77, 0.62-0.96). Furthermore, some circulating proteins are associated with an increased risk of (e.g., zinc-alpha-2-glycoprotein) or protection from severe COVID-19 (e.g., prostate-associated microseminoprotein).

Conclusions: Our study suggests that fat mass and white blood cells might be involved in the development of severe COVID-19. It also prioritizes potential risk and protective factors that might serve as drug targets and guide the effective protection of high-risk individuals.

Keywords: Epidemiology; Genetic association study.

Fig. 1. The workflow of our extensive MR study for severe COVID-19.

GWAS genome-wide association studies, IEU Integrative Epidemiology Unit, eqtl expression quantitative trait loci, HGI host genetics initiative, NEJM New England journal of medicine, IVW inverse-variance weighted, SNP single-nucleotide polymorphism, SNP# number of SNPs used as genetic instruments, Novel not reported before, Confirming confirming some previously reported results, even though previous results may be conflicting among themselves; Conflicting conflicting with previously reported results. The definition of novelty is by comparison to existing COVID-19 MR studies, as summarized in Supplementary Data 1. Detailed summary statistics could be found in Supplementary Data 5 and 6.

Fig. 2. Multivariable MR analysis reveals support for independent causal roles of fat mass in severe COVID-19.

The effects of fat mass at different body parts were shown. Each specific fat mass has two GWAS sources, whose ID in the Integrative Epidemiology Unit (IEU) OpenGWAS project was shown right after the exposure name. Odds ratios (OR) and 95% confidence intervals (CI) are scaled to a genetically predicted 1-standard-deviation (SD) increase in fat mass. Three COVID-19 GWAS were shown. HGI A2 host genetics initiative study A2, HGI B2 host genetics initiative study B2, NEJM the study published in New England Journal of Medicine. Associations with p-value < 0.05 were indicated with diamonds, while others with squares. Error bars stand for 95% CI. Detailed summary statistics could be found in supplementary Data 8.

Fig. 3. Multivariable MR analysis reveals no support for causal roles of fat-free mass in severe COVID-19.

The effects of fat-free mass at different body parts were shown. Each specific fat-free mass has two GWAS sources, whose ID in the Integrative Epidemiology Unit (IEU) OpenGWAS project was shown right after the exposure name. Odds ratios (OR) and 95% confidence intervals (CI) are scaled to a genetically predicted 1-standard-deviation (SD) increase in fat mass. Three COVID-19 GWAS were shown. HGI A2 host genetics initiative study A2, HGI B2 host genetics initiative study B2, NEJM the study published in New England Journal of Medicine. Associations with p-value < 0.05 were indicated with diamonds, while others with squares. Error bars stand for 95% CI. Detailed summary statistics could be found in Supplementary Data 8.

Fig. 4. MR analysis of white blood cell traits on severe COVID-19 risk.

The effects of counts of different white blood cells were shown. For each specific blood-cell count, its GWAS ID in the Integrative Epidemiology Unit (IEU) OpenGWAS project was shown right after the exposure name. Odds ratios (OR) and 95% confidence intervals (CI) are scaled to a genetically predicted 1-standard-deviation (SD) increase in white blood cell trait. Two COVID-19 GWAS were shown. HGI A2 host genetics initiative study A2, HGI B2 host genetics initiative study B2. Associations with p-value < 0.05 were indicated with diamonds, while others with squares. Error bars stand for 95% CI. Detailed summary statistics could be found in Supplementary Data 6.