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

Sun et al. perform a two-sample Mendelian randomization study of a large number of traits with the aim of identifying risk factors of severe COVID-19. They show that body mass index-related traits, specific white blood cells, and some circulating proteins are risk factors for the development of severe COVID-19. BackgroundIdentifying 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.MethodsHere, we perform a large-scale two-sample Mendelian randomization (MR) analysis to evaluate the causal roles of many traits in severe COVID-19.ResultsOur 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).ConclusionsOur 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. Plain language summaryPeople infected with SARS-CoV-2 can remain asymptomatic, have mild symptoms, or develop severe COVID-19 that increases their risk of death. Finding factors that directly contribute to the risk of developing severe COVID-19, so-called causal risk factors, may help in prevention by identifying individuals at higher risk and in treatment by providing clues of targets for therapies. We applied advanced statistical methods that leverage genetic variations among individuals to separate causal risk factors from coincidences, sifting through tens of thousands of candidate factors. We show that levels of fat mass, certain white blood cells, and multiple circulating proteins are potential causal risk factors for severe COVID-19. These findings help us better understand severe COVID-19 and guide future studies to develop strategies of prevention and treatment.

Automated summary

The study identified body mass index-related traits, specific white blood cells, and certain circulating proteins as potential risk factors for the development of severe COVID-19.