Causal associations between body fat accumulation and COVID-19 severity: A Mendelian randomization study

Purpose: The causal effects of body fat mass and body fat-free mass on coronavirus disease 2019 (COVID-19) severity remain unclear. Here, we used Mendelian randomization (MR) to evaluate the causal relationships between body fat-related traits and COVID-19 severity. Material and Methods: We identified single nucleotide polymorphisms associated with body mass index (BMI) and direct measures of body fat (i.e., body fat percentage, body fat mass, and body fat-free mass) in 461,460, 454,633, 454,137, and 454,850 individuals of European ancestry from the UK Biobank, respectively. We then performed two-sample MR to ascertain their effects on severe COVID-19 (cases: 4,792; controls: 1,054,664) from the COVID-19 Host Genetics Initiative. Results: We found that an increase in BMI, body fat percentage, and body fat mass by one standard deviation were each associated with severe COVID-19 (odds ratio (OR)BMI = 1.49, 95%CI: 1.19-1.87, P = 5.57x10-4; ORbody fat percentage = 1.94, 95%CI: 1.41-2.67, P = 5.07x10-5; and ORbody fat mass = 1.61, 95%CI: 1.28-2.04, P = 5.51x10-5). Further, we evaluated independent causal effects of body fat mass and body fat-free mass using multivariable MR and revealed that only body fat mass was independently associated with severe COVID-19 (ORbody fat mass = 2.91, 95%CI: 1.71-4.96, P = 8.85x10-5 and ORbody fat-free mass = 1.02, 95%CI: 0.61-1.67, P = 0.945). Conclusions: This study demonstrates the causal effects of body fat accumulation on COVID-19 severity and indicates that the biological pathways influencing the relationship between COVID-19 and obesity are likely mediated through body fat mass.