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

Previous studies reported associations between obesity measured by body mass index (BMI) and coronavirus disease 2019 (COVID-19). However, BMI is calculated only with height and weight and cannot distinguish between body fat mass and fat-free mass. Thus, it is not clear if one or both of these measures are mediating the relationship between obesity and COVID-19. Here, we used Mendelian randomization (MR) to compare the independent causal relationships of body fat mass and fat-free mass with COVID-19 severity. We identified single nucleotide polymorphisms associated with body fat mass and fat-free mass in 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. We found that an increase in body fat mass by one standard deviation was associated with severe COVID-19 (odds ratio (OR)_{body fat mass} = 1.61, 95% confidence interval [CI]: 1.28-2.04, P = 5.51 × 10^-5; OR_{body fat-free mass} = 1.31, 95% CI: 0.99-1.74, P = 5.77 × 10^-2). Considering that body fat mass and fat-free mass were genetically correlated with each other (r = 0.64), we further evaluated independent causal effects of body fat mass and fat-free mass using multivariable MR and revealed that only body fat mass was independently associated with severe COVID-19 (OR_{body fat mass} = 2.91, 95% CI: 1.71-4.96, P = 8.85 × 10^-5 and OR_{body fat-free mass} = 1.02, 95%CI: 0.61-1.67, P = 0.945). In summary, 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.