ABSTRACT
Obesity, type 2 diabetes (T2D), and severe coronavirus disease 2019 (COVID-19) are closely associated. The aim of this study was to elucidate the casual and mediating relationships of human serum metabolites on the pathways from obesity/T2D to COVID-19 using Mendelian randomization (MR) techniques. We performed two-sample MR to study the causal effects of 309 metabolites on COVID-19 severity and susceptibility, based on summary statistics from genome-wide association studies (GWAS) of metabolites (n = 7824), COVID-19 phenotypes (n = 2,586,691), and obesity (n = 322,154)/T2D traits (n = 898,130). We conducted two-sample network MR analysis to determine the mediating metabolites on the causal path from obesity/T2D to COVID-19 phenotypes. We used multivariable MR analysis (MVMR) to discover causal metabolites independent of body mass index (BMI). Our MR analysis yielded four causal metabolites that increased the risk of severe COVID-19, including 2-stearoylglycerophosphocholine (OR 2.15; 95% CI 1.48-3.11), decanoylcarnitine (OR 1.32; 95% CI 1.17-1.50), thymol sulfate (OR 1.20; 95% CI 1.10-1.30), and bradykinin-des-arg(9) (OR 1.09; 95% CI 1.05-1.13). One significant mediator, gamma-glutamyltyrosine, lay on the causal path from T2D/obesity to severe COVID-19, with 16.67% (0.64%, 32.70%) and 6.32% (1.76%, 10.87%) increased risk, respectively, per one-standard deviation increment of genetically predicted T2D and BMI. Our comprehensive MR analyses identified credible causative metabolites, mediators of T2D and obesity, and obesity-independent causative metabolites for severe COVID-19. These biomarkers provide a novel basis for mechanistic studies for risk assessment, prognostication, and therapeutic purposes in COVID-19.