Importance: Early epidemiological studies report associations of diverse cardiometabolic conditions especially body mass index (BMI), with COVID-19 susceptibility and severity, but causality has not been established. Identifying causal risk factors is critical to inform preventive strategies aimed at modifying disease risk. Objective: We sought to evaluate the causal associations of cardiometabolic conditions with COVID-19 susceptibility and severity. Design: Two-sample Mendelian Randomization (MR) Study. Setting: Population-based cohorts that contributed to the genome-wide association study (GWAS) meta-analysis by the COVID-19 Host Genetics Initiative. Participants: Patients hospitalized with COVID-19 diagnosed by RNA PCR, serologic testing, or clinician diagnosis. Population controls defined as anyone who was not a case in the cohorts. Exposures: Selected genetic variants associated with 17 cardiometabolic diseases, including diabetes, coronary artery disease, stroke, chronic kidney disease, and BMI, at p<5 x 10-8 from published largescale GWAS. Main outcomes: We performed an inverse-variance weighted averages of variant-specific causal estimates for susceptibility, defined as people who tested positive for COVID-19 vs. population controls, and severity, defined as patients hospitalized with COVID-19 vs. population controls, and repeated the analysis for BMI using effect estimates from UKBB. To estimate direct and indirect causal effects of BMI through obesity-related cardiometabolic diseases, we performed pairwise multivariable MR. We used p<0.05/17 exposure/2 outcomes=0.0015 to declare statistical significance. Results: Genetically increased BMI was causally associated with testing positive for COVID-19 [6,696 cases / 1,073,072 controls; p=6.7 x 10-4, odds ratio and 95% confidence interval 1.08 (1.03, 1.13) per kg/m2] and a higher risk of COVID-19 hospitalization [3,199 cases/897,488 controls; p=8.7 x 10-4, 1.12 (1.04, 1.21) per kg/m2]. In the multivariable MR, the direct effect of BMI was abolished upon conditioning on the effect on type 2 diabetes but persisted when conditioning on the effects on coronary artery disease, stroke, chronic kidney disease, and c-reactive protein. No other cardiometabolic exposures tested were associated with a higher risk of poorer COVID-19 outcomes. Conclusions and Relevance: Genetic evidence supports BMI as a causal risk factor for COVID-19 susceptibility and severity. This relationship may be mediated via type 2 diabetes. Obesity may have amplified the disease burden of the COVID-19 pandemic either single-handedly or through its metabolic consequences.
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