Cardiometabolic risk factors for COVID-19 susceptibility and severity: A Mendelian randomization analysis

Author summary Why was this study done? Diverse cardiometabolic risk factors have been described in the literature to be associated with COVID-19 illness, but causality has not been established. Preventive strategies targeting cardiometabolic risk factors that are both causal and modifiable may reduce the risk of COVID-19 illness, whereas interventions targeting risk factors that are only correlated with the outcome may not. What did the researchers do and find? We used 2-sample Mendelian randomization analyses to test whether 17 cardiometabolic diseases and traits had a causal relationship with risk of COVID-19 illness. We found that higher body mass index was the only cardiometabolic risk factor among those we studied that was associated with a higher risk of hospitalization for COVID-19 compared to the general population. Obesity-related cardiometabolic diseases-type 2 diabetes, chronic kidney disease, stroke, and coronary heart disease-may be mediators of the relationship between body mass index and higher risk of hospitalization for COVID-19. What do these findings mean? Our results suggest that people with a higher body mass index have a higher risk for hospitalization for COVID-19. If other cardiometabolic risk factors have causal associations with COVID-19 illness, their effects are likely modest. We provide genetic evidence supporting body mass index as a causal risk factor for COVID-19 severity, raising the possibility that obesity could have amplified the COVID-19 pandemic, directly or through obesity-related cardiometabolic diseases. Background Epidemiological studies report associations of diverse cardiometabolic conditions including obesity with COVID-19 illness, but causality has not been established. We sought to evaluate the associations of 17 cardiometabolic traits with COVID-19 susceptibility and severity using 2-sample Mendelian randomization (MR) analyses. Methods and findings We selected genetic variants associated with each exposure, including body mass index (BMI), at p < 5 x 10(-8) from genome-wide association studies (GWASs). We then calculated inverse-variance-weighted averages of variant-specific estimates using summary statistics for susceptibility and severity from the COVID-19 Host Genetics Initiative GWAS meta-analyses of population-based cohorts and hospital registries comprising individuals with self-reported or genetically inferred European ancestry. Susceptibility was defined as testing positive for COVID-19 and severity was defined as hospitalization with COVID-19 versus population controls (anyone not a case in contributing cohorts). We repeated the analysis for BMI with effect estimates from the UK Biobank and performed pairwise multivariable MR to estimate the direct effects and indirect effects of BMI through obesity-related cardiometabolic diseases. Using p < 0.05/34 tests = 0.0015 to declare statistical significance, we found a nonsignificant association of genetically higher BMI with testing positive for COVID-19 (14,134 COVID-19 cases/1,284,876 controls, p = 0.002; UK Biobank: odds ratio 1.06 [95% CI 1.02, 1.10] per kg/m(2); p = 0.004]) and a statistically significant association with higher risk of COVID-19 hospitalization (6,406 hospitalized COVID-19 cases/902,088 controls, p = 4.3 x 10(-5); UK Biobank: odds ratio 1.14 [95% CI 1.07, 1.21] per kg/m(2), p = 2.1 x 10(-5)). The implied direct effect of BMI was abolished upon conditioning on the effect on type 2 diabetes, coronary artery disease, stroke, and chronic kidney disease. No other cardiometabolic exposures tested were associated with a higher risk of poorer COVID-19 outcomes. Small study samples and weak genetic instruments could have limited the detection of modest associations, and pleiotropy may have biased effect estimates away from the null. Conclusions In this study, we found genetic evidence to support higher BMI as a causal risk factor for COVID-19 susceptibility and severity. These results raise the possibility that obesity could amplify COVID-19 disease burden independently or through its cardiometabolic consequences and suggest that targeting obesity may be a strategy to reduce the risk of severe COVID-19 outcomes.