Abstract
Observational studies have reported high comorbidity between type 2 diabetes (T2D) and severe COVID-19. However, the causality between T2D and COVID-19 has yet to be validated. We performed genetic correlation and Mendelian randomization (MR) analyses to assess genetic relationships and potential causal associations between T2D and three COVID-19 outcomes (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection, COVID-19 hospitalization, and critical COVID-19). Molecular pathways connecting SARS-CoV-2 and COVID-19 were reconstructed to extract insights into the potential mechanisms underlying the connection. We identified a high genetic overlap between T2D and each COVID-19 outcome (genetic correlations 0.21-0.28). The MR analyses indicated that genetic liability to T2D confers a causal effect on hospitalized COVID-19 (odds ratio 1.08, 95% confidence interval [CI] 1.04-1.12) and critical COVID-19 (1.09, 1.03-1.16), while genetic liability to SARS-CoV-2 infection exerts a causal effect on T2D (1.25, 1.00-1.56). There was suggestive evidence that T2D was associated with an increased risk for SARS-CoV-2 infection (1.02, 1.00-1.03), while critical COVID-19 (1.06, 1.00-1.13) and hospitalized COVID-19 (1.09, 0.99-1.19) were associated with an increased risk for T2D. Pathway analysis identified a panel of immunity-related genes that may mediate the links between T2D and COVID-19 at the molecular level. Our study provides robust support for the bidirectional causal associations between T2D and COVID-19. T2D may contribute to amplifying the severity of COVID-19, while the liability to COVID-19 may increase the risk for T2D.