ABSTRACT
Background: Allergic diseases (ADs) such as asthma are presumed risk factors for COVID-19 infection. However, recent observational studies suggest that the assumed correlation remains controversial. We therefore systematically investigated the genetic causal correlations of various ADs with COVID-19 infection/severity. Methods: : We systematically performed a two-sample, bidirectional Mendelian randomization (MR) study of five ADs and the latest round of COVID-19 GWAS meta-analysis datasets (critically ill, hospitalized, and infection cases). We also validated the significant causal correlations and further elucidated underlying molecular mechanisms. Results: : The most suitable MR method, for the first time, revealed significant causal effects of COVID-19 infection/severity on an increased asthma prevalence (OR>4.21), which obtained further validations. In contrast, asthma consistently demonstrated causally protective effects on critically ill and hospitalized COVID-19 cases upon adopting multiple MR methods (OR, 0.96–0.99). Our MR analyses also observed potential causal correlations of COVID-19 severity with atopic dermatitis, shrimp and peach allergy. Regarding underlying molecular mechanisms, we observed that COVID-19 phenotypes, especially those critically ill cases, were causally correlated to hematological traits and count data of immune-related cells. In contrast, ADs such as asthma and shrimp allergy may be causally correlated with COVID-19 infection/severity by affecting ACE2 protein expression. Conclusions: : Our MR analyses suggest a bidirectional causal effect between COVID-19 phenotypes and ADs, especially asthma. The potential underlying molecular mechanisms of the causal effects may be beneficial in developing effective therapeutic strategies for allergy patients with COVID-19 infection and call for more attention to their physical characteristics upon showing long-term COVID-19 symptoms.