Mendelian randomization analysis provides causality of smoking on the expression of ACE2, a putative SARS-CoV-2 receptor

Background: To understand a causal role of modifiable lifestyle factors in angiotensin-converting enzyme 2 (ACE2) expression (a putative severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] receptor) across 44 human tissues/organs, and in coronavirus disease 2019 (COVID-19) susceptibility and severity, we conducted a phenome-wide two-sample Mendelian randomization (MR) study. Methods: More than 500 genetic variants were used as instrumental variables to predict smoking and alcohol consumption. Inverse-variance weighted approach was adopted as the primary method to estimate a causal association, while MR-Egger regression, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO) were performed to identify potential horizontal pleiotropy. Results: We found that genetically predicted smoking intensity significantly increased ACE2 expression in thyroid (beta=1.468, p=1.8x10(-8)), and increased ACE2 expression in adipose, brain, colon, and liver with nominal significance. Additionally, genetically predicted smoking initiation significantly increased the risk of COVID-19 onset (odds ratio=1.14, p=8.7x 10(-5)). No statistically significant result was observed for alcohol consumption. Conclusions: Our work demonstrates an important role of smoking, measured by both status and intensity, in the susceptibility to COVID-19.

Automated summary

The study revealed that genetically predicted smoking significantly increased ACE2 expression in the thyroid and other tissues, as well as the risk of COVID-19 onset. No significant results were observed for genetically predicted alcohol consumption.