Mendelian randomization analysis identified genes pleiotropically associated with the risk and prognosis of COVID-19

Objectives COVID-19 has caused a large global pandemic. Patients with COVID-19 exhibited considerable variation in disease behavior. Pervious genome-wide association studies have identified potential genetic variants involved in the risk and prognosis of COVID-19, but the underlying biological interpretation remains largely unclear. Methods We applied the summary data-based Mendelian randomization (SMR) method to identify genes that were pleiotropically associated with the risk and various outcomes of COVID-19, including severe respiratory confirmed COVID-19 and hospitalized COVID-19. Results In blood, we identified 2 probes, ILMN_1765146 and ILMN_1791057 tagging IFNAR2 , that showed pleiotropic association with hospitalized COVID-19 (β [SE] = 0.42 [0.09], P = 4.75×10 −06 and β [SE] = –0.48 [0.11], P = 6.76×10 −06 , respectively). Although no other probes were significant after correction for multiple testing in both blood and lung, multiple genes as tagged by the top 5 probes were involved in inflammation or antiviral immunity, and several other tagged genes, such as PON2 and HPS5 , were involved in blood coagulation. Conclusions We identified IFNAR2 and other potential genes that could be involved in the susceptibility or prognosis of COVID-19. These findings provide important leads to a better understanding of the mechanisms of cytokine storm and venous thromboembolism in COVID-19 and potential therapeutic targets for the effective treatment of COVID-19.