Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19

In November 2021, the COVID-19 pandemic death toll surpassed five million individuals. We applied Mendelian randomization including >3,000 blood proteins as exposures to identify potential biomarkers that may indicate risk for hospitalization or need for respiratory support or death due to COVID-19, respectively. After multiple testing correction, using genetic instruments and under the assumptions of Mendelian Randomization, our results were consistent with higher blood levels of five proteins GCNT4, CD207, RAB14, C1GALT1C1, and ABO being causally associated with an increased risk of hospitalization or respiratory support/death due to COVID-19 (ORs = 1.12-1.35). Higher levels of FAAH2 were solely associated with an increased risk of hospitalization (OR = 1.19). On the contrary, higher levels of SELL, SELE, and PECAM-1 decrease risk of hospitalization or need for respiratory support/ death (ORs = 0.80-0.91). Higher levels of LCTL, SFTPD, KEL, and ATP2A3 were solely associated with a decreased risk of hospitalization (ORs = 0.86-0.93), whilst higher levels of ICAM-1 were solely associated with a decreased risk of respiratory support/death of COVID-19 (OR = 0.84). Our findings implicate blood group markers and binding proteins in both hospitalization and need for respiratory support/death. They, additionally, suggest that higher levels of endocannabinoid enzymes may increase the risk of hospitalization. Our research replicates findings of blood markers previously associated with COVID-19 and prioritises additional blood markers for risk prediction of severe forms of COVID-19. Furthermore, we pinpoint druggable targets potentially implicated in disease pathology. Author summary As of November 2021, more than five million people have died due to COVID-19. Although vaccinations provide good protection, it is important to fully understand the biology behind the severe forms of COVID-19. Mendelian randomization facilitates the identification of blood proteins that may be involved in the pathophysiology of severe forms. Here, we investigated whether >3,000 blood proteins might play a role in hospitalization due to COVID-19 or the requirement of respiratory support or death due to COVID-19. Using genetic instruments and under the assumption of Mendelian randomization, our results are consistent with higher levels of five proteins being causally associated with an increased risk of both COVID-19 outcomes and higher levels of one protein associated with hospitalization. Our results are also consistent with higher levels of four proteins-mainly playing a role in cell adhesion-being causally associated with a decreased risk of hospitalization and respiratory support/death, and higher levels of four proteins being causally associated with a decreased risk of hospitalization. These proteins may represent new biomarkers useful in risk prediction of severity and may lead to new therapeutics by prioritizing druggable targets.