Human genetics implicate thromboembolism in the pathogenesis of long COVID in individuals of European ancestry.
Schuermans A., Verstraete A., Lammi V., Nakanishi T., Ardissino M., Van den Eynde J., Sun BB., Georgakis MK., Guillen-Guio B., Wain LV., Brightling CE., PHOSP-COVID Collaborative Group ., Van Weyenbergh J., Lewandowski AJ., Raman B., Zeberg H., Ollila HM., Burgess S., Natarajan P., Honigberg MC., Freson K., Vanassche T., Verhamme P.
SARS-CoV-2 infection can result in long COVID, characterized by post-acute symptoms from multiple organs. Current hypotheses on mechanisms underlying long COVID include persistent inflammation and thromboembolism; however, compelling evidence from humans is limited and causal associations remain unclear. In this study, we tested the association of thromboembolism-related genetic variants with long COVID in the Long COVID Host Genetics Initiative (ncases = 3,018; ncontrols = 994,582). Primary analyses revealed that each unit increase in the log odds of genetically predicted venous thromboembolism risk was associated with 1.21-fold odds of long COVID (95% confidence interval (CI): 1.08-1.35; P = 1.2 × 10-3). This association was independent of acute COVID-19 severity, was robust across various sensitivity analyses and was replicated in external datasets. Downstream analyses using gene-specific instruments, along with protein and gene expression data, suggested the protease-activated receptor 1 (PAR-1) as a potential molecular contributor to long COVID. These findings provide human genetic evidence implicating shared pathogenetic pathways in thromboembolism and long COVID.