Despite rapid progress in characterizing the role of host genetics in SARS-Cov-2 infection, there is limited understanding of genes and pathways that contribute to COVID-19. Here, we integrated a genome-wide association study of COVID-19 hospitalization (7,885 cases and 961,804 controls from COVID-19 Host Genetics Initiative) with mRNA expression, splicing, and protein levels (n=18,502). We identified 27 genes related to inflammation and coagulation pathways whose genetically predicted expression was associated with COVID-19 hospitalization. We functionally characterized the 27 genes using phenome- and laboratory-wide association scans in Vanderbilt Biobank (BioVU; n=85,460) and identified coagulation-related clinical symptoms, immunologic, and blood-cell-related biomarkers. We replicated these findings across trans-ethnic studies and observed consistent effects in individuals of diverse ancestral backgrounds in BioVU, pan-UK Biobank, and Biobank Japan. Our study highlights putative causal genes impacting COVID-19 severity and symptomology through the host inflammatory response.