The course of disease in individuals infected with SARS-CoV-2 is hugely variable, ranging from asymptomatic infections to severe COVID-19 and death. The GenOMICC genome-wide association study, published in Nature, now identifies significant associations of severe disease with several genes involved in antiviral defence mechanisms or in host-driven inflammatory lung injury. These include a cluster of genes that encode antiviral restriction enzyme activators (OAS1, OAS2 and OAS3), TYK2, encoding a tyrosine kinase, the dipeptidyl peptidase gene DPP9 and the interferon receptor gene IFNAR2. Mendelian randomization revealed a causal link between severe disease, low expression of IFNAR2 and high expression of TYK2. Moreover, a transcriptome-wide association study showed the monocyte/macrophage chemotactic receptor CCR2 is associated with severe COVID-19. These findings indicate opportunities for the potential repurposing of existing drugs.