The study investigates genetic mechanisms underlying critical illness in COVID-19 patients. The GenOMICC genome-wide association study (GWAS) was conducted on 2,244 critically ill COVID-19 patients from 208 UK intensive care units. New genome-wide significant associations were identified on chromosomes 12q24.13, 19p13.2, 19p13.3, and 21q22.1, involving genes related to antiviral defense (OAS1, OAS2, OAS3), tyrosine kinase 2 (TYK2), dipeptidyl peptidase 9 (DPP9), and interferon receptor (IFNAR2). Mendelian randomization and transcriptome-wide association studies revealed potential therapeutic targets, such as IFNAR2 and TYK2, which may influence the severity of COVID-19. The findings highlight genetic signals related to antiviral defense and inflammatory lung injury, suggesting targeted treatments for critical illness in COVID-19. However, large-scale clinical trials are needed before any changes to clinical practice.The study investigates genetic mechanisms underlying critical illness in COVID-19 patients. The GenOMICC genome-wide association study (GWAS) was conducted on 2,244 critically ill COVID-19 patients from 208 UK intensive care units. New genome-wide significant associations were identified on chromosomes 12q24.13, 19p13.2, 19p13.3, and 21q22.1, involving genes related to antiviral defense (OAS1, OAS2, OAS3), tyrosine kinase 2 (TYK2), dipeptidyl peptidase 9 (DPP9), and interferon receptor (IFNAR2). Mendelian randomization and transcriptome-wide association studies revealed potential therapeutic targets, such as IFNAR2 and TYK2, which may influence the severity of COVID-19. The findings highlight genetic signals related to antiviral defense and inflammatory lung injury, suggesting targeted treatments for critical illness in COVID-19. However, large-scale clinical trials are needed before any changes to clinical practice.