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Critical Covid-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalisation following SARS-CoV-2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from critically-ill cases with population controls in order to find underlying disease mechanisms. This study uses whole genome sequencing in 7,491 critically-ill cases compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical Covid-19. The study identifies 16 new independent associations, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, there is evidence implicating multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease. Mendelian randomisation provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5, CD209) and coagulation factor F8, all of which are potentially druggable targets. The results are broadly consistent with a multi-component model of Covid-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication, or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. The study shows a comparison between critically-ill cases and population controls is highly efficient for detection of therapeutically-relevant mechanisms of disease.

These genetic associations implicate new biological mechanisms underlying the development of life-threatening Covid-19, several of which may be amenable to therapeutic targeting. Furthermore, the study demonstrates the value of whole genome sequencing in to fine map loci in a complex trait. In the context of the ongoing global pandemic, translation to clinical practice is an urgent priority.