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Abstract
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our 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. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.
Highlights
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R in Critical Care) study enables the comparison of genomes from critically-ill cases with population controls in order to find underlying disease mechanisms
A 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
Summary
Athanasios Kousathanas[1,36], Erola Pairo-Castineira[2,3,36], Konrad Rawlik[2], Alex Stuckey[1], Christopher A. Our genome-wide gene-based association tests did not replicate any findings from a previous pathway-specific study of rare deleterious variants[4], our results provide robust evidence implicating reduced interferon signalling in susceptibility to critical Covid-19. The strongest fine mapping signal at 5q31.1 (chr5:131995059:C:T, rs56162149) is in an intron of ACSL6 with significant effects on expression (Supplementary Material: TWAS.xlsx), the credible set includes a missense variant in CSF2 (granulocyte-macrophage colony stimulating factor, GMCSF) of uncertain significance (chr5:132075767:T:C, Extended Data Table 1). Colocalisation and TWAS provide evidence for increased expression of MUC1 as the mediator of the association with rs41264915 (Supplementary Table 12) This suggests a potentially therapeutically-important role for mucins in the development of critical illness in Covid-19. Mendelian randomisation reveals the first genetic evidence in support of a causal role for coagulation factors (F8) and platelet activation (PDGFRL) in critical Covid-19
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