Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 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

Causes of extinction of vertebrates during the Holocene of mainland Australia: arrival of the dingo, or human impact?

The arrival of the dingo in mainland Australia is believed to have caused the extinction of three native vertebrates: the thylacine, the Tasmanian devil and the Tasmanian native hen. The dingo is implicated in these extinctions because, while these three species disappeared during the late Holocene of mainland Australia in the presence of the dingo, they persisted in Tasmania in its absence. Moreover, the dingo might plausibly have competed with the thylacine and devil, and preyed on the native hen. However, another variable is similarly correlated with these extinctions: there is evidence for an increase in the human population on the mainland that gathered pace about 4000 years ago and was associated with innovations in hunting technology and more intensive use of resources. These changes may have combined to put increased hunting pressure on large vertebrates, and to reduce population size of many species that were hunted by people on the mainland. We suggest that these changes, which were quite dramatic on mainland Australia but were muted or absent in Tasmania, could have led to the mainland extinctions of the thylacine, devil and hen