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

Falcatifolium (Podocarpaceae) macrofossils from Paleogene sediments in south-eastern Australia: a reassessment

A re-investigation of macrofossils previously referred to the extantpodocarpaceous genus Falcatifolium Laubenfels shows thatno records can be sustained. Falcatifolium australisD.R.Greenwood from Middle Eocene sediments in Victoria bears littleresemblance to extant species in the genus and is transferred to the newfossil genus Sigmaphyllum R.S.Hill & L.J.Scriven.Specimens from Early Oligocene sediments in Tasmania previously assigned toFalcatifolium are described as a second species ofSigmaphyllum, S. tasmanensisR.S.Hill & L.J.Scriven, and specimens from mid to late Eocene sediments inTasmania previously assigned to Falcatifolium do notbelong to that genus, although their true generic affinities are uncertain.Dispersed cuticle specimens from Late Eocene–Oligocene sediments inSouth Australia referred to Falcatifolium are notreliable records of the genus and require further investigation. However,Dacrycarpus eocenica D.R.Greenwood, from Middle Eocenesediments in Victoria is transferred to Falcatifolium,and is similar to the extant species F. angustumLaubenfels, which has a leaf morphology unusual for the genus.Falcatifolium eocenica (D.R.Greenwood) R.S.Hill & L.J.Scriven is the only reliable record of the genus in the Australian fossil record to date.Robert S. Hill and Leonie J. Scrive