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

The Relationship of the Different Editions of Daniel: A History of Scholarship

The book of Daniel has one of the more complicated textual histories of any biblical book. It is written in two languages (Hebrew and Aramaic), and the content drastically differs in the two halves of the book (stories in chs. 1–6 and visions in chs. 7–12). Perhaps the most difficult attribute to explain, however, is that it is preserved in several distinct editions, which at times vastly diverge from one another. These are the Masoretic edition in Hebrew and Aramaic, and the Old Greek and Theodotionic editions in Greek. The relationship of these three editions of the book of Daniel has been disputed for more than two hundred years, and a scholarly consensus has not yet been reached. This overview surveys the history of scholarship on the different editions in hopes that future studies on the book of Daniel will give the OG edition equal status with the MT edition of the book, which it has hitherto not received