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 impact of a thermodynamic sea-ice module in the COSMO numerical weather prediction model on simulations for the Laptev Sea, Siberian Arctic

Previous versions of the Consortium for Small-scale Modelling (COSMO) numerical weather prediction model have used a constant sea-ice surface temperature, but observations show a high degree of variability on sub-daily timescales. To account for this, we have implemented a thermodynamic sea-ice module in COSMO and performed simulations at a resolution of 15 km and 5 km for the Laptev Sea area in April 2008. Temporal and spatial variability of surface and 2-m air temperature are verified by four automatic weather stations deployed along the edge of the western New Siberian polynya during the Transdrift XIII-2 expedition and by surface temperature charts derived from Moderate Resolution Imaging Spectroradiometer (MODIS) satellite data. A remarkable agreement between the new model results and these observations demonstrates that the implemented sea-ice module can be applied for short-range simulations. Prescribing the polynya areas daily, our COSMO simulations provide a high-resolution and high-quality atmospheric data set for the Laptev Sea for the period 14-30 April 2008. Based on this data set, we derive a mean total sea-ice production rate of 0.53 km3/day for all Laptev Sea polynyas under the assumption that the polynyas are ice-free and a rate of 0.30 km3/day if a 10-cm-thin ice layer is assumed. Our results indicate that ice production in Laptev Sea polynyas has been overestimated in previous studies