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

Internal flow variations and diachronous sedimentation within extensive, sustained, density-stratified pyroclastic density currents flowing down gentle slopes, as revealed by the internal architectures of ignimbrites on Tenerife

During a protracted explosive eruption, at least four laterally extensive and sustained pyroclastic density currents radiated across the flanks of Las Cañadas volcano, Tenerife. Each pyroclastic current developed marked local and regional spatial variations in response to the incised, gently concave substrate topography. The locations of these variations shifted in space as rapid sedimentation from the current progressively buried and modified the topography. This complex, shifting response of the density currents to minor topographic variations has been reconstructed in high-resolution over a wide area (>500 km2) using the internal architecture of cryptic time-surfaces (entrachrons) marked by compositional zoning in the deposit, including variations in clast types. Valley-side field relations reveal that the currents were density-stratified. Yet, at a single instant in time, the lower levels of each current comprised a granular-fluid at some locations but were fully dilute and turbulent at others. Moreover, the locations of these variations shifted geographically as the topography changed during the eruption. The variations within the current are recorded by numerous superbly exposed gradational transitions from various stratified to massive lithofacies, both laterally and in the downcurrent direction. Individual currents were regionally widespread and travelled >15 km, but deposited only in longitudinally restricted, localised zones that spanned several small valleys and interfluves. The currents bypassed slopes up- and downcurrent of the restricted depositional zones, without depositing. The locations of deposition then gradually shifted with time, such that the extensive deposit sheet was gradually assembled beneath the sustained current in a diachronous fashion. Onlap relationships of internal entrachrons reveal that the base of the ignimbrite sheet and even the bases of individual flow-units are markedly diachronous. Deposition of a flow-unit commenced and ceased at different times in different places. This study suggests that in hazard assessments: (a) models of density currents that incorporate only pre-existing topography (e.g. from DEMs) may give misleading results in the case of sustained currents because sedimentation from these significantly modifies the topography during emplacement, altering flow paths; (b) frequencies and scales of previous pyroclastic currents determined from pyroclastic successions are likely to be significantly under-estimated because currents commonly bypass without leaving a deposit record; and (c) even where preservation appears to be complete, an ignimbrite at a single exposure commonly will not record the current’s entire flow history at that site

Geochemical correlation of three large-volume ignimbrites from the Yellowstone hotspot track, Idaho, USA

Three voluminous rhyolitic ignimbrites have been identified along the southern margin of the central Snake River Plain. As a result of wide-scale correlations, new volume estimates can be made for these deposits: ~350 km<sup>3</sup> for the Steer Basin Tuff and Cougar Point Tuff XI, and ~1,000 km<sup>3</sup> for Cougar Point Tuff XIII. These volumes exclude any associated regional ashfalls and correlation across to the north side of the plain, which has yet to be attempted. Each correlation was achieved using a combination of methods including field logging, whole rock and mineral chemistry, magnetic polarity, oxygen isotope signature and high-precision <sup>40</sup>Ar/<sup>39</sup>Ar geochronology. The Steer Basin Tuff, Cougar Point Tuff XI and Cougar Point Tuff XIII have deposit characteristics typical of 18Snake River (SR)-type 19 volcanism: they are very dense, intensely welded and rheomorphic, unusually well sorted with scarce pumice and lithic lapilli. These features differ significantly from those of deposits from the better-known younger eruptions of Yellowstone. The ignimbrites also exhibit marked depletion in ;4<sup>18</sup>O, which is known to characterise the SR-type rhyolites of the central Snake River Plain, and cumulatively represent ~1,700 km<sup>3</sup> of low ;4<sup>18</sup>O rhyolitic magma (feldspar values 2.3 132.9 30) erupted within 800,000 years. Our work reduces the total number of ignimbrites recognised in the central Snake River Plain by 6, improves the link with the ashfall record of Yellowstone hotspot volcanism and suggests that more large-volume ignimbrites await discovery through detailed correlation work amidst the vast ignimbrite record of volcanism in this bimodal large igneous province

Anatomy of a submarine pyroclastic flow and associated turbidity current: July 2003 dome collapse, Soufrière Hills volcano, Montserrat, West Indies

The 12 to 13 July 2003 andesite lava dome collapse at the Soufrière Hills volcano, Montserrat, provides the first opportunity to document comprehensively both the sub-aerial and submarine sequence of events for an eruption. Numerous pyroclastic flows entered the ocean during the collapse, depositing approximately 90% of the total material into the submarine environment. During peak collapse conditions, as the main flow penetrated the air–ocean interface, phreatic explosions were observed and a surge cloud decoupled from the main flow body to travel 2 to 3 km over the ocean surface before settling. The bulk of the flow was submerged and rapidly mixed with sea water forming a water-saturated mass flow. Efficient sorting and physical differentiation occurred within the flow before initial deposition at 500 m water depth. The coarsest components (?60% of the total volume) were deposited proximally from a dense granular flow, while the finer components (?40%) were efficiently elutriated into the overlying part of the flow, which evolved into a far-reaching turbidity current.<br/