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

A new stratigraphy for the glacial deposits around Lowestoft, Great Yarmouth, North Walsham and Cromer, East Anglia, UK

A new stratigraphical model for the glacial deposits around Lowestoft, Great Yarmouth, North Walsham and Cromer (east of Weybourne and Edgefield) is presented, based on a combined research programme by the British Geological Survey and the Department of Geography, Royal Holloway University of London. This stratigraphical model is founded upon evidence derived from sedimentological descriptions, geological mapping and analytical lithological techniques including clast lithological analysis, derived pre- Quaternary palynomorphs and heavy mineralogy. The previously accepted ‘North Sea Drift’ / ‘Lowestoft Formation’ scheme is abandoned in favour of four formations that relate to assemblages of till units and associated outwash lithofacies, the mapping of major discontinuities, and morpho- and tectono-stratigraphical associations. The new scheme consists of the Happisburgh, redefined Lowestoft, Sheringham Cliffs and Briton’s Lane formations

Age limits on Middle Pleistocene glacial sediments from OSL dating, north Norfolk, UK

The lowland region of north Norfolk contains some of the best preserved evidence for glacial deposition during the Middle Pleistocene in northwest Europe. Despite the importance of these deposits, there is limited chronological control and it is debated whether they belong to a single glaciation, equated to the Anglian Glaciation (Marine Isotope Stage 12), or represent deposition over a number of Middle Pleistocene cold stages. In order to develop an improved chronology for glaciation in this region, we obtained 18 samples for optical stimulated luminescence (OSL) dating from glacial outwash facies. Samples of coarse-grained quartz sand were measured using the SAR (single aliquot regenerative-dose) protocol. The low radioactive isotope concentrations in sediments of this region enable the traditionally accepted age limit of luminescence dating to be extended. The form of the dose response curves, pre-heat plateaux tests, and dose recovery experiments also indicate that laboratory doses can be reliably measured in these samples. Age overestimation due to partial bleaching is thought to be insignificant. The OSL ages suggest that the glacial sediments studied were deposited during MIS 12 rather than in different post MIS 12 stages

Revised Pre-Devensian glacial stratigraphy in Norfolk, England, based on mapping and till provenance

Mapping combined with till provenance studies have resulted in a re-appraisal of the pre-Devensian glacial stratigraphy of Norfolk, England. The traditional model invoked two formations, a North Sea Drift Formation (NSDF) overlain by a Lowestoft Formation, formed by co-existing icesheets originating in Scandinavia and Northern Britain respectively. The NSDF included three diamictons, the First, Second and Third Cromer tills. The Briton’s Lane Sands and Gravels were considered to overlie the Lowestoft Formation. However, our work has shown this stratigraphy to be untenable, and we propose a model of several glaciations instead of co-existing ice-sheets. In our revised stratigraphy, the oldest formation, the Happisburgh Formation (including the Happisburgh or First Cromer Till) includes massive, sandy tills derived from northern Britain. The overlying Lowestoft Formation, including the Second Cromer (Walcott) Till is confirmed as derived from the west, introducing much Jurassic material as well as Chalk. The Sheringham Cliffs Formation includes both brown sandy tills (the Third Cromer Till) and ‘marly drift’, in a variety of tectonic relationships, and derived from the north and NNW. Finally the Briton’s Lane Formation is the only formation to include Scandinavian erratics. Dating of the four formations is at varying levels of confidence, with the Lowestoft Formation most confidently confirmed as MIS 12. The Happisburgh Formation is believed to represent an earlier glaciation, and MIS 16 is proposed. The Sheringham Cliffs Formation is tentatively believed to date from MIS 10, and the Briton’s Lane Formation is assigned to MIS 6

The age and stratigraphic context of the Easington Raised Beach, County Durham, UK.

The Easington Raised Beach, in Shippersea Bay, County Durham, is themost northerly known interglacial beach deposit in England. It lies directly on Magnesian Limestone bedrock at 33 mO.D. and is covered by glacial sediments attributed to the Devensian. Detailed sedimentological analysis suggests that it is an interglacial beach, which is supported by the presence of pebbles bored bymarine organisms and littoral, temperate-climate, marine macro- and micro-fossils. It comprises beds of unconsolidated, bedded, imbricated, well-rounded sands and gravels, overlain by similar, but calcreted, deposits. The gravel fraction is dominated by Magnesian and Carboniferous limestone, with orthoquartzite, flint, and porphyries also present; these are far-travelled erratics that must have derived from the erosion of older glacially transported sediments. Previous workers have described erratics derived from the Oslofjord region of Norway in the raised beach gravel, although rocks diagnostic of a Scandinavian origin have not been recovered as part of this study. The heavy-mineral suite is rich in epidote, dolomite, clinopyroxenes, garnet, tourmaline, and micas. The beach was dated previously by conventional amino acid analysis of the shells, which suggested a Marine Isotope Stage (MIS) 7 age, albeit with a reworked component from MIS 9. This has been confirmed by new optically stimulated luminescence (OSL) dates, which indicate that the beach formed between 240 and 200 ka BP. New amino acid racemisation analyses, using a modified technique, broadly support this interpretation but must await more comparative data before they can be assessed fully. The strong indication of an MIS 7 age for the formation of the beach has implications for the uplift history of northeastern England during the Pleistocene, and indicates an uplift rate of 0.19 mm a_1. The stable isotope geochemistry indicates that the cementation occurred during an interglacial period, whilst U-Series dating of the cement indicates that cementation occurred mostly during the Holocene, and is genetically related to the overlying Devensian till. This work has formed part of a full re-appraisal of the glacial sequence in eastern County Durham, the results of which suggest that the Warren House Formation pre-dates the raised beach, and that the Devensian Horden Till overlies the raised beach

Glacial Chronology over the Past 450 kyr Around the Margins of the Southern North Sea (UK and Netherlands) From Quartz Luminescence Dating

Terrestrial glacigenic deposits containing evidence for the repeated growth of former ice sheets are distributed widely in North America and continental Europe. The chronology of the younger component of these deposits during the Last Glacial Maximum (LGM) is relatively well established, but considerably less is known about the extent and timing of earlier periods of Pleistocene glaciation. This study focuses on the well preserved glacigenic sediment and landform assemblages that are exposed across lowland areas of eastern Britain and the northern Netherlands, which document the repeated advance of Pleistocene British/Fennoscandinavian ice sheets. Previously, it is unknown whether the deposits belong to a single glaciation equated with Marine Isotope Stage (MIS) 12, or represent deposition over a number of separate cold climate stages. We have collected > 80 samples from glaciofluvial and glaciolacustrine deposits in this region for luminescence (OSL) dating with the approach of obtaining 5-10 replicate dates per stratigraphical unit. The luminescence characteristics of the samples including thermal stability, dose response, ability to measure a known dose, and presence of desirable components separated using LM-OSL (linear modulation) indicate that equivalent doses can be reliably measured across the timescale of interest. Furthermore, low concentrations of radioactive isotopes in sediments of this region enable the traditionally accepted age limit of luminescence dating to be considerably extended. The luminescence ages confirm that the largest glaciation in the UK occurred during MIS 12 (427 ± 26 kyr). An additional tight cluster of ages at 166 ± 8 kyr also indicates that major ice advances occurred synchronously in the UK and Netherlands during MIS 6, although the dimensions of the ice sheet in the UK appears to be of a similar or lesser extent than the LGM. This work also justifies that coherent sets of luminescence ages can be obtained with an overall uncertainty of < 10%, sufficient to delineate glaciation events at the isotope stage level but precluding discrimination of sub-isotope stage advances

Quartz luminescence dating of Anglian Stage (MIS 12) fluvial sediments : comparison of SAR age estimates to the terrace chronology of the Middle Thames valley, UK

Quartz optically stimulated luminescence (OSL) is increasingly being used to constrain the depositional age of fluvial and glaciofluvial sequences over orbital (Milankovitch) timescales within the British Isles. Few of these previous studies have had any age control; however there is some evidence that OSL ages based on the single aliquot regenerative dose (SAR) protocol may be subject to systematic age underestimation as samples approach saturation. In this study, the age of 12 luminescence samples from a chronologically well-constrained site dating to 450 ka from the Thames terrace sequence, southern Britain, was measured using SAR in order to test the performance of the method close to its upper age limit. The characteristics, dose response and thermal stability of the OSL signal in these samples were assessed by investigating equivalent dose (De) as a function of stimulation time and component-resolved pulse annealing. Despite the fact that the samples are dominated by the quartz fast component, these results showed that both the medium and slow components have lower stabilities than the fast component, but with the unstable medium component most affecting the initial part of the OSL signal used in dating. Based on isolating the fast component either through curve fitting or eliminating the medium component using the early background subtraction method, OSL ages up to 450 Gy were found to compare well with the expected age of the site of 450 ± 23 ka. In contrast, a systematic age underestimation of 10% was manifested at lower doses when using the initial part of the OSL signal, contaminated by the medium component. These results suggest that the early background subtraction method should be used when dating in the non-linear part of the growth curve as it provides a better separation of thermally unstable signals and represents a more convenient approach than curve fitting in well-behaved samples

Timing and depositional environments of a Middle Pleistocene glaciation of northeast England: New evidence from Warren House Gill, County Durham

At various times during the Quaternary, north-eastern England was a zone of confluence between dynamic ice lobes sourced from the Pennines, northern Scotland, the Cheviots, and Scandinavia. The region thus has some of the most complex exposures of Middle to Late Pleistocene sediments in Britain, with both interglacial and glacial sediments deposited in terrestrial and marine settings. We investigated sedimentary sequences exposed on the coastline of County Durham at Warren House Gill, and present a new model of British and Fennoscandian Ice Sheet interaction in the North Sea Basin during the Middle Pleistocene. The stratigraphy at Warren House Gill consists of a lower diamicton and upper estuarine sediments, both part of the Warren House Formation. They are separated from the overlying Weichselian Blackhall and Horden tills by a substantial unconformity. The lower diamicton of the Warren House Formation is re-interpreted here as an MIS 8 to 12 glaciomarine deposit containing ice-rafted lithics from north-eastern Scotland and the northeast North Sea, and is renamed the ‘Ash Gill Member’. It is dated by lithological comparison to the Easington Raised Beach, Middle Pleistocene Amino Acid Racemisation values, and indirectly by optically stimulated luminescence. The overlying shallow subaqueous sediments were deposited in an estuarine environment by suspension settling and bottom current activity. They are named the ‘Whitesides Member’, and form the uppermost member of the Warren House Formation. During glaciation, ice-rafted material was deposited in a marine embayment. There is no evidence of a grounded, onshore Scandinavian ice sheet in County Durham during MIS 6, which has long been held as the accepted stratigraphy. This has major implications for the currently accepted British Quaternary Stratigraphy. Combined with recent work on the Middle Pleistocene North Sea Drift from Norfolk, which is now suggested to have been deposited by a Scottish ice sheet, the presence of a Scandinavian ice sheet in eastern England at any time during the Quaternary is becoming increasingly doubtful