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 hospitalization2–4 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

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

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

Hydrogeochemistry Studies in the Oil Sands Region to Investigate the Role of Terrain Connectivity in Nitrogen Critical Loads

Hydrology and geochemistry studies were conducted in the Athabasca Oil Sands region to better understand the water and nitrogen cycles at two selected sites in order to assess the potential for nitrogen transport between adjacent terrain units. A bog—poor fen—upland system was instrumented near Mariana Lakes (ML) (55.899° N, 112.090° W) and a rich fen—upland system was instrumented at JPH (57.122° N, 111.444° W), 100 km south and 45 km north of Fort McMurray, Alberta respectively. LiDAR surveys were initially conducted to delineate the watershed boundaries and topography and to select a range of specific locations for the installation of water table wells and groundwater piezometers. Field work, which included a range of physical measurements as well as water sampling for geochemical and isotopic characterization, was carried out mainly during the thaw seasons of 2011 to 2015. From analysis of the runoff response and nitrogen species abundances we estimate that nitrogen exchange between the wetlands and adjacent terrain units ranged between 2.2 and −3.1 kg/ha/year for rich fens, 0.6 to −1.1 kg/ha/year for poor fens, and between 0.6 and −2.5 kg/ha/year for bogs, predominantly via surface pathways and in the form of dissolved nitrate. A significant storage of dissolved ammonium (and also dissolved organic nitrogen) was found within the pore water of the bog-fen complex at Mariana Lakes, which we attribute to decomposition, although it is likely immobile under current hydrologic conditions, as suggested by tritium distributions. In comparison with the experimental loads of between 5 and 25 kg/ha/year, the potential nitrogen exchange with adjacent terrain units is expected to have only a minor or negligible influence, and is therefore of secondary importance for defining critical loads across the regional landscape. Climate change and development impacts may lead to significant mobilization of nitrogen storages, although more research is required to quantify the potential effects on local ecosystems

Utility of a multi-tracer approach as a component of adaptive monitoring for municipal wastewater impacts

Distinguishing municipal wastewater effluent (MWWE) from other industrial effluents or through an urbanized watershed can be challenging. In complex receiving environments, linking environmental responses to specific compounds or effluents is not always straight forward. In order to characterize the inherent complexity of tracing MWWE in aquatic systems influenced by multiple stressors, a proposed multi-tracer suite is intended to highlight areas of potential biological concern. Characterization and quantification of effluent exposure to aquatic biota in this manner is essential to shape policies intended to encourage wastewater infrastructure development (i.e. treatment plant upgrade) and broader environmental management. This paper describes the use of a comprehensive suite of tracers that includes isotopes in support of a core surveillance program, demonstrating its effectiveness both empirically and with respect to diagnostic value contributed to monitoring programs.Natural Sciences and Engineering Research Council (NSERC

Perchlorate in Lake Water from an Operating Diamond Mine

Mining-related perchlorate [ClO₄^–] in the receiving environment was investigated at the operating open-pit and underground Diavik diamond mine, Northwest Territories, Canada. Samples were collected over four years and ClO₄^– was measured in various mine waters, the 560 km² ultraoligotrophic receiving lake, background lake water and snow distal from the mine. Groundwaters from the underground mine had variable ClO₄^– concentrations, up to 157 μg L^–1, and were typically an order of magnitude higher than concentrations in combined mine waters prior to treatment and discharge to the lake. Snow core samples had a mean ClO₄^– concentration of 0.021 μg L^–1 (n=16). Snow and lake water Cl^–/ClO₄^– ratios suggest evapoconcentration was not an important process affecting lake ClO₄^– concentrations. The multiyear mean ClO₄^– concentrations in the lake were 0.30 μg L^–1 (<i>n</i> = 114) in open water and 0.24 μg L^–1 (<i>n</i> = 107) under ice, much below the Canadian drinking water guideline of 6 μg L^–1. Receiving lake concentrations of ClO₄^– generally decreased year over year and ClO₄^– was not likely [biogeo]­chemically attenuated within the receiving lake. The discharge of treated mine water was shown to contribute mining-related ClO₄^– to the lake and the low concentrations after 12 years of mining were attributed to the large volume of the receiving lake