GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A)

Stochastic Modeling of B Lymphocyte Terminal Differentiation and Its Suppression by Dioxin

<p>Abstract</p> <p>Background</p> <p>Upon antigen encounter, naïve B lymphocytes differentiate into antibody-secreting plasma cells. This humoral immune response is suppressed by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other dioxin-like compounds, which belong to the family of aryl hydrocarbon receptor (AhR) agonists.</p> <p>Results</p> <p>To achieve a better understanding of the immunotoxicity of AhR agonists and their associated health risks, we have used computer simulations to study the behavior of the gene regulatory network underlying B cell terminal differentiation. The core of this network consists of two coupled double-negative feedback loops involving transcriptional repressors Bcl-6, Blimp-1, and Pax5. Bifurcation analysis indicates that the feedback network can constitute a bistable system with two mutually exclusive transcriptional profiles corresponding to naïve B cells and plasma cells. Although individual B cells switch to the plasma cell state in an all-or-none fashion when stimulated by the polyclonal activator lipopolysaccharide (LPS), stochastic fluctuations in gene expression make the switching event probabilistic, leading to heterogeneous differentiation response among individual B cells. Moreover, stochastic gene expression renders the dose-response behavior of a population of B cells substantially graded, a result that is consistent with experimental observations. The steepness of the dose response curve for the number of plasma cells formed vs. LPS dose, as evaluated by the apparent Hill coefficient, is found to be inversely correlated to the noise level in Blimp-1 gene expression. Simulations illustrate how, through AhR-mediated repression of the AP-1 protein, TCDD reduces the probability of LPS-stimulated B cell differentiation. Interestingly, stochastic simulations predict that TCDD may destabilize the plasma cell state, possibly leading to a reversal to the B cell phenotype.</p> <p>Conclusion</p> <p>Our results suggest that stochasticity in gene expression, which renders a graded response at the cell population level, may have been exploited by the immune system to launch humoral immune response of a magnitude appropriately tuned to the antigen dose. In addition to suppressing the initiation of the humoral immune response, dioxin-like compounds may also disrupt the maintenance of the acquired immunity.</p

GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown to be highly efficient for discovery of genetic associations. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A)

An immunodominant NP105-113-B*07:02 cytotoxic T cell response controls viral replication and is associated with less severe COVID-19 disease.

Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265Funder: Chinese Academy of Medical Sciences (CAMS); doi: https://doi.org/10.13039/501100005150Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440NP105-113-B*07:02-specific CD8+ T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP105-113-B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP105-113-B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP105-113-B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP105-113-B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design

Dispersal of the introduced red fox (Vulpes vulpes) across Australia

Imported from Great Britain, the current Australian population of red foxes was predominantly founded by three separate deliberate releases for naturalisation around 1871, all in the far south-east of the continent. Successful establishment was first noted in 1874, thence the appearance of a red fox anywhere else in Australia was newsworthy until the early 1930s in the north and far south-west; over 3000\ua0km distant. This study reconstructs dispersal from nearly 800 such newspaper accounts, over half of which were expressly ‘the first fox’ with the remainder the first record. All concord. Data shows eight deliberate releases pre-1900 and their fate, including three failures in Tasmania. Another two releases are implied by sightings. Interpretation of proximate chronological records reveals nine paths of initial spread over eastern Australia south of the southern tropics. Many had converged by 1900. Eleven five-yearly contours of the frontier are mapped across the continent advancing the known temporal frontier, especially in the north-east. Slower progress clearly occurred on coastal ranges compared to semi-arid regions if not their watercourses. Colonisation transcended many habitats, severe drought and control efforts targeting the fox and its key predator Canis dingo, to literally follow naturalisation by the European rabbit (Oryctolagus cuniculus). The public resource utilised contains tremendous potential to further our understanding of foxes; indeed many alien, native, migratory, plague or endangered species

A land management history for central Queensland, Australia as determined from land-holder questionnaire and aerial photography

Features of the land management history over a 125,755 km2 area of central Queensland, Australia were determined from a variety of sources. A random sample of 205 site locations provided the basis for determining trends in land use. Trends in vegetation clearing were determined using sequential aerial photography for the sample sites, revealing a steady rate averaging nearly 1% of the region per annum over 41 years. This measure of sustained clearing over a large region is higher than recently published clearing rates from South America. Land types have been selectively cleared with over 90% of the Acacia on clay land type having been cleared. A land-holder questionnaire pertaining to the random sites yielded a response rate of 71% and provided information on vegetation clearing, ploughing, tree killing (ring-barking or tree poisoning), and fire frequency, season and intensity. The land-holder responses were compared with independent data sources where possible and revealed no mis-information. However, land-holders may have been marginally less likely to respond if the sample area had been cleared, although this effect was not statistically significant. Ploughing and tree killing are variable depending on land type, but the former has affected about 40% of the Acacia on clay land type, effectively eliminating options for natural regrowth. The proportion of decade-site combinations that were reported as having no fires increased from 22% in the 1950s to an average of 42% for subsequent decades, although the reporting of more than one fire per decade has been relatively constant through the study period. The reporting of at least one fire per decade varies from 46% for the Acacia on sand land type to 77% for the Eucalypt on sand land type for decade-site combinations. Fires are more intense when associated with clearing than in uncleared vegetation, but the proportion of cool and hot fires is relatively constant between land types in uncleared vegetation. Nearly all fires reported were either in spring or summer and this seasonally restricted regime is probably at variance with Aboriginal fire regimes. This study describes the rapid transformation of central Queensland. This has yielded substantially increased agricultural production but may also result in a range of negative impacts and these are discussed

Great Artesian Basin springs in southern Queensland 1911-2000

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Evaluation of aerial photography for predicting trends in structural attributes of Australian woodland including comparison with ground-based monitoring data

The accurate assessment of trends in the woody structure of savannas has important implications for greenhouse accounting and land-use industries such as pastoralism. Two recent assessments of live woody biomass change from north-east Australian eucalypt woodland between the 1980s and 1990s present divergent results. The first estimate is derived from a network of permanent monitoring plots and the second from woody cover assessments from aerial photography. The differences between the studies are reviewed and include sample density, spatial scale and design. Further analyses targeting potential biases in the indirect aerial photography technique are conducted including a comparison of basal area estimates derived from 28 permanent monitoring sites with basal area estimates derived by the aerial photography technique. It is concluded that the effect of photo-scale; or the failure to include appropriate back-transformation of biomass estimates in the aerial photography study are not likely to have contributed significantly to the discrepancy. However, temporal changes in the structure of woodlands, for example, woodlands maturing from many smaller trees to fewer larger trees or seasonal changes, which affect the relationship between cover and basal area could impact on the detection of trends using the aerial photography technique. It is also possible that issues concerning photo-quality may bias assessments through time, and that the limited sample of the permanent monitoring network may inadequately represent change at regional scales

Spring wetlands in seasonally arid Queensland: floristics, environmental relations, classification and conservation values

The vegetation and environmental setting of permanent spring wetlands are described from a survey of 269 spring complexes throughout seasonally arid Queensland. Wetlands associated with springs in the western and southern discharge areas of the Great Artesian Basin are floristically distinct from other spring wetlands. Ordination analysis suggests that the biogeographic regions and the broad geological substrates that support spring wetlands provide a meaningful representation of floristic range. An existing classificatory system that defines ‘regional ecosystems’ on the basis of the biogeographic region and broad geological substrate is adopted to define 15 spring-wetland types in seasonally arid Queensland. The conservation value of the springs is assessed by a scheme that weights plant species populations on the basis of their endemicity and isolation from other populations, demonstrating that both Great Artesian Basin and non-Great Artesian Basin springs have similar conservation values. Australian Journal of Botany 52(5) 583–59