Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

Genetic mechanisms of critical illness in Covid-19.

Host-mediated lung inflammation is present,1 and drives mortality,2 in critical illness caused by Covid-19. Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development.3 Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study(GWAS) in 2244 critically ill Covid-19 patients from 208 UK intensive care units (ICUs). We identify and replicate novel genome-wide significant associations, on chr12q24.13 (rs10735079, p=1.65 [Formula: see text] 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), on chr19p13.2 (rs2109069, p=2.3 [Formula: see text] 10-12) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 [Formula: see text] 10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 [Formula: see text] 10-8) in the interferon receptor gene IFNAR2. We identify potential targets for repurposing of licensed medications: using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease; 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. Large-scale randomised clinical trials will be essential before any change to clinical practice

Polarisation, violent extremism and resilience in Europe today : an analytical framework

This paper aims to conduct a systematic and critical review of contemporary literature on processes of polarisation, the role they are perceived as playing in creating a matrix of adversities that can lead to increased vulnerability to what is often termed ‘violent extremism’, and the potential impact of practices that are understood as building pro-social resilience to such adversities. Through a wide-ranging review, taking in studies and practice on polarisation and ‘violent extremism’, the authors aim to identify a schema of what are broadly conceptualised as vulnerabilities – factors, operating on macro, meso and micro levels, which may either increase or decrease the likelihood that communities become fragmented and polarised within a European context.The BRaVE project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement number 82218

What will 2020 bring? Finding our way in a more polarised world

No abstract available

Polarisation, Violent Extremism and Resilience in Europe Today : an Analytical Framework

This paper aims to conduct a systematic and critical review of contemporary literature on processes of polarisation, the role they are perceived as playing in creating a matrix of adversities that can lead to increased vulnerability to what is often termed ‘violent extremism’, and the potential impact of practices that are understood as building pro-social resilience to such adversities. Through a wide-ranging review, taking in studies and practice on polarisation and ‘violent extremism’, the authors aim to identify a schema of what are broadly conceptualised as vulnerabilities – factors, operating on macro, meso and micro levels, which may either increase or decrease the likelihood that communities become fragmented and polarised within a European context

Polarisation, Violent Extremism and Resilience in Europe Today : an Analytical Framework

This paper aims to conduct a systematic and critical review of contemporary literature on processes of polarisation, the role they are perceived as playing in creating a matrix of adversities that can lead to increased vulnerability to what is often termed ‘violent extremism’, and the potential impact of practices that are understood as building pro-social resilience to such adversities. Through a wide-ranging review, taking in studies and practice on polarisation and ‘violent extremism’, the authors aim to identify a schema of what are broadly conceptualised as vulnerabilities – factors, operating on macro, meso and micro levels, which may either increase or decrease the likelihood that communities become fragmented and polarised within a European context