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

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

Ideology and armed conflict

A growing wave of scholarship suggests that ideology has demonstrable effects on various forms of armed conflict. But ideology remains a relative theoretical newcomer in conflict research, and scholars lack developed microfoundations for analyzing ideologies and their effects. Typically, existing research has primarily presented ideology as either an instrumental tool for conflict actors or a source of sincere political and normative commitments. But neither approach captures the diverse ways in which contemporary social science theorizes the causal connection between ideas and action, and both struggle to reconcile the apparently strong effects of ideology on conflict at the collective level with the relative rarity of ‘true believers’ at the individual level. This article addresses such problems by providing key microfoundations for conceptualizing ideologies, analyzing ideological change, and explaining ideologies’ influence over conflict behavior. I emphasize that ideology overlaps with other drivers of conflict such as strategic interests and group identities, show how ideologies can affect conflict behavior through four distinct mechanisms – commitment, adoption, conformity and instrumentalization – and clarify the role of both conflict pressures and preexisting ideological conditions in ideological change. These microfoundational claims integrate existing empirical findings and offer a foundation for building deeper explanations and middle-range theories of ideology’s role in armed conflict

Ideology and armed conflict

A growing wave of scholarship suggests that ideology has demonstrable effects on various forms of armed conflict. But ideology remains a relative theoretical newcomer in conflict research, and scholars lack developed microfoundations for analyzing ideologies and their effects. Typically, existing research has primarily presented ideology as either an instrumental tool for conflict actors or a source of sincere political and normative commitments. But neither approach captures the diverse ways in which contemporary social science theorizes the causal connection between ideas and action, and both struggle to reconcile the apparently strong effects of ideology on conflict at the collective level with the relative rarity of ‘true believers’ at the individual level. This article addresses such problems by providing key microfoundations for conceptualizing ideologies, analyzing ideological change, and explaining ideologies’ influence over conflict behavior. I emphasize that ideology overlaps with other drivers of conflict such as strategic interests and group identities, show how ideologies can affect conflict behavior through four distinct mechanisms – commitment, adoption, conformity and instrumentalization – and clarify the role of both conflict pressures and preexisting ideological conditions in ideological change. These microfoundational claims integrate existing empirical findings and offer a foundation for building deeper explanations and middle-range theories of ideology’s role in armed conflict

Convergence and divergence in the study of ideology: a critical review

Dedicated research on ideology has proliferated over the last few decades. Many different disciplines and methodologies have sought to make a contribution, with the welcome consequence that specialist thinking about ideology is at a high-water mark of richness, diversity and theoretical sophistication. Yet this proliferation of research has fragmented the study of ideology by producing independent communities of scholars differentiated by geographical location and by disciplinary attachment. This review draws together research on ideology from several disciplines on different sides of the Atlantic, in order to address three questions that appear to be of great relevance to political scientists: (1) What do we mean by ideology? (2) How do we model ideology? (3) Why do people adopt the ideologies they do? In doing so, it argues that many important axes of debate cut across disciplinary and geographic boundaries, and points to a series of significant intellectual convergences that offer a framework for productive interdisciplinary engagement and integration

Convergence and divergence in the study of ideology: a critical review

Dedicated research on ideology has proliferated over the last few decades. Many different disciplines and methodologies have sought to make a contribution, with the welcome consequence that specialist thinking about ideology is at a high-water mark of richness, diversity and theoretical sophistication. Yet this proliferation of research has fragmented the study of ideology by producing independent communities of scholars differentiated by geographical location and by disciplinary attachment. This review draws together research on ideology from several disciplines on different sides of the Atlantic, in order to address three questions that appear to be of great relevance to political scientists: (1) What do we mean by ideology? (2) How do we model ideology? (3) Why do people adopt the ideologies they do? In doing so, it argues that many important axes of debate cut across disciplinary and geographic boundaries, and points to a series of significant intellectual convergences that offer a framework for productive interdisciplinary engagement and integration

A Complex Systems Approach to the Study of Ideology: Cognitive-Affective Structures and the Dynamics of Belief Systems

We propose a complex systems approach to the study of political belief systems, to overcome some of the fragmentation in the current scholarship on ideology. We review relevant work in psychology, sociology, and political science and identify major cleavages in the literature: the spatial vs. non-spatial divide (ideologies as reducible to a spatially organized set of dimensions vs. as complex conceptual structures) and the person-group problem (ideologies as driven by psychological needs of individuals vs. by institutional and power structures of society). We argue that construing ideologies as conceptual networks of cognitive-affective representations embedded in social networks of people may provide a path for bridging these existing gaps and epistemological disputes. Tools from cognitive science and computational social science such as cognitive-affective mapping, connectionist simulations, and agent-based modeling are appropriate methods for a new research program that substantiates our complex systems perspective on ideology

Facts, principles, and global justice: does the ‘real world’ matter?

The world is undeniably full of injustice. Many feel that much political philosophy is practically impotent and engaged instead in overly abstract theorising insufficiently sensitive to the realities of the world. One response to this concern is David Miller’s influential model of evidence-based political philosophy, which claims to be sensitive to empirical evidence from the social sciences, takes seriously people’s opinions, and defends the role of facts in grounding normative principles. Using various examples from the field of global justice, one of Miller’s key areas of work, I show that Miller’s method is unconvincing on two-levels. His theoretical argument for fact-dependence is flawed, and his practical argument for an opinion-sensitive political theory is either guilty of status quo bias or, in an attempt to escape it, becomes self-defeating. While the paper is primarily critical, I endeavour also to draw out the implications of my critiques for the role of the ‘real world’ in theorising