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 global agenda for household water security: Measurement, monitoring, and management

Water scholarship has advanced considerably in recent decades. Despite this remarkable progress, water challenges may be growing more quickly than our capacity to solve them. While much progress has been made toward achieving Sustainable Development Goal 6 — water and sanitation for all — new stressors have emerged to threaten this progress. Far from being a problem of the Global South, recent research shows that water insecurity is very much a global phenomenon — and one that has been, until recently, seriously neglected in the Global North. This indicates a strong need for innovative measurement of who experiences water insecurity, new approaches for monitoring the efficacy of water interventions, and more effective management of complex, mobile, and multiple water infrastructures to achieve water security. In this paper, we introduce the Household Water Insecurity approach to addressing these concerns. First, we suggest ways to improve the measurement of water insecurity — pinpointing problems at the household and individual levels — in ways that can inform policymaking with improved precision. Second, we discuss ways that new information and communication technology can improve monitoring and indicate where water infrastructure repairs and investments are most needed. Third, we highlight the need for new approaches to managing complex water infrastructures in more inclusive and democratic ways