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

Abordagem Bayesiana da curva de lactação de cabras Saanen de primeira e segunda ordem de parto Bayesian approach in the lactation curve of Saanen goats from first and second calving orders

O objetivo deste trabalho foi utilizar o método Bayesiano no ajuste do modelo de Wood a dados de produção de leite de cabras da raça Saanen. Dois grupos de animais da primeira e segunda lactação foram considerados. Amostras das distribuições marginais a posteriori dos parâmetros do modelo de Wood e das funções de produção derivadas desses parâmetros - pico de produção, tempo do pico de produção, persistência e produção total de leite - foram obtidas pelo algoritmo Gibbs Sampler. As inferências foram feitas em cada população e os resultados mostraram diferenças na taxa de decréscimo da produção após o pico e na persistência, indicando maior produção nos animais de segunda lactação. Realizou-se um estudo de simulação de dados para avaliar o método Bayesiano sob diferentes estruturas de matrizes de covariâncias dos parâmetros. Os resultados desse estudo indicam que o método é eficiente no estudo das curvas de lactação quando a matriz de covariância apresenta alta correlação dos parâmetros.<br>The objective of this work was to use the Bayesian method in the fitting of the Wood&acute;s model for milk production of Saanen goats. Two groups of animals from first and second lactation were considered in the analysis. The posterior marginal distributions for each parameter and production functions, peak milk yield, time of peak yield, persistency and total milk production, were obtained via Gibbs Sampler algorithm. The inference was done for each population. The results showed differences in the slope of the curve after the peak and in persistency, indicating highest production for the second lactation. The data were simulated for evaluating Bayesian method under several covariance matrices structures. The simulation results indicate the efficiency of this method for lactation curves studies when the covariance matrices show high correlation for parameters