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

Metabolic cost, mechanical work, and efficiency during walking in young and older men

AIM: To investigate mechanical work, efficiency, and antagonist muscle co-activation with a view to better understand the cause of the elevated metabolic cost of walking (C(W)) in older adults. METHODS: Metabolic, mechanical and electromyographic measurements were made as healthy young (YOU; n = 12, age = 27 +/- 3 years) and older (OLD; n = 20, age = 74 +/- 3 years) men of equivalent body mass and leg length walked on a treadmill at four speeds (ranging from 0.83 to 1.67 m s(-1)). RESULTS: Net (above resting) C(W), determined by indirect calorimetry was 31% higher (average across speeds) in OLD (P < 0.05). The integrity of the passive pendulum like interchange of mechanical energies of the centre of mass (COM(B)), an energy-saving mechanism, was maintained in OLD. Furthermore, total mechanical work, determined from fluctuations in mechanical energy of COM(B) and of body segments relative to COM(B), was not significantly elevated in OLD. This resulted in a lower efficiency in OLD (-17%, P < 0.05). Co-activation, temporally quantified from electromyography recordings, was 31% higher in OLD for antagonist muscles of the thigh (P < 0.05). Thigh co-activation was moderately correlated with C(W) at three speeds (r = 0.38-0.52, P < 0.05). CONCLUSION: Healthy septuagenarians with no gait impairment have an elevated C(W) which is not explained by an elevation in whole body mechanical work. Increased antagonist muscle co-activation (possibly an adaptation to ensure adequate joint stability) may offer partial explanation of the elevated C(W)

Publisher Correction: Whole-genome sequencing of a sporadic primary immunodeficiency cohort (Nature, (2020), 583, 7814, (90-95), 10.1038/s41586-020-2265-1)

An amendment to this paper has been published and can be accessed via a link at the top of the paper