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

The phase response of primary auditory afferents in a songbird (Sturnus vulgaris L.)

The effects of stimulus frequency and intensity on phase-locking characteristics of cochlear ganglion cells were studied in the starling. All cells showed phase-locking to tone stimuli within their response area. Phase-locking at CF is found on average 9 dB below discharge rate threshold. Phase-locking is best at 0.4 kHz and deteriorates with increasing frequency almost independently of CF. No phase-locking was evident for test frequencies above 3–4 kHz. Phase-locking in cells with CFs above 1.0 kHz is better below CF than at CF. For constant sound pressure, an increase in stimulus frequency always produced an increase in phase lag of the neural response. The phase vs. frequency data obtained at constant sound pressure can be reasonably approximated by straight line functions. The slopes of these functions indicate the latency of the neural response, and are correlated with the CFs of the respective cells; the latency tends to be longer in low-CF cells and shorter in high-CF cells. The latency decreases by 0.04 ms per l dB sound pressure increase. The response phase at CF is nearly stimulus level-independent. Increasing stimulus intensity causes increasing phase lag below CF and decreasing phase lag above CF. These results are compared to findings in other vertebrates and demonstrate the similarities of phase-locking characteristics despite the substantial anatomical differences among the vertebrate groups