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

Myopes experience greater contrast adaptation during reading

In this study, we investigated whether reading influences contrast adaptation differently in young adult emmetropic and myopic participants at the spatial frequencies created by text rows and character strokes. Pre-adaptation contrast sensitivity was measured for test gratings with spatial frequencies of 1 cdeg−1 and 4 cdeg−1, presented horizontally and vertically. Participants then adapted to reading text corresponding to the horizontal “row frequency” of text (1 cdeg−1), and vertical “stroke frequency” of the characters (4 cdeg−1) for 180 s. Following this, post-adaptation contrast sensitivity was measured. Twenty young adults (10 myopes, 10 emmetropes) optimally corrected for the viewing distance participated. There was a significant reduction in logCS post-text adaptation (relative to pre-adaptation logCS) at the row frequency (1 cdeg−1 horizontal) but not at the stroke frequency (4 cdeg−1 vertical). logCS changes due to adaptation at 1 cdeg−1 horizontal were significant in both emmetropes and myopes. Comparing the two refractive groups, myopic participants showed significantly greater adaptation compared to emmetropic participants. Reading text on a screen induces contrast adaptation in young adult observers. Myopic participants were found to exhibit greater contrast adaptation than emmetropes at the spatial frequency corresponding to the text row frequency. No contrast adaptation was observed at the text stroke frequency in either participant group. The greater contrast adaptation experienced by myopes after reading warrants further investigation to better understand the relationship between near work and myopia development