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

Sural nerve fibre pathology in diabetic patients with mild neuropathy: relationship to pain, quantitative sensory testing and peripheral nerve electrophysiology

Nerve fibre pathology is poorly described in diabetic patients with mild neuropathy and has not been adequately related to clinical evaluation, quantitative sensory examination and neurophysiology. Sural nerve myelinated and unmyelinated fibre pathology was morphometrically quantified and related to the presence of pain and conventional measures of neuropathic severity in 15 diabetic patients with mild neuropathy and 14 control subjects. Diabetic patients demonstrated a significant (P < 0.01) reduction in myelinated fibre density, but no change in fibre/axonal area, or g-ratio, compared to control subjects. Unmyelinated fibre degeneration was evidenced by an increase in the percentage of unassociated Schwann cell profiles (P < 0.0001) and a reduction in axon density (P < 0.0008) in diabetic patients. This was associated with a significant reduction in unmyelinated axon diameter (P < 0.001) with a shift of the size frequency distribution to the left (P < 0.02). Neurophysiology, quantitative sensory testing and nerve fibre pathology failed to differentiate diabetic patients with painful and painless neuropathy and failed to correlate with any measure of unmyelinated fibre pathology