SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

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 hospitalization2–4 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

Orbscan Topography in Primary Open-Angle Glaucoma

Purpose: To compare anterior and posterior corneal curvatures between eyes with primary open-angle glaucoma (POAG) and healthy eyes. Methods: This is a prospective, cross-sectional, observer-masked study. A total of 138 white subjects (one eye per patient) were consecutively recruited; 69 eyes had POAG (study group), and the other 69 comprised a group of healthy control eyes matched for age and central corneal pachymetry with the study ones. Exclusion criteria included any corneal or ocular inflammatory disease, previous ocular surgery, or treatment with carbonic anhydrase inhibitors. The same masked observer performed Goldmann applanation tonometry, ultrasound pachymetry, and Orbscan II topography in all cases. Central corneal thickness, intraocular pressure, and anterior and posterior topographic elevation maps were analyzed and compared between both groups. Results: Patients with POAG had greater forward shifting of the posterior corneal surface than that in healthy control eyes (p < 0.01). Significant differences in anterior corneal elevation between controls and POAG eyes were also found (p < 0.01). Conclusions: Primary open-angle glaucoma eyes have a higher elevation of the posterior corneal surface than that in central corneal thickness–matched nonglaucomatous eyes

Effect of Laser in Situ Keratomileusis on Schiøtz, Goldmann, and Dynamic Contour Tonometric Measurements

Purpose: To assess the effect of laser in situ keratomileusis (LASIK) on ocular rigidity and compare its effect on intraocular pressure (IOP) readings with Goldmann applanation tonometry (GAT), Schiøtz indentation tonometry (ST), and dynamic contour tonometry (DCT). Patients and Methods: Prospective, observational, single-masked study. Eighty-one patients who underwent myopic LASIK and 108 unoperated myopic control patients were included in the study. The IOP was measured using GAT, DCT, and ST. The coefficient of ocular rigidity (Ko) was obtained from the regression analysis of the 3 readings obtained with each weight of the ST. Linear multiple regression analysis was performed with dummy variables to assess the effects of age, central corneal thickness (CCT), and refractive surgery on measured IOP values. Results: Age, CCT, and previous LASIK explained 39.41% of the IOP readings with GAT, 25.31% with DCT, and 3.28% with ST. LASIK caused a mean decrease of 2.51mm Hg in IOP readings (P=0.000) with GAT, 1.29mm Hg (P=0.036) with DCT, and no significant change in IOP readings with ST (P=0.299). Significant differences in the Ko were observed between the LASIK and control groups. The Ko values were unrelated to age and CCT in the LASIK and control groups. Conclusions: ST seems to be less affected by previous LASIK procedures. There is a difference in the ocular rigidity between the unoperated and LASIK eyes that is not correlated with the CCT. Therefore, ST seems to measure changes in the biomechanical behavior of corneas that underwent LASIK surgery