Genetic mechanisms of critical illness in Covid-19 (preprint)

ABSTRACT

The subset of patients who develop critical illness in Covid-19 have extensive inflammation affecting the lungs and are strikingly different from other patients immunosuppressive therapy benefits critically-ill patients, but may harm some non-critical cases. Since susceptibility to life-threatening infections and immune-mediated diseases are both strongly heritable traits, we reasoned that host genetic variation may identify mechanistic targets for therapeutic development in Covid-19. GenOMICC (Genetics Of Mortality In Critical Care, genomicc.org) is a global collaborative study to understand the genetic basis of critical illness. Here we report the results of a genome-wide association study (GWAS) in 2790 critically-ill Covid-19 patients from 208 UK intensive care units (ICUs), representing >95% of all ICU beds. Random controls were drawn from three distinct UK population studies. We identify and replicate several novel genome-wide significant associations including variants chr19p13.3 (rs2109069, P = 3.98 x 10-12), within the gene encoding dipeptidyl peptidase 9 (DPP9), and at chr21q22.1 (rs2236757, P = 4.99 x 10-8) in the interferon receptor IFNAR2. Consistent with our focus on extreme disease in younger patients with less comorbidity, we detect a stronger signal at the known 3p21.31 locus than previous studies (rs73064425, P = 1.2 x 10-27). We identify potential targets for repurposing of existing licensed medications. Using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease. Transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19. We detected genome-wide significant gene-level associations for genes with central roles in viral restriction (OAS1, OAS2, OAS3). These results identify specific loci associated with life-threatening disease, and potential targets for host-directed therapies. Randomised clinical trials will be necessary before any change to clinical practice.