Genetic mechanisms of severe Covid-19

MedRxiv September 2020; Nature online December 2020

In collaboration with the ISARIC GenOMICC study we discovered multiple genes that underlie critical illness in Covid-19, including several that led directly to potential therapeutic targets. In 2244 Covid cases, we compared severely ill patients with matched members of the population from three other studies (UK Biobank, Generation Scotland and 100,000 Genomes). We found genes involved in two molecular processes - antiviral immunity and lung inflammation - were important in determining the development of severe Covid-19. We replicated our findings in additional studies (Covid-19 HGI and 23andme). The associations with disease are robustly confirmed in these studies. Although we know the DNA associations are real, we can’t always be sure exactly how these variants lead to disease. The most likely genes underlying each of the four new discoveries are IFNAR2, TYK2, OAS1, DPP9. The action of some genetic variants is similar the the action of drugs - either increasing or decreasing the amount of a particular molecule or signal. We can use this to predict new treatments. This evidence has influenced the inclusion of baricitinib in the RECOVERY trial.