A functional genomics approach to understand host genetic regulation ofCOVID-19 severity

Kuijpers, Y.; Chu, X.; Jaeger, M.; Moorlag, S.; Koeken, V.; Mourits, V.; J. de Bree, L. C.; De Mast, Q.; van de Veerdonk, F.; Joosten, L.; Li, Y.; Netea, M.; Xu, C.-J.

A recent genome-wide association study of European ancestry has identified 3p21.31 and 9q34.2 (ABO gene) to be significantly associated with COVID-19 respiratory failure (1). Here, we employed the detailed clinical, immunological and multi-omics data of the Human Functional Genomics Projects (HFGP) to explore the physiological significance of the host genetic variants that influence susceptibility to severe COVID-19. A functional genomics investigation based on functional characterization of individuals with high genetic risk for severe COVID-19 susceptibility identified several major patterns: i. a large impact of genetically determined innate immune responses in COVID-19, with increased susceptibility for severe disease in individuals with defective monocyte-derived cytokine production; ii. genetic susceptibility related to ABO blood groups is probably mediated through the von Willebrand factor (VWF) and endothelial dysfunction; and iii. the increased susceptibility for severe COVID-19 in men is at least partially mediated by chromosome X-mediated genetic variation. These insights allow a physiological understanding of genetic susceptibility to severe COVID-19, and indicate pathways that could be targeted for prevention and therapy.