TWAS-based translational genomics approach identifies IL10RB as the top candidate gene for COVID-19 host susceptibility and severity

Recent efforts have identified genetic loci that are associated with coronavirus disease 2019 (COVID-19) infection rates and disease outcome severity. Translating these genetic findings into druggable genes that regulate COVID-19 host susceptibility is a critical next step. Using a translational genomics approach that integrates COVID-19 genetic susceptibility variants, multi-tissue genetically regulated gene expression (GReX) and perturbagen signatures, we identify IL10RB as the top key regulator of COVID-19 host susceptibility. In a series of validation steps we show that predicted GReX up-regulation of IL10RB and higher IL10RB expression in COVID-19 patient blood is associated with worse COVID-19 outcomes, and that in vitro IL10RB overexpression is associated with increased viral load and activation of disease-relevant molecular pathways. Overall design: 3 samples each matching the following conditions/treatments (48 total): NPCs;CoV+;CRISPRa;IL10RB-1 gRNA NPCs;CoV+;CRISPRa;IL10RB-2 gRNA NPCs;CoV+;CRISPRa;IL10RB-3 gRNA NPCs;CoV+;CRISPRa;IL10RB-4 gRNA NPCs;CoV+;CRISPRa;Scramble gRNA NPCs;CoV+;shRNA;IFNAR2 shRNA NPCs;CoV+;shRNA;IL10RB shRNA NPCs;CoV+;shRNA;Scramble shRNA NPCs;CoV-;CRISPRa;IL10RB-1 gRNA NPCs;CoV-;CRISPRa;IL10RB-2 gRNA NPCs;CoV-;CRISPRa;IL10RB-3 gRNA NPCs;CoV-;CRISPRa;IL10RB-4 gRNA NPCs;CoV-;CRISPRa;Scramble gRNA NPCs;CoV-;shRNA;IFNAR2 shRNA NPCs;CoV-;shRNA;IL10RB shRNA NPCs;CoV-;shRNA;Scramble shRNA