Georgios Voloudakis, James M. Vicari, Sanan Venkatesh, Gabriel E. Hoffman, Kristina Dobrindt, Wen Zhang, Noam D. Beckmann, Christina A. Higgins, Stathis Argyriou, Shan Jiang, Daisy Hoagland, Lina Gao, André Corvelo, Kelly Cho, Kyung Min Lee, Jiantao Bian, Jennifer S. Lee, Sudha K. Iyengar, Shiuh-Wen Luoh, Schahram Akbarian, Robert Striker, Themistocles L. Assimes, Eric E. Schadt, Julie A. Lynch, Miriam Merad, Benjamin R. tenOever, Alexander W. Charney, Mount Sinai COVID-19 Biobank, VA Million Veteran Program COVID-19 Science Initiative, Kristen J. Brennand, John F. Fullard & Panos Roussos
NPJ genomic medicine, 2022 7(1), 52. 05/09/2022
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 reduce 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 identified IL10RB as the top candidate gene target for COVID-19 host susceptibility. In a series of validation steps, we show that predicted GReX upregulation 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.