TY - JOUR
T1 - A translational genomics approach identifies IL10RB as the top candidate gene target for COVID-19 susceptibility
AU - VA Million Veteran Program COVID-19 Science Initiative
AU - Mount Sinai COVID-19 Biobank
AU - Voloudakis, Georgios
AU - Vicari, James M.
AU - Venkatesh, Sanan
AU - Hoffman, Gabriel E.
AU - Dobrindt, Kristina
AU - Zhang, Wen
AU - Beckmann, Noam D.
AU - Higgins, Christina A.
AU - Argyriou, Stathis
AU - Jiang, Shan
AU - Hoagland, Daisy
AU - Gao, Lina
AU - Corvelo, André
AU - Cho, Kelly
AU - Lee, Kyung Min
AU - Bian, Jiantao
AU - Lee, Jennifer S.
AU - Iyengar, Sudha K.
AU - Luoh, Shiuh Wen
AU - Akbarian, Schahram
AU - Striker, Robert
AU - Assimes, Themistocles L.
AU - Schadt, Eric E.
AU - Lynch, Julie A.
AU - Merad, Miriam
AU - tenOever, Benjamin R.
AU - Charney, Alexander W.
AU - Brennand, Kristen J.
AU - Fullard, John F.
AU - Roussos, Panos
N1 - Funding Information:
We would like to thank Chris Chatzinakos and Nikolaos P. Daskalakis for providing valuable feedback on their JEPEGMIX2-P method and software. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by award #MVP035. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. This study was also supported by the National Institutes of Health (NIH), Bethesda, MD under award numbers K08MH122911 (Georgios Voloudakis), R01AG050986, R01AG065582, R01AG067025, U01MH116442, R01MH109677 (Panos Roussos), and by the Veterans Affairs Merit grants BX002395 and BX004189 (Panos Roussos). This study has also been funded in part by the Brain & Behavior Research Foundation via the 2020 NARSAD Young Investigator Grant #29350 (Georgios Voloudakis) and the Icahn School of Medicine at Mount Sinai via a COVID-19 Pilot Grant (Schahram Akbarian, Benjamin R. tenOever, Kristen J. Brennand).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41525-022-00324-x
DO - 10.1038/s41525-022-00324-x
M3 - Article
AN - SCOPUS:85137685301
SN - 2056-7944
VL - 7
JO - npj Genomic Medicine
JF - npj Genomic Medicine
IS - 1
M1 - 52
ER -