Journal Article

Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19

Valentine, Dennis, Tsao, Philip S., Beckham, Jean C., Gaziano, Liam, Tartaglia, Gian Gaetano, Angelantonio, Emanuele Di, Lundtoft, Christian, Chang, Kyong-Mi, Ho, Yuk-Lam, Casas, Juan P., Gustincich, Stefano, Cho, Kelly, Giambartolomei, Claudia, Vujkovic, Marijana, Zhou, Jin J., Gagnon, David R., Ramoni, Rachel, Zhao, Jing Hua, Peters, James E., Leach, Andrew R., Hagberg, Niklas, Huffman, Jennifer E., Pereira, Alexandre C., Beltrao, Pedro, O’Donnell, Christopher J., Thomann, Lauren O., Surendran, Praveen, Kosik, Nicole M., Garcon, Helene, Burgess, Stephen, Posner, Daniel C., DuVall, Scott L., Joseph, Jacob, Barrio-Hernandez, Inigo, Iyengar, Sudha K., Allara, Elias, Huang, Grant D., Langenberg, Claudia, Sun, Yan V., Gorman, Bryan R., Danesh, John, Butterworth, Adam S., Shi, Yunling, Bento, A. Patrícia, Hung, Adriana M., Gaulton, Anna, Devineni, Poornima, Swanson, Sonja A., Lynch, Kristine E., Pyarajan, Saiju, Muralidhar, Sumitra, Gaziano, J. Michael, Pietzner, Maik, Rönnblom, Lars, Edwards, Todd L., Prins, Bram P.

2021

Overview

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P  = 1.6 × 10 −6 ; IFNAR2, P  = 9.8 × 10 −11 and IL-10RB, P  = 2.3 × 10 −14 ) using cis -expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2 , we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19. Large-scale Mendelian randomization and colocalization analyses using gene expression and soluble protein data for 1,263 actionable druggable genes, which encode protein targets for approved drugs or drugs in clinical development, identify IFNAR2 and ACE2 as the most promising therapeutic targets for early management of COVID-19.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 692/308/174 / 692/308/2056 / Angiotensin-Converting Enzyme 2 - genetics / Angiotensin-Converting Enzyme 2 - physiology / Biomedical and Life Sciences / Biomedicine / Cancer Research / Clinical trials / Coronaviruses / COVID-19 / COVID-19 - genetics / COVID-19 Drug Treatment / Drug delivery / Drug development / Drug Repositioning / Drugs / Gene expression / Gene mapping / Genetic analysis / Genetics / Genome-Wide Association Study / Genomes / Humans / Infectious Diseases / Interleukin 1 / Interleukin-10 Receptor beta Subunit - genetics / Interleukin-10 Receptor beta Subunit - physiology / Mendelian Randomization Analysis - methods / Metabolic Diseases / Molecular Medicine / Neurosciences / Proteins / Proteomics / Quantitative Trait Loci / Randomization / Receptor, Interferon alpha-beta - genetics / Receptor, Interferon alpha-beta - physiology / SARS-CoV-2 / Statistical analysis / Target recognition / Therapeutic applications / Therapeutic targets