Author: ["Liam Gaziano","Claudia Giambartolomei","Alexandre C. Pereira","Anna Gaulton","Daniel C. Posner","Sonja A. Swanson","Yuk-Lam Ho","Sudha K. Iyengar","Nicole M. Kosik","Marijana Vujkovic","David R. Gagnon","A. Patrícia Bento","Inigo Barrio-Hernandez","Lars Rönnblom","Niklas Hagberg","Christian Lundtoft","Claudia Langenberg","Maik Pietzner","Dennis Valentine","Stefano Gustincich","Gian Gaetano Tartaglia","Elias Allara","Praveen Surendran","Stephen Burgess","Jing Hua Zhao","James E. Peters","Bram P. Prins","Emanuele Di Angelantonio","Poornima Devineni","Yunling Shi","Kristine E. Lynch","Scott L. DuVall","Helene Garcon","Lauren O. Thomann","Jin J. Zhou","Bryan R. Gorman","Jennifer E. Huffman","Christopher J. O’Donnell","Philip S. Tsao","Jean C. Beckham","Saiju Pyarajan","Sumitra Muralidhar","Grant D. Huang","Rachel Ramoni","Pedro Beltrao","John Danesh","Adriana M. Hung","Kyong-Mi Chang","Yan V. Sun","Jacob Joseph","Andrew R. Leach","Todd L. Edwards","Kelly Cho","J. Michael Gaziano","Adam S. Butterworth","Juan P. Casas"]
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Abstract
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.Cite this article
Gaziano, L., Giambartolomei, C., Pereira, A.C. et al. Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19. Nat Med (2021). https://doi.org/10.1038/s41591-021-01310-z 