@article{205fc1e0459d422997981be003d5244b,
title = "Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19",
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.",
author = "{VA Million Veteran Program COVID-19 Science Initiative} and Liam Gaziano and Claudia Giambartolomei and Pereira, {Alexandre C.} and Anna Gaulton and Posner, {Daniel C.} and Swanson, {Sonja A.} and Ho, {Yuk Lam} and Iyengar, {Sudha K.} and Kosik, {Nicole M.} and Marijana Vujkovic and Gagnon, {David R.} and Bento, {A. Patr{\'i}cia} and Inigo Barrio-Hernandez and Lars R{\"o}nnblom and Niklas Hagberg and Christian Lundtoft and Claudia Langenberg and Maik Pietzner and Dennis Valentine and Stefano Gustincich and Tartaglia, {Gian Gaetano} and Elias Allara and Praveen Surendran and Stephen Burgess and Zhao, {Jing Hua} and Peters, {James E.} and Prins, {Bram P.} and Angelantonio, {Emanuele Di} and Poornima Devineni and Yunling Shi and Lynch, {Kristine E.} and DuVall, {Scott L.} and Helene Garcon and Thomann, {Lauren O.} and Zhou, {Jin J.} and Gorman, {Bryan R.} and Huffman, {Jennifer E.} and O{\textquoteright}Donnell, {Christopher J.} and Tsao, {Philip S.} and Beckham, {Jean C.} and Saiju Pyarajan and Sumitra Muralidhar and Huang, {Grant D.} and Rachel Ramoni and Pedro Beltrao and John Danesh and Hung, {Adriana M.} and Chang, {Kyong Mi} and Sun, {Yan V.} and Jacob Joseph",
note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = apr,
doi = "10.1038/s41591-021-01310-z",
language = "English",
volume = "27",
pages = "668--676",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "4",
}