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

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Title: Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19
Authors: Gaziano, L
Giambartolomei, C
Pereira, AC
Gaulton, A
Posner, DC
Swanson, SA
Ho, Y-L
Iyengar, SK
Kosik, NM
Vujkovic, M
Gagnon, DR
Bento, AP
Barrio-Hernandez, I
Rönnblom, L
Hagberg, N
Lundtoft, C
Langenberg, C
Pietzner, M
Valentine, D
Gustincich, S
Tartaglia, GG
Allara, E
Surendran, P
Burgess, S
Zhao, JH
Peters, JE
Prins, BP
Angelantonio, ED
Devineni, P
Shi, Y
Lynch, KE
DuVall, SL
Garcon, H
Thomann, LO
Zhou, JJ
Gorman, BR
Huffman, JE
O'Donnell, CJ
Tsao, PS
Beckham, JC
Pyarajan, S
Muralidhar, S
Huang, GD
Ramoni, R
Beltrao, P
Danesh, J
Hung, AM
Chang, K-M
Sun, YV
Joseph, J
Leach, AR
Edwards, TL
Cho, K
Gaziano, JM
Butterworth, AS
Casas, JP
VA Million Veteran Program COVID-19 Science Initiative
Item Type: Journal Article
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.
Issue Date: 9-Apr-2021
Date of Acceptance: 5-Mar-2021
URI: http://hdl.handle.net/10044/1/87573
DOI: 10.1038/s41591-021-01310-z
ISSN: 1078-8956
Publisher: Nature Research
Start Page: 668
End Page: 676
Journal / Book Title: Nature Medicine
Volume: 27
Issue: 4
Copyright Statement: © The Author(s), under exclusive licence to Springer Nature America, Inc. 2021. The final publication is available at Springer via https://doi.org/10.1038/s41591-021-01310-z
Sponsor/Funder: Medical Research Council (MRC)
Funder's Grant Number: MR/S004068/2
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
Medicine, Research & Experimental
Research & Experimental Medicine
VA Million Veteran Program COVID-19 Science Initiative
Quantitative Trait Loci
Receptor, Interferon alpha-beta
Interleukin-10 Receptor beta Subunit
Genome-Wide Association Study
Mendelian Randomization Analysis
Drug Repositioning
Angiotensin-Converting Enzyme 2
11 Medical and Health Sciences
Publication Status: Published
Conference Place: United States
Online Publication Date: 2021-04-09
Appears in Collections:Department of Immunology and Inflammation
Faculty of Medicine
Imperial College London COVID-19