Actionable druggable genome-wide Mendelian randomization identifies repurposingopportunities for COVID-19
By
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,
Pedro Beltrao,
Inigo Barrio-Hernandez,
Lars Rönnblom,
Niklas Hagberg,
Christian Lundtoft,
Claudia Langenberg,
Maik Pietzner,
Dennis Valentine,
Elias Allara,
Praveen Surendran,
Stephen Burgess,
Jing Hua Zhao,
James E. Peters,
Bram P. Prins,
John Danesh,
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,
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,
on behalf VA Million Veteran Program COVID-19 Science Initiative
Posted 23 Nov 2020
medRxiv DOI: 10.1101/2020.11.19.20234120
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 (MR) 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=1.6x10-6, IFNAR2: P=9.8x10-11, and IL-10RB: P=1.9x10-14) using cis-eQTL genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared eQTL 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.
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