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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited 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,

Published Date

  • April 2021

Published In

Volume / Issue

  • 27 / 4

Start / End Page

  • 668 - 676

PubMed ID

  • 33837377

Pubmed Central ID

  • PMC7612986

Electronic International Standard Serial Number (EISSN)

  • 1546-170X

Digital Object Identifier (DOI)

  • 10.1038/s41591-021-01310-z


  • eng

Conference Location

  • United States