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

Nat Med. 2021 Apr;27(4):668-676. doi: 10.1038/s41591-021-01310-z. Epub 2021 Apr 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angiotensin-Converting Enzyme 2 / genetics
  • Angiotensin-Converting Enzyme 2 / physiology
  • COVID-19 / drug therapy
  • COVID-19 / genetics*
  • Drug Repositioning*
  • Genome-Wide Association Study
  • Humans
  • Interleukin-10 Receptor beta Subunit / genetics
  • Interleukin-10 Receptor beta Subunit / physiology
  • Mendelian Randomization Analysis / methods*
  • Quantitative Trait Loci
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / physiology
  • SARS-CoV-2*

Substances

  • IFNAR2 protein, human
  • IL10RB protein, human
  • Interleukin-10 Receptor beta Subunit
  • Receptor, Interferon alpha-beta
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2