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

Area of Science:

• Genetics
• Pharmacology
• Infectious Diseases

Background:

• Drug repurposing is crucial for rapid COVID-19 therapeutic development.
• Identifying host genetic factors influencing COVID-19 severity is key to finding new treatments.

Purpose of the Study:

• To identify actionable therapeutic targets for COVID-19 using genetic data.
• To prioritize drug targets by analyzing proteins with existing drug candidates.

Main Methods:

• Mendelian randomization analysis was performed on genetic data from over a million individuals.
• Genetic instruments were derived from transcriptomic and proteomic data for 1,263 drug-targeted proteins.
• Colocalization analysis was used to assess the association of genetic variants with COVID-19 hospitalization.

Main Results:

• Significant associations were found for ACE2, IFNAR2, and IL-10RB with COVID-19 hospitalization.
• IFNAR2 showed a stronger association with COVID-19 hospitalization compared to IL-10RB after further analysis.
• Genetic evidence supported ACE2 and IFNAR2 as key targets.

Conclusions:

• ACE2 and IFNAR2 are prioritized as therapeutic targets for early COVID-19 management.
• Drug repurposing efforts should focus on agents targeting ACE2 and IFNAR2.
• Genetic association studies can effectively guide the discovery of novel therapeutic strategies for infectious diseases.