Systematic Druggable Genome-Wide Mendelian Randomization Identifies Therapeutic Targets for Functional Outcome After Ischemic Stroke.

Background: Stroke is a leading cause of death worldwide, with a lack of effective treatments for improving the prognosis. The aim of the present study was to identify novel therapeutic targets for functional outcome after ischemic stroke .

Methods And Results: Cis-expression quantitative trait loci data for druggable genes were used as instrumental variables. The primary outcome was the modified Rankin Scale score at 3 months after ischemic stroke, evaluated as a dichotomous variable (3-6 versus 0-2) and also as an ordinal variable. Drug target Mendelian randomization, Steiger filtering analysis, and colocalization analysis were performed. Additionally, phenome-wide Mendelian randomization analysis was performed to identify the safety of the drug target genes at the genetic level. Among >2600 druggable genes, genetically predicted expression of 16 genes (, , , , , , , , , , , , , , , and ) demonstrated the causal associations with ordinal modified Rankin Scale (<1.892×10) or poor functional outcome (modified Rankin Scale 3-6 versus 0-2, <1.893×10). Steiger filtering analysis suggested potential directional stability (<0.05). Colocalization analysis provided further support for the associations between genetically predicted expression of , , , and with functional outcome after ischemic stroke. Furthermore, phenome-wide Mendelian randomization revealed additional beneficial indications and few potential safety concerns of therapeutics targeting , , , and , but the robustness of these results was limited by low power.

Conclusions: The present study revealed 4 candidate therapeutic targets for improving functional outcome after ischemic stroke, while the underlying mechanisms need further investigation.