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 (
ABCC2
,
ATRAID
,
BLK
,
CD93
,
CHST13
,
NR1H3
,
NRBP1
,
PI3
,
RIPK4
,
SEMG1
,
SLC22A4
,
SLC22A5
,
SLCO3A1
,
TEK
,
TLR4
, and
WNT10B
) demonstrated the causal associations with ordinal modified Rankin Scale (
P
<1.892×10
−5
) or poor functional outcome (modified Rankin Scale 3–6 versus 0–2,
P
<1.893×10
−5
). Steiger filtering analysis suggested potential directional stability (
P
<0.05). Colocalization analysis provided further support for the associations between genetically predicted expression of
ABCC2
,
NRBP1
,
PI3
, and
SEMG1
with functional outcome after ischemic stroke. Furthermore, phenome‐wide Mendelian randomization revealed additional beneficial indications and few potential safety concerns of therapeutics targeting
ABCC2
,
NRBP1
,
PI3
, and
SEMG1
, 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.