Genetic liability to frailty in relation to functional outcome after ischemic stroke

Background: Frailty appears to be associated with unfavorable prognosis after stroke in observational studies, but the causality remains largely unknown. Aims: The aim of this study is to investigate the potential causal effect of frailty on functional outcome at 3 months after ischemic stroke using the Mendelian randomization (MR) framework. Methods: Genetic instruments for frailty index were identified in a genome-wide association study meta-analysis including 175,226 individuals of European descent. Corresponding genetic association estimates for functional outcome after ischemic stroke at 90 days were taken from the Genetic of Ischemic Stroke Functional Outcome (GISCOME) network of 6021 patients. We performed inverse-variance weighted MR as the main analyses, followed by several alternate methods and sensitivity analyses. Results: In univariable MR, we found evidence that genetically predicted higher frailty index (odds ratio (OR) = 5.12; 95% confidence interval (CI) = 1.31–20.09; p = 0.019) was associated with worse functional outcome (modified Rankin Scale score ⩾3) after ischemic stroke. In further multivariable MR adjusting for potential confounding traits including body mass index, C-reactive protein, inflammatory bowel disease, and smoking initiation, the overall patterns between genetic liability to frailty and poor functional outcome status remained. Sensitivity analyses with complementary methods and with model unadjusted for baseline stroke severity (OR = 4.19; 95% CI = 1.26–13.90; p = 0.019) yielded broadly concordant results. Conclusions: The present MR study suggested a possible causal effect of frailty on poor functional outcome after ischemic stroke. Frailty might represent a potential target for intervention to improve recovery after ischemic stroke.