Investigating the causal relationship between genetically determined metabolites and ischemic stroke functional...

Area of Science:

• Genetics and Metabolomics
• Neurology and Stroke Research
• Biostatistics and Epidemiology

Background:

• Understanding metabolic influences on ischemic stroke functional outcomes is crucial for improving recovery.
• Mendelian randomization (MR) offers a robust approach to infer causal relationships by leveraging genetic variants.
• This study investigated the causal links between genetically determined metabolites and post-stroke functional recovery.

Purpose of the Study:

• To explore the causal relationships between genetically determined metabolites and functional recovery after ischemic stroke.
• To identify specific metabolites that influence long-term functional outcomes post-stroke.
• To provide a foundation for developing targeted, personalized treatment strategies.

Main Methods:

• A two-sample Mendelian randomization (MR) framework was employed.
• Genome-wide association study (GWAS) data from 6,165 stroke patients were analyzed.
• 1,400 metabolites were assessed, with instrumental variables (IVs) selected based on strong genetic associations (P<1×10^-6) and minimal pleiotropy.

Main Results:

• 59 metabolites demonstrated potentially causal relationships with ischemic stroke functional outcomes using the inverse-variance weighted (IVW) method.
• Metabolite X-17146 showed a significant protective causal effect (OR=0.48, P<0.001), remaining significant after FDR correction.
• Eight metabolites showed consistent causal relationships in both adjusted and baseline groups, with sensitivity analyses confirming robustness.

Conclusions:

• Specific metabolites causally impact functional recovery following ischemic stroke.
• Metabolite X-17146 presents a potential target for improving stroke recovery.
• Further validation in diverse populations and experimental models is recommended to enhance clinical applicability.