Exploring the causal association between genetically determined circulating metabolome and hemorrhagic stroke

Area of Science:

• Biomolecular mechanisms
• Metabolomics
• Neuroscience

Background:

• Hemorrhagic stroke (HS) is a major cause of death and disability globally.
• The underlying biomolecular mechanisms of HS development remain unclear.
• Circulating metabolites have recently shown associations with HS.

Purpose of the Study:

• To explore the causal association between circulating metabolomes and HS.
• To identify the molecular mechanisms underlying HS development.
• To investigate the potential of serum metabolites for HS management.

Main Methods:

• Utilized a bidirectional two-sample Mendelian randomization (MR) analysis.
• Employed five MR methods (weighted median, MR Egger, simple mode, weighted mode, MR-PRESSO) for robustness.
• Conducted sensitivity analyses using Cochran Q-test, MR-Egger intercept, and MR-PRESSO; assessed reverse causality with Steiger and reverse MR tests.

Main Results:

• Identified four metabolites with significant causal relationships to HS: biliverdin, linoleate (18:2n6), 1-eicosadienoylglycerophosphocholine, and 7-alpha-hydroxy-3-oxo-4-cholestenoate (7-Hoca).
• Provided odds ratios (OR) and confidence intervals (CI) for each significant metabolite, indicating varying degrees of association.
• Confirmed causal links through multivariate MR and metabolic pathway analyses.

Conclusions:

• Established significant causal associations between specific circulating serum metabolites and hemorrhagic stroke.
• Highlighted the potential value of serum metabolites for monitoring, diagnosing, and treating HS.
• Suggests a novel avenue for understanding and managing HS through metabolomic profiling.