Proteome-wide Mendelian randomization and colocalization analysis identify therapeutic targets for stroke

Area of Science:

• Genetics
• Proteomics
• Neurology

Background:

• Stroke is a major global cause of death and disability with limited treatment options.
• Mendelian randomization (MR) is a valuable tool for identifying biomarkers and therapeutic targets.
• Identifying novel therapeutic targets for stroke remains a critical unmet medical need.

Purpose of the Study:

• To identify potential therapeutic targets for stroke within the human plasma proteome.
• To leverage Mendelian randomization to investigate causal relationships between plasma proteins and stroke.
• To validate identified proteins as drug targets using complementary methods.

Main Methods:

• A two-sample Mendelian randomization (MR) study was performed.
• Utilized data from the UK Biobank-Proteome-wide Association Study (UKB-PPP) and Icelandic cohorts.
• Employed Bayesian colocalization, Summary data-based Mendelian randomization (SMR), and protein-protein interaction (PPI) network analysis for validation.

Main Results:

• Eleven plasma proteins were found to be significantly associated with stroke or its subtypes.
• FURIN, F11, DDHD2, and VSIR were identified as potential drug targets for specific stroke types.
• FURIN is linked to stroke and cardiovascular diseases; F11 is in drug development; DDHD2 and VSIR have roles in synaptic plasticity and immune response, respectively.

Conclusions:

• Plasma proteins FURIN, F11, DDHD2, and VSIR represent promising therapeutic targets for stroke.
• Provides genetic evidence supporting precision medicine approaches for stroke drug development.
• Offers insights into the molecular mechanisms underlying stroke pathology.