Genetically determined platelet traits impact stroke risk through multiple mechanisms and cell types

Area of Science:

• Cardiovascular Science
• Genetics
• Hematology

Background:

• Stroke is a major global cause of death and disability.
• Current antiplatelet and anticoagulant therapies have limitations.
• The role of heritable blood and platelet traits in stroke risk is not fully understood.

Purpose of the Study:

• To identify causal blood-related cells and mechanisms influencing stroke risk.
• To determine the specific contribution of platelet traits to stroke pathogenesis.
• To explore genetic underpinnings of platelet traits in stroke.

Main Methods:

• Two-sample Mendelian Randomization (MR) was employed to assess causal relationships.
• Bayesian Model Averaging (MR-BMA) identified key blood traits associated with stroke.
• Noise-augmented directional clustering (NAvMix) analyzed genetic variants for platelet count.
• Pathway and colocalization analyses were performed on identified genetic loci.

Main Results:

• Increased platelet count and mean platelet volume were identified as significant risk factors for stroke.
• Two distinct clusters of platelet count variants strongly predicted increased stroke risk.
• Pathway analysis revealed enrichment for endothelial cell adhesion and platelet reactivity.
• Genes such as RIN3, PEX6, and PEX29 were implicated in stroke risk through platelet traits.

Conclusions:

• Platelet traits are critical determinants of stroke risk, surpassing other blood cell traits.
• Genetic variations influencing platelet count and reactivity play a key role in stroke pathogenesis.
• Novel MR methods combined with subclustering can elucidate complex causal mechanisms in related traits.