A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for...

Area of Science:

• Genetics
• Cardiology
• Neurology

Background:

• Occult atrial fibrillation (AF) is a primary cause of embolic stroke of undetermined source (ESUS).
• Identifying the etiology of ESUS is crucial for reducing stroke recurrence and optimizing anticoagulant therapy.
• Understanding cardioembolic strokes (CES) aids in selecting patients who benefit from anticoagulants.

Purpose of the Study:

• To discover novel genetic loci associated with CES.
• To develop a polygenic risk score (PRS) for improved CES risk stratification.
• To identify genetic markers for patients with ESUS or AF who may benefit from anticoagulation.

Main Methods:

• Multitrait analysis of GWAS (MTAG) was conducted using large cohorts for CES and AF.
• Significant variants influencing both traits were identified and replicated in an independent cohort.
• A PRS was constructed using PRSice-2 and validated for CES prediction.

Main Results:

• Eleven loci associated with CES were identified and replicated, with eight being novel.
• Seven novel loci (CAV1, ESR2, GORAB, IGF1R, NEURL1, WIPF1, ZEB2) were previously linked to AF.
• A novel locus, KIAA1755, was associated with CES/AF, featuring a missense variant (R1045W).
• The developed PRS significantly improved CES prediction and patient reclassification in clinical models.

Conclusions:

• The identified genetic loci and PRS can aid in guiding future clinical trials for anticoagulant therapy in ESUS and AF patients.
• This genetic approach may enhance the precision of identifying patients who would benefit from anticoagulation.