AUTHOR=Cárcel-Márquez Jara , Muiño Elena , Gallego-Fabrega Cristina , Cullell Natalia , Lledós Miquel , Llucià-Carol Laia , Sobrino Tomás , Campos Francisco , Castillo José , Freijo Marimar , Arenillas Juan Francisco , Obach Victor , Álvarez-Sabín José , Molina Carlos A. , Ribó Marc , Jiménez-Conde Jordi , Roquer Jaume , Muñoz-Narbona Lucia , Lopez-Cancio Elena , Millán Mònica , Diaz-Navarro Rosa , Vives-Bauza Cristòfol , Serrano-Heras Gemma , Segura Tomás , Ibañez Laura , Heitsch Laura , Delgado Pilar , Dhar Rajat , Krupinski Jerzy , Delgado-Mederos Raquel , Prats-Sánchez Luis , Camps-Renom Pol , Blay Natalia , Sumoy Lauro , de Cid Rafael , Montaner Joan , Cruchaga Carlos , Lee Jin-Moo , Martí-Fàbregas Joan , Férnandez-Cadenas Israel TITLE=A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke Subtype JOURNAL=Frontiers in Cardiovascular Medicine VOLUME=9 YEAR=2022 URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.940696 DOI=10.3389/fcvm.2022.940696 ISSN=2297-055X ABSTRACT=Background

Occult atrial fibrillation (AF) is one of the major causes of embolic stroke of undetermined source (ESUS). Knowing the underlying etiology of an ESUS will reduce stroke recurrence and/or unnecessary use of anticoagulants. Understanding cardioembolic strokes (CES), whose main cause is AF, will provide tools to select patients who would benefit from anticoagulants among those with ESUS or AF. We aimed to discover novel loci associated with CES and create a polygenetic risk score (PRS) for a more efficient CES risk stratification.

Methods

Multitrait analysis of GWAS (MTAG) was performed with MEGASTROKE-CES cohort (n = 362,661) and AF cohort (n = 1,030,836). We considered significant variants and replicated those variants with MTAG p-value < 5 × 10−8 influencing both traits (GWAS-pairwise) with a p-value < 0.05 in the original GWAS and in an independent cohort (n = 9,105). The PRS was created with PRSice-2 and evaluated in the independent cohort.

Results

We found and replicated eleven loci associated with CES. Eight were novel loci. Seven of them had been previously associated with AF, namely, CAV1, ESR2, GORAB, IGF1R, NEURL1, WIPF1, and ZEB2. KIAA1755 locus had never been associated with CES/AF, leading its index variant to a missense change (R1045W). The PRS generated has been significantly associated with CES improving discrimination and patient reclassification of a model with age, sex, and hypertension.

Conclusion

The loci found significantly associated with CES in the MTAG, together with the creation of a PRS that improves the predictive clinical models of CES, might help guide future clinical trials of anticoagulant therapy in patients with ESUS or AF.