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A polygenic risk score based on a cardioembolic stroke multitrait analysis improves a clinical prediction model for this stroke subtype

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dc.contributor.author Cárcel-Márquez, Jara
dc.contributor.author Jiménez Conde, Jordi
dc.contributor.author Roquer, Jaume
dc.contributor.author Fernández-Cadenas, Israel
dc.date.accessioned 2023-02-08T08:49:04Z
dc.date.available 2023-02-08T08:49:04Z
dc.date.issued 2022
dc.identifier.citation Cárcel-Márquez J, Muiño E, Gallego-Fabrega C, Cullell N, Lledós M, Llucià-Carol L, et al. A polygenic risk score based on a cardioembolic stroke multitrait analysis improves a clinical prediction model for this stroke subtype. Front Cardiovasc Med. 2022 Jul 8; 9: 940696. DOI: 10.3389/fcvm.2022.940696
dc.identifier.issn 2297-055X
dc.identifier.uri http://hdl.handle.net/10230/55676
dc.description.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.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Frontiers
dc.rights Copyright © 2022 Cárcel-Márquez, Muiño, Gallego-Fabrega, Cullell, Lledós, Llucià-Carol, Sobrino, Campos, Castillo, Freijo, Arenillas, Obach, Álvarez-Sabín, Molina, Ribó, Jiménez-Conde, Roquer, Muñoz-Narbona, Lopez-Cancio, Millán, Diaz-Navarro, Vives-Bauza, Serrano-Heras, Segura, Ibañez, Heitsch, Delgado, Dhar, Krupinski, Delgado-Mederos, Prats-Sánchez, Camps-Renom, Blay, Sumoy, de Cid, Montaner, Cruchaga, Lee, Martí-Fàbregas and Férnandez-Cadenas. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) http://creativecommons.org/licenses/by/4.0/. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title A polygenic risk score based on a cardioembolic stroke multitrait analysis improves a clinical prediction model for this stroke subtype
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.3389/fcvm.2022.940696
dc.subject.keyword ESUs
dc.subject.keyword GWAS
dc.subject.keyword Multi-trait analysis
dc.subject.keyword Polygenic risk score
dc.subject.keyword Stroke
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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