A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke Subtype
BackgroundOccult 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,...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2022.940696/full |
| _version_ | 1818535853988773888 |
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| author | Jara Cárcel-Márquez Jara Cárcel-Márquez Elena Muiño Cristina Gallego-Fabrega Cristina Gallego-Fabrega Natalia Cullell Natalia Cullell Miquel Lledós Laia Llucià-Carol Laia Llucià-Carol Tomás Sobrino Francisco Campos José Castillo Marimar Freijo Juan Francisco Arenillas Victor Obach José Álvarez-Sabín Carlos A. Molina Marc Ribó Jordi Jiménez-Conde Jaume Roquer Lucia Muñoz-Narbona Elena Lopez-Cancio Mònica Millán Rosa Diaz-Navarro Cristòfol Vives-Bauza Gemma Serrano-Heras Tomás Segura Laura Ibañez Laura Heitsch Laura Heitsch Pilar Delgado Rajat Dhar Jerzy Krupinski Raquel Delgado-Mederos Luis Prats-Sánchez Pol Camps-Renom Natalia Blay Lauro Sumoy Rafael de Cid Joan Montaner Carlos Cruchaga Carlos Cruchaga Jin-Moo Lee Joan Martí-Fàbregas Israel Férnandez-Cadenas |
| author_facet | Jara Cárcel-Márquez Jara Cárcel-Márquez Elena Muiño Cristina Gallego-Fabrega Cristina Gallego-Fabrega Natalia Cullell Natalia Cullell Miquel Lledós Laia Llucià-Carol Laia Llucià-Carol Tomás Sobrino Francisco Campos José Castillo Marimar Freijo Juan Francisco Arenillas Victor Obach José Álvarez-Sabín Carlos A. Molina Marc Ribó Jordi Jiménez-Conde Jaume Roquer Lucia Muñoz-Narbona Elena Lopez-Cancio Mònica Millán Rosa Diaz-Navarro Cristòfol Vives-Bauza Gemma Serrano-Heras Tomás Segura Laura Ibañez Laura Heitsch Laura Heitsch Pilar Delgado Rajat Dhar Jerzy Krupinski Raquel Delgado-Mederos Luis Prats-Sánchez Pol Camps-Renom Natalia Blay Lauro Sumoy Rafael de Cid Joan Montaner Carlos Cruchaga Carlos Cruchaga Jin-Moo Lee Joan Martí-Fàbregas Israel Férnandez-Cadenas |
| author_sort | Jara Cárcel-Márquez |
| collection | DOAJ |
| description | BackgroundOccult 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.MethodsMultitrait 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.ResultsWe 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.ConclusionThe 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. |
| first_indexed | 2024-12-11T18:30:28Z |
| format | Article |
| id | doaj.art-59cc2ac670ff4756af4144e6cde2a58a |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-12-11T18:30:28Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-59cc2ac670ff4756af4144e6cde2a58a2022-12-22T00:54:56ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2022-07-01910.3389/fcvm.2022.940696940696A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke SubtypeJara Cárcel-Márquez0Jara Cárcel-Márquez1Elena Muiño2Cristina Gallego-Fabrega3Cristina Gallego-Fabrega4Natalia Cullell5Natalia Cullell6Miquel Lledós7Laia Llucià-Carol8Laia Llucià-Carol9Tomás Sobrino10Francisco Campos11José Castillo12Marimar Freijo13Juan Francisco Arenillas14Victor Obach15José Álvarez-Sabín16Carlos A. Molina17Marc Ribó18Jordi Jiménez-Conde19Jaume Roquer20Lucia Muñoz-Narbona21Elena Lopez-Cancio22Mònica Millán23Rosa Diaz-Navarro24Cristòfol Vives-Bauza25Gemma Serrano-Heras26Tomás Segura27Laura Ibañez28Laura Heitsch29Laura Heitsch30Pilar Delgado31Rajat Dhar32Jerzy Krupinski33Raquel Delgado-Mederos34Luis Prats-Sánchez35Pol Camps-Renom36Natalia Blay37Lauro Sumoy38Rafael de Cid39Joan Montaner40Carlos Cruchaga41Carlos Cruchaga42Jin-Moo Lee43Joan Martí-Fàbregas44Israel Férnandez-Cadenas45Stroke Pharmacogenomics and Genetics Group, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, SpainDepartament de Medicina, Universitat Autònoma de Barcelona, Barcelona, SpainStroke Pharmacogenomics and Genetics Group, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, SpainStroke Pharmacogenomics and Genetics Group, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, SpainStroke Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, SpainStroke Pharmacogenomics and Genetics Group, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, SpainStroke Pharmacogenomics and Genetics Laboratory, Fundación Docència i Recerca Mútua Terrassa, Hospital Mútua Terrassa, Terrassa, SpainStroke Pharmacogenomics and Genetics Group, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, SpainStroke Pharmacogenomics and Genetics Group, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, SpainDepartment de Genética i de Microbiologia, Universitat Autónoma de Barcelona, Barcelona, SpainClinical Neurosciences Research Laboratory, Hospital Clínico Universitario de Santiago de Compostela, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, SpainClinical Neurosciences Research Laboratory, Hospital Clínico Universitario de Santiago de Compostela, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, SpainClinical Neurosciences Research Laboratory, Hospital Clínico Universitario de Santiago de Compostela, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, SpainDepartment of Neurology, Biocruces-Bizkaia Health Research Institute, Bilbao, SpainStroke Unit, Department of Neurology, University Hospital of Valladolid, Valladolid, SpainDepartment of Neurology, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain0Stroke Unit, Department of Neurology, Hospital Universitari Vall d'Hebron, Barcelona, Spain0Stroke Unit, Department of Neurology, Hospital Universitari Vall d'Hebron, Barcelona, Spain0Stroke Unit, Department of Neurology, Hospital Universitari Vall d'Hebron, Barcelona, Spain1Department of Neurology, IMIM-Hospital del Mar; Neurovascular Research Group, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain1Department of Neurology, IMIM-Hospital del Mar; Neurovascular Research Group, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain2Department of Neurosciences, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain3Department of Neurology, University Hospital Central de Asturias (HUCA).Oviedo, Spain2Department of Neurosciences, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain4Department of Neurology, Son Espases University Hospital, Illes Balears Health Research Institute (IdISBa), Palma, Spain4Department of Neurology, Son Espases University Hospital, Illes Balears Health Research Institute (IdISBa), Palma, Spain5Department of Neurology, University Hospital of Albacete, Albacete, Spain5Department of Neurology, University Hospital of Albacete, Albacete, Spain6Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States7Department of Emergency Medicine, Washington University School of Medicine, Saint Louis, MO, United States8Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States9Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Barcelona, Spain8Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States0Neurology Service, Hospital Universitari Mútua Terrassa, Terrassa, SpainStroke Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, SpainStroke Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, SpainStroke Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain1GenomesForLife-GCAT Lab, Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain2High Content Genomics and Bioinformatics Unit, Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain1GenomesForLife-GCAT Lab, Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain3Institute de Biomedicine of Seville, IBiS/Hospital Universitario Virgen del Rocío/CSIC/University of Seville and Department of Neurology, Hospital Universitario Virgen Macarena, Seville, Spain6Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States4Neurogenomics and Informatics Center at Washington University in St. Louis, Saint Louis, MO, United States8Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United StatesStroke Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, SpainStroke Pharmacogenomics and Genetics Group, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, SpainBackgroundOccult 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.MethodsMultitrait 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.ResultsWe 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.ConclusionThe 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.https://www.frontiersin.org/articles/10.3389/fcvm.2022.940696/fullpolygenic risk scoreGWASmulti-trait analysisstrokeESUs |
| spellingShingle | Jara Cárcel-Márquez Jara Cárcel-Márquez Elena Muiño Cristina Gallego-Fabrega Cristina Gallego-Fabrega Natalia Cullell Natalia Cullell Miquel Lledós Laia Llucià-Carol Laia Llucià-Carol Tomás Sobrino Francisco Campos José Castillo Marimar Freijo Juan Francisco Arenillas Victor Obach José Álvarez-Sabín Carlos A. Molina Marc Ribó Jordi Jiménez-Conde Jaume Roquer Lucia Muñoz-Narbona Elena Lopez-Cancio Mònica Millán Rosa Diaz-Navarro Cristòfol Vives-Bauza Gemma Serrano-Heras Tomás Segura Laura Ibañez Laura Heitsch Laura Heitsch Pilar Delgado Rajat Dhar Jerzy Krupinski Raquel Delgado-Mederos Luis Prats-Sánchez Pol Camps-Renom Natalia Blay Lauro Sumoy Rafael de Cid Joan Montaner Carlos Cruchaga Carlos Cruchaga Jin-Moo Lee Joan Martí-Fàbregas Israel Férnandez-Cadenas A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke Subtype Frontiers in Cardiovascular Medicine polygenic risk score GWAS multi-trait analysis stroke ESUs |
| title | A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke Subtype |
| title_full | A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke Subtype |
| title_fullStr | A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke Subtype |
| title_full_unstemmed | A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke Subtype |
| title_short | A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke Subtype |
| title_sort | polygenic risk score based on a cardioembolic stroke multitrait analysis improves a clinical prediction model for this stroke subtype |
| topic | polygenic risk score GWAS multi-trait analysis stroke ESUs |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2022.940696/full |
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polygenicriskscorebasedonacardioembolicstrokemultitraitanalysisimprovesaclinicalpredictionmodelforthisstrokesubtype AT rafaeldecid polygenicriskscorebasedonacardioembolicstrokemultitraitanalysisimprovesaclinicalpredictionmodelforthisstrokesubtype AT joanmontaner polygenicriskscorebasedonacardioembolicstrokemultitraitanalysisimprovesaclinicalpredictionmodelforthisstrokesubtype AT carloscruchaga polygenicriskscorebasedonacardioembolicstrokemultitraitanalysisimprovesaclinicalpredictionmodelforthisstrokesubtype AT carloscruchaga polygenicriskscorebasedonacardioembolicstrokemultitraitanalysisimprovesaclinicalpredictionmodelforthisstrokesubtype AT jinmoolee polygenicriskscorebasedonacardioembolicstrokemultitraitanalysisimprovesaclinicalpredictionmodelforthisstrokesubtype AT joanmartifabregas polygenicriskscorebasedonacardioembolicstrokemultitraitanalysisimprovesaclinicalpredictionmodelforthisstrokesubtype AT israelfernandezcadenas polygenicriskscorebasedonacardioembolicstrokemultitraitanalysisimprovesaclinicalpredictionmodelforthisstrokesubtype |