TY - JOUR
T1 - A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke Subtype
AU - GeneStroke Consortium and International Stroke Genetics Consortium
AU - Cárcel-Márquez, Jara
AU - Muiño, Elena
AU - Gallego-Fabrega, Cristina
AU - Cullell, Natalia
AU - Lledós, Miquel
AU - Llucià-Carol, Laia
AU - Sobrino, Tomás
AU - Campos, Francisco
AU - Castillo, José
AU - Freijo, Marimar
AU - Arenillas, Juan Francisco
AU - Obach, Victor
AU - Álvarez-Sabín, José
AU - Molina, Carlos A.
AU - Ribó, Marc
AU - Jiménez-Conde, Jordi
AU - Roquer, Jaume
AU - Muñoz-Narbona, Lucia
AU - Lopez-Cancio, Elena
AU - Millán, Mònica
AU - Diaz-Navarro, Rosa
AU - Vives-Bauza, Cristòfol
AU - Serrano-Heras, Gemma
AU - Segura, Tomás
AU - Ibañez, Laura
AU - Heitsch, Laura
AU - Delgado, Pilar
AU - Dhar, Rajat
AU - Krupinski, Jerzy
AU - Delgado-Mederos, Raquel
AU - Prats-Sánchez, Luis
AU - Camps-Renom, Pol
AU - Blay, Natalia
AU - Sumoy, Lauro
AU - de Cid, Rafael
AU - Montaner, Joan
AU - Cruchaga, Carlos
AU - Lee, Jin Moo
AU - Martí-Fàbregas, Joan
AU - Férnandez-Cadenas, Israel
N1 - Funding Information:
The Genotype-Tissue Expression (GTEx) Project was funded by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 03/30/20. This study uses data generated by the GCAT, Genomes for Life. Cohort study of the Genomes of Catalonia, IGTP. A full list of the investigators who contributed to the generation of the data is available from http://www.genomesforlife.com/. IGTP is part of the CERCA Program/Generalitat de Catalunya. This study was carried out using anonymized data provided by the Catalan Agency for Quality and Health Assessment, within the framework of the PADRIS Program.
Funding Information:
J. Cárcel-Márquez has received funding through an AGAUR Contract (Agència de Gestió d'Ajuts Universitaris i de Recerca; FI_DGR 2019, grant number 2020FI_B1 00157) co-financed with Fons Social Europeu (FSE) ( https://agaur.gencat.cat ). From Instituto de Salud Carlos III: E. Muiño is funded by a Río Hortega Contract (CM18/00198), M. Lledós is funded by a PFIS Contract (Contratos Predoctorales de Formación en Investigación en Salud, FI19/00309), C. Gallego-Fabrega is supported by a Sara Borrell Contract (CD20/00043) and Fondo Europeo de Desarrollo Regional (ISCIII-FEDER), T. Sobrino (CPII17/00027), and F. Campos (CPII19/00020) are recipients of research contracts from the Miguel Servet Program ( https://www.isciii.es ). This study has been funded by Instituto de Salud Carlos III PI15/01978, PI17/02089, PI18-01338, and RICORS-ICTUS RD21/0006/0006 (Instituto de Salud Carlos III), by Marató TV3 support of the Epigenesis study ( https://www.ccma.cat/tv3/marato/ ), by the Fundació Docència i Recerca FMT grant for the Epigenesis project ( https://www.mutuaterrassa.com ), by Eranet-Neuron of the Ibiostroke project (AC19/00106) ( https://www.neuron-eranet.eu ), by Boehringer Ingelheim of the SEDMAN Study ( https://www.boehringer-ingelheim.it ), and GCAT Cession Research Project PI-2018-01 ( http://www.gcatbiobank.org ). GCAT was funded by Acción de Dinamización del ISCIII-MINECO and the Ministry of Health of the Generalitat of Catalunya (ADE 10/00026); and have additional suport by the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR 529).
Funding Information:
The Genotype-Tissue Expression (GTEx) Project was funded by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 03/30/20. This study uses data generated by the GCAT, Genomes for Life. Cohort study of the Genomes of Catalonia, IGTP. A full list of the investigators who contributed to the generation of the data is available from http://www.genomesforlife.com/ . IGTP is part of the CERCA Program/Generalitat de Catalunya. This study was carried out using anonymized data provided by the Catalan Agency for Quality and Health Assessment, within the framework of the PADRIS Program.
Publisher Copyright:
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.
PY - 2022/7/8
Y1 - 2022/7/8
N2 - 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.
AB - 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.
KW - ESUs
KW - GWAS
KW - multi-trait analysis
KW - polygenic risk score
KW - stroke
UR - http://www.scopus.com/inward/record.url?scp=85134625578&partnerID=8YFLogxK
U2 - 10.3389/fcvm.2022.940696
DO - 10.3389/fcvm.2022.940696
M3 - Article
C2 - 35872910
AN - SCOPUS:85134625578
SN - 2297-055X
VL - 9
JO - Frontiers in Cardiovascular Medicine
JF - Frontiers in Cardiovascular Medicine
M1 - 940696
ER -