Sex-Stratified Genome-Wide Association Study in the Spanish Population Identifies a Novel Locus for Lacunar Stroke

Jara Cárcel-Márquez¹, Elena Muiño^{1

2}, Cristina Gallego-Fabrega¹, Natalia Cullell^{1

3}, Miquel Lledós¹, Laia Llucià-Carol¹, Jesús M Martín-Campos¹, Tomás Sobrino⁴, Francisco Campos^{4

5}, José Castillo⁴, Marimar Freijo⁶, Juan Francisco Arenillas⁷, Victor Obach⁸, José Álvarez-Sabín⁹, Carlos A Molina⁹, Marc Ribó⁹, Jordi Jiménez-Conde¹⁰, Jaume Roquer¹⁰, Lucia Muñoz-Narbona¹¹, Elena Lopez-Cancio¹², Mònica Millán¹¹, Rosa Diaz-Navarro¹³, Cristòfol Vives-Bauza¹³, Gemma Serrano-Heras¹⁴, Tomás Segura¹⁴, Laura Ibañez^{15

16

17}, Laura Heitsch^{16

18}, Pilar Delgado¹⁹, Rajat Dhar¹⁶, Jerzy Krupinski²⁰, Luis Prats-Sánchez²¹, Pol Camps-Renom²¹, Marina Guasch²¹, Garbiñe Ezcurra²¹, Natalia Blay²², Lauro Sumoy²³, Rafael de Cid²², Joan Montaner²⁴, Carlos Cruchaga^{15

17}, Jin-Moo Lee¹⁶, Joan Martí-Fàbregas²¹, Israel Férnandez-Cadenas¹

Affiliations

¹ Stroke Pharmacogenomics and Genetics Group, Institut de Recerca Sant Pau, Barcelona, Spain (J.C.-M., E.M., C.G.-F., N.C., M.L., L.L.-C., J.M.M.-C., I.F.-C.).
² Epilepsy Unit (E.M.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
³ Stroke Pharmacogenomics and Genetics Laboratory, Fundación Docència I Recerca Mútua Terrassa, Hospital Mútua Terrassa, Spain (N.C.).
⁴ Clinical Neurosciences Research Laboratory, Health Research Institute of Santiago de Compostela (T. Sobrino, F.C., J.C.), La Coruña, Spain.
⁵ Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain (F.C.).
⁶ Biocruces-Bizkaia Health Research Institute, Department of Neurology, Bilbao, Spain (M.F.).
⁷ Stroke Unit, Department of Neurology, University Hospital of Valladolid, Spain (J.F.A.).
⁸ Department of Neurology, Hospital Clínic de Barcelona, IDIBAPS, Spain (V.O.).
⁹ Stroke Unit, Department of Neurology, Hospital Universitari Vall d'Hebron, Barcelona, Spain (J.A.-S., C.A.M., M.R.).
¹⁰ Department of Neurology, IMIM-Hospital del Mar; Neurovascular Research Group, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain (J.J.-C., J.R.).
¹¹ Department of Neurosciences, Hospital Germans Trias I Pujol (L.M.-N., M.M.), Universitat Autònoma de Barcelona, Spain.
¹² Departament of Neurology, University Hospital Central de Asturias, Spain (E.L.-C.).
¹³ Department of Neurology, Son Espases University Hospital, Illes Balears Health Research Institute, Spain (R.D.-N., C.V.-B.).
¹⁴ Department of Neurology, University Hospital of Albacete, Spain (G.S.-H., T. Segura).
¹⁵ Department of Psychiatry (L.I., C.C.), Washington University School of Medicine, St. Louis, MO.
¹⁶ Department of Neurology (L.I., L.H., R.D., J.-M.L.), Washington University School of Medicine, St. Louis, MO.
¹⁷ Neurogenomics and Informatics Center at Washington University in St. Louis, MO (L.I., C.C.).
¹⁸ Department of Emergency Medicine (L.H.), Washington University School of Medicine, St. Louis, MO.
¹⁹ Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (P.D.), Universitat Autònoma de Barcelona, Spain.
²⁰ Neurology Service, Hospital Universitari Mútua Terrassa, Spain (J.K.).
²¹ Stroke Unit (L.P.-S., P.C.-R., M.G., G.E., J.M.-F.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
²² GenomesForLife-GCAT Lab (N.B., R.d.C.), Germans Trias i Pujol Research Institute, Barcelona, Spain.
²³ High Content Genomics and Bioinformatics Unit (L.S.), Germans Trias i Pujol Research Institute, Barcelona, Spain.
²⁴ Institute de Biomedicine of Seville, IBiS/Hospital Universitario Virgen del Rocío/CSIC/University of Seville and Department of Neurology, Hospital Universitario Virgen Macarena, Spain (J.M.).

PMID: 39315829
PMCID: PMC12039539
DOI: 10.1161/STROKEAHA.124.047833

Sex-Stratified Genome-Wide Association Study in the Spanish Population Identifies a Novel Locus for Lacunar Stroke

Jara Cárcel-Márquez et al. Stroke. 2024 Oct.

. 2024 Oct;55(10):2462-2471.

doi: 10.1161/STROKEAHA.124.047833. Epub 2024 Sep 24.

Authors

Affiliations

¹ Stroke Pharmacogenomics and Genetics Group, Institut de Recerca Sant Pau, Barcelona, Spain (J.C.-M., E.M., C.G.-F., N.C., M.L., L.L.-C., J.M.M.-C., I.F.-C.).
² Epilepsy Unit (E.M.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
³ Stroke Pharmacogenomics and Genetics Laboratory, Fundación Docència I Recerca Mútua Terrassa, Hospital Mútua Terrassa, Spain (N.C.).
⁴ Clinical Neurosciences Research Laboratory, Health Research Institute of Santiago de Compostela (T. Sobrino, F.C., J.C.), La Coruña, Spain.
⁵ Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain (F.C.).
⁶ Biocruces-Bizkaia Health Research Institute, Department of Neurology, Bilbao, Spain (M.F.).
⁷ Stroke Unit, Department of Neurology, University Hospital of Valladolid, Spain (J.F.A.).
⁸ Department of Neurology, Hospital Clínic de Barcelona, IDIBAPS, Spain (V.O.).
⁹ Stroke Unit, Department of Neurology, Hospital Universitari Vall d'Hebron, Barcelona, Spain (J.A.-S., C.A.M., M.R.).
¹⁰ Department of Neurology, IMIM-Hospital del Mar; Neurovascular Research Group, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain (J.J.-C., J.R.).
¹¹ Department of Neurosciences, Hospital Germans Trias I Pujol (L.M.-N., M.M.), Universitat Autònoma de Barcelona, Spain.
¹² Departament of Neurology, University Hospital Central de Asturias, Spain (E.L.-C.).
¹³ Department of Neurology, Son Espases University Hospital, Illes Balears Health Research Institute, Spain (R.D.-N., C.V.-B.).
¹⁴ Department of Neurology, University Hospital of Albacete, Spain (G.S.-H., T. Segura).
¹⁵ Department of Psychiatry (L.I., C.C.), Washington University School of Medicine, St. Louis, MO.
¹⁶ Department of Neurology (L.I., L.H., R.D., J.-M.L.), Washington University School of Medicine, St. Louis, MO.
¹⁷ Neurogenomics and Informatics Center at Washington University in St. Louis, MO (L.I., C.C.).
¹⁸ Department of Emergency Medicine (L.H.), Washington University School of Medicine, St. Louis, MO.
¹⁹ Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (P.D.), Universitat Autònoma de Barcelona, Spain.
²⁰ Neurology Service, Hospital Universitari Mútua Terrassa, Spain (J.K.).
²¹ Stroke Unit (L.P.-S., P.C.-R., M.G., G.E., J.M.-F.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
²² GenomesForLife-GCAT Lab (N.B., R.d.C.), Germans Trias i Pujol Research Institute, Barcelona, Spain.
²³ High Content Genomics and Bioinformatics Unit (L.S.), Germans Trias i Pujol Research Institute, Barcelona, Spain.
²⁴ Institute de Biomedicine of Seville, IBiS/Hospital Universitario Virgen del Rocío/CSIC/University of Seville and Department of Neurology, Hospital Universitario Virgen Macarena, Spain (J.M.).

PMID: 39315829
PMCID: PMC12039539
DOI: 10.1161/STROKEAHA.124.047833

Abstract

Background: Ischemic stroke (IS) represents a significant health burden globally, necessitating a better understanding of its genetic underpinnings to improve prevention and treatment strategies. Despite advances in IS genetics, studies focusing on the Spanish population and sex-stratified analyses are lacking.

Methods: A case-control genome-wide association study was conducted with 9081 individuals (3493 IS cases and 5588 healthy controls). IS subtypes using Trial of ORG 10172 in Acute Stroke Treatment criteria were explored in a sex-stratified approach. Replication efforts involved the MEGASTROKE, GIGASTROKE, and the UK Biobank international cohorts. Post-genome-wide association study analysis included: in silico proteomic analysis, gene-based analysis, quantitative trait loci annotation, transcriptome-wide association analysis, and bioinformatic analysis using chromatin accessibility data.

Results: Identified as associated with IS and its subtypes were 4 significant and independent loci. Replication confirmed 5p15.2 as a new locus associated with small-vessel occlusion stroke, with rs59970332-T as the lead variant (beta [SE], 0.13 [0.02]; P=4.34×10^-8). Functional analyses revealed CTNND2 given proximity and its implication in pathways involved in vascular integrity and angiogenesis. Integration of Hi-C data identified additional potentially modulated genes, and in silico proteomic analysis suggested a distinctive blood proteome profile associated with the lead variant. Gene-set enrichment analyses highlighted pathways consistent with small-vessel disease pathogenesis. Gene-based associations with known stroke-related genes such as F2 and FGG were also observed, reinforcing the relevance of our findings.

Conclusions: We found CTNND2 as a potential key molecule in small-vessel occlusion stroke risk, and predominantly in males. This study sheds light on the genetic architecture of IS in the Spanish population, providing novel insights into sex-specific associations and potential molecular mechanisms. Further research, including replication in larger cohorts, is essential for a comprehensive understanding of these findings and for their translation to clinical practice.

Keywords: Spain; genome-wide association study; genomics; ischemic stroke; stroke.

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Conflict of interest statement

Dr Arenillas reports compensation from Medtronic, Daiichi Sankyo, Boehringer Ingelheim, and Pfizer for consultant services; grants from AstraZeneca, Instituto de Salud Carlos III, European Commission and Gerencia de Salud Castilla y León; compensation from Philips for data and safety monitoring services; travel support from Daiichi Sankyo Company. Dr Ribo reports stock holdings in Methinks, Nora, and Ancaonda Biomed; compensation from Cerenovus, Vesalio, Stryker Corporation, Philips, Rapid Pulse, AptaTargets, and Medtronic MiniMed Inc for consultant services; compensation from Sensome for data and safety monitoring services. Dr Heitsch reports employment by Washington University School of Medicine in St. Louis; reports funding from National Institutes of Health and American Heart Association. Dr Dhar reports grants from National Institute of Neurological Disorders and Stroke. The other authors report no conflicts.

Figures

**Figure 2.**
Panel A: Genomic context of locus 5p15.2 in locus-zoom plot. Panel B: Hi-C interaction of variant rs59970332.

See this image and copyright information in PMC

References

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Sex-Stratified Genome-Wide Association Study in the Spanish Population Identifies a Novel Locus for Lacunar Stroke

Affiliations

Sex-Stratified Genome-Wide Association Study in the Spanish Population Identifies a Novel Locus for Lacunar Stroke

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous