TY - JOUR
T1 - Sex-Stratified Genome-Wide Association Study in the Spanish Population Identifies a Novel Locus for Lacunar Stroke
AU - Cárcel-Márquez, Jara
AU - Muiño, Elena
AU - Gallego-Fabrega, Cristina
AU - Cullell, Natalia
AU - Lledós, Miquel
AU - Llucià-Carol, Laia
AU - Martín-Campos, Jesús M.
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 - Prats-Sánchez, Luis
AU - Camps-Renom, Pol
AU - Guasch, Marina
AU - Ezcurra, Garbiñe
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 - Publisher Copyright:
© 2024 American Heart Association, Inc.
PY - 2024/10/1
Y1 - 2024/10/1
N2 - 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.
AB - 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.
KW - genome-wide association study
KW - genomics
KW - ischemic stroke
KW - Spain
KW - stroke
UR - http://www.scopus.com/inward/record.url?scp=85205084214&partnerID=8YFLogxK
U2 - 10.1161/STROKEAHA.124.047833
DO - 10.1161/STROKEAHA.124.047833
M3 - Article
C2 - 39315829
AN - SCOPUS:85205084214
SN - 0039-2499
VL - 55
SP - 2462
EP - 2471
JO - Stroke
JF - Stroke
IS - 10
ER -