{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T08:00:33Z","timestamp":1769932833728,"version":"3.49.0"},"reference-count":60,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              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];\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =4.34\u00d710\n              <jats:sup>\u22128<\/jats:sup>\n              ). Functional analyses revealed\n              <jats:italic toggle=\"yes\">CTNND2<\/jats:italic>\n              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\n              <jats:italic toggle=\"yes\">F2<\/jats:italic>\n              and\n              <jats:italic toggle=\"yes\">FGG<\/jats:italic>\n              were also observed, reinforcing the relevance of our findings.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>\n              We found\n              <jats:italic toggle=\"yes\">CTNND2<\/jats:italic>\n              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.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/strokeaha.124.047833","type":"journal-article","created":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T13:03:45Z","timestamp":1727183025000},"page":"2462-2471","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Sex-Stratified Genome-Wide Association Study in the Spanish Population Identifies a Novel Locus for Lacunar Stroke"],"prefix":"10.1161","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6949-0699","authenticated-orcid":true,"given":"Jara","family":"C\u00e1rcel-M\u00e1rquez","sequence":"first","affiliation":[{"name":"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.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5839-7328","authenticated-orcid":true,"given":"Elena","family":"Mui\u00f1o","sequence":"additional","affiliation":[{"name":"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.)."},{"name":"Epilepsy Unit (E.M.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3229-5512","authenticated-orcid":true,"given":"Cristina","family":"Gallego-Fabrega","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5118-1014","authenticated-orcid":true,"given":"Natalia","family":"Cullell","sequence":"additional","affiliation":[{"name":"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.)."},{"name":"Stroke Pharmacogenomics and Genetics Laboratory, Fundaci\u00f3n Doc\u00e8ncia I Recerca M\u00fatua Terrassa, Hospital M\u00fatua Terrassa, Spain (N.C.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8832-789X","authenticated-orcid":true,"given":"Miquel","family":"Lled\u00f3s","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7732-0665","authenticated-orcid":true,"given":"Laia","family":"Lluci\u00e0-Carol","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0414-037X","authenticated-orcid":true,"given":"Jes\u00fas M.","family":"Mart\u00edn-Campos","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9760-8690","authenticated-orcid":true,"given":"Tom\u00e1s","family":"Sobrino","sequence":"additional","affiliation":[{"name":"Clinical Neurosciences Research Laboratory, Health Research Institute of Santiago de Compostela (T. 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