Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

• Published in: Nature genetics Vol. 50; no. 4; pp. 524 - 537
• Main Authors: Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Giese, Anne-Katrin, van der Laan, Sander W., Gretarsdottir, Solveig, Anderson, Christopher D., Almgren, Peter, Amouyel, Philippe, Bartz, Traci M., Benavente, Oscar R., Boncoraglio, Giorgio B., Butterworth, Adam S., Carrera, Caty, Chasman, Daniel I., Cotlarciuc, Ioana, Cruchaga, Carlos, de Bakker, Paul I. W., Duan, Qing, Gottesman, Rebecca F., Harris, Tamara B., Hassan, Ahamad, Havulinna, Aki S., Heckbert, Susan R., Hyacinth, Hyacinth I., Ikram, M. Arfan, Ingelsson, Erik, Jian, Xueqiu, Jukema, J. Wouter, Kanai, Masahiro, Keene, Keith L., Kissela, Brett M., Kleindorfer, Dawn O., Kooperberg, Charles, Lange, Leslie A., Langenberg, Claudia, Launer, Lenore J., Lemmens, Robin, Lewis, Cathryn M., Lin, Wei-Yu, Lorentzen, Erik, Magnusson, Patrik K., Meschia, James F., Mitchell, Braxton D., Mosley, Thomas H., Nalls, Michael A., O’Donnell, Martin J., Pulit, Sara L., Reiner, Alexander P., Ridker, Paul M., Rothwell, Peter M., Rotter, Jerome I., Sale, Michele M., Salomaa, Veikko, Sapkota, Bishwa R., Schmidt, Reinhold, Schmidt, Carsten O., Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie L. M., Tanislav, Christian, Thijs, Vincent N. S., Thorsteinsdottir, Unnur, Tiedt, Steffen, Trompet, Stella, Wareham, Nicholas J., Wassertheil-Smoller, Sylvia, Wilson, James G., Pastinen, Tomi, Ruusalepp, Arno, Koplev, Simon, Björkegren, Johan L. M., Codoni, Veronica, Civelek, Mete, Christophersen, Ingrid E., Roselli, Carolina, Ellinor, Patrick T., Kato, Norihiro, van der Harst, Pim, Elliott, Paul, Takeuchi, Fumihiko, Johnson, Andrew D., Sanghera, Dharambir K., Melander, Olle, Strbian, Daniel, Fernandez-Cadenas, Israel, Rolfs, Arndt, Hata, Jun, Woo, Daniel, Pare, Guillaume, Hopewell, Jemma C., Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B., Seshadri, Sudha, Markus, Hugh S., Debette, Stephanie, Dichgans, Martin
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2018; Nature Publishing Group
• Subjects: 631/208; 631/208/205/2138; 692/699/375/534; Agriculture; Animal Genetics and Genomics; Asian people; atrial-fibrillation; Basic Medicine; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Blood pressure; Cancer Research; Cardiovascular disease; complex traits; Computational Biology; Consortia; coronary-artery-disease; Databases, Genetic; Epigenesis, Genetic; Etiology; Female; Gene Function; Gene Regulatory Networks; Genes; Genetic diversity; Genetic Loci; Genetic Predisposition to Disease; Genome-wide association studies; Genome-Wide Association Study; Genomes; Health risks; hemorrhagic stroke; human genetic-variation; Human Genetics; Humans; INDEL Mutation; ischemic-stroke; Life Sciences; Linkage Disequilibrium; Loci; Male; Medical and Health Sciences; Medical Genetics; Medical Genetics and Genomics; Medical Genetics and Genomics (including Gene Therapy); Medicin och hälsovetenskap; Medicinsk genetik; Medicinsk genetik och genomik; Medicinsk genetik och genomik (Här ingår: Genterapi); Medicinska och farmaceutiska grundvetenskaper; Meta-analysis; Models, Genetic; Neurosciences; Neurovetenskaper; Pleiotropy; Polymorphism, Single Nucleotide; Regression analysis; Risk; Risk Factors; small-vessel disease; Stroke; Stroke - classification; Stroke - genetics; Stroke - physiopathology; sudden cardiac death; susceptibility; Thromboembolism; white-matter hyperintensities
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-018-0058-3

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci ( n  = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy. Multiancestry genome-wide association analyses identify new risk loci for stroke and stroke subtypes. Fine mapping and bioinformatics analyses of these risk loci point to mechanisms not previously implicated in stroke pathophysiology.