Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke

Thomas Jaworek, Huichun Xu, Brady J. Gaynor, John W. Cole, Kristiina Rannikmae, Tara M. Stanne, Liisa Tomppo, Vida Abedi, Philippe Amouyel, Nicole D. Armstrong, John Attia, Steven Bell, Oscar R. Benavente, Giorgio B. Boncoraglio, Adam Butterworth, Jara Carcel-Marquez, Zhengming Chen, Michael Chong, Carlos Cruchaga, Mary CushmanJohn Danesh, Stéphanie Debette, David J. Duggan, Jon Peter Durda, Gunnar Engstrom, Chris Enzinger, Jessica D. Faul, Natalie S. Fecteau, Israel Fernandez-Cadenas, Christian Gieger, Anne Katrin Giese, Raji P. Grewal, Ulrike Grittner, Aki S. Havulinna, Laura Heitsch, Marc C. Hochberg, Elizabeth Holliday, Jie Hu, Andreea Ilinca, Marguerite R. Irvin, Rebecca D. Jackson, Mina A. Jacob, Raquel Rabionet, Jordi Jimenez-Conde, Julie A. Johnson, Yoichiro Kamatani, Sharon L.R. Kardia, Masaru Koido, Michiaki Kubo, Leslie Lange, Jin Moo Lee, Robin Lemmens, Christopher R. Levi, Jiang Li, Liming Li, Kuang Lin, Haley Lopez, Sothear Luke, Jane Maguire, Patrick F. McArdle, Caitrin W. McDonough, James F. Meschia, Tiina Metso, Martina Müller-Nurasyid, Timothy D. O'Connor, Martin O'Donnell, Leema R. Peddareddygari, Joanna Pera, James A. Perry, Annette Peters, Jukka Putaala, Debashree Ray, Kathryn Rexrode, Marta Ribases, Jonathan Rosand, Peter M. Rothwell, Tatjana Rundek, Kathleen A. Ryan, Ralph L. Sacco, Veikko Salomaa, Cristina Sanchez-Mora, Reinhold Schmidt, Pankaj Sharma, Agnieszka Slowik, Jennifer A. Smith, Nicholas L. Smith, Sylvia Wassertheil-Smoller, Martin Söderholm, O. Colin Stine, Daniel Strbian, Cathie L.M. Sudlow, Turgut Tatlisumak, Chikashi Terao, Vincent Thijs, Nuria P. Torres-Aguila, David Alexandre Trégouët, Anil M. Tuladhar, Jan H. Veldink, Robin G. Walters, David R. Weir, Daniel Woo, Bradford B. Worrall, Charles C. Hong, Owen A. Ross, Ramin Zand, Frank Erik De Leeuw, Arne G. Lindgren, Guillaume Pare, Christopher D. Anderson, Hugh S. Markus, Christina Jern, Rainer Malik, Martin Dichgans, Braxton D. Mitchell, Steven J. Kittner

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Background and ObjectivesCurrent genome-wide association studies of ischemic stroke have focused primarily on late-onset disease. As a complement to these studies, we sought to identify the contribution of common genetic variants to risk of early-onset ischemic stroke.MethodsWe performed a meta-analysis of genome-wide association studies of early-onset stroke (EOS), ages 18-59 years, using individual-level data or summary statistics in 16,730 cases and 599,237 nonstroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late-onset stroke (LOS) and compared polygenic risk scores (PRS) for venous thromboembolism (VTE) between EOS and LOS.ResultsWe observed genome-wide significant associations of EOS with 2 variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared with LOS. The odds ratio (OR) for rs529565, tagging O1, was 0.88 (95% confidence interval [CI]: 0.85-0.91) in EOS vs 0.96 (95% CI: 0.92-1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11-1.21) for EOS vs 1.05 (0.99-1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using PRSs, we observed that greater genetic risk for VTE, another prothrombotic condition, was more strongly associated with EOS compared with LOS (p = 0.008).DiscussionThe ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.

Original languageEnglish
Pages (from-to)E1738-E1754
Issue number16
StatePublished - Oct 18 2022


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