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Jaworek, Thomas; Xu, Huichun; Gaynor, Brady J.; Cole, John W.; Rannikmae, Kristiina; Stanne, Tara M.; Tomppo, Liisa; Abedi, Vida; Amouyel, Philippe; Armstrong, Nicole D.; Attia, John; Bell, Steven; Benavente, Oscar R.; Boncoraglio, Giorgio B.; Butterworth, Adam; Carcel-Marquez, Jara; Chen, Zhengming; Chong, Michael; Cruchaga, Carlos; Cushman, Mary; Danesh, John; Debette, Stephanie; Duggan, David J.; Durda, Jon Peter; Engstrom, Gunnar; Enzinger, Chris; Faul, Jessica D.; Fecteau, Natalie S.; Fernandez-Cadenas, Israel; Gieger, Christian; Giese, Anne-Katrin; Grewal, Raji P.; Grittner, Ulrike; Havulinna, Aki S.; Heitsch, Laura; Hochberg, Marc C.; Holliday, Elizabeth; Hu, Jie; Ilinca, Andreea; Irvin, Marguerite R.; Jackson, Rebecca D.; Jacob, Mina A.; Rabionet, Raquel; Jimenez-Conde, Jordi; Johnson, Julie A.; Kamatani, Yoichiro; Kardia, Sharon L. R.; Koido, Masaru; Kubo, Michiaki; Lange, Leslie; Lee, Jin-Moo; Lemmens, Robin; Levi, Christopher R.; Li, Jiang; Li, Liming; Lin, Kuang; Lopez, Haley; Luke, Sothear; Maguire, Jane; McArdle, Patrick F.; McDonough, Caitrin W.; Meschia, James F.; Metso, Tiina; Müller-Nurasyid, Martina; O'Connor, Timothy D.; O'Donnell, Martin; Peddareddygari, Leema R.; Pera, Joanna; Perry, James A.; Peters, Annette; Putaala, Jukka; Ray, Debashree; Rexrode, Kathryn; Ribases, Marta; Rosand, Jonathan; Rothwell, Peter M.; Rundek, Tatjana; Ryan, Kathleen A.; Sacco, Ralph L.; Salomaa, Veikko; Sanchez-Mora, Cristina; Schmidt, Reinhold; Sharma, Pankaj; Slowik, Agnieszka; Smith, Jennifer A.; Smith, Nicholas L.; Wassertheil-Smoller, Sylvia; Soderholm, Martin; Stine, O. Colin; Strbian, Daniel; Sudlow, Cathie L. M.; Tatlisumak, Turgut; Terao, Chikashi; Thijs, Vincent; Torres-Aguila, Nuria P.; Tregouet, David-Alexandre; Tuladhar, Anil M.; Veldink, Jan H.; Walters, Robin G.; Weir, David R.; Woo, Daniel; Worrall, Bradford B.; Hong, Charles C.; Ross, Owen A.; Zand, Ramin; Leeuw, Frank-Erik de; Lindgren, Arne G.; Pare, Guillaume; Anderson, Christopher D.; Markus, Hugh S.; Jern, Christina; Malik, Rainer; Dichgans, Martin; Mitchell, Braxton D. and Kittner, Steven J. (2022): Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke. In: Neurology, Vol. 99, No. 16, E1738-E1754

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Background and Objectives Current 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. Methods We 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. Results We 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). Discussion The 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.

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