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Genetic Contributions to Early and Late Onset Ischemic Stroke

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

Posted 08 Nov 2021
medRxiv DOI: 10.1101/2021.11.06.21265795

Abstract Objective: To determine the contribution of common genetic variants to risk of early onset ischemic stroke (IS). Methods: We performed a meta-analysis of genome-wide association studies of early onset IS, ages 18-59, using individual level data or summary statistics in 16,927 cases and 576,353 non-stroke controls from 48 different studies across North America, Europe, and Asia. We further compared effect sizes at our most genome-wide significant loci between early and late onset IS and compared polygenic risk scores for venous thromboembolism between early versus later onset IS. Results: We observed an association between early onset IS and ABO, a known stroke locus. The effect size of the peak ABO SNP, rs8176685, was significantly larger in early compared to late onset IS (OR 1.17 (95% C.I.: 1.11-1.22) vs 1.05 (0.99-1.12); p for interaction = 0.008). Analysis of genetically determined ABO blood groups revealed that early onset IS cases were more likely to have blood group A and less likely to have blood group O compared to both non-stroke controls and to late onset IS cases. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with early, compared to late, onset IS (p=0.008). Conclusion: The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with early onset IS, compared with late onset IS, supporting a stronger role of prothrombotic factors in early onset IS.

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