Genetic Contributions to Early and Late Onset Ischemic Stroke
Authors: Jaworek Thomas , Xu Huichun , Gaynor Brady J. , Cole John W. , Rannikmäe 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 ,   the Cervical Artery Dissections and Ischemic Stroke Patients (CADISP) Consortium, Cárcel-Márquez Jara , Chen Zhengming , Chong Michael , Cruchaga Carlos , Cushman Mary , Danesh John , Debette Stephanie , Duggan David J. , Durda Jon Peter , Engstrom Gunnar , Enzinger Christian , Faul Jessica D. , Fecteau Natalie S. , Fernández-Cadenas Israel , Geiger Christian , Giese Anne-Katrin , Grewal Raji P. , Grittner Ulrike , Havulinna Aki S. , Heitsch Laura , Hochberg Marc C. , Holliday Elizabeth , Hu Jie , Ilinca Andreea ,   the International Stroke Genetics Consortium (ISGC),   the INVENT Consortium, Irvin Marguerite R. , Jackson Rebecca D. , Jacob Mina A. , Janssen Raquel Rabionet , 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 , 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 , O’Donnell Martin , Peddareddygari Leema Reddy , 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 LM , Tatlisumak Turgut , Terao Chikashi , Thijs Vincent , Torres-Aguila Nuria P. , Trégouët David-Alexandre , Tuladhar Anil Man , Veldink Jan H. , Walters Robin G. , Weir David R. , Woo Daniel , Worrall Bradford B. , Hong Charles C , Ross Owen , Zand Ramin , de Leeuw F-E , Lindgren Arne G. , Pare Guillaume , Anderson Christopher D. , Markus Hugh S. , Jern Christina , Malik Rainer , Dichgans Martin , Mitchell Braxton D. , Kittner Steven J. ,   International Stroke Genetics Consortium,   Early Onset Stroke Genetics Consortium
Published: November 2021

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.