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

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

doi:10.1212/WNL.0000000000201006

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

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

Abstract

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 identifythe 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, using individual level data or summary statistics in 16,730 cases and 599,237 non-stroke 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 for venous thromboembolism between EOS and LOS.

RESULTS: We observed genome-wide significant associations of EOS with two 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 to LOS. The odds ratio (OR) for rs529565, tagging O1, 0.88 (95% 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 polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared to 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.

Original language	English
Pages (from-to)	e1738-e1754
Journal	Neurology
Volume	99
Issue number	16
Early online date	31 Aug 2022
DOIs	https://doi.org/10.1212/WNL.0000000000201006
Publication status	Published - 18 Oct 2022

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Jaworek, T., Xu, H., Gaynor, B., Cole, J., Rannikmae, K., Stanne, T. M., Tomppo, L., Abedi, V., Amouyel, P., Armstrong, N., Attia, J., Bell, S., Benavente, O. R., Boncoraglio, G. B., Butterworth, A. S., Carcel-Marquez, J., Chen, Z., Chong, M., Cruchaga, C., ... Kittner, S. J. (2022). Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke. Neurology, 99(16), e1738-e1754. https://doi.org/10.1212/WNL.0000000000201006

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title = "Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke",

abstract = "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 identifythe 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, using individual level data or summary statistics in 16,730 cases and 599,237 non-stroke 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 for venous thromboembolism between EOS and LOS.RESULTS: We observed genome-wide significant associations of EOS with two 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 to LOS. The odds ratio (OR) for rs529565, tagging O1, 0.88 (95\% 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 polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared to 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. ",

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

note = "Funding Information: The Article Processing Charge was funded by the authors. Publisher Copyright: {\textcopyright} American Academy of Neurology.",

year = "2022",

month = oct,

day = "18",

doi = "10.1212/WNL.0000000000201006",

language = "English",

volume = "99",

pages = "e1738--e1754",

journal = "Neurology",

issn = "0028-3878",

publisher = "Lippincott Williams and Wilkins",

number = "16",

}

Jaworek, T, Xu, H, Gaynor, B, Cole, J, Rannikmae, K, Stanne, TM, Tomppo, L, Abedi, V, Amouyel, P, Armstrong, N, Attia, J, Bell, S, Benavente, OR, Boncoraglio, GB, Butterworth, AS, Carcel-Marquez, J, Chen, Z, Chong, M, Cruchaga, C, Cushman, M, Danesh, J, Debette, S, Duggan, D, Durda, JP, Engstrom, G, Enzinger, C, Faul, JD, Fecteau, N, Fernandez-Cadenas, I, Gieger, C, Giese, A-K, Grewal, RP, Grittner, U, Havulinna, AS, Heitsch, L, Hochberg, M, Holliday, EG, Zhu, J, Llinca, A, Irvin, MR, Jackson, RD, Jacob, M, Rabionet-Janssen, R, Jimenez-Conde, J, Johnson, JA, Kamatani, Y, Kardia, SLR, Koido, M, Kubo, M, Lange, LA, Lee, J-M, Lemmens, R, Levi, C, Li, J, Lin, K, Lopez, H, Maguire, JM, Luke, S, McArdle, PF, McDonough, CW, Meschia, J, Metso, TM, Müller-Nurasyid, M, O'Connor, T, Peddareddygari, LR, O'Donnell, M, Pera, J, Perry, J, Peters, A, Putaala, J, Ray, D, Rexrode, KM, Ribases, M, Rosand, J, Rothwell, PM, Rundek, T, Ryan, K, Sacco, RL, Salomaa, V, Sánchez-Mora, C, Schmidt, R, Sharma, P, Slowik, A, Smith, J, Smith, NL, Wassertheil-Smoller, S, Söderholm, M, Stine, C, Strbian, D, Sudlow, CLM, Tatlisumak, T, Terao, C, Thijs, V, Torres-Aguila, N, Tregouet, D-A, Tuladhar, AM, Veldink, JH, Walters, RG, Weir, DR, Woo, D, Worrall, BB, Hong, C, Ross, OA, Zand, R, de Leeuw, F-E, Lindgren, A, Pare, G, Anderson, CD, Markus, HS, Jern, C, Malik, R, Dichgans, M, Mitchell, BD & Kittner, SJ 2022, 'Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke', Neurology, vol. 99, no. 16, pp. e1738-e1754. https://doi.org/10.1212/WNL.0000000000201006

TY - JOUR

T1 - Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke

AU - Jaworek, Thomas

AU - Xu, Huichun

AU - Gaynor, Brady

AU - Cole, John

AU - Rannikmae, Kristiina

AU - Stanne, Tara M

AU - Tomppo, Liisa

AU - Abedi, Vida

AU - Amouyel, Phillippe

AU - Armstrong, Nicole

AU - Attia, John

AU - Bell, Steven

AU - Benavente, Oscar R.

AU - Boncoraglio, Giorgio B

AU - Butterworth, Adam S

AU - Carcel-Marquez, Jara

AU - Chen, Zhengming

AU - Chong, Michael

AU - Cruchaga, Carlos

AU - Cushman, Mary

AU - Danesh, John

AU - Debette, Stephanie

AU - Duggan, David

AU - Durda, John Peter

AU - Engstrom, Gunnar

AU - Enzinger, Chrstine

AU - Faul, Jessica D

AU - Fecteau, Natalie

AU - Fernandez-Cadenas, Israel

AU - Gieger, Christian

AU - Giese, Anne-Katrin

AU - Grewal, Raji P

AU - Grittner, Ulrika

AU - Havulinna, Aki S.

AU - Heitsch, Laura

AU - Hochberg, Marc

AU - Holliday, Elizabeth G

AU - Zhu, Jie

AU - Llinca, Andreea

AU - Irvin, Marguerite R

AU - Jackson, Rebecca D.

AU - Jacob, Mina

AU - Rabionet-Janssen, Raquel

AU - Jimenez-Conde, Jordi

AU - Johnson, Julie A

AU - Kamatani, Yoichiro

AU - Kardia, Sharon L R

AU - Koido, Masaru

AU - Kubo, Michiaki

AU - Lange, Leslie A.

AU - Lee, Jin-Moo

AU - Lemmens, Robin

AU - Levi, Christopher

AU - Li, Jiang

AU - Lin, Kuang

AU - Lopez, Haley

AU - Maguire, Jane M

AU - Luke, Sothear

AU - McArdle, Patrick F

AU - McDonough, Caitrin W

AU - Meschia, Jessica

AU - Metso, Tiina M

AU - Müller-Nurasyid, Martina

AU - O'Connor, Timothy

AU - Peddareddygari, Leema Reddy

AU - O'Donnell, Martin

AU - Pera, Joanna

AU - Perry, James

AU - Peters, Annette

AU - Putaala, Jukka

AU - Ray, Debashree

AU - Rexrode, Kathryn M

AU - Ribases, Marta

AU - Rosand, Jonathan

AU - Rothwell, Peter M.

AU - Rundek, Tatjana

AU - Ryan, Kathleen

AU - Sacco, Ralph L.

AU - Salomaa, Veikko

AU - Sánchez-Mora, Cristina

AU - Schmidt, Reinhold

AU - Sharma, Pankaj

AU - Slowik, Agnieszka

AU - Smith, Jennifer

AU - Smith, Nicholas L.

AU - Wassertheil-Smoller, Sylvia

AU - Söderholm, Martin

AU - Stine, Colin

AU - Strbian, Daniel

AU - Sudlow, Cathie L M

AU - Tatlisumak, Turgut

AU - Terao, Chikashi

AU - Thijs, Vincent

AU - Torres-Aguila, Nina

AU - Tregouet, David-Alexandre

AU - Tuladhar, Anil M

AU - Veldink, Jan H

AU - Walters, Robin G

AU - Weir, David R

AU - Woo, Daniel

AU - Worrall, Bradford B

AU - Hong, Charles

AU - Ross, Owen A.

AU - Zand, Ramin

AU - de Leeuw, Frank-Erik

AU - Lindgren, Arne

AU - Pare, Guillaume

AU - Anderson, Christopher D.

AU - Markus, Hugh S.

AU - Jern, Christina

AU - Malik, Rainer

AU - Dichgans, Martin

AU - Mitchell, Braxton D.

AU - Kittner, Steven J

N1 - Funding Information: The Article Processing Charge was funded by the authors. Publisher Copyright: © American Academy of Neurology.

PY - 2022/10/18

Y1 - 2022/10/18

N2 - 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 identifythe 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, using individual level data or summary statistics in 16,730 cases and 599,237 non-stroke 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 for venous thromboembolism between EOS and LOS.RESULTS: We observed genome-wide significant associations of EOS with two 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 to LOS. The odds ratio (OR) for rs529565, tagging O1, 0.88 (95% 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 polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared to 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.

AB - 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 identifythe 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, using individual level data or summary statistics in 16,730 cases and 599,237 non-stroke 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 for venous thromboembolism between EOS and LOS.RESULTS: We observed genome-wide significant associations of EOS with two 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 to LOS. The odds ratio (OR) for rs529565, tagging O1, 0.88 (95% 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 polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared to 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.

UR - https://www.scopus.com/pages/publications/85140635183

U2 - 10.1212/WNL.0000000000201006

DO - 10.1212/WNL.0000000000201006

M3 - Article

C2 - 36240095

SN - 0028-3878

VL - 99

SP - e1738-e1754

JO - Neurology

JF - Neurology

IS - 16

ER -

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

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