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 Cushman; John Danesh; Stephanie 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 Janssen; Jordi Jimenez-Conde; Julie A Johnson; Yoichiro Kamatani; Sharon L 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 Muller-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 Soederholm; O C Stine; Daniel Strbian; Cathie L Sudlow; Turgut Tatlisumak; Chikashi Terao; Vincent Thijs; Nuria P Torres-Aguila; David-Alexandre Tregouet; Anil M Tuladhar; Jan H Veldink; Robin G Walters; David R Weir; Daniel Woo; Bradford B Worrall; Charles C Hong; Owen 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; Cervical Artery Dissections and Ischemic Stroke Patients (CADSIP) Consortium

doi:10.1212/WNL.0000000000201006

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

Standard

Contribution of Common Genetic Variants to Risk of Early Onset Ischemic Stroke. / 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; Janssen, Raquel Rabionet; Jimenez-Conde, Jordi; Johnson, Julie A; Kamatani, Yoichiro; Kardia, Sharon L; 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; Muller-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; Soederholm, Martin; Stine, O C; Strbian, Daniel; Sudlow, Cathie L; 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; 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; Kittner, Steven J; Cervical Artery Dissections and Ischemic Stroke Patients (CADSIP) Consortium.

In: NEUROLOGY, Vol. 99, No. 16, 17.10.2022, p. e1738-e1754.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Jaworek, T, Xu, H, Gaynor, BJ, Cole, JW, Rannikmae, K, Stanne, TM, Tomppo, L, Abedi, V, Amouyel, P, Armstrong, ND, Attia, J, Bell, S, Benavente, OR, Boncoraglio, GB, Butterworth, A, Carcel-Marquez, J, Chen, Z, Chong, M, Cruchaga, C, Cushman, M, Danesh, J, Debette, S, Duggan, DJ, Durda, JP, Engstrom, G, Enzinger, C, Faul, JD, Fecteau, NS, Fernandez-Cadenas, I, Gieger, C, Giese, A-K, Grewal, RP, Grittner, U, Havulinna, AS, Heitsch, L, Hochberg, MC, Holliday, E, Hu, J, Ilinca, A, Irvin, MR, Jackson, RD, Jacob, MA, Janssen, RR, Jimenez-Conde, J, Johnson, JA, Kamatani, Y, Kardia, SL, Koido, M, Kubo, M, Lange, L, Lee, J-M, Lemmens, R, Levi, CR, Li, J, Li, L, Lin, K, Lopez, H, Luke, S, Maguire, J, McArdle, PF, McDonough, CW, Meschia, JF, Metso, T, Muller-Nurasyid, M, O'Connor, TD, O'Donnell, M, Peddareddygari, LR, Pera, J, Perry, JA, Peters, A, Putaala, J, Ray, D, Rexrode, K, Ribases, M, Rosand, J, Rothwell, PM, Rundek, T, Ryan, KA, Sacco, RL, Salomaa, V, Sanchez-Mora, C, Schmidt, R, Sharma, P, Slowik, A, Smith, JA, Smith, NL, Wassertheil-Smoller, S, Soederholm, M, Stine, OC, Strbian, D, Sudlow, CL, Tatlisumak, T, Terao, C, Thijs, V, Torres-Aguila, NP, Tregouet, D-A, Tuladhar, AM, Veldink, JH, Walters, RG, Weir, DR, Woo, D, Worrall, BB, Hong, CC, Ross, O, Zand, R, Leeuw, F-ED, Lindgren, AG, Pare, G, Anderson, CD, Markus, HS, Jern, C, Malik, R, Dichgans, M, Mitchell, BD, Kittner, SJ & Cervical Artery Dissections and Ischemic Stroke Patients (CADSIP) Consortium 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

APA

Jaworek, T., Xu, H., Gaynor, B. J., Cole, J. W., Rannikmae, K., Stanne, T. M., Tomppo, L., Abedi, V., Amouyel, P., Armstrong, N. D., Attia, J., Bell, S., Benavente, O. R., Boncoraglio, G. B., Butterworth, A., Carcel-Marquez, J., Chen, Z., Chong, M., Cruchaga, C., ... Cervical Artery Dissections and Ischemic Stroke Patients (CADSIP) Consortium (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

Vancouver

Jaworek T, Xu H, Gaynor BJ, Cole JW, Rannikmae K, Stanne TM et al. Contribution of Common Genetic Variants to Risk of Early Onset Ischemic Stroke. NEUROLOGY. 2022 Oct 17;99(16):e1738-e1754. https://doi.org/10.1212/WNL.0000000000201006

Bibtex

@article{7f9947f978074449a5c939f4c9c6799f,

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 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.",

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

note = "{\textcopyright} 2022 American Academy of Neurology.",

year = "2022",

month = oct,

day = "17",

doi = "10.1212/WNL.0000000000201006",

language = "English",

volume = "99",

pages = "e1738--e1754",

journal = "NEUROLOGY",

issn = "0028-3878",

publisher = "Lippincott Williams and Wilkins",

number = "16",

}

RIS

TY - JOUR

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

AU - Jaworek, Thomas

AU - Xu, Huichun

AU - Gaynor, Brady J

AU - Cole, John W

AU - Rannikmae, Kristiina

AU - Stanne, Tara M

AU - Tomppo, Liisa

AU - Abedi, Vida

AU - Amouyel, Philippe

AU - Armstrong, Nicole D

AU - Attia, John

AU - Bell, Steven

AU - Benavente, Oscar R

AU - Boncoraglio, Giorgio B

AU - Butterworth, Adam

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 J

AU - Durda, Jon Peter

AU - Engstrom, Gunnar

AU - Enzinger, Chris

AU - Faul, Jessica D

AU - Fecteau, Natalie S

AU - Fernandez-Cadenas, Israel

AU - Gieger, Christian

AU - Giese, Anne-Katrin

AU - Grewal, Raji P

AU - Grittner, Ulrike

AU - Havulinna, Aki S

AU - Heitsch, Laura

AU - Hochberg, Marc C

AU - Holliday, Elizabeth

AU - Hu, Jie

AU - Ilinca, Andreea

AU - Irvin, Marguerite R

AU - Jackson, Rebecca D

AU - Jacob, Mina A

AU - Janssen, Raquel Rabionet

AU - Jimenez-Conde, Jordi

AU - Johnson, Julie A

AU - Kamatani, Yoichiro

AU - Kardia, Sharon L

AU - Koido, Masaru

AU - Kubo, Michiaki

AU - Lange, Leslie

AU - Lee, Jin-Moo

AU - Lemmens, Robin

AU - Levi, Christopher R

AU - Li, Jiang

AU - Li, Liming

AU - Lin, Kuang

AU - Lopez, Haley

AU - Luke, Sothear

AU - Maguire, Jane

AU - McArdle, Patrick F

AU - McDonough, Caitrin W

AU - Meschia, James F

AU - Metso, Tiina

AU - Muller-Nurasyid, Martina

AU - O'Connor, Timothy D

AU - O'Donnell, Martin

AU - Peddareddygari, Leema R

AU - Pera, Joanna

AU - Perry, James A

AU - Peters, Annette

AU - Putaala, Jukka

AU - Ray, Debashree

AU - Rexrode, Kathryn

AU - Ribases, Marta

AU - Rosand, Jonathan

AU - Rothwell, Peter M

AU - Rundek, Tatjana

AU - Ryan, Kathleen A

AU - Sacco, Ralph L

AU - Salomaa, Veikko

AU - Sanchez-Mora, Cristina

AU - Schmidt, Reinhold

AU - Sharma, Pankaj

AU - Slowik, Agnieszka

AU - Smith, Jennifer A

AU - Smith, Nicholas L

AU - Wassertheil-Smoller, Sylvia

AU - Soederholm, Martin

AU - Stine, O C

AU - Strbian, Daniel

AU - Sudlow, Cathie L

AU - Tatlisumak, Turgut

AU - Terao, Chikashi

AU - Thijs, Vincent

AU - Torres-Aguila, Nuria P

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 C

AU - Ross, Owen

AU - Zand, Ramin

AU - Leeuw, Frank-Erik de

AU - Lindgren, Arne G

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

AU - Cervical Artery Dissections and Ischemic Stroke Patients (CADSIP) Consortium

PY - 2022/10/17

Y1 - 2022/10/17

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 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.

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 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.

U2 - 10.1212/WNL.0000000000201006

DO - 10.1212/WNL.0000000000201006

M3 - SCORING: Journal article

C2 - 36240095

VL - 99

SP - e1738-e1754

JO - NEUROLOGY

JF - NEUROLOGY

SN - 0028-3878

IS - 16

ER -