Stroke genetics informs drug discovery and risk prediction across ancestries

abstract

AbstractPrevious genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

authors

O'Donnell, Martin
Mishra, Aniket
Malik, Rainer
Hachiya, Tsuyoshi
Jürgenson, Tuuli
Namba, Shinichi
Posner, Daniel C
Kamanu, Frederick K
Koido, Masaru
Le Grand, Quentin
Shi, Mingyang
He, Yunye
Georgakis, Marios K
Caro, Ilana
Krebs, Kristi
Liaw, Yi-Ching
Vaura, Felix C
Lin, Kuang
Winsvold, Bendik Slagsvold
Srinivasasainagendra, Vinodh
Parodi, Livia
Bae, Hee-Joon
Chauhan, Ganesh
Chong, Michael R
Tomppo, Liisa
Akinyemi, Rufus
Roshchupkin, Gennady V
Habib, Naomi
Jee, Yon Ho
Thomassen, Jesper Qvist
Abedi, Vida
Cárcel-Márquez, Jara
Nygaard, Marianne
Leonard, Hampton L
Yang, Chaojie
Yonova-Doing, Ekaterina
Knol, Maria J
Lewis, Adam J
Judy, Renae L
Ago, Tetsuro
Amouyel, Philippe
Armstrong, Nicole D
Bakker, Mark K
Bartz, Traci M
Bennett, David A
Bis, Joshua C
Bordes, Constance
Børte, Sigrid
Cain, Anael
Ridker, Paul M
Cho, Kelly
Chen, Zhengming
Cruchaga, Carlos
Cole, John W
de Jager, Phil L
de Cid, Rafael
Endres, Matthias
Ferreira, Leslie E
Geerlings, Mirjam I
Gasca, Natalie C
Gudnason, Vilmundur
Hata, Jun
He, Jing
Heath, Alicia K
Ho, Yuk-Lam
Havulinna, Aki S
Hopewell, Jemma C
Hyacinth, Hyacinth I
Inouye, Michael
Jacob, Mina A
Jeon, Christina E
Jern, Christina
Kamouchi, Masahiro
Keene, Keith L
Kitazono, Takanari
Kittner, Steven J
Konuma, Takahiro
Kumar, Amit
Lacaze, Paul
Launer, Lenore J
Lee, Keon-Joo
Lepik, Kaido
Li, Jiang
Li, Liming
Manichaikul, Ani
Markus, Hugh S
Marston, Nicholas A
Meitinger, Thomas
Mitchell, Braxton D
Montellano, Felipe A
Morisaki, Takayuki
Mosley, Thomas H
Nalls, Mike A
Nordestgaard, Børge G
O’Donnell, Martin J
Okada, Yukinori
Onland-Moret, N Charlotte
Ovbiagele, Bruce
Peters, Annette
Psaty, Bruce M
Rich, Stephen S
Rosand, Jonathan
Sabatine, Marc S
Sacco, Ralph L
Saleheen, Danish
Sandset, Else Charlotte
Salomaa, Veikko
Sargurupremraj, Muralidharan
Sasaki, Makoto
Satizabal, Claudia L
Schmidt, Carsten O
Shimizu, Atsushi
Smith, Nicholas L
Sloane, Kelly L
Sutoh, Yoichi
Sun, Yan V
Tanno, Kozo
Tiedt, Steffen
Tatlisumak, Turgut
Torres-Aguila, Nuria P
Tiwari, Hemant K
Trégouët, David-Alexandre
Trompet, Stella
Tuladhar, Anil Man
Tybjærg-Hansen, Anne
van Vugt, Marion
Vibo, Riina
Verma, Shefali S
Wiggins, Kerri L
Wennberg, Patrik
Woo, Daniel
Wilson, Peter WF
Xu, Huichun
Yang, Qiong
Yoon, Kyungheon
Bis, Joshua C
Lee, Jin-Moo
Cheng, Yu-Ching
Meschia, James F
Chen, Wei Min
Sale, Michèle M
Zonderman, Alan B
Evans, Michele K
Wilson, James G
Correa, Adolfo
Traylor, Matthew
Lewis, Cathryn M
Carty, Cara L
Reiner, Alexander
Haessler, Jeffrey
Langefeld, Carl D
Gottesman, Rebecca F
Yaffe, Kristine
Liu, Yong Mei
Kooperberg, Charles
Lange, Leslie A
Furie, Karen L
Arnett, Donna K
Benavente, Oscar R
Grewal, Raji P
Peddareddygari, Leema Reddy
Kooperberg, Charles
Hveem, Kristian
Lindstrom, Sara
Wang, Lu
Smith, Erin N
Gordon, William
van Hylckama Vlieg, Astrid
de Andrade, Mariza
Brody, Jennifer A
Pattee, Jack W
Haessler, Jeffrey
Brumpton, Ben M
Suchon, Pierre
Chen, Ming-Huei
Frazer, Kelly A
Turman, Constance
Germain, Marine
MacDonald, James
Braekkan, Sigrid K
Armasu, Sebastian M
Pankratz, Nathan
Jackson, Rebecca D
Nielsen, Jonas B
Giulianini, Franco
Puurunen, Marja K
Ibrahim, Manal
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Bammler, Theo K
McCauley, Bryan M
Taylor, Kent D
Pankow, James S
Reiner, Alexander P
Gabrielsen, Maiken E
Deleuze, Jean-François
O’Donnell, Chris J
Kim, Jihye
McKnight, Barbara
Kraft, Peter
Hansen, John-Bjarne
Rosendaal, Frits R
Heit, John A
Tang, Weihong
Morange, Pierre-Emmanuel
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Kabrhel, Christopher
van Dijk, Ewoud J
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Luijckx, Gert-Jan
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Wermer, Marieke JH
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Esko, Tõnu
Metspalu, Andres
Mägi, Reedik
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de Leeuw, Frank-Erik
Levi, Christopher R
Maguire, Jane
Jiménez-Conde, Jordi
Sharma, Pankaj
Sudlow, Cathie LM
Rannikmäe, Kristiina
Schmidt, Reinhold
Slowik, Agnieszka
Pera, Joanna
Thijs, Vincent NS
Lindgren, Arne G
Ilinca, Andreea
Melander, Olle
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Rexrode, Kathryn M
Rothwell, Peter M
Stanne, Tara M
Johnson, Julie A
Danesh, John
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Kubo, Michiaki
Pezzini, Alessandro
Rolfs, Arndt
Giese, Anne-Katrin
Weir, David
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Ross, Owen A
Lemmons, Robin
Soderholm, Martin
Cushman, Mary
Jood, Katarina
McDonough, Caitrin W
Bell, Steven
Linkohr, Birgit
Lee, Tsong-Hai
Putaala, Jukka
Anderson, Christopher D
Lopez, Oscar L
Jian, Xueqiu
Schminke, Ulf
Cullell, Natalia
Delgado, Pilar
Ibañez, Laura
Krupinski, Jerzy
Lioutas, Vasileios
Matsuda, Koichi
Montaner, Joan
Muiño, Elena
Roquer, Jaume
Sarnowski, Chloe
Sattar, Naveed
Sibolt, Gerli
Teumer, Alexander
Rutten-Jacobs, Loes
Kanai, Masahiro
Giese, Anne-Katrin
Gretarsdottir, Solveig
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Yusuf, Salim
Almgren, Peter
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Bevan, Steve
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Chen, Wei-Min
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de Bakker, Paul IW
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den Hoed, Marcel
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Gottesman, Rebecca F
Gustafsson, Stefan
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Howard, George
Hsu, Fang-Chi
Ingelsson, Erik
Harris, Tamara B
Kissela, Brett M
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Langenberg, Claudia
Lemmens, Robin
Leys, Didier
Lin, Wei-Yu
Lorentzen, Erik
Magnusson, Patrik K
McArdle, Patrick F
Pulit, Sara L
Rice, Kenneth
Sakaue, Saori
Sapkota, Bishwa R
Tanislav, Christian
Thorleifsson, Gudmar
Thorsteinsdottir, Unnur
Tzourio, Christophe
van Duijn, Cornelia M
Walters, Matthew
Wareham, Nicholas J
Amin, Najaf
Aparicio, Hugo J
Attia, John
Beiser, Alexa S
Berr, Claudine
Bustamante, Mariana
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Choi, Seung Hoan
Chowhan, Ayesha
Dartigues, Jean-François
Delavaran, Hossein
Dörr, Marcus
Ford, Ian
Gurpreet, Wander S
Hamsten, Anders
Hozawa, Atsushi
Ingelsson, Martin
Iwasaki, Motoki
Kaffashian, Sara
Kalra, Lalit
Kjartansson, Olafur
Kloss, Manja
Labovitz, Daniel L
Laurie, Cathy C
Li, Linxin
Lind, Lars
Lindgren, Cecilia M
Makoto, Hirata
Minegishi, Naoko
Morris, Andrew P
Müller-Nurasyid, Martina
Norrving, Bo
Ogishima, Soichi
Parati, Eugenio A
Pedersen, Nancy L
Perola, Markus
Jousilahti, Pekka
Pileggi, Silvana
Rabionet, Raquel
Riba-Llena, Iolanda
Ribasés, Marta
Romero, Jose R
Rudd, Anthony G
Sarin, Antti-Pekka
Sarju, Ralhan
Satoh, Mamoru
Sawada, Norie
Sigurdsson, Ásgeir
Smith, Albert
Stine, O Colin
Stott, David J
Strauch, Konstantin
Takai, Takako
Tanaka, Hideo
Touze, Emmanuel
Tsugane, Shoichiro
Uitterlinden, Andre G
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van der Lee, Sven J
Wakai, Kenji
Williams, Stephen R
Wolfe, Charles DA
Wong, Quenna
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Taylor, Kent D
Martinez-Majander, Nicolas
Sobue, Kenji
Soriano-Tárraga, Carolina
Völzke, Henry
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Sarfo, Fred S
Akpalu, Albert
Obiako, Reginald
Wahab, Kolawole
Osaigbovo, Godwin
Owolabi, Lukman
Komolafe, Morenikeji
Jenkins, Carolyn
Arulogun, Oyedunni
Ogbole, Godwin
Adeoye, Abiodun M
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Fakunle, Adekunle G
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Olalere, Abimbola
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Collins, Rory
Guo, Yu
Wang, Chen
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Peto, Richard
Chen, Yiping
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Hill, Michael
Pozarickij, Alfred
Schmidt, Dan
Stevens, Becky
Turnbull, Iain
Yu, Canqing
Le Grand, Quentin
Ferreira, Leslie E
Nagai, Akiko
Murakami, Yoishinori
Geerlings, Mirjam I
Gasca, Natalie C
Gudnason, Vilmundur
van Vugt, Marion
Gottesman, Rebecca F
Shiroma, Eric J
Sigurdsson, Sigurdur
Ghanbari, Mohsen
Boerwinkle, Eric
Beiser, Alexa S
Fongang, Bernard
Wang, Ruiqi
Ikram, Mohammad K
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de Jager, Phil L
de Cid, Rafael
Nordestgaard, Børge G
Sargurupremraj, Muralidharan
Verma, Shefali S
de Laat, Karlijn F
van Norden, Anouk GW
de Kort, Paul L
Vermeer, Sarah E
Brouwers, Paul JAM
Gons, Rob AR
Nederkoorn, Paul J
den Heijer, Tom
van Dijk, Gert W
van Rooij, Frank GW
Aamodt, Anne H
Skogholt, Anne H
Brumpton, Ben M
Willer, Cristen J
Heuch, Ingrid
Hagen, Knut
Fritsche, Lars G
Pedersen, Linda M
Gabrielsen, Maiken E
Ellekjær, Hanne
Zhou, Wei
Martinsen, Amy E
Kristoffersen, Espen S
Nielsen, Jonas B
Hveem, Kristian
Thomas, Laurent F
Kleinschnitz, Christoph
Frantz, Stefan
Ungethüm, Kathrin
Gallego-Fabrega, Cristina
Lledós, Miquel
Llucià-Carol, Laia
Sobrino, Tomas
Campos, Francisco
Castillo, José
Freijó, Marimar
Arenillas, Juan Francisco
Obach, Victor
Álvarez-Sabín, José
Molina, Carlos A
Ribó, Marc
Muñoz-Narbona, Lucia
Lopez-Cancio, Elena
Millán, Mònica
Diaz-Navarro, Rosa
Vives-Bauza, Cristòfol
Serrano-Heras, Gemma
Segura, Tomás
Delgado, Pilar
Dhar, Rajat
Delgado-Mederos, Raquel
Prats-Sánchez, Luis
Camps-Renom, Pol
Blay, Natalia
Sumoy, Lauro
Martí-Fàbregas, Joan
Schnohr, Peter
Jensen, Gorm B
Benn, Marianne
Afzal, Shoaib
Kamstrup, Pia R
van Setten, Jessica
van der Laan, Sander W
Vonk, Jet MJ
Kim, Bong-Jo
Curtze, Sami
Tiainen, Marjaana
Kinnunen, Janne
Menon, Vilas
Sung, Yun Ju
Yang, Chengran
Saillour-Glenisson, Florence
Gravel, Simon
Onland-Moret, N Charlotte
Heath, Alicia K
Millwood, Iona Y
Gieger, Christian
Ninomiya, Toshiharu
Grabe, Hans J
Jukema, J Wouter
Rissanen, Ina L
Strbian, Daniel
Kim, Young Jin
Chen, Pei-Hsin
Mayerhofer, Ernst
Howson, Joanna MM
Irvin, Marguerite R
Adams, Hieab
Wassertheil-Smoller, Sylvia
Christensen, Kaare
Ikram, Mohammad A
Rundek, Tatjana
Worrall, Bradford B
Lathrop, G Mark
Riaz, Moeen
Simonsick, Eleanor M
Kõrv, Janika
França, Paulo HC
Zand, Ramin
Prasad, Kameshwar
Frikke-Schmidt, Ruth
de Leeuw, Frank-Erik
Liman, Thomas
Haeusler, Karl Georg
Ruigrok, Ynte M
Heuschmann, Peter Ulrich
Longstreth, WT
Jung, Keum Ji
Bastarache, Lisa
Pare, Guillaume
Damrauer, Scott M
Chasman, Daniel I
Rotter, Jerome I
Anderson, Christopher D
Zwart, John-Anker
Niiranen, Teemu J
Fornage, Myriam
Liaw, Yung-Po
Seshadri, Sudha
Fernández-Cadenas, Israel
Walters, Robin G
Ruff, Christian T
Owolabi, Mayowa O
Huffman, Jennifer E
Milani, Lili
Kamatani, Yoichiro
Dichgans, Martin
Debette, Stephanie

Stroke genetics informs drug discovery and risk prediction across ancestries Journal Articles

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