Stroke genetics informs drug discovery and risk prediction across ancestries

Authors: Aniket Mishra, Rainer Malik, Tsuyoshi Hachiya, Tuuli Jürgenson, Shinichi Namba, Daniel Posner, Frederick Kamanu, Masaru Koido, Quentin Le Grand, Mingyang Shi, Yunye He, Marios K. Georgakis, Ilana Caro, Kristi Krebs, Yi‐Ching Liaw, Felix Vaura, Kuang Lin, Bendik S. Winsvold, Vinodh Srinivasasainagendra, Livia Parodi, Hee‐Joon Bae, Ganesh Chauhan, Michael Chong, Liisa Tomppo, Rufus Akinyemi, Gennady V. Roshchupkin, Naomi Habib, Yon Ho Jee, Jesper Qvist Thomassen, Vida Abedi, Jara Cárcel‐Márquez, Marianne Nygaard, Hampton L. Leonard, Chaojie Yang, Ekaterina Yonova-Doing, Maria J. Knol, Adam Lewis, Renae Judy, Tetsuro Ago, Philippe Amouyel, Nicole D. Armstrong, Mark K. Bakker, Traci M. Bartz, David A. Bennett, Joshua C. Bis, Constance Bordes, Sigrid Børte, Anael Cain, Paul M. Ridker, Kelly Cho, Zhengming Chen, Carlos Cruchaga, John W. Cole, Phil L. de Jager, Rafael de Cid, Matthias Endres, Leslie Ecker Ferreira, Mirjam I. Geerlings, Natalie C. Gasca, Vilmundur Guðnason, Jun Hata, Jing He, Alicia K. Heath, Yuk‐Lam Ho, Aki S. Havulinna, Jemma C. Hopewell, Hyacinth I. Hyacinth, Michael Inouye, Mina A. Jacob, Christina Jeon, Christina Jern, Masahiro Kamouchi, Keith L. Keene, Takanari Kitazono, Steven J. Kittner, Takahiro Konuma, Amit Kumar, Paul Lacaze, Lenore J. Launer, Keon‐Joo Lee, Kaido Lepik, Jiang Li, Liming Li, Ani Manichaikul, Hugh S. Markus, Nicholas A. Marston, Thomas Meitinger, Braxton D. Mitchell, Felipe A. Montellano, Takayuki Morisaki, Thomas H. Mosley, Mike A. Nalls, Børge G. Nordestgaard, Martin O’Donnell, Yukinori Okada, N. Charlotte Onland-Moret, Bruce Ovbiagele, Annette Peters, Bruce M. Psaty, Stephen S. Rich, Jonathan Rosand, Marc S. Sabatine, Ralph L. Sacco, Danish Saleheen, Else Charlotte Sandset, Veikko Salomaa, Muralidharan Sargurupremraj, Makoto Sasaki, Claudia L. Satizábal, Carsten Oliver Schmidt, Atsushi Shimizu, Nicholas Smith, Kelly L. Sloane, Yoichi Sutoh, Yan V. Sun, Kozo Tanno, Steffen Tiedt, Turgut Tatlisumak, Nuria P. Torres‐Aguila, Hemant K. Tiwari, David‐Alexandre Trégouët, Stella Trompet, Anil M Tuladhar, Anne Tybjærg‐Hansen, Marion van Vugt, Riina Vibo, Shefali S. Verma, Kerri L. Wiggins, Patrik Wennberg, Daniel Woo, Peter W. F. Wilson, Huichun Xu, Qiong Yang, Kyungheon Yoon, Joshua C. Bis, Jin‐Moo Lee, Yu‐Ching Cheng, James F. Meschia, Wei Min Chen, Michèle M. Sale, Alan B. Zonderman, Michele K. Evans, James G. Wilson, Adolfo Correa, Matthew Traylor, Cathryn M. Lewis, Cara L. Carty, Alexander Reiner, Jeffrey Haessler, Carl D. Langefeld, Rebecca F. Gottesman, Kristine Yaffe, Yong Mei Liu, Charles Kooperberg, Leslie A. Lange, Karen L. Furie, Donna K. Arnett, Oscar R. Benavente, Raji P. Grewal, Leema Reddy Peddareddygari, Charles Kooperberg, Kristian Hveem, Sara Lindstrom, Lu Wang, Erin N. Smith, William Gordon, Astrid van Hylckama Vlieg, Mariza de Andrade, Jennifer A. Brody, Jack Pattee, Jeffrey Haessler, Ben M. Brumpton, Pierre Suchon, Ming‐Huei Chen, Kelly A. Frazer, Constance Turman, Marine Germain, James W. MacDonald, Sigrid K. Brækkan, Sebastian M. Armasu, Nathan Pankratz, Rebecca D. Jackson, Jonas B. Nielsen, Franco Giulianini, Marja K. Puurunen, Manal Ibrahim, Susan R. Heckbert, Theo K. Bammler, Bryan M. McCauley, Kent D. Taylor, James S. Pankow, Alex P. Reiner, Maiken E. Gabrielsen, Jean-François Deleuze, Chris O’Donnell, Jihye Kim, Barbara McKnight, Peter Kraft, John‐Bjarne Hansen, Frits R. Rosendaal, John A. Heit, Weihong Tang, Pierre‐Emmanuel Morange, Andrew D. Johnson, Christopher Kabrhel, The Dutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group, Ewoud J. van Dijk, Peter J. Koudstaal, Gert-Jan Luijckx, Paul J. Nederkoorn, Robert J van Oostenbrugge, Marieke C. Visser, Marieke J.H. Wermer, L. Jaap Kappelle, The Estonian Biobank, Tõnu Esko, Andres Metspalu, Reedik Mägi, Mari Nelis, The NINDS Stroke Genetics Network (SiGN), Marguerite R. Irvin, Frank-Erik de Leeuw, Christopher Levi, Jane Maguire, Jordi Jiménez‐Conde, Pankaj Sharma, Cathie Sudlow, Kristiina Rannikmäe, Reinhold Schmidt, Agnieszka Slowik, Joanna Pera, Vincent Thijs, Arne G. Lindgren, Andreea Ilinca, Olle Melander, Gunnar Engström, Kathryn M. Rexrode, Peter M. Rothwell, Tara M. Stanne, Julie A. Johnson, John Danesh, Adam S. Butterworth, Laura Heitsch, Giorgio B. Boncoraglio, Michiaki Kubo, Alessandro Pezzini, Arndt Rolfs, Anne‐Katrin Giese, David R. Weir, Rebecca D. Jackson, Owen A. Ross, Robin Lemmons, Martin Söderholm, Mary Cushman, Katarina Jood, Caitrin W. McDonough, Steven Bell, Birgit Linkohr, Tsong-Hai Lee, Jukka Putaala, Christopher D. Anderson, Oscar L. Lopez, Xueqiu Jian, Ulf Schminke, Natàlia Cullell, Pilar Delgado, Laura Ibáñez, Jerzy Krupiński, Vasileios Lioutas, Koichi Matsuda, Joan Montaner, Elena Muiño, Jaume Roquer, Chloé Sarnowski, Naveed Sattar, Gerli Sibolt, Alexander Teumer, Loes C.A. Rutten‐Jacobs, Masahiro Kanai, Anne‐Katrin Giese, Sólveig Grétarsdóttir, Natalia S. Rost, Salim Yusuf, Peter Almgren, Hakan Ay, Steve Bevan, Robert D. Brown, Caty Carrera, Julie E. Buring, Wei‐Min Chen, Ioana Cotlarciuc, Paul I. W. de Bakker, Anita L. DeStefano, Marcel den Hoed, Qing Duan, Stefan T. Engelter, Guido J. Falcone, Rebecca F. Gottesman, Stefan Gustafsson, Ahamad Hassan, Elizabeth G. Holliday, George Howard, Fang‐Chi Hsu, Erik Ingelsson, Tamara B. Harris, Brett Kissela, Dawn Kleindorfer, Claudia Langenberg, Robin Lemmens, Didier Leys, Wei‐Yu Lin, Erik Lorentzen, Patrik K. E. Magnusson, Patrick F. McArdle, Sara L. Pulit, Kenneth Rice, Saori Sakaue, Bishwa R. Sapkota, Christian Tanislav, Gudmar Thorleifsson, U. Thorsteinsdottir, Christophe Tzourio, Cornelia M. van Duijn, James Walters, Nicholas J. Wareham, Najaf Amin, Hugo J. Aparicio, John Attia, Alexa Beiser, Claudine Berr, Mariana Bustamante, Valeria Caso, Seung Hoan Choi, Ayesha Chowhan, Jean‐François Dartigues, Hossein Delavaran, Marcus Dörr, Ian Ford, Wander S. Gurpreet, Anders Hamsten, Atsushi Hozawa, Martin Ingelsson, Motoki Iwasaki, Sara Kaffashian, Lalit Kalra, Ólafur Kjartansson, Manja Kloß, Daniel Labovitz, Cathy C. Laurie, Linxin Li, Lars Lind, Cecilia M. Lindgren, Makoto Hirata, Naoko Minegishi, Andrew P. Morris, Martina Müller‐Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio Parati, Nancy L. Pedersen, Markus Perola, Pekka Jousilahti, Silvana Pileggi, Raquel Rabionet, Iolanda Riba‐Llena, Marta Ribasés, José R. Romero, Anthony G. Rudd, Antti-Pekka Sarin, Sarju Ralhan, Mamoru Satoh, Norie Sawada, Ásgeir Sigurðsson, Albert V. Smith, O. Colin Stine, David J. Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Emmanuel Touzé, Shoichiro Tsugane, André G. Uitterlinden, Einar Már Valdimarsson, Sven J. van der Lee, Kenji Wakai, Stephen R. Williams, Charles Wolfe, Quenna Wong, Taiki Yamaji, Dharambir K. Sanghera, Kari Stefansson, Kent D. Taylor, Nicolas Martinez‐Majander, Kenji Sobue, Carolina Soriano‐Tárraga, Henry Völzke, Onoja Akpa, Fred Stephen Sarfo, Albert Akpalu, Reginald Obiako, Kolawole Wahab, Godwin Osaigbovo, Lukman Owolabi, Morenikeji Komolafe, Carolyn Jenkins, Oyedunni Arulogun, Godwin Ogbole, Abiodun M. Adeoye, Joshua Akinyemi, Atinuke Agunloye, Adekunle Fakunle, Ezinne Uvere, Abimbola Olalere, Olayinka Adebajo, The China Kadoorie Biobank Collaborative Group, Junshi Chen, Robert Clarke, Rory Collins, Yu Guo, Chen Wang, Jun Lv, Richard Peto, Yiping Chen, Zammy Fairhurst-Hunter, Michael Hill, Alfred Pozarickij, Dan Schmidt, Becky Stevens, Iain Turnbull, Canqing Yu, The VA Million Veteran Program, Quentin Le Grand, Leslie Ecker Ferreira, The Biobank Japan, Akiko Nagai, Yoishinori Murakami, Mirjam I. Geerlings, Natalie C. Gasca, Vilmundur Guðnason, Marion van Vugt, Rebecca F. Gottesman, Eric J. Shiroma, Sigurður Sigurðsson, Mohsen Ghanbari, Eric Boerwinkle, Alexa Beiser, Bernard Fongang, Ruiqi Wang, M. Kamran Ikram, Uwe Völker, Phil L. de Jager, Rafael de Cid, Børge G. Nordestgaard, Muralidharan Sargurupremraj, Shefali S. Verma, The ODYSSEY Study, Karlijn F. de Laat, Anouk G.W. van Norden, Paul L.M. de Kort, Sarah E. Vermeer, Paul J.A.M. Brouwers, Rob A.R. Gons, Paul J. Nederkoorn, Tom den Heijer, Gert W. van Dijk, Frank G. W. van Rooij, HUNT All-In Stroke, Anne Hege Aamodt, Anne Heidi Skogholt, Ben M. Brumpton, Cristen J. Willer, Ingrid Heuch, Knut Hagen, Lars G. Fritsche, Linda M. Pedersen, Maiken E. Gabrielsen, Hanne Ellekjær, Wei Zhou, Amy E. Martinsen, Espen Saxhaug Kristoffersen, Jonas B. Nielsen, Kristian Hveem, Laurent F. Thomas, The SICFAIL Study, Christoph Kleinschnitz, Stefan Frantz, Kathrin Ungethüm, The Generacion Study, Cristina Gallego-Fábrega, Miquel Lledós, Laia Llucià‐Carol, Tomás Sobrino, Francisco Campos, José Castillo, Marimar Freijó, Juan F. Arenillas, Vı́ctor Obach, José Álvarez‐Sabín, Carlos A. Molina, Marc Ribó, Lucía Muñoz-Narbona, Elena López‐Cancio, Mónica Millán, Rosa Díaz-Navarro, Cristòfol Vives-Bauzá, Gemma Serrano‐Heras, Tomás Segura, Pilar Delgado, Rajat Dhar, Raquel Delgado‐Mederos, Luis Prats-Sánchez, Pol Camps‐Renom, Natàlia Blay, Lauro Sumoy, Joan Martí‐Fábregas, The Copenhagen City Heart Study, Peter Schnohr, Gorm Boje Jensen, Marianne Benn, Shoaib Afzal, Pia R. Kamstrup, The SMART Study, Jessica van Setten, Sander W. van der Laan, Jet M. J. Vonk, Bong‐Jo Kim, Helsinki Stroke Project, Sami Curtze, Marjaana Tiainen, Janne Kinnunen, Follow-up Studies, Vilas Menon, Yun Ju Sung, Chengran Yang, Florence Saillour-Glenisson, Simon Gravel, EPIC-CVD, N. Charlotte Onland-Moret, Alicia K. Heath, Iona Y. Millwood, Christian Gieger, Toshiharu Ninomiya, Hans J. Grabe, J. Wouter Jukema, Ina L. Rissanen, Daniel Strbian, Young Jin Kim, Pei-Hsin Chen, Ernst Mayerhofer, Joanna M. M. Howson, Marguerite R. Irvin, Hieab H.H. Adams, Sylvia Wassertheil‐Smoller, Kaare Christensen, M. Arfan Ikram, Tatjana Rundek, Bradford B. Worrall, G.M. Lathrop, Moeen Riaz, Eleanor M. Simonsick, Janika Kõrv, Paulo Henrique Condeixa de França, Ramin Zand, Kameshwar Prasad, Ruth Frikke‐Schmidt, Frank-Erik de Leeuw, Thomas Liman, Karl Georg Hæusler, Ynte M. Ruigrok, Peter U. Heuschmann, W. T. Longstreth, Keum Ji Jung, Lisa Bastarache, Guillaume Paré, Scott M. Damrauer, Daniel I. Chasman, Jerome I. Rotter, Christopher D. Anderson, John‐Anker Zwart, Teemu Niiranen, Myriam Fornage, Yung‐Po Liaw, Sudha Seshadri, Israel Fernández‐Cadenas, Robin Walters, Christian T. Ruff, Mayowa Owolabi, Jennifer E. Huffman, Lili Milani, Yoichiro Kamatani, Martin Dichgans, Stéphanie Debette - Nature 2022 cited by 623

Abstract Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry 1,2 . 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 analysis 3 , 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 approach 4 , 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 ancestry 5 . 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.