Stroke genetics informs drug discovery and risk prediction across ancestries

作者：Aniket Mishra, Rainer Malik, Tsuyoshi Hachiya, Tuuli Jürgenson, Shinichi Namba, Daniel C. Posner, Frederick Kamanu, Masaru Koido, Quentin Le Grand, Mingyang Shi, Yunye He, Marios K. Georgakis, Ilana Caro, Kristi Krebs, Yi‐Ching Liaw, Felix C. Vaura, Kuang Lin, Bendik Slagsvold 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 J. Lewis, Renae Judy, Tetsuro Ago, Philippe Amouyel, Nicole D. Armstrong, Mark K. Bakker, Traci M. Bartz, David A. 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 G. Gudnason, Jun Hata, Jing He, Alicia K. Heath, Yuk-Lam Anne Ho, Aki Samuli Havulinna, Jemma C. Hopewell, Hyacinth I. Hyacinth, Michael Inouye, Mina Ayad Jacob, Christina E. Jeon, Christina Jern, Masahiro Kamouchi, Keith L. Keene, Takanari Kitazono, Steven J. Kittner, Takahiro Konuma, Amit Kumar, Paul A Lacaze, Lenore J. Launer, Keon‐Joo Lee, Kaido Lepik, Jiang Li, Liming Li, Ani W Manichaikul, Hugh S. Markus, Nicholas A. Marston, Thomas Meitinger, Braxton D. Mitchell, Felipe A. Montellano, Takayuki Morisaki, Thomas H. Mosley, Mike A. Nalls, Børge Grønne Nordestgaard, Martin James 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 V Salomaa, Muralidharan Sargurupremraj, Makoto Sasaki, Claudia Liliana 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 Man 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 S. 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 W. Pattee, Jeffrey Haessler, Ben M. Brumpton, Pierre Suchon, Ming‐Huei Chen, Kelly A. Frazer, Constance Turman, Marine Germain, James W. MacDonald, Sigrid Kufaas 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 Elvestad Gabrielsen, Jean-François Deleuze, Chris J. 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 H de 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 Royce Levi, Jane Margaret Maguire, Jordi Jiménez‐Conde, Pankaj Kumar Sharma, Cathie L. M. Sudlow, Kristiina Rannikmäe, Reinhold Schmidt, Agnieszka Slowik, Joanna Pera, Vincent Thijs, Arne G. Lindgren, Andreea Ilinca, Olle Melander, Gunnar Engström, Kathryn M. Rexrode, Peter Malcolm Rothwell, Tara M. Stanne, Julie A. Johnson, John Danesh, Adam S. Butterworth, Laura Heitsch, Giorgio Battista 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 M. 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 M. 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 Javier Aparicio, John Attia, Alexa S. 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 Paul Morris, Martina Müller‐Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio Agostino Parati, Nancy L. Pedersen, Markus Perola, Pekka Jousilahti, Silvana Pileggi, Raquel Rabionet, Iolanda Riba Llena, Marta Ribasés, Jose Rafael Romero, Anthony G. Rudd, Antti-Pekka Sarin, Sarju Ralhan, Mamoru Satoh, Norie Sawada, Ásgeir Sigurðsson, Albert V. Smith, Oscar Colin Stine, David J. Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Emmanuel Touzé, Shoichiro Tsugane, André Gerardus Uitterlinden, Einar Már Valdimarsson, Sven J. van der Lee, Kenji Wakai, Stephen R. Williams, Charles D.A. Wolfe, Quenna Wong, Taiki Yamaji, Dharambir K. Sanghera, Kari Stefansson, Kent D. Taylor, Nicolas Martinez‐Majander, Kenji Sobue, Carolina Soriano‐Tárraga, Henry Völzke, Onoja Matthew Akpa, Fred Stephen Sarfo, Albert Kwaku Akpalu, Reginald Obiako, Kolawole Wahab, Godwin Osaigbovo, Lukman Owolabi, Morenikeji Adeyoyin Komolafe, Carolyn H. Jenkins, Oyedunni Arulogun, Godwin Inalegwu Ogbole, Abiodun Moshood Adeoye, Joshua Odunayo Akinyemi, Atinuke M. Agunloye, Adekunle Gregory Fakunle, Ezinne Uvere, Abimbola Olalere, Olayinka J. 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 R S 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 G. Gudnason, Marion van Vugt, Rebecca F. Gottesman, Eric J. Shiroma, Sigurdur Oli Sigurdsson, Mohsen Ghanbari, Eric Boerwinkle, Alexa S. Beiser, Bernard Fongang, Ruiqi Wang, M. Kamran Ikram, Uwe Völker, Phil L. de Jager, Rafael de Cid, Børge Grønne 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 Margareth Pedersen, Maiken Elvestad 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 Francisco Arenillas, Vı́ctor Obach, José Álvarez‐Sabín, Carlos A. Molina, Marc Ribó, Lucía Muñoz-Narbona, Elena López‐Cancio, Monica A. Millan, 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 W 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 Ulrich Heuschmann, Will 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 S. Seshadri, Israel Fernández‐Cadenas, Robin G. Walters, Christian Thomas Ruff, Mayowa Ojo Owolabi, Jennifer E. Huffman, Lili A. Milani, Yoichiro Kamatani, Martin Dichgans, Stéphanie Debette · 发表于：Nature · 年份：2022 · DOI：10.1038/s41586-022-05165-3 · 被引用次数：636 · 研究领域：Genetic Associations and Epidemiology、Bioinformatics and Genomic Networks、Lipoproteins and Cardiovascular Health

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 predict...