Stroke genetics informs drug discovery and risk prediction across ancestries
Authors: 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 W. F. , Xu Huichun , Yang Qiong , Yoon Kyungheon ,   The COMPASS Consortium, 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 ,   The INVENT Consortium, 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 , Heckbert Susan R. , 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 , Johnson Andrew D. , Kabrhel Christopher ,   The Dutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group, van Dijk Ewoud J. , Koudstaal Peter J. , Luijckx Gert-Jan , Nederkoorn Paul J. , van Oostenbrugge Robert J. , Visser Marieke C. , Wermer Marieke J. H. , Kappelle L. Jaap ,   The Estonian Biobank, Esko Tõnu , Metspalu Andres , Mägi Reedik , Nelis Mari ,   The PRECISE4Q Consortium,   The FinnGen Consortium,   The NINDS Stroke Genetics Network (SiGN), Irvin Marguerite R. , de Leeuw Frank-Erik , Levi Christopher R. , Maguire Jane , Jiménez-Conde Jordi , Sharma Pankaj , Sudlow Cathie L. M. , Rannikmäe Kristiina , Schmidt Reinhold , Slowik Agnieszka , Pera Joanna , Thijs Vincent N. S. , Lindgren Arne G. , Ilinca Andreea , Melander Olle , Engström Gunnar , Rexrode Kathryn M. , Rothwell Peter M. , Stanne Tara M. , Johnson Julie A. , Danesh John , Butterworth Adam S. , Heitsch Laura , Boncoraglio Giorgio B. , Kubo Michiaki , Pezzini Alessandro , Rolfs Arndt , Giese Anne-Katrin , Weir David , Jackson Rebecca D. , Ross Owen A. , Lemmons Robin , Soderholm Martin , Cushman Mary , Jood Katarina , McDonough Caitrin W. , Bell Steven , Linkohr Birgit , Lee Tsong-Hai , Putaala Jukka ,   The MEGASTROKE Consortium, 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 , Rost Natalia S. , Yusuf Salim , Almgren Peter , Ay Hakan , Bevan Steve , Brown Robert D. , Carrera Caty , Buring Julie E. , Chen Wei-Min , Cotlarciuc Ioana , de Bakker Paul I. W. , DeStefano Anita L. , den Hoed Marcel , Duan Qing , Engelter Stefan T. , Falcone Guido J. , Gottesman Rebecca F. , Gustafsson Stefan , Hassan Ahamad , Holliday Elizabeth G. , Howard George , Hsu Fang-Chi , Ingelsson Erik , Harris Tamara B. , Kissela Brett M. , Kleindorfer Dawn O. , 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 , Caso Valeria , 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. , Valdimarsson Einar M. , van der Lee Sven J. , Wakai Kenji , Williams Stephen R. , Wolfe Charles D. A. , Wong Quenna , Yamaji Taiki , Sanghera Dharambir K. , Stefansson Kari , Taylor Kent D. , Martinez-Majander Nicolas , Sobue Kenji , Soriano-Tárraga Carolina , Völzke Henry ,   The SIREN Consortium, Akpa Onoja , Sarfo Fred S. , Akpalu Albert , Obiako Reginald , Wahab Kolawole , Osaigbovo Godwin , Owolabi Lukman , Komolafe Morenikeji , Jenkins Carolyn , Arulogun Oyedunni , Ogbole Godwin , Adeoye Abiodun M. , Akinyemi Joshua , Agunloye Atinuke , Fakunle Adekunle G. , Uvere Ezinne , Olalere Abimbola , Adebajo Olayinka J. ,   The China Kadoorie Biobank Collaborative Group, Chen Junshi , Clarke Robert , Collins Rory , Guo Yu , Wang Chen , Lv Jun , Peto Richard , Chen Yiping , Fairhurst-Hunter Zammy , Hill Michael , Pozarickij Alfred , Schmidt Dan , Stevens Becky , Turnbull Iain , Yu Canqing ,   The VA Million Veteran Program,   The International Stroke Genetics Consortium (ISGC), Le Grand Quentin , Ferreira Leslie E. ,   The Biobank Japan, Nagai Akiko , Murakami Yoishinori ,   The CHARGE Consortium, 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. , Völker Uwe ,   The GIGASTROKE Consortium, de Jager Phil L. , de Cid Rafael , Nordestgaard Børge G. , Sargurupremraj Muralidharan , Verma Shefali S. ,   Regeneron Genetics Center,   The ODYSSEY Study, de Laat Karlijn F. , van Norden Anouk G. W. , de Kort Paul L. , Vermeer Sarah E. , Brouwers Paul J. A. M. , Gons Rob A. R. , Nederkoorn Paul J. , den Heijer Tom , van Dijk Gert W. , van Rooij Frank G. W. ,   HUNT All-In Stroke, 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. ,   The SICFAIL Study, Kleinschnitz Christoph , Frantz Stefan , Ungethüm Kathrin ,   The Generacion Study, 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 ,   The Copenhagen City Heart Study, Schnohr Peter , Jensen Gorm B. , Benn Marianne , Afzal Shoaib , Kamstrup Pia R. ,   The SMART Study, van Setten Jessica , van der Laan Sander W. , Vonk Jet M. J. ,   Clinical Research Collaboration for Stroke in Korea (CRCS-K) and Korea Biobank Array (KBA) Project, Kim Bong-Jo ,   Helsinki Stroke Project, Curtze Sami , Tiainen Marjaana , Kinnunen Janne ,   Follow-up Studies, Menon Vilas , Sung Yun Ju , Yang Chengran , Saillour-Glenisson Florence , Gravel Simon ,   EPIC-CVD, 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 M. M. , 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 H. C. , Zand Ramin , Prasad Kameshwar , Frikke-Schmidt Ruth , de Leeuw Frank-Erik , Liman Thomas , Haeusler Karl Georg , Ruigrok Ynte M. , Heuschmann Peter Ulrich , Longstreth W. T. , Jung Keum Ji , Bastarache Lisa , Paré 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 
Published: September 2022

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.