Stroke genetics informs drug discovery and risk prediction across ancestries

Author:

Mishra AniketORCID,Malik Rainer,Hachiya TsuyoshiORCID,Jürgenson Tuuli,Namba ShinichiORCID,Posner Daniel C.ORCID,Kamanu Frederick K.ORCID,Koido MasaruORCID,Le Grand QuentinORCID,Shi Mingyang,He YunyeORCID,Georgakis Marios K.ORCID,Caro IlanaORCID,Krebs KristiORCID,Liaw Yi-ChingORCID,Vaura Felix C.ORCID,Lin Kuang,Winsvold Bendik SlagsvoldORCID,Srinivasasainagendra Vinodh,Parodi Livia,Bae Hee-Joon,Chauhan Ganesh,Chong Michael R.,Tomppo LiisaORCID,Akinyemi Rufus,Roshchupkin Gennady V.ORCID,Habib NaomiORCID,Jee Yon Ho,Thomassen Jesper QvistORCID,Abedi VidaORCID,Cárcel-Márquez Jara,Nygaard MarianneORCID,Leonard Hampton L.ORCID,Yang Chaojie,Yonova-Doing Ekaterina,Knol Maria J.ORCID,Lewis Adam J.,Judy Renae L.,Ago Tetsuro,Amouyel PhilippeORCID,Armstrong Nicole D.,Bakker Mark K.ORCID,Bartz Traci M.,Bennett David A.,Bis Joshua C.ORCID,Bordes ConstanceORCID,Børte SigridORCID,Cain Anael,Ridker Paul M.,Cho Kelly,Chen ZhengmingORCID,Cruchaga Carlos,Cole John W.,de Jager Phil L.ORCID,de Cid RafaelORCID,Endres MatthiasORCID,Ferreira Leslie E.ORCID,Geerlings Mirjam I.,Gasca Natalie C.ORCID,Gudnason VilmundurORCID,Hata JunORCID,He Jing,Heath Alicia K.ORCID,Ho Yuk-Lam,Havulinna Aki S.ORCID,Hopewell Jemma C.,Hyacinth Hyacinth I.,Inouye MichaelORCID,Jacob Mina A.,Jeon Christina E.ORCID,Jern Christina,Kamouchi Masahiro,Keene Keith L.ORCID,Kitazono Takanari,Kittner Steven J.,Konuma Takahiro,Kumar AmitORCID,Lacaze PaulORCID,Launer Lenore J.ORCID,Lee Keon-Joo,Lepik KaidoORCID,Li JiangORCID,Li LimingORCID,Manichaikul AniORCID,Markus Hugh S.,Marston Nicholas A.,Meitinger Thomas,Mitchell Braxton D.,Montellano Felipe A.ORCID,Morisaki Takayuki,Mosley Thomas H.,Nalls Mike A.,Nordestgaard Børge G.ORCID,O’Donnell Martin J.,Okada YukinoriORCID,Onland-Moret N. Charlotte,Ovbiagele Bruce,Peters AnnetteORCID,Psaty Bruce M.ORCID,Rich Stephen S.ORCID,Rosand Jonathan,Sabatine Marc S.,Sacco Ralph L.,Saleheen DanishORCID,Sandset Else Charlotte,Salomaa VeikkoORCID,Sargurupremraj MuralidharanORCID,Sasaki MakotoORCID,Satizabal Claudia L.ORCID,Schmidt Carsten O.,Shimizu AtsushiORCID,Smith Nicholas L.,Sloane Kelly L.,Sutoh Yoichi,Sun Yan V.ORCID,Tanno KozoORCID,Tiedt SteffenORCID,Tatlisumak Turgut,Torres-Aguila Nuria P.,Tiwari Hemant K.,Trégouët David-Alexandre,Trompet StellaORCID,Tuladhar Anil Man,Tybjærg-Hansen Anne,van Vugt MarionORCID,Vibo RiinaORCID,Verma Shefali S.,Wiggins Kerri L.ORCID,Wennberg Patrik,Woo Daniel,Wilson Peter W. F.,Xu HuichunORCID,Yang QiongORCID,Yoon KyungheonORCID,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,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,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,Esko Tõnu,Metspalu Andres,Mägi Reedik,Nelis Mari,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,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,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.,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,Le Grand Quentin,Ferreira Leslie E.,Nagai Akiko,Murakami Yoishinori,Geerlings Mirjam I.,Gasca Natalie C.ORCID,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,de Jager Phil L.,de Cid Rafael,Nordestgaard Børge G.,Sargurupremraj Muralidharan,Verma Shefali S.,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.,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 M. J.,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 ChristianORCID,Ninomiya ToshiharuORCID,Grabe Hans J.,Jukema J. WouterORCID,Rissanen Ina L.,Strbian Daniel,Kim Young JinORCID,Chen Pei-Hsin,Mayerhofer ErnstORCID,Howson Joanna M. M.ORCID,Irvin Marguerite R.,Adams HieabORCID,Wassertheil-Smoller SylviaORCID,Christensen KaareORCID,Ikram Mohammad A.ORCID,Rundek TatjanaORCID,Worrall Bradford B.ORCID,Lathrop G. Mark,Riaz Moeen,Simonsick Eleanor M.,Kõrv JanikaORCID,França Paulo H. C.ORCID,Zand Ramin,Prasad Kameshwar,Frikke-Schmidt RuthORCID,de Leeuw Frank-Erik,Liman Thomas,Haeusler Karl GeorgORCID,Ruigrok Ynte M.,Heuschmann Peter UlrichORCID,Longstreth W. T.,Jung Keum Ji,Bastarache Lisa,Paré GuillaumeORCID,Damrauer Scott M.,Chasman Daniel I.ORCID,Rotter Jerome I.,Anderson Christopher D.,Zwart John-AnkerORCID,Niiranen Teemu J.ORCID,Fornage MyriamORCID,Liaw Yung-Po,Seshadri SudhaORCID,Fernández-Cadenas Israel,Walters Robin G.ORCID,Ruff Christian T.,Owolabi Mayowa O.ORCID,Huffman Jennifer E.ORCID,Milani LiliORCID,Kamatani Yoichiro,Dichgans MartinORCID,Debette Stephanie, , , , , , , , , , , , , , , , , , , , , , , , , ,

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.

Publisher

Springer Science and Business Media LLC

Subject

Multidisciplinary

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