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Stroke genetics informs drug discovery and risk prediction across ancestries
Nature ( IF 50.5 ) Pub Date : 2022-09-30 , DOI: 10.1038/s41586-022-05165-3
Aniket Mishra , Rainer Malik , Tsuyoshi Hachiya , Tuuli Jürgenson , Shinichi Namba , Daniel C. Posner , Frederick K. 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 R. 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 L. 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 E. Ferreira , Mirjam I. Geerlings , Natalie C. Gasca , Vilmundur Gudnason , 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 E. 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 J. 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. Satizabal , Carsten O. Schmidt , Atsushi Shimizu , Nicholas L. 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 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 MacDonald , Sigrid K. Braekkan , 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 , Alexander P. Reiner , Maiken E. 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 , 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 , Tõnu Esko , Andres Metspalu , Reedik Mägi , Mari Nelis , Marguerite R. Irvin , Frank-Erik de Leeuw , Christopher R. Levi , Jane Maguire , Jordi Jiménez-Conde , Pankaj Sharma , Cathie L. M. Sudlow , Kristiina Rannikmäe , Reinhold Schmidt , Agnieszka Slowik , Joanna Pera , Vincent N. S. 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 Weir , Rebecca D. Jackson , Owen A. Ross , Robin Lemmons , Martin Soderholm , 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 , Natalia Cullell , Pilar Delgado , Laura Ibañez , Jerzy Krupinski , Vasileios Lioutas , Koichi Matsuda , Joan Montaner , Elena Muiño , Jaume Roquer , Chloe Sarnowski , Naveed Sattar , Gerli Sibolt , Alexander Teumer , Loes Rutten-Jacobs , Masahiro Kanai , Anne-Katrin Giese , Solveig Gretarsdottir , 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 O. Kleindorfer , Claudia Langenberg , Robin Lemmens , Didier Leys , Wei-Yu Lin , Erik Lorentzen , Patrik K. Magnusson , Patrick F. McArdle , Sara L. Pulit , Kenneth Rice , Saori Sakaue , Bishwa R. Sapkota , Christian Tanislav , Gudmar Thorleifsson , Unnur Thorsteinsdottir , Christophe Tzourio , Cornelia M. van Duijn , Matthew Walters , Nicholas J. Wareham , Najaf Amin , Hugo J. 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 , Olafur Kjartansson , Manja Kloss , Daniel L. Labovitz , Cathy C. Laurie , Linxin Li , Lars Lind , Cecilia M. Lindgren , Hirata Makoto , Naoko Minegishi , Andrew P. Morris , Martina Müller-Nurasyid , Bo Norrving , Soichi Ogishima , Eugenio A. Parati , Nancy L. Pedersen , Markus Perola , Pekka Jousilahti , Silvana Pileggi , Raquel Rabionet , Iolanda Riba-Llena , Marta Ribasés , Jose R. Romero , Anthony G. Rudd , Antti-Pekka Sarin , Ralhan Sarju , Mamoru Satoh , Norie Sawada , Ásgeir Sigurdsson , Albert Smith , O. Colin Stine , David J. Stott , Konstantin Strauch , Takako Takai , Hideo Tanaka , Emmanuel Touze , Shoichiro Tsugane , Andre G. Uitterlinden , Einar M. 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 Akpa , Fred S. 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 G. Fakunle , Ezinne Uvere , Abimbola Olalere , Olayinka J. Adebajo , 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 , Quentin Le Grand , Leslie E. Ferreira , Akiko Nagai , Yoishinori Murakami , Mirjam I. Geerlings , Natalie C. Gasca , Vilmundur Gudnason , Marion van Vugt , Rebecca F. Gottesman , Eric J. Shiroma , Sigurdur Sigurdsson , Mohsen Ghanbari , Eric Boerwinkle , Alexa S. Beiser , Bernard Fongang , Ruiqi Wang , Mohammad K. Ikram , Uwe Völker , Phil L. de Jager , Rafael de Cid , Børge G. Nordestgaard , Muralidharan Sargurupremraj , Shefali S. Verma , Karlijn F. de Laat , Anouk G. W. van Norden , Paul L. 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 , Anne H. Aamodt , Anne H. 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 S. Kristoffersen , Jonas B. Nielsen , Kristian Hveem , Laurent F. Thomas , Christoph Kleinschnitz , Stefan Frantz , Kathrin Ungethüm , Cristina Gallego-Fabrega , Miquel Lledós , Laia Llucià-Carol , Tomas Sobrino , Francisco Campos , José Castillo , Marimar Freijó , Juan Francisco Arenillas , Victor Obach , José Álvarez-Sabín , Carlos A. Molina , Marc Ribó , Lucia Muñoz-Narbona , Elena Lopez-Cancio , Mònica Millán , Rosa Diaz-Navarro , Cristòfol Vives-Bauza , Gemma Serrano-Heras , Tomás Segura , Pilar Delgado , Rajat Dhar , Raquel Delgado-Mederos , Luis Prats-Sánchez , Pol Camps-Renom , Natalia Blay , Lauro Sumoy , Joan Martí-Fàbregas , Peter Schnohr , Gorm B. Jensen , Marianne Benn , Shoaib Afzal , Pia R. Kamstrup , Jessica van Setten , Sander W. van der Laan , Jet M. J. Vonk , Bong-Jo Kim , Sami Curtze , Marjaana Tiainen , Janne Kinnunen , Vilas Menon , Yun Ju Sung , Chengran Yang , Florence Saillour-Glenisson , Simon Gravel , 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 Adams , Sylvia Wassertheil-Smoller , Kaare Christensen , Mohammad A. Ikram , Tatjana Rundek , Bradford B. Worrall , G. Mark Lathrop , Moeen Riaz , Eleanor M. Simonsick , Janika Kõrv , Paulo H. C. França , Ramin Zand , Kameshwar Prasad , Ruth Frikke-Schmidt , Frank-Erik de Leeuw , Thomas Liman , Karl Georg Haeusler , Ynte M. Ruigrok , Peter Ulrich 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 J. Niiranen , Myriam Fornage , Yung-Po Liaw , Sudha Seshadri , Israel Fernández-Cadenas , Robin G. Walters , Christian T. Ruff , Mayowa O. Owolabi , Jennifer E. Huffman , Lili Milani , Yoichiro Kamatani , Martin Dichgans , Stephanie Debette , , , , , , , , , , , , , , , , , , , , , , , , , ,

Previous 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.



中文翻译:


中风遗传学为跨血统的药物发现和风险预测提供信息



此前针对中风(全球第二大死因)的全基因组关联研究 (GWAS) 主要在欧洲血统人群中进行1,2 。在这里,在对 110,182 名中风患者(5 个血统,33% 非欧洲人)和 1,503,898 名对照个体进行的跨血统 GWAS 荟萃分析中,我们在 89 个(61 个新的)独立位点识别出中风及其亚型的关联信号:主要逆方差加权分析为 60,次要元回归和多性状分析为 29。根据内部跨血统验证和对另外 89,084 例中风病例(30% 非欧洲)和 1,013,843 名对照个体的独立随访,87% 的主要中风风险位点和 60% 的继发中风风险位点重复( P < 0.05)。不同血统的效应大小高度相关。跨祖先精细作图、计算机诱变分析3以及全转录组和全蛋白质组关联分析揭示了假定的因果基因(例如SH3PXD2AFURIN )和变异(例如GRK5NOS3 )。我们采用三管齐下的方法4 ,为假定的药物效应提供遗传证据,强调 F11、KLKB1、PROC、GP1BA、LAMC2 和 VCAM1 作为可能的靶标,并且已经在研究针对 F11 和 PROC 的中风药物。将跨血统和血统特异性中风 GWAS 与血管危险因素 GWAS(综合多基因评分)相结合的多基因评分强烈预测欧洲、东亚和非洲血统人群中的缺血性中风5 。 在 52,600 名患有心脏代谢疾病的临床试验参与者中,中风遗传风险评分可预测缺血性中风,与临床危险因素无关。我们的研究结果为生物学提供了见解,揭示了潜在的药物靶点,并得出跨祖先的遗传风险预测工具。

更新日期:2022-09-30
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