← Back to cohort
Stroke genetics informs drug discovery and risk prediction across ancestries
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, Kristian Hveem, Sara Lindstrom, Lu Wang, Erin N. Smith, William Gordon, Astrid van Hylckama Vlieg, Mariza de Andrade, Jennifer A. Brody, Jack Pattee, 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, 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, Christopher Levi, Jane Maguire, Jordi Jiménez‐Conde, Pankaj Sharma, Cathie Sudlow, Kristiina Rannikmäe, Reinhold Schmidt, Agnieszka Slowik, Joanna Pera, Vincent Thijs, 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, Owen A. Ross, Robin Lemmons, Martin Söderholm, Mary Cushman, Katarina Jood, Caitrin W. McDonough, Steven Bell, Birgit Linkohr, Tsong-Hai Lee, Jukka Putaala, 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, 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, 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, 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, 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, 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, Akiko Nagai, Yoishinori Murakami, Eric J. Shiroma, Sigurður Sigurðsson, Mohsen Ghanbari, Eric Boerwinkle, Bernard Fongang, Ruiqi Wang, M. Kamran Ikram, Uwe Völker, 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, Tom den Heijer, Gert W. van Dijk, Frank G. W. van Rooij, Anne Hege Aamodt, Anne Heidi Skogholt, Cristen J. Willer, Ingrid Heuch, Knut Hagen, Lars G. Fritsche, Linda M. Pedersen, Hanne Ellekjær, Wei Zhou, Amy E. Martinsen, Espen Saxhaug Kristoffersen, Laurent F. Thomas, Christoph Kleinschnitz, Stefan Frantz, Kathrin Ungethüm, Cristina Gallego-Fábrega, Miquel Lledós, Laia Llucià‐Carol, Tomás Sobrino, Francisco Campos, José Castillo, 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, Rajat Dhar, Raquel Delgado‐Mederos, Pol Camps‐Renom, Natàlia Blay, Lauro Sumoy, Joan Martí‐Fábregas, Peter Schnohr, Gorm Boje 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, Chengran Yang, Florence Saillour-Glenisson, Simon Gravel, 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, 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, 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, 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, Martin Dichgans, Stéphanie Debette
Bibliographic record
VenueNature · 2022
Typereview
Languageen
FieldBiochemistry, Genetics and Molecular Biology
TopicGenetic Associations and Epidemiology
Canadian institutionsMcGill Genome CentreImpactMcGill UniversityPopulation Health Research InstituteMcMaster UniversityUniversity of TorontoUniversity Health NetworkUniversity of British ColumbiaOntario Brain InstituteThrombosis and Atherosclerosis Research Institute
FundersFaculty of Medicine and Health, University of SydneyNational Heart, Lung, and Blood InstituteErasmus Universitair Medisch Centrum RotterdamCenter for Clinical and Translational Science, Ohio State UniversityOhio State UniversityUniversity of TokyoAgence Nationale de la RechercheUniversiteit MaastrichtUniversiteit van AmsterdamMedical Research CouncilLeids Universitair Medisch CentrumUniversiteit LeidenStatens Serum InstitutUniversity of BristolInstitut National de la Santé et de la Recherche MédicaleInstitut National de Recherche pour l'Agriculture, l'Alimentation et l'EnvironnementNational Human Genome Research InstituteAmsterdam University Medical CentersU.S. National Library of MedicineNational Institute of Neurological Disorders and StrokeBritish Heart FoundationWellcome TrustNational Institute of Diabetes and Digestive and Kidney DiseasesNorges Teknisk-Naturvitenskapelige UniversitetUniversity of WashingtonLundbeckfondenMassachusetts General HospitalUniversity of MinnesotaNational Institute on AgingNational Institute for Health and Care ResearchUniversitair Medisch Centrum GroningenMcKnight FoundationMaastricht Universitair Medisch CentrumUniversity of California, San DiegoU.S. Department of Veterans Affairs
KeywordsGenome-wide association studyStroke (engine)Genetic associationGeneticsBiologyMedicineBioinformaticsGeneSingle-nucleotide polymorphismGenotype
Abstract
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.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
metaresearch head score (Codex)0.007
metaresearch head score (Gemma)0.014
Version: metacan-v3-hybrid-931329e0061cValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Systematic review · Consensus signal: none
GenreCandidate signal: Review · Consensus signal: none
Teacher disagreement score0.007
Threshold uncertainty score0.035
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.007 | 0.014 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.003 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
Opus teacher head0.014
GPT teacher head0.315
Teacher spread0.301 · how far apart the two teachers sit on this one work
Validation status
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
The models applied no category: nothing in the taxonomy fit this work.
Study designSystematic review
Domainnot available
GenreReview
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".
Quick stats
Citations603
Published2022
Admission routes1
Has abstractyes