Matthew Traylor1,2, Christopher D Anderson3,4,5,6, Loes C A Rutten-Jacobs7, Guido J Falcone8, Mary E Comeau9, Hakan Ay10,11, Cathie L M Sudlow12,13, Huichun Xu14, Braxton D Mitchell14,15, John W Cole16,17, Kathryn Rexrode18, Jordi Jimenez-Conde19,20, Reinhold Schmidt21, Raji P Grewal22, Ralph Sacco23, Marta Ribases24,25,26, Tatjana Rundek23, Jonathan Rosand3,4,5,6, Martin Dichgans27,28, Jin-Moo Lee29, Carl D Langefeld9, Steven J Kittner16,17, Hugh S Markus1, Daniel Woo30, Rainer Malik27. 1. Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge (M.T., H.S.M.). 2. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London (M.T.). 3. Center for Genomic Medicine (C.D.A., J.R.), Massachusetts General Hospital, Boston. 4. J. Philip Kistler Stroke Research Center, Department of Neurology (C.D.A., J.R.), Massachusetts General Hospital, Boston. 5. Division of Neurocritical Care and Emergency Neurology, Department of Neurology (C.D.A., J.R.), Massachusetts General Hospital, Boston. 6. Program in Medical and Population Genetics, Broad Inst, Cambridge, MA (C.D.A., J.R.). 7. German Center for Neurodegenerative Diseases, Population Health Sciences, Bonn, Germany (L.C.A.R.-J.). 8. Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT (G.J.F.). 9. Department of Biostatistical Sciences, Division of Public Health Sciences, School of Medicine, Wake Forest University, Winston-Salem, NC (M.E.C., C.D.L.). 10. Stroke Service (H.A.), Massachusetts General Hospital, Boston. 11. A.A. Martinos Center for Biomedical Imaging, Department of Radiology (H.A.), Massachusetts General Hospital, Boston. 12. Center for Clinical Brain Sciences, University of Edinburgh (C.L.M.S.). 13. Usher Institute of Population Health Sciences and Informatics, Nine Bioquarter, Edinburgh, United Kingdom (C.L.M.S.). 14. Division of Endocrinology, Diabetes and Nutrition, Department of Medicine (H.X., B.D.M.,), University of Maryland School of Medicine. 15. Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center (B.D.M.). 16. Department of Neurology (S.J.K., J.W.C), University of Maryland School of Medicine. 17. Department of Neurology, Veterans Affairs Medical Center, Baltimore, MD (J.W.C., S.J.K). 18. Channing Division of Network Medicine and Division of Women's Health, Department of Medicine, Brigham and Women's Hospital, Boston, MA (K.R.). 19. Neurovascular Research Unit, Department of Neurology (J.J.-C.), Institut Municipal d'Investigacio´ Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Spain. 20. Program in Inflammation and Cardiovascular Disorders (J.J.-C.), Institut Municipal d'Investigacio´ Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Spain. 21. Department of Neurology, Medical University of Graz, Austria (R. Schmidt). 22. Neuroscience Institute, Saint Francis Medical Center, School of Health and Medical Sciences, Seton Hall University, South Orange, NJ (R.P.G.). 23. Department of Neurology, Miller School of Medicine, University of Miami, FL (R. Sacco, T.R.). 24. Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (M.R.). 25. Department of Psychiatry, Hospital Universitari Vall d'Hebron (M.R.). 26. Biomedical Network Research Center on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain (M.R.). 27. Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München (M.D., R.M.). 28. Munich Cluster for Systems Neurology (SyNergy), Germany (M.D.). 29. Department of Neurology, Radiology, and Biomedical Engineering, Washington University School of Medicine, St Louis, MO (J.-M.L.). 30. Department of Neurology and Rehabilitation Medicine and Comprehensive Stroke Center, University of Cincinnati, OH (D.W.).
Abstract
BACKGROUND: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes. METHODS: We performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. RESULTS: Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes. CONCLUSIONS: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.
BACKGROUND: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes. METHODS: We performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. RESULTS: Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes. CONCLUSIONS: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.
Authors: Daniel Woo; Guido J Falcone; William J Devan; W Mark Brown; Alessandro Biffi; Timothy D Howard; Christopher D Anderson; H Bart Brouwers; Valerie Valant; Thomas W K Battey; Farid Radmanesh; Miriam R Raffeld; Sylvia Baedorf-Kassis; Ranjan Deka; Jessica G Woo; Lisa J Martin; Mary Haverbusch; Charles J Moomaw; Guangyun Sun; Joseph P Broderick; Matthew L Flaherty; Sharyl R Martini; Dawn O Kleindorfer; Brett Kissela; Mary E Comeau; Jeremiasz M Jagiella; Helena Schmidt; Paul Freudenberger; Alexander Pichler; Christian Enzinger; Björn M Hansen; Bo Norrving; Jordi Jimenez-Conde; Eva Giralt-Steinhauer; Roberto Elosua; Elisa Cuadrado-Godia; Carolina Soriano; Jaume Roquer; Peter Kraft; Alison M Ayres; Kristin Schwab; Jacob L McCauley; Joanna Pera; Andrzej Urbanik; Natalia S Rost; Joshua N Goldstein; Anand Viswanathan; Eva-Maria Stögerer; David L Tirschwell; Magdy Selim; Devin L Brown; Scott L Silliman; Bradford B Worrall; James F Meschia; Chelsea S Kidwell; Joan Montaner; Israel Fernandez-Cadenas; Pilar Delgado; Rainer Malik; Martin Dichgans; Steven M Greenberg; Peter M Rothwell; Arne Lindgren; Agnieszka Slowik; Reinhold Schmidt; Carl D Langefeld; Jonathan Rosand Journal: Am J Hum Genet Date: 2014-03-20 Impact factor: 11.025
Authors: Danny Ramzy; Vivek Rao; Laura C Tumiati; Ning Xu; Rohit Sheshgiri; Santiago Miriuka; Diego H Delgado; Heather J Ross Journal: Circulation Date: 2006-07-04 Impact factor: 29.690
Authors: Peter M Visscher; Naomi R Wray; Qian Zhang; Pamela Sklar; Mark I McCarthy; Matthew A Brown; Jian Yang Journal: Am J Hum Genet Date: 2017-07-06 Impact factor: 11.025
Authors: Padhraig Gormley; Verneri Anttila; Bendik S Winsvold; Priit Palta; Tonu Esko; Tune H Pers; Kai-How Farh; Ester Cuenca-Leon; Mikko Muona; Nicholas A Furlotte; Tobias Kurth; Andres Ingason; George McMahon; Lannie Ligthart; Gisela M Terwindt; Mikko Kallela; Tobias M Freilinger; Caroline Ran; Scott G Gordon; Anine H Stam; Stacy Steinberg; Guntram Borck; Markku Koiranen; Lydia Quaye; Hieab H H Adams; Terho Lehtimäki; Antti-Pekka Sarin; Juho Wedenoja; David A Hinds; Julie E Buring; Markus Schürks; Paul M Ridker; Maria Gudlaug Hrafnsdottir; Hreinn Stefansson; Susan M Ring; Jouke-Jan Hottenga; Brenda W J H Penninx; Markus Färkkilä; Ville Artto; Mari Kaunisto; Salli Vepsäläinen; Rainer Malik; Andrew C Heath; Pamela A F Madden; Nicholas G Martin; Grant W Montgomery; Mitja I Kurki; Mart Kals; Reedik Mägi; Kalle Pärn; Eija Hämäläinen; Hailiang Huang; Andrea E Byrnes; Lude Franke; Jie Huang; Evie Stergiakouli; Phil H Lee; Cynthia Sandor; Caleb Webber; Zameel Cader; Bertram Muller-Myhsok; Stefan Schreiber; Thomas Meitinger; Johan G Eriksson; Veikko Salomaa; Kauko Heikkilä; Elizabeth Loehrer; Andre G Uitterlinden; Albert Hofman; Cornelia M van Duijn; Lynn Cherkas; Linda M Pedersen; Audun Stubhaug; Christopher S Nielsen; Minna Männikkö; Evelin Mihailov; Lili Milani; Hartmut Göbel; Ann-Louise Esserlind; Anne Francke Christensen; Thomas Folkmann Hansen; Thomas Werge; Jaakko Kaprio; Arpo J Aromaa; Olli Raitakari; M Arfan Ikram; Tim Spector; Marjo-Riitta Järvelin; Andres Metspalu; Christian Kubisch; David P Strachan; Michel D Ferrari; Andrea C Belin; Martin Dichgans; Maija Wessman; Arn M J M van den Maagdenberg; John-Anker Zwart; Dorret I Boomsma; George Davey Smith; Kari Stefansson; Nicholas Eriksson; Mark J Daly; Benjamin M Neale; Jes Olesen; Daniel I Chasman; Dale R Nyholt; Aarno Palotie Journal: Nat Genet Date: 2016-06-20 Impact factor: 38.330
Authors: Joanna M M Howson; Wei Zhao; Daniel R Barnes; Weang-Kee Ho; Robin Young; Dirk S Paul; Lindsay L Waite; Daniel F Freitag; Eric B Fauman; Elias L Salfati; Benjamin B Sun; John D Eicher; Andrew D Johnson; Wayne H H Sheu; Sune F Nielsen; Wei-Yu Lin; Praveen Surendran; Anders Malarstig; Jemma B Wilk; Anne Tybjærg-Hansen; Katrine L Rasmussen; Pia R Kamstrup; Panos Deloukas; Jeanette Erdmann; Sekar Kathiresan; Nilesh J Samani; Heribert Schunkert; Hugh Watkins; Ron Do; Daniel J Rader; Julie A Johnson; Stanley L Hazen; Arshed A Quyyumi; John A Spertus; Carl J Pepine; Nora Franceschini; Anne Justice; Alex P Reiner; Steven Buyske; Lucia A Hindorff; Cara L Carty; Kari E North; Charles Kooperberg; Eric Boerwinkle; Kristin Young; Mariaelisa Graff; Ulrike Peters; Devin Absher; Chao A Hsiung; Wen-Jane Lee; Kent D Taylor; Ying-Hsiang Chen; I-Te Lee; Xiuqing Guo; Ren-Hua Chung; Yi-Jen Hung; Jerome I Rotter; Jyh-Ming J Juang; Thomas Quertermous; Tzung-Dau Wang; Asif Rasheed; Philippe Frossard; Dewan S Alam; Abdulla Al Shafi Majumder; Emanuele Di Angelantonio; Rajiv Chowdhury; Yii-Der Ida Chen; Børge G Nordestgaard; Themistocles L Assimes; John Danesh; Adam S Butterworth; Danish Saleheen Journal: Nat Genet Date: 2017-05-22 Impact factor: 41.307
Authors: Céline Bellenguez; Steve Bevan; Andreas Gschwendtner; Chris C A Spencer; Annette I Burgess; Matti Pirinen; Caroline A Jackson; Matthew Traylor; Amy Strange; Zhan Su; Gavin Band; Paul D Syme; Rainer Malik; Joanna Pera; Bo Norrving; Robin Lemmens; Colin Freeman; Renata Schanz; Tom James; Deborah Poole; Lee Murphy; Helen Segal; Lynelle Cortellini; Yu-Ching Cheng; Daniel Woo; Michael A Nalls; Bertram Müller-Myhsok; Christa Meisinger; Udo Seedorf; Helen Ross-Adams; Steven Boonen; Dorota Wloch-Kopec; Valerie Valant; Julia Slark; Karen Furie; Hossein Delavaran; Cordelia Langford; Panos Deloukas; Sarah Edkins; Sarah Hunt; Emma Gray; Serge Dronov; Leena Peltonen; Solveig Gretarsdottir; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Kari Stefansson; Giorgio B Boncoraglio; Eugenio A Parati; John Attia; Elizabeth Holliday; Chris Levi; Maria-Grazia Franzosi; Anuj Goel; Anna Helgadottir; Jenefer M Blackwell; Elvira Bramon; Matthew A Brown; Juan P Casas; Aiden Corvin; Audrey Duncanson; Janusz Jankowski; Christopher G Mathew; Colin N A Palmer; Robert Plomin; Anna Rautanen; Stephen J Sawcer; Richard C Trembath; Ananth C Viswanathan; Nicholas W Wood; Bradford B Worrall; Steven J Kittner; Braxton D Mitchell; Brett Kissela; James F Meschia; Vincent Thijs; Arne Lindgren; Mary Joan Macleod; Agnieszka Slowik; Matthew Walters; Jonathan Rosand; Pankaj Sharma; Martin Farrall; Cathie L M Sudlow; Peter M Rothwell; Martin Dichgans; Peter Donnelly; Hugh S Markus Journal: Nat Genet Date: 2012-02-05 Impact factor: 38.330
Authors: Carolina Roselli; Mark D Chaffin; Lu-Chen Weng; Stefanie Aeschbacher; Gustav Ahlberg; Christine M Albert; Peter Almgren; Alvaro Alonso; Christopher D Anderson; Krishna G Aragam; Dan E Arking; John Barnard; Traci M Bartz; Emelia J Benjamin; Nathan A Bihlmeyer; Joshua C Bis; Heather L Bloom; Eric Boerwinkle; Erwin B Bottinger; Jennifer A Brody; Hugh Calkins; Archie Campbell; Thomas P Cappola; John Carlquist; Daniel I Chasman; Lin Y Chen; Yii-Der Ida Chen; Eue-Keun Choi; Seung Hoan Choi; Ingrid E Christophersen; Mina K Chung; John W Cole; David Conen; James Cook; Harry J Crijns; Michael J Cutler; Scott M Damrauer; Brian R Daniels; Dawood Darbar; Graciela Delgado; Joshua C Denny; Martin Dichgans; Marcus Dörr; Elton A Dudink; Samuel C Dudley; Nada Esa; Tonu Esko; Markku Eskola; Diane Fatkin; Stephan B Felix; Ian Ford; Oscar H Franco; Bastiaan Geelhoed; Raji P Grewal; Vilmundur Gudnason; Xiuqing Guo; Namrata Gupta; Stefan Gustafsson; Rebecca Gutmann; Anders Hamsten; Tamara B Harris; Caroline Hayward; Susan R Heckbert; Jussi Hernesniemi; Lynne J Hocking; Albert Hofman; Andrea R V R Horimoto; Jie Huang; Paul L Huang; Jennifer Huffman; Erik Ingelsson; Esra Gucuk Ipek; Kaoru Ito; Jordi Jimenez-Conde; Renee Johnson; J Wouter Jukema; Stefan Kääb; Mika Kähönen; Yoichiro Kamatani; John P Kane; Adnan Kastrati; Sekar Kathiresan; Petra Katschnig-Winter; Maryam Kavousi; Thorsten Kessler; Bas L Kietselaer; Paulus Kirchhof; Marcus E Kleber; Stacey Knight; Jose E Krieger; Michiaki Kubo; Lenore J Launer; Jari Laurikka; Terho Lehtimäki; Kirsten Leineweber; Rozenn N Lemaitre; Man Li; Hong Euy Lim; Henry J Lin; Honghuang Lin; Lars Lind; Cecilia M Lindgren; Marja-Liisa Lokki; Barry London; Ruth J F Loos; Siew-Kee Low; Yingchang Lu; Leo-Pekka Lyytikäinen; Peter W Macfarlane; Patrik K Magnusson; Anubha Mahajan; Rainer Malik; Alfredo J Mansur; Gregory M Marcus; Lauren Margolin; Kenneth B Margulies; Winfried März; David D McManus; Olle Melander; Sanghamitra Mohanty; Jay A Montgomery; Michael P Morley; Andrew P Morris; Martina Müller-Nurasyid; Andrea Natale; Saman Nazarian; Benjamin Neumann; Christopher Newton-Cheh; Maartje N Niemeijer; Kjell Nikus; Peter Nilsson; Raymond Noordam; Heidi Oellers; Morten S Olesen; Marju Orho-Melander; Sandosh Padmanabhan; Hui-Nam Pak; Guillaume Paré; Nancy L Pedersen; Joanna Pera; Alexandre Pereira; David Porteous; Bruce M Psaty; Sara L Pulit; Clive R Pullinger; Daniel J Rader; Lena Refsgaard; Marta Ribasés; Paul M Ridker; Michiel Rienstra; Lorenz Risch; Dan M Roden; Jonathan Rosand; Michael A Rosenberg; Natalia Rost; Jerome I Rotter; Samir Saba; Roopinder K Sandhu; Renate B Schnabel; Katharina Schramm; Heribert Schunkert; Claudia Schurman; Stuart A Scott; Ilkka Seppälä; Christian Shaffer; Svati Shah; Alaa A Shalaby; Jaemin Shim; M Benjamin Shoemaker; Joylene E Siland; Juha Sinisalo; Moritz F Sinner; Agnieszka Slowik; Albert V Smith; Blair H Smith; J Gustav Smith; Jonathan D Smith; Nicholas L Smith; Elsayed Z Soliman; Nona Sotoodehnia; Bruno H Stricker; Albert Sun; Han Sun; Jesper H Svendsen; Toshihiro Tanaka; Kahraman Tanriverdi; Kent D Taylor; Maris Teder-Laving; Alexander Teumer; Sébastien Thériault; Stella Trompet; Nathan R Tucker; Arnljot Tveit; Andre G Uitterlinden; Pim Van Der Harst; Isabelle C Van Gelder; David R Van Wagoner; Niek Verweij; Efthymia Vlachopoulou; Uwe Völker; Biqi Wang; Peter E Weeke; Bob Weijs; Raul Weiss; Stefan Weiss; Quinn S Wells; Kerri L Wiggins; Jorge A Wong; Daniel Woo; Bradford B Worrall; Pil-Sung Yang; Jie Yao; Zachary T Yoneda; Tanja Zeller; Lingyao Zeng; Steven A Lubitz; Kathryn L Lunetta; Patrick T Ellinor Journal: Nat Genet Date: 2018-06-11 Impact factor: 38.330