Rainer Malik1, Steve Bevan, Michael A Nalls, Elizabeth G Holliday, William J Devan, Yu-Ching Cheng, Carla A Ibrahim-Verbaas, Benjamin F J Verhaaren, Joshua C Bis, Aron Y Joon, Anita L de Stefano, Myriam Fornage, Bruce M Psaty, M Arfan Ikram, Lenore J Launer, Cornelia M van Duijn, Pankaj Sharma, Braxton D Mitchell, Jonathan Rosand, James F Meschia, Christopher Levi, Peter M Rothwell, Cathie Sudlow, Hugh S Markus, Sudha Seshadri, Martin Dichgans. 1. From the Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany (R.M., M.D.); Stroke and Dementia Research Centre, St George's University of London, London, United Kingdom (S.B., H.S.M.); Laboratory of Neurogenetics (M.A.N.) and Laboratory of Epidemiology and Population Sciences (L.J.L.), National Institute on Aging, National Institutes of Health, Bethesda, MD; Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health (E.G.H.) and Center for Translational Neuroscience and Mental Health Research (C.L.), University of Newcastle, Callaghan, NSW, Australia; Center for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, New Lambton, NSW, Australia (E.G.H.); Department of Neurology, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA (W.J.D., J.R.); Department of Medicine, University of Maryland School of Medicine, Baltimore, MD (Y.-C.C., B.D.M.); Department of Veterans Affairs and Veterans Affairs Medical Center, Baltimore Geriatric Research, Education, and Clinical Center (GRECC), Baltimore, MD (Y.-C.C., B.D.M.); Department of Epidemiology (C.A.I.-V., B.F.J.V., M.A.I., C.M.v.D.), Department of Neurology (C.A.I.-V., M.A.I.), and Department of Radiology (B.F.J.V., M.A.I.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Cardiovascular Health Research Unit (J.C.B., B.M.P.), Department of Medicine (J.C.B., B.M.P.), Department of Epidemiology (B.M.P.), and Department of Health Services (B.M.P.), University of Washington, Seattle, WA; Institute for Molecular Medicine (A.Y.J., M.F.) and Human Genetics Center (M.F.), University of Texas Health Science Center at Houston; Department of Neurology, Boston University School of Medicine, Boston, MA (A.L.d.S., S.S.); Department of Biostatistics, Boston University School of Public Health, Boston, MA (A.L.d.S.); The National Heart, Lung and
Abstract
BACKGROUND AND PURPOSE: Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts. METHODS: Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS. RESULTS: A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification. CONCLUSIONS: A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small.
BACKGROUND AND PURPOSE: Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts. METHODS: Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS. RESULTS: A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification. CONCLUSIONS: A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small.
Authors: Sholom Wacholder; Patricia Hartge; Ross Prentice; Montserrat Garcia-Closas; Heather Spencer Feigelson; W Ryan Diver; Michael J Thun; David G Cox; Susan E Hankinson; Peter Kraft; Bernard Rosner; Christine D Berg; Louise A Brinton; Jolanta Lissowska; Mark E Sherman; Rowan Chlebowski; Charles Kooperberg; Rebecca D Jackson; Dennis W Buckman; Peter Hui; Ruth Pfeiffer; Kevin B Jacobs; Gilles D Thomas; Robert N Hoover; Mitchell H Gail; Stephen J Chanock; David J Hunter Journal: N Engl J Med Date: 2010-03-18 Impact factor: 91.245
Authors: Lucia A Hindorff; Praveen Sethupathy; Heather A Junkins; Erin M Ramos; Jayashri P Mehta; Francis S Collins; Teri A Manolio Journal: Proc Natl Acad Sci U S A Date: 2009-05-27 Impact factor: 11.205
Authors: Patrick T Ellinor; Kathryn L Lunetta; Christine M Albert; Nicole L Glazer; Marylyn D Ritchie; Albert V Smith; Dan E Arking; Martina Müller-Nurasyid; Bouwe P Krijthe; Steven A Lubitz; Joshua C Bis; Mina K Chung; Marcus Dörr; Kouichi Ozaki; Jason D Roberts; J Gustav Smith; Arne Pfeufer; Moritz F Sinner; Kurt Lohman; Jingzhong Ding; Nicholas L Smith; Jonathan D Smith; Michiel Rienstra; Kenneth M Rice; David R Van Wagoner; Jared W Magnani; Reza Wakili; Sebastian Clauss; Jerome I Rotter; Gerhard Steinbeck; Lenore J Launer; Robert W Davies; Matthew Borkovich; Tamara B Harris; Honghuang Lin; Uwe Völker; Henry Völzke; David J Milan; Albert Hofman; Eric Boerwinkle; Lin Y Chen; Elsayed Z Soliman; Benjamin F Voight; Guo Li; Aravinda Chakravarti; Michiaki Kubo; Usha B Tedrow; Lynda M Rose; Paul M Ridker; David Conen; Tatsuhiko Tsunoda; Tetsushi Furukawa; Nona Sotoodehnia; Siyan Xu; Naoyuki Kamatani; Daniel Levy; Yusuke Nakamura; Babar Parvez; Saagar Mahida; Karen L Furie; Jonathan Rosand; Raafia Muhammad; Bruce M Psaty; Thomas Meitinger; Siegfried Perz; H-Erich Wichmann; Jacqueline C M Witteman; W H Linda Kao; Sekar Kathiresan; Dan M Roden; Andre G Uitterlinden; Fernando Rivadeneira; Barbara McKnight; Marketa Sjögren; Anne B Newman; Yongmei Liu; Michael H Gollob; Olle Melander; Toshihiro Tanaka; Bruno H Ch Stricker; Stephan B Felix; Alvaro Alonso; Dawood Darbar; John Barnard; Daniel I Chasman; Susan R Heckbert; Emelia J Benjamin; Vilmundur Gudnason; Stefan Kääb Journal: Nat Genet Date: 2012-04-29 Impact factor: 38.330
Authors: Daniel F Gudbjartsson; Hilma Holm; Solveig Gretarsdottir; Gudmar Thorleifsson; G Bragi Walters; Gudmundur Thorgeirsson; Jeffrey Gulcher; Ellisiv B Mathiesen; Inger Njølstad; Audhild Nyrnes; Tom Wilsgaard; Erin M Hald; Kristian Hveem; Camilla Stoltenberg; Gayle Kucera; Tanya Stubblefield; Shannon Carter; Dan Roden; Maggie C Y Ng; Larry Baum; Wing Yee So; Ka Sing Wong; Juliana C N Chan; Christian Gieger; H-Erich Wichmann; Andreas Gschwendtner; Martin Dichgans; Gregor Kuhlenbäumer; Klaus Berger; E Bernd Ringelstein; Steve Bevan; Hugh S Markus; Konstantinos Kostulas; Jan Hillert; Sigurlaug Sveinbjörnsdóttir; Einar M Valdimarsson; Maja-Lisa Løchen; Ronald C W Ma; Dawood Darbar; Augustine Kong; David O Arnar; Unnur Thorsteinsdottir; Kari Stefansson Journal: Nat Genet Date: 2009-07-13 Impact factor: 38.330
Authors: Panos Deloukas; Stavroula Kanoni; Christina Willenborg; Martin Farrall; Themistocles L Assimes; John R Thompson; Erik Ingelsson; Danish Saleheen; Jeanette Erdmann; Benjamin A Goldstein; Kathleen Stirrups; Inke R König; Jean-Baptiste Cazier; Asa Johansson; Alistair S Hall; Jong-Young Lee; Cristen J Willer; John C Chambers; Tõnu Esko; Lasse Folkersen; Anuj Goel; Elin Grundberg; Aki S Havulinna; Weang K Ho; Jemma C Hopewell; Niclas Eriksson; Marcus E Kleber; Kati Kristiansson; Per Lundmark; Leo-Pekka Lyytikäinen; Suzanne Rafelt; Dmitry Shungin; Rona J Strawbridge; Gudmar Thorleifsson; Emmi Tikkanen; Natalie Van Zuydam; Benjamin F Voight; Lindsay L Waite; Weihua Zhang; Andreas Ziegler; Devin Absher; David Altshuler; Anthony J Balmforth; Inês Barroso; Peter S Braund; Christof Burgdorf; Simone Claudi-Boehm; David Cox; Maria Dimitriou; Ron Do; Alex S F Doney; NourEddine El Mokhtari; Per Eriksson; Krista Fischer; Pierre Fontanillas; Anders Franco-Cereceda; Bruna Gigante; Leif Groop; Stefan Gustafsson; Jörg Hager; Göran Hallmans; Bok-Ghee Han; Sarah E Hunt; Hyun M Kang; Thomas Illig; Thorsten Kessler; Joshua W Knowles; Genovefa Kolovou; Johanna Kuusisto; Claudia Langenberg; Cordelia Langford; Karin Leander; Marja-Liisa Lokki; Anders Lundmark; Mark I McCarthy; Christa Meisinger; Olle Melander; Evelin Mihailov; Seraya Maouche; Andrew D Morris; Martina Müller-Nurasyid; Kjell Nikus; John F Peden; N William Rayner; Asif Rasheed; Silke Rosinger; Diana Rubin; Moritz P Rumpf; Arne Schäfer; Mohan Sivananthan; Ci Song; Alexandre F R Stewart; Sian-Tsung Tan; Gudmundur Thorgeirsson; C Ellen van der Schoot; Peter J Wagner; George A Wells; Philipp S Wild; Tsun-Po Yang; Philippe Amouyel; Dominique Arveiler; Hanneke Basart; Michael Boehnke; Eric Boerwinkle; Paolo Brambilla; Francois Cambien; Adrienne L Cupples; Ulf de Faire; Abbas Dehghan; Patrick Diemert; Stephen E Epstein; Alun Evans; Marco M Ferrario; Jean Ferrières; Dominique Gauguier; Alan S Go; Alison H Goodall; Villi Gudnason; Stanley L Hazen; Hilma Holm; Carlos Iribarren; Yangsoo Jang; Mika Kähönen; Frank Kee; Hyo-Soo Kim; Norman Klopp; Wolfgang Koenig; Wolfgang Kratzer; Kari Kuulasmaa; Markku Laakso; Reijo Laaksonen; Ji-Young Lee; Lars Lind; Willem H Ouwehand; Sarah Parish; Jeong E Park; Nancy L Pedersen; Annette Peters; Thomas Quertermous; Daniel J Rader; Veikko Salomaa; Eric Schadt; Svati H Shah; Juha Sinisalo; Klaus Stark; Kari Stefansson; David-Alexandre Trégouët; Jarmo Virtamo; Lars Wallentin; Nicholas Wareham; Martina E Zimmermann; Markku S Nieminen; Christian Hengstenberg; Manjinder S Sandhu; Tomi Pastinen; Ann-Christine Syvänen; G Kees Hovingh; George Dedoussis; Paul W Franks; Terho Lehtimäki; Andres Metspalu; Pierre A Zalloua; Agneta Siegbahn; Stefan Schreiber; Samuli Ripatti; Stefan S Blankenberg; Markus Perola; Robert Clarke; Bernhard O Boehm; Christopher O'Donnell; Muredach P Reilly; Winfried März; Rory Collins; Sekar Kathiresan; Anders Hamsten; Jaspal S Kooner; Unnur Thorsteinsdottir; John Danesh; Colin N A Palmer; Robert Roberts; Hugh Watkins; Heribert Schunkert; Nilesh J Samani Journal: Nat Genet Date: 2012-12-02 Impact factor: 38.330
Authors: James B Meigs; Peter Shrader; Lisa M Sullivan; Jarred B McAteer; Caroline S Fox; Josée Dupuis; Alisa K Manning; Jose C Florez; Peter W F Wilson; Ralph B D'Agostino; L Adrienne Cupples Journal: N Engl J Med Date: 2008-11-20 Impact factor: 91.245
Authors: Frances M K Williams; Angela M Carter; Pirro G Hysi; Gabriela Surdulescu; Dylan Hodgkiss; Nicole Soranzo; Matthew Traylor; Steve Bevan; Martin Dichgans; Peter M W Rothwell; Cathie Sudlow; Martin Farrall; Kaisa Silander; Mari Kaunisto; Peter Wagner; Olli Saarela; Kari Kuulasmaa; Jarmo Virtamo; Veikko Salomaa; Philippe Amouyel; Dominique Arveiler; Jean Ferrieres; Per-Gunnar Wiklund; M Arfan Ikram; Albert Hofman; Giorgio B Boncoraglio; Eugenio A Parati; Anna Helgadottir; Solveig Gretarsdottir; Unnur Thorsteinsdottir; Gudmar Thorleifsson; Kari Stefansson; Sudha Seshadri; Anita DeStefano; Andreas Gschwendtner; Bruce Psaty; Will Longstreth; Braxton D Mitchell; Yu-Ching Cheng; Robert Clarke; Marco Ferrario; Joshua C Bis; Christopher Levi; John Attia; Elizabeth G Holliday; Rodney J Scott; Myriam Fornage; Pankaj Sharma; Karen L Furie; Jonathan Rosand; Mike Nalls; James Meschia; Thomas H Mosely; Alun Evans; Aarno Palotie; Hugh S Markus; Peter J Grant; Tim D Spector Journal: Ann Neurol Date: 2013-01 Impact factor: 10.422
Authors: Steven A Lubitz; Owen E Parsons; Christopher D Anderson; Emelia J Benjamin; Rainer Malik; Lu-Chen Weng; Martin Dichgans; Cathie L Sudlow; Peter M Rothwell; Jonathan Rosand; Patrick T Ellinor; Hugh S Markus; Matthew Traylor Journal: Stroke Date: 2017-05-03 Impact factor: 7.914
Authors: Nicholas A Marston; Parth N Patel; Steven A Lubitz; Marc S Sabatine; Christian T Ruff; Frederick K Kamanu; Francesco Nordio; Giorgio M Melloni; Carolina Roselli; Yared Gurmu; Lu-Chen Weng; Marc P Bonaca; Robert P Giugliano; Benjamin M Scirica; Michelle L O'Donoghue; Christopher P Cannon; Christopher D Anderson; Deepak L Bhatt; Philippe Gabriel Steg; Marc Cohen; Robert F Storey; Peter Sever; Anthony C Keech; Itamar Raz; Ofri Mosenzon; Elliott M Antman; Eugene Braunwald; Patrick T Ellinor Journal: Circulation Date: 2020-11-13 Impact factor: 29.690
Authors: Hayato Tada; Dov Shiffman; Sekar Kathiresan; Olle Melander; J Gustav Smith; Marketa Sjögren; Steven A Lubitz; Patrick T Ellinor; Judy Z Louie; Joseph J Catanese; Gunnar Engström; James J Devlin Journal: Stroke Date: 2014-08-14 Impact factor: 7.914