Yao Hu1, Jeffrey W Haessler1, Regina Manansala2, Kerri L Wiggins3, Arden Moscati4, Alexa Beiser5,6, Nancy L Heard-Costa5, Chloe Sarnowski6, Laura M Raffield7, Jaeyoon Chung8,9, Sandro Marini9,10, Christopher D Anderson9,11,10, Jonathan Rosand9,11,10, Huichun Xu12, Xiao Sun13, Tanika N Kelly13, Quenna Wong14, Leslie A Lange15, Jerome I Rotter16, Adolfo Correa17, Ramachandran S Vasan8, Sudha Seshadri5,18, Stephen S Rich19, Ron Do4,20, Ruth J F Loos4,21, William T Longstreth22,23, Joshua C Bis3, Bruce M Psaty3,23,24, David L Tirschwell22, Themistocles L Assimes25, Brian Silver26, Simin Liu27, Rebecca Jackson28, Sylvia Wassertheil-Smoller29, Braxton D Mitchell12,30, Myriam Fornage31, Paul L Auer2, Alex P Reiner1,23, Charles Kooperberg1. 1. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (Y.H., J.W.H., A.P.R., C.K.). 2. School of Public Health, University of Wisconsin-Milwaukee (R.M., P.L.A.). 3. Cardiovascular Health Research Unit, Department of Medicine (K.L.W., J.C.B., B.M.P.). 4. The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, NY (A.M., R.D., R.J.F.L.). 5. Department of Neurology (A.B., N.L.H.-C., S.S.), Boston University School of Medicine, MA. 6. Department of Biostatistics (A.B., C.S.), Boston University School of Public Health, MA. 7. Department of Genetics, University of North Carolina, Chapel Hill (L.M.R). 8. Department of Medicine (J.C., R.S.V.), Boston University School of Medicine, MA. 9. Center for Genomic Medicine (J.C., S.M., C.D.A., J.R.), Massachusetts General Hospital, Boston. 10. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (S.M., C.D.A., J.R.). 11. Henry and Allison McCance Center for Brain Health (C.D.A., J.R.), Massachusetts General Hospital, Boston. 12. Department of Medicine, University of Maryland School of Medicine, Baltimore (H.X., B.D.M.). 13. Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (X.S., T.N.K.). 14. Department of Biostatistics (Q.W.), University of Washington, Seattle. 15. Department of Medicine, University of Colorado, Denver, CO (L.A.L.). 16. The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA (J.I.R.). 17. Department of Pediatrics and Medicine, University of Mississippi Medical Center, Jackson, MS (A.C.). 18. Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio (S.S.). 19. Center for Public Health Genomics, University of Virginia, Charlottesville (S.S.R.). 20. Department of Genetics and Genomic Sciences (R.D.), The Icahn School of Medicine at Mount Sinai, NY. 21. The Mindich Child Health and Development Institute (R.J.F.L.), The Icahn School of Medicine at Mount Sinai, NY. 22. Department of Neurology (W.T.L., D.L.T.), University of Washington, Seattle. 23. Department of Epidemiology (W.T.L., B.M.P., A.P.R.), University of Washington, Seattle. 24. Department of Health Services (B.M.P.), University of Washington, Seattle. 25. Department of Medicine, Stanford University, CA (T.L.A.). 26. Department of Neurology, University of Massachusetts Medical School, Worcester (B.S.). 27. Center for Global Cardiometabolic Health, Departments of Epidemiology, Medicine, and Surgery, Brown University, Providence, RI (S.L.). 28. Division of Endocrinology Diabetes and Metabolism, The Ohio State University, Columbus (R.J.). 29. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, NY (S.W.-S.). 30. Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD (B.D.M.). 31. Institute of Molecular Medicine, University of Texas Health Science Center at Houston (M.F.).
Abstract
BACKGROUND AND PURPOSE: Stroke is the leading cause of death and long-term disability worldwide. Previous genome-wide association studies identified 51 loci associated with stroke (mostly ischemic) and its subtypes among predominantly European populations. Using whole-genome sequencing in ancestrally diverse populations from the Trans-Omics for Precision Medicine (TOPMed) Program, we aimed to identify novel variants, especially low-frequency or ancestry-specific variants, associated with all stroke, ischemic stroke and its subtypes (large artery, cardioembolic, and small vessel), and hemorrhagic stroke and its subtypes (intracerebral and subarachnoid). METHODS: Whole-genome sequencing data were available for 6833 stroke cases and 27 116 controls, including 22 315 European, 7877 Black, 2616 Hispanic/Latino, 850 Asian, 54 Native American, and 237 other ancestry participants. In TOPMed, we performed single variant association analysis examining 40 million common variants and aggregated association analysis focusing on rare variants. We also combined TOPMed European populations with over 28 000 additional European participants from the UK BioBank genome-wide array data through meta-analysis. RESULTS: In the single variant association analysis in TOPMed, we identified one novel locus 13q33 for large artery at whole-genome-wide significance (P<5.00×10-9) and 4 novel loci at genome-wide significance (P<5.00×10-8), all of which need confirmation in independent studies. Lead variants in all 5 loci are low-frequency but are more common in non-European populations. An aggregation of synonymous rare variants within the gene C6orf26 demonstrated suggestive evidence of association for hemorrhagic stroke (P<3.11×10-6). By meta-analyzing European ancestry samples in TOPMed and UK BioBank, we replicated several previously reported stroke loci including PITX2, HDAC9, ZFHX3, and LRCH1. CONCLUSIONS: We represent the first association analysis for stroke and its subtypes using whole-genome sequencing data from ancestrally diverse populations. While our findings suggest the potential benefits of combining whole-genome sequencing data with populations of diverse genetic backgrounds to identify possible low-frequency or ancestry-specific variants, they also highlight the need to increase genome coverage and sample sizes.
BACKGROUND AND PURPOSE: Stroke is the leading cause of death and long-term disability worldwide. Previous genome-wide association studies identified 51 loci associated with stroke (mostly ischemic) and its subtypes among predominantly European populations. Using whole-genome sequencing in ancestrally diverse populations from the Trans-Omics for Precision Medicine (TOPMed) Program, we aimed to identify novel variants, especially low-frequency or ancestry-specific variants, associated with all stroke, ischemic stroke and its subtypes (large artery, cardioembolic, and small vessel), and hemorrhagic stroke and its subtypes (intracerebral and subarachnoid). METHODS: Whole-genome sequencing data were available for 6833 stroke cases and 27 116 controls, including 22 315 European, 7877 Black, 2616 Hispanic/Latino, 850 Asian, 54 Native American, and 237 other ancestry participants. In TOPMed, we performed single variant association analysis examining 40 million common variants and aggregated association analysis focusing on rare variants. We also combined TOPMed European populations with over 28 000 additional European participants from the UK BioBank genome-wide array data through meta-analysis. RESULTS: In the single variant association analysis in TOPMed, we identified one novel locus 13q33 for large artery at whole-genome-wide significance (P<5.00×10-9) and 4 novel loci at genome-wide significance (P<5.00×10-8), all of which need confirmation in independent studies. Lead variants in all 5 loci are low-frequency but are more common in non-European populations. An aggregation of synonymous rare variants within the gene C6orf26 demonstrated suggestive evidence of association for hemorrhagic stroke (P<3.11×10-6). By meta-analyzing European ancestry samples in TOPMed and UK BioBank, we replicated several previously reported stroke loci including PITX2, HDAC9, ZFHX3, and LRCH1. CONCLUSIONS: We represent the first association analysis for stroke and its subtypes using whole-genome sequencing data from ancestrally diverse populations. While our findings suggest the potential benefits of combining whole-genome sequencing data with populations of diverse genetic backgrounds to identify possible low-frequency or ancestry-specific variants, they also highlight the need to increase genome coverage and sample sizes.
Entities:
Keywords:
atherosclerosis; blood pressure; cause of death; embolic stroke; sample size
Authors: Sonja R Fuqua; Sharon B Wyatt; Michael E Andrew; Daniel F Sarpong; Frances R Henderson; Margie F Cunningham; Herman A Taylor Journal: Ethn Dis Date: 2005 Impact factor: 1.847
Authors: Raphael Carandang; Sudha Seshadri; Alexa Beiser; Margaret Kelly-Hayes; Carlos S Kase; William B Kannel; Philip A Wolf Journal: JAMA Date: 2006-12-27 Impact factor: 56.272
Authors: Miikka Korja; Karri Silventoinen; Peter McCarron; Slobodan Zdravkovic; Axel Skytthe; Arto Haapanen; Ulf de Faire; Nancy L Pedersen; Kaare Christensen; Markku Koskenvuo; Jaakko Kaprio Journal: Stroke Date: 2010-09-16 Impact factor: 7.914
Authors: Emmanuel Keku; Wayne Rosamond; Herman A Taylor; Robert Garrison; Sharon B Wyatt; Michelle Richard; Brenda Jenkins; Lisa Reeves; Daniel Sarpong Journal: Ethn Dis Date: 2005 Impact factor: 1.847
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: William J Astle; Heather Elding; Tao Jiang; Dave Allen; Dace Ruklisa; Alice L Mann; Daniel Mead; Heleen Bouman; Fernando Riveros-Mckay; Myrto A Kostadima; John J Lambourne; Suthesh Sivapalaratnam; Kate Downes; Kousik Kundu; Lorenzo Bomba; Kim Berentsen; John R Bradley; Louise C Daugherty; Olivier Delaneau; Kathleen Freson; Stephen F Garner; Luigi Grassi; Jose Guerrero; Matthias Haimel; Eva M Janssen-Megens; Anita Kaan; Mihir Kamat; Bowon Kim; Amit Mandoli; Jonathan Marchini; Joost H A Martens; Stuart Meacham; Karyn Megy; Jared O'Connell; Romina Petersen; Nilofar Sharifi; Simon M Sheard; James R Staley; Salih Tuna; Martijn van der Ent; Klaudia Walter; Shuang-Yin Wang; Eleanor Wheeler; Steven P Wilder; Valentina Iotchkova; Carmel Moore; Jennifer Sambrook; Hendrik G Stunnenberg; Emanuele Di Angelantonio; Stephen Kaptoge; Taco W Kuijpers; Enrique Carrillo-de-Santa-Pau; David Juan; Daniel Rico; Alfonso Valencia; Lu Chen; Bing Ge; Louella Vasquez; Tony Kwan; Diego Garrido-Martín; Stephen Watt; Ying Yang; Roderic Guigo; Stephan Beck; Dirk S Paul; Tomi Pastinen; David Bujold; Guillaume Bourque; Mattia Frontini; John Danesh; David J Roberts; Willem H Ouwehand; Adam S Butterworth; Nicole Soranzo Journal: Cell Date: 2016-11-17 Impact factor: 41.582