Keith L Keene1, Hyacinth I Hyacinth2, Joshua C Bis3, Steven J Kittner4, Braxton D Mitchell4, Yu-Ching Cheng4, Guillaume Pare5, Michael Chong5, Martin O'Donnell6, James F Meschia7, Wei-Min Chen8, Michèle M Sale8, Stephen S Rich8, Mike A Nalls9,10, Alan B Zonderman11, Michele K Evans11, James G Wilson12, Adolfo Correa12, Hugh S Markus13, Matthew Traylor14, Cathryn M Lewis15, Cara L Carty16, Alexander Reiner17, Jeff Haessler17, Carl D Langefeld18, Rebecca Gottesman19, Thomas H Mosley12, Daniel Woo20, Kristine Yaffe21, YongMei Liu18, William T Longstreth3, Bruce M Psaty22,23, Charles Kooperberg17, Leslie A Lange24, Ralph Sacco25, Tatjana Rundek25, Jin-Moo Lee26, Carlos Cruchaga26, Karen L Furie27, Donna K Arnett28, Oscar R Benavente29, Raji P Grewal30, Leema Reddy Peddareddygari30, Martin Dichgans31,32, Rainer Malik31, Bradford B Worrall33, Myriam Fornage34. 1. Department of Biology; Brody School of Medicine Center for Health Disparities, East Carolina University, Greenville, NC (K.L.K.). 2. Aflac Cancer and Blood Disorder Center of Emory University and Children's Healthcare of Atlanta University, GA (H.I.H.). 3. University of Washington, Seattle, WA (J.C.B., W.T.L.). 4. Baltimore Veterans Administration Medical Center and University of Maryland School of Medicine, Baltimore, MD (S.J.K., B.D.M., Y.-C.C.). 5. McMaster University and Population Health Research Institute, Hamilton Ontario (G.P., M.C.). 6. National University of Ireland Galway, Ireland (M.O.). 7. Mayo Clinic Florida, Jacksonville (J.F.M.). 8. Center for Public Health Genomics, University of Virginia, Charlottesville (W.-M.C., M.M.S., S.S.R.). 9. Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD (M.A.N.). 10. Data Tecnica International, Glen Echo, MD (M.A.N.). 11. Laboratory of Epidemiology and Population Science, National Institute on Aging, Baltimore, MD (A.B.Z., M.K.E.). 12. University of Mississippi Medical Center, Jackson (J.G.W., A.C., T.H.M.). 13. University of Cambridge, England, United Kingdom (H.S.M.). 14. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (M.T.). 15. Social, Genetic and Developmental Psychiatry Centre, King's College London, United Kingdom (C.M.L.). 16. Initiative for Research and Education to Advance Community Health, Washington State University, Seattle (C.L.C.). 17. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (A.R., J.H., C.K.). 18. Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC (C.D.L., C.L.). 19. Johns Hopkins University School of Medicine, Baltimore, MD (R.G.). 20. Department of Neurology, University of Cincinnati, OH (D.W.). 21. University of California, San Francisco (K.Y.). 22. Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle (B.M.P.). 23. Kaiser Permanente Washington Health Research Institute, Seattle, WA (B.M.P.). 24. University of Colorado Anschutz Medical Campus, Denver (L.A.L.). 25. University of Miami, Miller School of Medicine, FL (R.S., T.R.). 26. Washington University School of Medicine, St. Louis, MO (J.-M.L., C.C.). 27. Brown University Warren Alpert Medical School, Providence, RI (K.L.F.). 28. University of Kentucky, College of Public Health, Lexington (D.K.A.). 29. University of British Columbia, Vancouver, (O.R.B.). 30. Neuroscience Institute, Saint Francis Medical Center, Trenton, NJ (R.P.G., L.R.P.). 31. Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Germany (M.D., R.M.). 32. Munich Cluster for Systems Neurology (SyNergy), Germany (M.D.). 33. Department of Neurology, University of Virginia, Charlottesville (B.B.W.). 34. Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston (M.F.).
Abstract
BACKGROUND AND PURPOSE: Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans. METHODS: The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts. RESULTS: In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the HNF1A gene that reached genome-wide significance (P=4.62×10-8) and an additional 29 variants with suggestive evidence of association (P<1×10-6), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction P value of 2.08×10-3 (0.05/24 unique loci), we were able to validate associations at the HNF1A locus in both SiGN (P=8.18×10-4) and METASTROKE (P=1.72×10-3) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the HNF1A gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the SFXN4 and TMEM108 genes represent potential novel ischemic stroke loci. CONCLUSIONS: These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.
BACKGROUND AND PURPOSE: Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans. METHODS: The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts. RESULTS: In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the HNF1A gene that reached genome-wide significance (P=4.62×10-8) and an additional 29 variants with suggestive evidence of association (P<1×10-6), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction P value of 2.08×10-3 (0.05/24 unique loci), we were able to validate associations at the HNF1A locus in both SiGN (P=8.18×10-4) and METASTROKE (P=1.72×10-3) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the HNF1A gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the SFXN4 and TMEM108 genes represent potential novel ischemic stroke loci. CONCLUSIONS: These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.
Authors: George Howard; Brett M Kissela; Dawn O Kleindorfer; Leslie A McClure; Elsayed Z Soliman; Suzanne E Judd; J David Rhodes; Mary Cushman; Claudia S Moy; Kara A Sands; Virginia J Howard Journal: Neurology Date: 2016-01-20 Impact factor: 9.910
Authors: Stephen R Williams; Fang-Chi Hsu; Keith L Keene; Wei-Min Chen; Sarah Nelson; Andrew M Southerland; Ebony B Madden; Bruce Coull; Stephanie M Gogarten; Karen L Furie; Godfrey Dzhivhuho; Joe L Rowles; Prachi Mehndiratta; Rainer Malik; Josée Dupuis; Honghuang Lin; Sudha Seshadri; Stephen S Rich; Michèle M Sale; Bradford B Worrall Journal: Neurology Date: 2015-12-30 Impact factor: 9.910
Authors: J D Spence; V J Howard; L E Chambless; M R Malinow; L C Pettigrew; M Stampfer; J F Toole Journal: Neuroepidemiology Date: 2001-02 Impact factor: 3.282
Authors: Solveig Gretarsdottir; Gudmar Thorleifsson; Andrei Manolescu; Unnur Styrkarsdottir; Anna Helgadottir; Andreas Gschwendtner; Konstantinos Kostulas; Gregor Kuhlenbäumer; Steve Bevan; Thorbjorg Jonsdottir; Hjordis Bjarnason; Jona Saemundsdottir; Stefan Palsson; David O Arnar; Hilma Holm; Gudmundur Thorgeirsson; Einar Mar Valdimarsson; Sigurlaug Sveinbjörnsdottir; Christian Gieger; Klaus Berger; H-Erich Wichmann; Jan Hillert; Hugh Markus; Jeffrey Robert Gulcher; E Bernd Ringelstein; Augustine Kong; Martin Dichgans; Daniel Fannar Gudbjartsson; Unnur Thorsteinsdottir; Kari Stefansson Journal: Ann Neurol Date: 2008-10 Impact factor: 10.422
Authors: M Arfan Ikram; Sudha Seshadri; Joshua C Bis; Myriam Fornage; Anita L DeStefano; Yurii S Aulchenko; Stephanie Debette; Thomas Lumley; Aaron R Folsom; Evita G van den Herik; Michiel J Bos; Alexa Beiser; Mary Cushman; Lenore J Launer; Eyal Shahar; Maksim Struchalin; Yangchun Du; Nicole L Glazer; Wayne D Rosamond; Fernando Rivadeneira; Margaret Kelly-Hayes; Oscar L Lopez; Josef Coresh; Albert Hofman; Charles DeCarli; Susan R Heckbert; Peter J Koudstaal; Qiong Yang; Nicholas L Smith; Carlos S Kase; Kenneth Rice; Talin Haritunians; Gerwin Roks; Paul L M de Kort; Kent D Taylor; Lonneke M de Lau; Ben A Oostra; Andre G Uitterlinden; Jerome I Rotter; Eric Boerwinkle; Bruce M Psaty; Thomas H Mosley; Cornelia M van Duijn; Monique M B Breteler; W T Longstreth; Philip A Wolf Journal: N Engl J Med Date: 2009-04-15 Impact factor: 91.245
Authors: Yu-Ching Cheng; Jeffrey R O'Connell; John W Cole; O Colin Stine; Nicole Dueker; Patrick F McArdle; Mary J Sparks; Jess Shen; Cathy C Laurie; Sarah Nelson; Kimberly F Doheny; Hua Ling; Elizabeth W Pugh; Thomas G Brott; Robert D Brown; James F Meschia; Michael Nalls; Stephen S Rich; Bradford Worrall; Christopher D Anderson; Alessandro Biffi; Lynelle Cortellini; Karen L Furie; Natalia S Rost; Jonathan Rosand; Teri A Manolio; Steven J Kittner; Braxton D Mitchell Journal: G3 (Bethesda) Date: 2011-11-01 Impact factor: 3.154
Authors: Matthew Traylor; Steve Bevan; Jean-Claude Baron; Ahamad Hassan; Cathryn M Lewis; Hugh S Markus Journal: Stroke Date: 2015-08-04 Impact factor: 7.914
Authors: Nicole D Armstrong; Vinodh Srinivasasainagendra; Amit Patki; Rikki M Tanner; Bertha A Hidalgo; Hemant K Tiwari; Nita A Limdi; Ethan M Lange; Leslie A Lange; Donna K Arnett; Marguerite R Irvin Journal: Front Genet Date: 2021-12-21 Impact factor: 4.772
Authors: Emy A Thomas; Nitesh Enduru; Adrienne Tin; Eric Boerwinkle; Michael E Griswold; Thomas H Mosley; Rebecca F Gottesman; Myriam Fornage Journal: J Am Heart Assoc Date: 2022-07-20 Impact factor: 6.106
Authors: Segun Fatumo; Ville Karhunen; Tinashe Chikowore; Toure Sounkou; Brenda Udosen; Chisom Ezenwa; Mariam Nakabuye; Opeyemi Soremekun; Iyas Daghlas; David K Ryan; Amybel Taylor; Amy M Mason; Scott M Damrauer; Marijana Vujkovic; Keith L Keene; Myriam Fornage; Marjo-Riitta Järvelin; Stephen Burgess; Dipender Gill Journal: Stroke Date: 2021-06-03 Impact factor: 7.914