Marina Mola-Caminal1,2, Caty Carrera3, Carolina Soriano-Tárraga1, Eva Giralt-Steinhauer1, Rosa M Díaz-Navarro4, Sílvia Tur4, Carmen Jiménez4, Aina Medina-Dols5, Natàlia Cullell6, Nuria P Torres-Aguila6, Elena Muiño6, Ana Rodríguez-Campello1, Angel Ois1, Elisa Cuadrado-Godia1, Rosa M Vivanco-Hidalgo1, Mar Hernandez-Guillamon3, Montse Solé3, Pilar Delgado3, Alejandro Bustamante3, Teresa García-Berrocoso3, Maite Mendióroz3, Mar Castellanos7, Joaquín Serena8, Joan Martí-Fàbregas9, Tomás Segura10, Gemma Serrano-Heras11, Victor Obach12, Marc Ribó13, Carlos A Molina13, José Alvarez-Sabín13, Ernest Palomeras14, Mar Freijo15, Maria A Font16, Jonathan Rosand1, Natalia S Rost17, Cristina Gallego-Fabrega18,19, Jin-Moo Lee20, Laura Heitsch20,21, Laura Ibanez20, Carlos Cruchaga20, Chia-Ling Phuah20, Robin Lemmens22,23,24, Vincent Thijs25,26, Arne Lindgren27,28, Jane Maguire29,30, Kristiina Rannikmae31, Catherine L Sudlow31, Christina Jern32, Tara M Stanne32, Erik Lorentzen33, Lucía Muñoz-Narbona34, Antonio Dávalos34, Elena López-Cancio35, Bradford B Worrall36, Daniel Woo37, Steven J Kittner38, Braxton D Mitchell39,40, Joan Montaner3,41,42, Jaume Roquer17,18,19, Jurek Krupinski43, Xavier Estivill44,45, Raquel Rabionet46, Cristòfol Vives-Bauzá5, Israel Fernández-Cadenas3,6,47, Jordi Jiménez-Conde1. 1. From the Department of Neurology, Neurovascular Research Group, Hospital del Mar Medical Research Institute, Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra (M.M.-C., C.S.-T., E.G.-S., A.R.-C., A.O., E.C.-G., R.M.V.-H., J.R., J.J.-C.). 2. Department of Genetics, Universitat de Barcelona (M.M.-C.). 3. Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (C.C., M.H.-G., M.S., P.D., A.B., T.G.-B., M.M., J.M., I.F.-C.), Universitat Autònoma de Barcelona. 4. Department of Neurology (R.M.D.-N., S.T., C.J.), Son Espases University Hospital, Institut d'Investigació Sanitària de Les Illes Balears, Palma de Mallorca. 5. Research Unit (A.M.-D., C.V.-B.), Son Espases University Hospital, Institut d'Investigació Sanitària de Les Illes Balears, Palma de Mallorca. 6. Stroke Pharmacogenomics and Genetics Group, Fundació Docència i Recerca Mútua Terrassa (N.C., N.P.T.-A., E.M., I.F.-C.). 7. Neurology Service, A Coruña University Hospital and Biomedical Research Institute, La Coruña (M.C.). 8. Department of Neurology, Doctor Josep Trueta University Hospital, Girona Institute of Biomedical Investigation (J.S.). 9. Stroke Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona (J.M.-F.S.). 10. Department of Neurology (T.S.), Complejo Hospitalario Universitario de Albacete. 11. Research Unit (G.S.-H.), Complejo Hospitalario Universitario de Albacete. 12. Department of Neurology, Hospital Clínic i Provincial de Barcelona (V.O.). 13. Stroke Unit, Department of Neurology, Hospital Universitari Vall d'Hebron, Barcelona (M.R., C.A.M., J.A.-S.). 14. Department of Neurology, Hospital de Mataró (E.P.). 15. Department of Neurology, Hospital de Basurto, Bilbao (M.F.). 16. Department of Neurology, Hospital de Bellvitge, Hospitalet de Llobregat (M.A.F.). 17. Department of Neurology, J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (J.R., N.S.R.). 18. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA (J.R., C.G.-F.). 19. Center for Genomic Medicine, Massachusetts General Hospital, Boston (J.R., C.G.F.). 20. Department of Neurology (J.-M.L., L.H., L.I., C.C., C.-L.P.), Washington University School of Medicine, St. Louis, MO. 21. The Division of Emergency Medicine (L.H.), Washington University School of Medicine, St. Louis, MO. 22. Department of Neurosciences, Experimental Neurology, KU Leuven - University of Leuven, Belgium (R.L.). 23. Laboratory of Neurobiology, VIB, Center for Brain & Disease Research, Leuven (R.L.). 24. Department of Neurology, University Hospitals Leuven (R.L.). 25. Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, Australia (V.T.). 26. Department of Neurology, Austin Health, Heidelberg, Australia (V.T.). 27. Clinical Sciences Lund, Neurology, Lund University, Sweden (A.L.). 28. Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden (A.L.). 29. Faculty of Health, University of Technology, Sidney (J. Maguire). 30. Priority Research Centre for Stroke and Brain Injury, Hunter Medical Research Institute, University of Newcastle, Australia (J. Maguire). 31. Division of Clinical Brain Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, United Kingdom (K.R., C.L.S.). 32. Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg (C.J., T.M.S.). 33. Bioinformatics Core Facility, University of Gothenburg (E.L.). 34. Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol (L.M.-N., A.D.), Universitat Autònoma de Barcelona. 35. Stroke Unit, Hospital Universitario Central de Asturias (HUCA), Oviedo (E.L.-C.). 36. Neurology and Department of Public Health Sciences, University of Virginia, Charlottesville (B.B.W.). 37. Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, OH (D.W.). 38. Department of Neurology, University of Maryland School of Medicine and Baltimore VAMC, MD (S.J.K.). 39. Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, MD (B.D.M.). 40. Department of Medicine, University of Maryland School of Medicine, Baltimore, MD (B.D.M.). 41. Neurovascular Research Laboratory, Institute of Biomedicine of Seville, Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla (J. Montaner). 42. Department of Neurology, Hospital Universitario Virgen Macarena, Sevilla (J. Montaner). 43. Neurology Unit, Neuroscience Department, Mútua de Terrassa Hospital (J.K.). 44. Research Department, Sidra Medicine, Doha, Qatar (X.E.). 45. Genomics Unit, Dexeus Woman's Health, Barcelona (X.E.). 46. Centre for Genomic Regulation, Barcelona (R.R.). 47. Stroke Pharmacogenomics and Genetics Group, Institut de Recerca Hospital de la Santa Creu i Sant Pau, Barcelona (I.F.-C.).
Abstract
RATIONALE: Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. OBJECTIVE: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date. METHODS AND RESULTS: A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P=1.70×10-9). CONCLUSIONS: Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.
RATIONALE: Ischemic strokeis among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. OBJECTIVE: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date. METHODS AND RESULTS: A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P=1.70×10-9). CONCLUSIONS: Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.
Authors: Rick M Dijkhuizen; Aneesh B Singhal; Joseph B Mandeville; Ona Wu; Elkan F Halpern; Seth P Finklestein; Bruce R Rosen; Eng H Lo Journal: J Neurosci Date: 2003-01-15 Impact factor: 6.167
Authors: Jane M Maguire; Steve Bevan; Tara M Stanne; Erik Lorenzen; Israel Fernandez-Cadenas; Graeme J Hankey; Jordi Jimenez-Conde; Katarina Jood; Jin-Moo Lee; Robin Lemmens; Christopher Levi; Bo Norrving; Kristiina Rannikmae; Natalia Rost; Jonathan Rosand; Peter M Rothwell; Rodney Scott; Daniel Strbian; Jonathan Sturm; Cathie Sudlow; Matthew Traylor; Vincent Thijs; Turgut Tatlisumak; Tadeusz Wieloch; Daniel Woo; Bradford B Worrall; Christina Jern; Arne Lindgren Journal: Eur Stroke J Date: 2017-04-19
Authors: Jacqueline M Lane; Jingjing Liang; Irma Vlasac; Simon G Anderson; David A Bechtold; Jack Bowden; Richard Emsley; Shubhroz Gill; Max A Little; Annemarie I Luik; Andrew Loudon; Frank A J L Scheer; Shaun M Purcell; Simon D Kyle; Deborah A Lawlor; Xiaofeng Zhu; Susan Redline; David W Ray; Martin K Rutter; Richa Saxena Journal: Nat Genet Date: 2016-12-19 Impact factor: 38.330
Authors: Nuria P Torres-Aguila; Caty Carrera; Anne-Katrine Giese; Natalia Cullell; Elena Muiño; Jara Cárcel-Márquez; Cristina Gallego-Fabrega; Jonathan González-Sánchez; María Del Mar Freijo; José Álvarez-Sabín; Carlos Molina; Marc Ribó; Jordi Jimenez-Conde; Jaume Roquer; Tomás Sobrino; Francisco Campos; José Castillo; Lucia Muñoz-Narbona; Elena Lopez-Cancio; Antoni Dàvalos; Rosa Diaz-Navarro; Silvia Tur; Cristòfol Vives-Bauza; Gemma Serrano-Heras; Tomás Segura; Jerzy Krupinski; Raquel Delgado-Mederos; Joan Martí-Fàbregas; Laura Heitsch; Laura Ibañez; Carlos Cruchaga; Natalia S Rost; Joan Montaner; Jin-Moo Lee; Israel Fernandez-Cadenas Journal: Stroke Date: 2019-10-07 Impact factor: 7.914
Authors: Nuria P Torres-Aguila; Caty Carrera; Elena Muiño; Natalia Cullell; Jara Cárcel-Márquez; Cristina Gallego-Fabrega; Jonathan González-Sánchez; Alejandro Bustamante; Pilar Delgado; Laura Ibañez; Laura Heitsch; Jerzy Krupinski; Joan Montaner; Joan Martí-Fàbregas; Carlos Cruchaga; Jin-Moo Lee; Israel Fernandez-Cadenas Journal: J Stroke Date: 2019-09-30 Impact factor: 6.967
Authors: Laura Ibanez; Laura Heitsch; Caty Carrera; Fabiana H G Farias; Rajat Dhar; John Budde; Kristy Bergmann; Joseph Bradley; Oscar Harari; Chia-Ling Phuah; Robin Lemmens; Alessandro A Viana Oliveira Souza; Francisco Moniche; Antonio Cabezas-Juan; Juan Francisco Arenillas; Jerzy Krupinksi; Natalia Cullell; Nuria Torres-Aguila; Elena Muiño; Jara Cárcel-Márquez; Joan Marti-Fabregas; Raquel Delgado-Mederos; Rebeca Marin-Bueno; Alejandro Hornick; Cristofol Vives-Bauza; Rosa Diaz Navarro; Silvia Tur; Carmen Jimenez; Victor Obach; Tomas Segura; Gemma Serrano-Heras; Jong-Won Chung; Jaume Roquer; Carol Soriano-Tarraga; Eva Giralt-Steinhauer; Marina Mola-Caminal; Joanna Pera; Katarzyna Lapicka-Bodzioch; Justyna Derbisz; Antoni Davalos; Elena Lopez-Cancio; Lucia Muñoz; Turgut Tatlisumak; Carlos Molina; Marc Ribo; Alejandro Bustamante; Tomas Sobrino; Jose Castillo-Sanchez; Francisco Campos; Emilio Rodriguez-Castro; Susana Arias-Rivas; Manuel Rodríguez-Yáñez; Christina Herbosa; Andria L Ford; Antonio Arauz; Iscia Lopes-Cendes; Theodore Lowenkopf; Miguel A Barboza; Hajar Amini; Boryana Stamova; Bradley P Ander; Frank R Sharp; Gyeong Moon Kim; Oh Young Bang; Jordi Jimenez-Conde; Agnieszka Slowik; Daniel Stribian; Ellen A Tsai; Linda C Burkly; Joan Montaner; Israel Fernandez-Cadenas; Jin-Moo Lee; Carlos Cruchaga Journal: medRxiv Date: 2020-11-03