PATJ Low Frequency Variants Are Associated With Worse Ischemic Stroke Functional Outcome A Genome-Wide Meta-Analysis
Por:
Mola-Caminal, M, Carrera, C, Soriano-Tarraga, C, Giralt-Steinhauer, E, Diaz-Navarro, RM, Tur, S, Jimenez, C, Medina-Dols, A, Cullell, N, Torres-Aguila, NP, Muino, E, Rodriguez-Campello, A, Ois, A, Cuadrado-Godia, E, Vivanco-Hidalgo, RM, Hernandez-Guillamon, M, Sol, M, Delgado, P, Bustamante, A, Garcia-Berrocoso, T, Mendioroz, M, Castellanos, M, Serena, J, Marti-Fabregas, J, Segura, T, Serrano-Heras, G, Obach, V, Rib, M, Molina, CA, Alvarez-Sabin, J, Palomeras, E, Freijo, M, Font, MA, Rosand, J, Rost, NS, Gallego-Fabrega, C, Lee, JM, Heitsch, L, Ibanez, L, Cruchaga, C, Phuah, CL, Lemmens, R, Thijs, V, Lindgren, A, Maguire, J, Rannikmae, K, Sudlow, CL, Jern, C, Stanne, TM, Lorentzen, E, Munoz-Narbona, L, Davalos, A, Lopez-Cancio, E, Worrall, BB, Woo, D, Kittner, SJ, Mitchell, BD, Montaner, J, Roquer, J, Krupinski, J, Estivill, X, Rabionet, R, Vives-Bauz, C, Fernandez-Cadenas, I, Jimenez-Conde, J
Publicada:
4 ene 2019
Resumen:
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, beta=0.40, P=1.70x10-9).
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.
Filiaciones:
Mola-Caminal, M:
Univ Autonoma Barcelona, DCEXS Univ Pompeu Fabra, Dept Neurol, Neurovasc Res Grp,Hosp del Mar,Med Res Inst, Barcelona, Spain
Univ Barcelona, Dept Genet, Barcelona, Spain
Carrera, C:
Univ Autonoma Barcelona, Neurovasc Res Lab, Vall dHebron Inst Res, Barcelona, Spain
Soriano-Tarraga, C:
Univ Autonoma Barcelona, DCEXS Univ Pompeu Fabra, Dept Neurol, Neurovasc Res Grp,Hosp del Mar,Med Res Inst, Barcelona, Spain
Giralt-Steinhauer, E:
Univ Autonoma Barcelona, DCEXS Univ Pompeu Fabra, Dept Neurol, Neurovasc Res Grp,Hosp del Mar,Med Res Inst, Barcelona, Spain
Diaz-Navarro, RM:
Son Espases Univ Hosp, Dept Neurol, Inst Invest Sanitaria Illes Balears, Barcelona, Spain
Tur, S:
Son Espases Univ Hosp, Dept Neurol, Inst Invest Sanitaria Illes Balears, Barcelona, Spain
Jimenez, C:
Son Espases Univ Hosp, Dept Neurol, Inst Invest Sanitaria Illes Balears, Barcelona, Spain
Medina-Dols, A:
Son Espases Univ Hosp, Res Unit, Inst Invest Sanitaria Illes Balears, Palma de Mallorca, Spain
Cullell, N:
Fundacio Docencia & Recerca Mutua Terrassa, Stroke Pharmacogen & Genet Grp, Barcelona, Spain
Torres-Aguila, NP:
Fundacio Docencia & Recerca Mutua Terrassa, Stroke Pharmacogen & Genet Grp, Barcelona, Spain
Muino, E:
Fundacio Docencia & Recerca Mutua Terrassa, Stroke Pharmacogen & Genet Grp, Barcelona, Spain
Rodriguez-Campello, A:
Univ Autonoma Barcelona, DCEXS Univ Pompeu Fabra, Dept Neurol, Neurovasc Res Grp,Hosp del Mar,Med Res Inst, Barcelona, Spain
Ois, A:
Univ Autonoma Barcelona, DCEXS Univ Pompeu Fabra, Dept Neurol, Neurovasc Res Grp,Hosp del Mar,Med Res Inst, Barcelona, Spain
Cuadrado-Godia, E:
Univ Autonoma Barcelona, DCEXS Univ Pompeu Fabra, Dept Neurol, Neurovasc Res Grp,Hosp del Mar,Med Res Inst, Barcelona, Spain
Vivanco-Hidalgo, RM:
Univ Autonoma Barcelona, DCEXS Univ Pompeu Fabra, Dept Neurol, Neurovasc Res Grp,Hosp del Mar,Med Res Inst, Barcelona, Spain
Hernandez-Guillamon, M:
Univ Autonoma Barcelona, Neurovasc Res Lab, Vall dHebron Inst Res, Barcelona, Spain
Sol, M:
Univ Autonoma Barcelona, Neurovasc Res Lab, Vall dHebron Inst Res, Barcelona, Spain
Delgado, P:
Univ Autonoma Barcelona, Neurovasc Res Lab, Vall dHebron Inst Res, Barcelona, Spain
Bustamante, A:
Univ Autonoma Barcelona, Neurovasc Res Lab, Vall dHebron Inst Res, Barcelona, Spain
Garcia-Berrocoso, T:
Univ Autonoma Barcelona, Neurovasc Res Lab, Vall dHebron Inst Res, Barcelona, Spain
Mendioroz, M:
Univ Autonoma Barcelona, Neurovasc Res Lab, Vall dHebron Inst Res, Barcelona, Spain
Castellanos, M:
A Coruna Univ Hosp, Neurol Serv, La Coruna, Spain
Biomed Res Inst, La Coruna, Spain
Serena, J:
Doctor Josep Trueta Univ Hosp, Dept Neurol, Girona Inst Biomed Invest, Girona, Spain
Marti-Fabregas, J:
Hosp Santa Creu & Sant Pau, Stroke Unit, Dept Neurol, Barcelona, Spain
Segura, T:
Complejo Hosp Univ Albacete, Dept Neurol, Ciudad Real, Spain
Serrano-Heras, G:
Complejo Hosp Univ Albacete, Res Unit, Ciudad Real, Spain
Obach, V:
Hosp Clin Barcelona, Dept Neurol, Barcelona, Spain
Rib, M:
Hosp Univ Vail dHebron, Dept Neurol, Stroke Unit, Barcelona, Spain
Molina, CA:
Hosp Univ Vail dHebron, Dept Neurol, Stroke Unit, Barcelona, Spain
Alvarez-Sabin, J:
Hosp Univ Vail dHebron, Dept Neurol, Stroke Unit, Barcelona, Spain
Palomeras, E:
Hosp Mataro, Dept Neurol, Mataro, Spain
Freijo, M:
Hosp Basurto, Dept Neurol, Bilbao, Spain
Font, MA:
Hosp Bellvitge Princeps Espanya, Dept Neurol, Lhospitalet De Llobregat, Spain
Rosand, J:
Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA USA
Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA
Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA
Rost, NS:
Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA USA
Gallego-Fabrega, C:
Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA
Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA
Lee, JM:
Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
Heitsch, L:
Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
Washington Univ, Sch Med, Div Emergency Med, St Louis, MO 63110 USA
Ibanez, L:
Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
Cruchaga, C:
Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
Phuah, CL:
Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
Lemmens, R:
KU Leuven Univ Leuven, Dept Neurosci, Expt Neurol, Leuven, Belgium
VIB, Ctr Brain & Dis Res, Lab Neurobiol, Leuven, Belgium
Univ Hosp Leuven, Dept Neurol, Leuven, Belgium
Thijs, V:
Univ Melbourne, Stroke Div, Florey Inst Neurosci & Mental Hlth, Heidelberg, Vic, Australia
Austin Hlth, Dept Neurol, Heidelberg, Vic, Australia
Lindgren, A:
Lund Univ, Clin Sci Lund, Neurol, Lund, Sweden
Skane Univ Hosp, Neurol & Rehabil Med, Lund, Sweden
Maguire, J:
Univ Autonoma Barcelona, Neurovasc Res Lab, Vall dHebron Inst Res, Barcelona, Spain
Univ Technol, Fac Hlth, Sydney, NSW, Australia
Univ Newcastle, Hunter Med Res Inst, Prior Res Ctr Stroke & Brain Injury, Newcastle, NSW, Australia
Rannikmae, K:
Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Div Clin Brain Sci, Edinburgh, Midlothian, Scotland
Sudlow, CL:
Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Div Clin Brain Sci, Edinburgh, Midlothian, Scotland
Jern, C:
Univ Gothenburg, Inst Biomed, Sahlgrenska Acad, Gothenburg, Sweden
Stanne, TM:
Univ Gothenburg, Inst Biomed, Sahlgrenska Acad, Gothenburg, Sweden
Lorentzen, E:
Univ Gothenburg, Bioinformat Core Facil, Gothenburg, Sweden
Munoz-Narbona, L:
Univ Autonoma Barcelona, Stroke Unit, Dept Neurosci, Hosp Univ Germans Trias i Pujol, Barcelona, Spain
Davalos, A:
Univ Autonoma Barcelona, Stroke Unit, Dept Neurosci, Hosp Univ Germans Trias i Pujol, Barcelona, Spain
Lopez-Cancio, E:
HUCA, Stroke Unit, Oviedo, Spain
Worrall, BB:
Univ Virginia, Neurol, Charlottesville, VA USA
Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA
Woo, D:
Univ Cincinnati, Coll Med, Dept Neurol & Rehabil Med, Cincinnati, OH USA
Kittner, SJ:
Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA
Baltimore VAMC, Baltimore, MD USA
Mitchell, BD:
Baltimore Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA
Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA
Montaner, J:
Univ Seville, CSIC, Hosp Univ Virgen Rocio, Neurovasc Res Lab,Inst Biomed Seville, Seville, Spain
Hosp Univ Virgen Macarena, Dept Neurol, Seville, Spain
Roquer, J:
Univ Autonoma Barcelona, DCEXS Univ Pompeu Fabra, Dept Neurol, Neurovasc Res Grp,Hosp del Mar,Med Res Inst, Barcelona, Spain
Krupinski, J:
Mutua Terrassa Hosp, Neurol Unit, Neurosci Dept, Doha, Qatar
Estivill, X:
Sidra Med, Res Dept, Doha, Qatar
Dexeus Womans Hlth, Genom Unit, Barcelona, Spain
Rabionet, R:
Ctr Genom Regulat, Barcelona, Spain
Vives-Bauz, C:
Son Espases Univ Hosp, Res Unit, Inst Invest Sanitaria Illes Balears, Palma de Mallorca, Spain
Fernandez-Cadenas, I:
Univ Autonoma Barcelona, Neurovasc Res Lab, Vall dHebron Inst Res, Barcelona, Spain
Fundacio Docencia & Recerca Mutua Terrassa, Stroke Pharmacogen & Genet Grp, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Inst Recerca, Stroke Pharmacogen & Genet Grp, Barcelona, Spain
Jimenez-Conde, J:
Univ Autonoma Barcelona, DCEXS Univ Pompeu Fabra, Dept Neurol, Neurovasc Res Grp,Hosp del Mar,Med Res Inst, Barcelona, Spain
Green Accepted, Bronze
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