Multi-ancestry genetic study in 5,876 patients identifies an association between excitotoxic genes and early outcomes after acute ischemic stroke.

Autor:	Ibanez L; Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis (63110), Missouri, US.; NeuroGenomics and Informatics, Washington University School of Medicine, 425 S. Euclid Avenue, Saint Louis (63110), Missouri, US., Heitsch L; Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue; Campus Box 8111; Saint Louis (63110), Missouri, US.; Emergency Medicine, Washington University School of Medicine, 660 S. Euclid Avenue; Campus Box 8072; Saint Louis (63110), Missouri, US., Carrera C; Stroke Unit, Vall d'Hebron University Hospital, Universitat de Barcelona, Passeig de la Vall d'Hebron, 1198; Barcelona (08035), Spain., Farias FHG; Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis (63110), Missouri, US.; NeuroGenomics and Informatics, Washington University School of Medicine, 425 S. Euclid Avenue, Saint Louis (63110), Missouri, US., Dhar R; Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue; Campus Box 8111; Saint Louis (63110), Missouri, US., Budde J; Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis (63110), Missouri, US.; NeuroGenomics and Informatics, Washington University School of Medicine, 425 S. Euclid Avenue, Saint Louis (63110), Missouri, US., Bergmann K; Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis (63110), Missouri, US.; NeuroGenomics and Informatics, Washington University School of Medicine, 425 S. Euclid Avenue, Saint Louis (63110), Missouri, US., Bradley J; Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis (63110), Missouri, US.; NeuroGenomics and Informatics, Washington University School of Medicine, 425 S. Euclid Avenue, Saint Louis (63110), Missouri, US., Harari O; Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis (63110), Missouri, US.; NeuroGenomics and Informatics, Washington University School of Medicine, 425 S. Euclid Avenue, Saint Louis (63110), Missouri, US.; The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, 4488 Forest Park Avenue; Saint Louis (63110), Missouri, US.; Department of Neuroscience, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N2; Herestraat 49 box 1021; Leuven (BE-3000), Belgium., Phuah CL; Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue; Campus Box 8111; Saint Louis (63110), Missouri, US., Lemmens R; Department of Neuroscience, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N2; Herestraat 49 box 1021; Leuven (BE-3000), Belgium., Souza AAVO; Department of Neurology, School of Medical Sciences, University of Campinas (UNICAMP), R. Tessalia Viera de Camargo, 126; Cidade Universitaria, Campinas (13083-887), Brazil.; Brazilian Institute of Neuroscience and Neurotecnology (BRAINN), R. Tessalia Viera de Camargo, 126; Cidade Universitaria, Campinas (13083-887), Brazil., Moniche F; Department of neurology, Hospital Virgen del Rocio, University of Seville, Avenida Manuel Siurot, s/n; Seville (41013), Spain., Cabezas-Juan A; Department of neurology, Hospital Virgen del Rocio, University of Seville, Avenida Manuel Siurot, s/n; Seville (41013), Spain.; Hospital Virgen de la Macarena, University of Seville, Calle Dr. Fedriani, 3; Seville (41009), Spain., Arenillas JF; Department of Neurology, Hospital Clinico Universitario Valladolid, Valladolid University, Avenida Ramon y Cajal, 3; Valladolid (47003), Spain., Krupinksi J; Department of Neurology, Mutua Terrassa University Hospital, Universitat de Barcelona, Plaça del Dr. Robert, 5; Terrassa (08221), Spain.; Fundacio Docencia i Recerca Mutua Terrassa, Universitat de Barcelona, Carrer Sant Antoni, 19; Terrassa (08221), Spain., Cullell N; Fundacio Docencia i Recerca Mutua Terrassa, Universitat de Barcelona, Carrer Sant Antoni, 19; Terrassa (08221), Spain.; Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Carrer de Sant Quinti, 89; Barcelona (08041), Spain., Torres-Aguila N; Fundacio Docencia i Recerca Mutua Terrassa, Universitat de Barcelona, Carrer Sant Antoni, 19; Terrassa (08221), Spain.; Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Carrer de Sant Quinti, 89; Barcelona (08041), Spain., Muiño E; Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Carrer de Sant Quinti, 89; Barcelona (08041), Spain., Cárcel-Márquez J; Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Carrer de Sant Quinti, 89; Barcelona (08041), Spain., Marti-Fabregas J; Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Carrer de Sant Quinti, 89; Barcelona (08041), Spain., Delgado-Mederos R; Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Carrer de Sant Quinti, 89; Barcelona (08041), Spain., Marin-Bueno R; Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Carrer de Sant Quinti, 89; Barcelona (08041), Spain., Hornick A; Department of Neurology, Southern Illinois Healthcare Memorial Hospital of Carbondale, 405 W Jackson Street, Carbondale (62901), Illinois, US., Vives-Bauza C; Department of Biology, Universitat de les Illes Balears, Carretera de Valldemossa, km 7,5, Palma (07122), Spain., Navarro RD; Department of Neurology, Hospital Universitari Son Espases, Universitat de les Illes Balears, Carretera de Valldemossa, 79, Palma (07120), Spain., Tur S; Department of Neurology, Hospital Universitari Son Espases, Universitat de les Illes Balears, Carretera de Valldemossa, 79, Palma (07120), Spain., Jimenez C; Department of Neurology, Hospital Universitari Son Espases, Universitat de les Illes Balears, Carretera de Valldemossa, 79, Palma (07120), Spain., Obach V; Department of Neurology, Hospital Clinic de Barcelona, Universitat de Barcelona, Carrer Villarroel, 170, Barcelona (08036), Spain., Segura T; Research Unit, Complejo Hospitalario Universitario de Albacete. Calle Laurel s/n. Albacete (02008), Spain., Serrano-Heras G; Research Unit, Complejo Hospitalario Universitario de Albacete. Calle Laurel s/n. Albacete (02008), Spain., Chung JW; Department of Neurology, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul, South Korea., Roquer J; Neurovascular Research Group, Institut Hospital del Mar de Investigations Mediques, Passeig Maritim, 25-29, Barcelona (08003), Spain., Soriano-Tarraga C; Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis (63110), Missouri, US.; NeuroGenomics and Informatics, Washington University School of Medicine, 425 S. Euclid Avenue, Saint Louis (63110), Missouri, US.; Neurovascular Research Group, Institut Hospital del Mar de Investigations Mediques, Passeig Maritim, 25-29, Barcelona (08003), Spain., Giralt-Steinhauer E; Neurovascular Research Group, Institut Hospital del Mar de Investigations Mediques, Passeig Maritim, 25-29, Barcelona (08003), Spain., Mola-Caminal M; Neurovascular Research Group, Institut Hospital del Mar de Investigations Mediques, Passeig Maritim, 25-29, Barcelona (08003), Spain.; Department of Surgical Sciences, Orthopedics, Uppsala University, Uppsala, 75185, Sweden., Pera J; Department of Neurology, Jagiellonian University, Golebia, 24, Krakow(31-007), Poland., Lapicka-Bodzioch K; Department of Neurology, Jagiellonian University, Golebia, 24, Krakow(31-007), Poland., Derbisz J; Department of Neurology, Jagiellonian University, Golebia, 24, Krakow(31-007), Poland., Davalos A; Department of Neurology, Hospital Germans Trias i Pujol, Universitat Autonoma de Barcelona, Carretera de Canyet, s/n; Badalona (08916), Spain., Lopez-Cancio E; Department of Neurology, Hospital Universitario Central de Asturias, Oviedo, Spain., Muñoz L; Department of Neurology, Hospital Germans Trias i Pujol, Universitat Autonoma de Barcelona, Carretera de Canyet, s/n; Badalona (08916), Spain., Tatlisumak T; Department of Neurology, Sahlgrenska University Hospital, University of Gothenburg, Bla straket, 5; Gothenburg (413 45), Sweden.; Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden., Molina C; Stroke Unit, Vall d'Hebron University Hospital, Universitat de Barcelona, Passeig de la Vall d'Hebron, 1198; Barcelona (08035), Spain., Ribo M; Stroke Unit, Vall d'Hebron University Hospital, Universitat de Barcelona, Passeig de la Vall d'Hebron, 1198; Barcelona (08035), Spain., Bustamante A; Department of Neurology, Hospital Germans Trias i Pujol, Universitat Autonoma de Barcelona, Carretera de Canyet, s/n; Badalona (08916), Spain., Sobrino T; Clinical Neurosciences Research Laboratory, Health Research Institute of Santiago de Compostela (IDIS), Avda. Travesa da Choupana s/n; Santiago de Compostela (15706), Spain., Castillo-Sanchez J; Clinical Neurosciences Research Laboratory, Health Research Institute of Santiago de Compostela (IDIS), Avda. Travesa da Choupana s/n; Santiago de Compostela (15706), Spain., Campos F; Clinical Neurosciences Research Laboratory, Health Research Institute of Santiago de Compostela (IDIS), Avda. Travesa da Choupana s/n; Santiago de Compostela (15706), Spain., Rodriguez-Castro E; Clinical Neurosciences Research Laboratory, Health Research Institute of Santiago de Compostela (IDIS), Avda. Travesa da Choupana s/n; Santiago de Compostela (15706), Spain., Arias-Rivas S; Clinical Neurosciences Research Laboratory, Health Research Institute of Santiago de Compostela (IDIS), Avda. Travesa da Choupana s/n; Santiago de Compostela (15706), Spain., Rodríguez-Yáñez M; Clinical Neurosciences Research Laboratory, Health Research Institute of Santiago de Compostela (IDIS), Avda. Travesa da Choupana s/n; Santiago de Compostela (15706), Spain., Herbosa C; Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue; Campus Box 8111; Saint Louis (63110), Missouri, US., Ford AL; Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue; Campus Box 8111; Saint Louis (63110), Missouri, US.; Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Avenue; Campus Box 8111; Saint Louis (63110), Missouri, US.; Department of Radiology, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis (63110), Missouri, US., Arauz A; Instituto Nacional de Neurologia y Neurocirurgia de Mexico, Avenida Insurgentes Sur 3877, Ciudad de Mexico (14269), Mexico., Lopes-Cendes I; Department of Neurology, School of Medical Sciences, University of Campinas (UNICAMP), R. Tessalia Viera de Camargo, 126; Cidade Universitaria, Campinas (13083-887), Brazil.; Brazilian Institute of Neuroscience and Neurotecnology (BRAINN), R. Tessalia Viera de Camargo, 126; Cidade Universitaria, Campinas (13083-887), Brazil., Lowenkopf T; Department of Neurology, Providence St. Vincent Medical Center, 9205 SW Barnes Rd, Portland (97225), Oregon, US., Barboza MA; Neurosciences Department, Hospital Rafael A. Calderon Guardia, Avenidas 7 y 9, calles 15 y 17, Aranjuez, San José, Costa Rica., Amini H; Department of Neurology and MIND Institute, University of California at Davis, 2825 5 street, Sacramento (95817), California, US., Stamova B; Department of Neurology and MIND Institute, University of California at Davis, 2825 5 street, Sacramento (95817), California, US., Ander BP; Department of Neurology and MIND Institute, University of California at Davis, 2825 5 street, Sacramento (95817), California, US., Sharp FR; Department of Neurology and MIND Institute, University of California at Davis, 2825 5 street, Sacramento (95817), California, US., Kim GM; Department of Neurology, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul, South Korea., Bang OY; Department of Neurology, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul, South Korea., Jimenez-Conde J; Neurovascular Research Group, Institut Hospital del Mar de Investigations Mediques, Passeig Maritim, 25-29, Barcelona (08003), Spain., Slowik A; Department of Neurology, Jagiellonian University, Golebia, 24, Krakow(31-007), Poland., Stribian D; Department of Neurology, Helsinki University Hospital, Haartmaninkatu 4 Rakennus 1, Helsinki (00290), Finland., Tsai EA; Translational Biology, Biogen, Inc, 115 Brodway, Cambridge (02142), Massachusetts, US., Burkly LC; Genetics and Neurodevelomental Disease Research Unit, Biogen, Inc, 115 Brodway, Cambridge (02142), Massachusetts, US., Montaner J; Stroke Unit, Vall d'Hebron University Hospital, Universitat de Barcelona, Passeig de la Vall d'Hebron, 1198; Barcelona (08035), Spain.; Department of neurology, Hospital Virgen del Rocio, University of Seville, Avenida Manuel Siurot, s/n; Seville (41013), Spain.; Hospital Virgen de la Macarena, University of Seville, Calle Dr. Fedriani, 3; Seville (41009), Spain., Fernandez-Cadenas I; Stroke Unit, Vall d'Hebron University Hospital, Universitat de Barcelona, Passeig de la Vall d'Hebron, 1198; Barcelona (08035), Spain.; Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Carrer de Sant Quinti, 89; Barcelona (08041), Spain., Lee JM; Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue; Campus Box 8111; Saint Louis (63110), Missouri, US.; Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Avenue; Campus Box 8111; Saint Louis (63110), Missouri, US.; Department of Radiology, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis (63110), Missouri, US.; Department of Biomedical Engineering, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis (63110), Missouri, US.; Stroke and Cerebrovascular Center, Washington University School of Medicine, One Barnes-Jewish Hospital Plaza, Saint Louis (63110), Missouri, US., Cruchaga C; Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis (63110), Missouri, US.; NeuroGenomics and Informatics, Washington University School of Medicine, 425 S. Euclid Avenue, Saint Louis (63110), Missouri, US.; Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue; Campus Box 8111; Saint Louis (63110), Missouri, US.; Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Avenue; Campus Box 8111; Saint Louis (63110), Missouri, US.; The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, 4488 Forest Park Avenue; Saint Louis (63110), Missouri, US.; Department of Genetics, Washington University School of Medicine, 4515 McKinley Ave, Saint Louis (63110), Missouri, US.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2020 Nov 03. Date of Electronic Publication: 2020 Nov 03.
DOI:	10.1101/2020.10.29.20222257
Abstrakt:	During the first hours after stroke onset neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between NIH stroke scale (NIHSS) within six hours of stroke onset and NIHSS at 24h (ΔNIHSS). A total of 5,876 individuals from seven countries (Spain, Finland, Poland, United States, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of ΔNIHSS variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture than that of stroke risk. Seven loci (2p25.1, 2q31.2, 2q33.3, 4q34.3, 5q33.2, 6q26 and 7p21.1) were genome-wide significant and explained 2.1% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each loci. eQTL mapping and SMR indicate that ADAM23 (log Bayes Factor (LBF)=6.34) was driving the association for 2q33.3. Gene based analyses suggested that GRIA1 (LBF=5.26), which is predominantly expressed in brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated PARK2 (LBF=5.30) and ABCB5 (LBF=5.70) for the 6q26 and 7p21.1 loci. Human brain single nuclei RNA-seq indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23 , a pre-synaptic protein, and GRIA1 , a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provides the first evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischemic stroke. Research Into Context: Evidence before this study: No previous genome-wide association studies have investigated the genetic architecture of early outcomes after ischemic stroke. Added Value of this study: This is the first study that investigated genetic influences on early outcomes after ischemic stroke using a genome-wide approach, revealing seven genome-wide significant loci. A unique aspect of this genetic study is the inclusion of all of the major ethnicities by recruiting from participants throughout the world. Most genetic studies to date have been limited to populations of European ancestry. Implications of all available evidence: The findings provide the first evidence that genes implicating excitotoxicity contribute to human acute ischemic stroke, and demonstrates proof of principle that GWAS of acute ischemic stroke patients can reveal mechanisms involved in ischemic brain injury.
Databáze:	MEDLINE
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