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

Laura Ibanez, Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis (63110), Missouri, US.
Laura Heitsch, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue; Campus Box 8111; Saint Louis (63110), Missouri, US.
Caty Carrera, Stroke Unit, Vall d'Hebron University Hospital, Universitat de Barcelona, Passeig de la Vall d'Hebron, 1198; Barcelona (08035), Spain.
Fabiana H. Farias, Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis (63110), Missouri, US.
Rajat Dhar, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue; Campus Box 8111; Saint Louis (63110), Missouri, US.
John Budde, Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis (63110), Missouri, US.
Kristy Bergmann, Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis (63110), Missouri, US.
Joseph Bradley, Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis (63110), Missouri, US.
Oscar Harari, Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis (63110), Missouri, US.
Chia-Ling Phuah, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue; Campus Box 8111; Saint Louis (63110), Missouri, US.
Robin Lemmens, Department of Neuroscience, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N2; Herestraat 49 box 1021; Leuven (BE-3000), Belgium.
Alessandro A. Souza, Department of Neurology, School of Medical Sciences, University of Campinas (UNICAMP), R. Tessalia Viera de Camargo, 126; Cidade Universitaria, Campinas (13083-887), Brazil.
Francisco Moniche, Department of neurology, Hospital Virgen del Rocio, University of Seville, Avenida Manuel Siurot, s/n; Seville (41013), Spain.
Antonio Cabezas-Juan, Department of neurology, Hospital Virgen del Rocio, University of Seville, Avenida Manuel Siurot, s/n; Seville (41013), Spain.
Juan Francisco Arenillas, Department of Neurology, Hospital Clinico Universitario Valladolid, Valladolid University, Avenida Ramon y Cajal, 3; Valladolid (47003), Spain.
Jerzy Krupinksi, Department of Neurology, Mutua Terrassa University Hospital, Universitat de Barcelona, Plaça del Dr. Robert, 5; Terrassa (08221), Spain.
Natalia Cullell, Fundacio Docencia i Recerca Mutua Terrassa, Universitat de Barcelona, Carrer Sant Antoni, 19; Terrassa (08221), Spain.
Nuria Torres-Aguila, Fundacio Docencia i Recerca Mutua Terrassa, Universitat de Barcelona, Carrer Sant Antoni, 19; Terrassa (08221), Spain.
Elena Muiño, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Carrer de Sant Quinti, 89; Barcelona (08041), Spain.
Jara Cárcel-Márquez, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Carrer de Sant Quinti, 89; Barcelona (08041), Spain.
Joan Marti-Fabregas, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Carrer de Sant Quinti, 89; Barcelona (08041), Spain.
Raquel Delgado-Mederos, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Carrer de Sant Quinti, 89; Barcelona (08041), Spain.
Rebeca Marin-Bueno, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Carrer de Sant Quinti, 89; Barcelona (08041), Spain.
Alejandro Hornick, Department of Neurology, Southern Illinois Healthcare Memorial Hospital of Carbondale, 405 W Jackson Street, Carbondale (62901), Illinois, US.
Cristofol Vives-Bauza, Department of Biology, Universitat de les Illes Balears, Carretera de Valldemossa, km 7,5, Palma (07122), Spain.
Rosa Diaz Navarro, Department of Neurology, Hospital Universitari Son Espases, Universitat de les Illes Balears, Carretera de Valldemossa, 79, Palma (07120), Spain.
Silvia Tur, Department of Neurology, Hospital Universitari Son Espases, Universitat de les Illes Balears, Carretera de Valldemossa, 79, Palma (07120), Spain.
Carmen Jimenez, Department of Neurology, Hospital Universitari Son Espases, Universitat de les Illes Balears, Carretera de Valldemossa, 79, Palma (07120), Spain.
Victor Obach, Department of Neurology, Hospital Clinic de Barcelona, Universitat de Barcelona, Carrer Villarroel, 170, Barcelona (08036), Spain.
Tomas Segura, Research Unit, Complejo Hospitalario Universitario de Albacete. Calle Laurel s/n. Albacete (02008), Spain.
Gemma Serrano-Heras, Research Unit, Complejo Hospitalario Universitario de Albacete. Calle Laurel s/n. Albacete (02008), Spain.

Document Type

Article

Abstract

UNLABELLED: 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 (log Bayes Factor (LBF)=6.34) was driving the association for 2q33.3. Gene based analyses suggested that (LBF=5.26), which is predominantly expressed in brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated (LBF=5.30) and (LBF=5.70) for the 6q26 and 7p21.1 loci. Human brain single nuclei RNA-seq indicates that the gene expression of and is enriched in neurons. , a pre-synaptic protein, and , 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: No previous genome-wide association studies have investigated the genetic architecture of early outcomes after ischemic stroke. 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. 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.

Publication Date

11-3-2020

Publication Title

medRxiv : the preprint server for health sciences

PubMed ID

33173895

Digital Object Identifier (DOI)

10.1101/2020.10.29.20222257

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