Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke

Laura Ibanez, Department of Psychiatry, School of Medicine, Washington University, Saint Louis 63110, MO, USA.
Laura Heitsch, Department of Neurology, School of Medicine, Washington University, Saint Louis 63110, MO, USA.
Caty Carrera, Stroke Unit, Vall d'Hebron University Hospital, Universitat de Barcelona, Barcelona 08035, Spain.
Fabiana H. Farias, Department of Psychiatry, School of Medicine, Washington University, Saint Louis 63110, MO, USA.
Jorge L. Del Aguila, Department of Psychiatry, School of Medicine, Washington University, Saint Louis 63110, MO, USA.
Rajat Dhar, Department of Neurology, School of Medicine, Washington University, Saint Louis 63110, MO, USA.
John Budde, Department of Psychiatry, School of Medicine, Washington University, Saint Louis 63110, MO, USA.
Kristy Bergmann, Department of Psychiatry, School of Medicine, Washington University, Saint Louis 63110, MO, USA.
Joseph Bradley, Department of Psychiatry, School of Medicine, Washington University, Saint Louis 63110, MO, USA.
Oscar Harari, Department of Psychiatry, School of Medicine, Washington University, Saint Louis 63110, MO, USA.
Chia Ling Phuah, Department of Neurology, School of Medicine, Washington University, Saint Louis 63110, MO, USA.
Robin Lemmens, Department of Neuroscience, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N2, Leuven BE-3000, Belgium.
Alessandro A. Viana Oliveira Souza, Department of Neurology, School of Medical Sciences, University of Campinas (UNICAMP), Cidade Universitaria, Campinas 13083-887, Brazil.
Francisco Moniche, Department of Neurology, Hospital Virgen del Rocio, University of Seville, Seville 41013, Spain.
Antonio Cabezas-Juan, Department of Neurology, Hospital Virgen del Rocio, University of Seville, Seville 41013, Spain.
Juan Francisco Arenillas, Department of Neurology, Hospital Clinico Universitario Valladolid, Valladolid University, Valladolid 47003, Spain.
Jerzy Krupinksi, Department of Neurology, Mutua Terrassa University Hospital, Universitat de Barcelona, Terrassa 08221, Spain.
Natalia Cullell, Fundacio Docencia i Recerca Mutua Terrassa, Universitat de Barcelona, Terrassa 08221, Spain.
Nuria Torres-Aguila, Fundacio Docencia i Recerca Mutua Terrassa, Universitat de Barcelona, Terrassa 08221, Spain.
Elena Muiño, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona 08041, Spain.
Jara Cárcel-Márquez, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona 08041, Spain.
Joan Marti-Fabregas, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona 08041, Spain.
Raquel Delgado-Mederos, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona 08041, Spain.
Rebeca Marin-Bueno, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona 08041, Spain.
Alejandro Hornick, Department of Neurology, Southern Illinois Healthcare Memorial Hospital of Carbondale, Carbondale 62901, IL, USA.
Cristofol Vives-Bauza, Department of Biology, Universitat de les Illes Balears, Palma 07122, Spain.
Rosa Diaz Navarro, Department of Neurology, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma 07120, Spain.
Silvia Tur, Department of Neurology, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma 07120, Spain.
Carmen Jimenez, Department of Neurology, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma 07120, Spain.
Victor Obach, Department of Neurology, Hospital Clinic de Barcelona, Universitat de Barcelona, Barcelona 08036, Spain.
Tomas Segura, Research Unit, Complejo Hospitalario Universitario de Albacete, Albacete 02008, Spain.

Document Type

Article

Abstract

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 the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% 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 locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke.

Medical Subject Headings

Bayes Theorem; Brain Ischemia (complications, genetics); Genome-Wide Association Study; Humans; Ischemic Stroke; Stroke (complications, genetics); United States

Publication Date

7-29-2022

Publication Title

Brain : a journal of neurology

E-ISSN

1460-2156

Volume

145

Issue

7

First Page

2394

Last Page

2406

PubMed ID

35213696

Digital Object Identifier (DOI)

10.1093/brain/awac080

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