RT Journal Article
T1 Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke.
A1 Ibanez, Laura
A1 Heitsch, Laura
A1 Carrera, Caty
A1 Farias, Fabiana H G
A1 Del Aguila, Jorge L
A1 Dhar, Rajat
A1 Budde, John
A1 Bergmann, Kristy
A1 Bradley, Joseph
A1 Harari, Oscar
A1 Phuah, Chia Ling
A1 Lemmens, Robin
A1 Viana Oliveira Souza, Alessandro A
A1 Moniche, Francisco
A1 Cabezas-Juan, Antonio
A1 Arenillas, Juan Francisco
A1 Krupinksi, Jerzy
A1 Cullell, Natalia
A1 Torres-Aguila, Nuria
A1 Muiño, Elena
A1 Cárcel-Márquez, Jara
A1 Marti-Fabregas, Joan
A1 Delgado-Mederos, Raquel
A1 Marin-Bueno, Rebeca
A1 Hornick, Alejandro
A1 Vives-Bauza, Cristofol
A1 Navarro, Rosa Diaz
A1 Tur, Silvia
A1 Jimenez, Carmen
A1 Obach, Victor
A1 Segura, Tomas
A1 Serrano-Heras, Gemma
A1 Chung, Jong Won
A1 Roquer, Jaume
A1 Soriano-Tarraga, Carol
A1 Giralt-Steinhauer, Eva
A1 Mola-Caminal, Marina
A1 Pera, Joanna
A1 Lapicka-Bodzioch, Katarzyna
A1 Derbisz, Justyna
A1 Davalos, Antoni
A1 Lopez-Cancio, Elena
A1 Muñoz, Lucia
A1 Tatlisumak, Turgut
A1 Molina, Carlos
A1 Ribo, Marc
A1 Bustamante, Alejandro
A1 Sobrino, Tomas
A1 Castillo-Sanchez, Jose
A1 Campos, Francisco
A1 Rodriguez-Castro, Emilio
A1 Arias-Rivas, Susana
A1 Rodríguez-Yáñez, Manuel
A1 Herbosa, Christina
A1 Ford, Andria L
A1 Gutierrez-Romero, Alonso
A1 Uribe-Pacheco, Rodrigo
A1 Arauz, Antonio
A1 Lopes-Cendes, Iscia
A1 Lowenkopf, Theodore
A1 Barboza, Miguel A
A1 Amini, Hajar
A1 Stamova, Boryana
A1 Ander, Bradley P
A1 Sharp, Frank R
A1 Kim, Gyeong Moon
A1 Bang, Oh Young
A1 Jimenez-Conde, Jordi
A1 Slowik, Agnieszka
A1 Stribian, Daniel
A1 Tsai, Ellen A
A1 Burkly, Linda C
A1 Montaner, Joan
A1 Fernandez-Cadenas, Israel
A1 Lee, Jin Moo
A1 Cruchaga, Carlos
K1 NIHSS
K1 genetics
K1 ischaemic stroke
K1 neuroprotection
AB 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.
YR 2022
FD 2022
LK http://hdl.handle.net/10668/19729
UL http://hdl.handle.net/10668/19729
LA en
DS RISalud
RD Apr 29, 2025