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

2022; Oxford University Press; Volume: 145; Issue: 7 Linguagem: Inglês

10.1093/brain/awac080

1460-2156

Laura Ibáñez, Laura Heitsch, Caty Carrera, Fabiana H.G. Farias, Jorge L. Del-Águila, Rajat Dhar, John Budde, Kristy Bergmann, Joseph Bradley, Oscar Harari, Chia‐Ling Phuah, Robin Lemmens, Alessandro A. Viana Oliveira Souza, Francisco Moniche, Antonio Cabezas-Juan, Juan F. Arenillas, Jerzy Krupinksi, Natàlia Cullell, Nuria P. Torres‐Aguila, Elena Muiño, Jara Cárcel‐Márquez, Joan Martí‐Fàbregas, Raquel Delgado‐Mederos, Rebeca Marín‐Bueno, Alejandro Hornick, Cristòfol Vives-Bauzà, Rosa Díaz-Navarro, Sílvia Tur, Carmen Jiménez, Vı́ctor Obach, Tomás Segura, Gemma Serrano‐Heras, Jong Won Chung, Jaume Roquer, Carolina Soriano‐Tárraga, Eva Giralt‐Steinhauer, Marina Mola-Caminal, Joanna Pera, Katarzyna Lapicka-Bodzioch, Justyna Derbisz, Antoni Dávalos, Elena López‐Cancio, Lucía Muñoz-Narbona, Turgut Tatlisumak, Carlos A. Molina, Marc Ribó, Alejandro Bustamante, Tomás Sobrino, Jose Castillo-Sanchez, Francisco Campos, Emilio Rodríguez‐Castro, Susana Arias‐Rivas, Manuel Rodríguez‐Yáñez, C. Herbosa, Andria L. Ford, Alonso Gutiérrez, Rodrigo Uribe-Pacheco, Antonio Araúz, Íscia Lopes‐Cendes, Theodore Lowenkopf, Miguel A. Barboza, Hajar Amini, Boryana Stamova, Bradley P. Ander, Frank R. Sharp, Gyeong Moon Kim, Oh Young Bang, Jordi Jiménez‐Conde, Agnieszka Słowik, Daniel Stribian, Ellen Tsai, Linda C. Burkly, Joan Montaner, Israel Fernández‐Cadenas, Jin‐Moo Lee, Carlos Cruchaga,

Genetic Associations and Epidemiology

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.