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

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.