Multi-ancestry genetic study in 5,876 patients identifies an association between excitotoxic genes and early outcomes after acute ischemic stroke
Authors: Ibanez Laura , Heitsch Laura , Carrera Caty , Farias Fabiana H.G. , Dhar Rajat , Budde John , Bergmann Kristy , Bradley Joseph , Harari Oscar , Phuah Chia-Ling , Lemmens Robin , Oliveira Souza Alessandro A. Viana , 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. , 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: November 2020

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 ADAM23 (log Bayes Factor (LBF)=6.34) was driving the association for 2q33.3. Gene based analyses suggested that GRIA1 (LBF=5.26), which is predominantly expressed in brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated PARK2 (LBF=5.30) and ABCB5 (LBF=5.70) for the 6q26 and 7p21.1 loci. Human brain single nuclei RNA-seq indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a pre-synaptic protein, and GRIA1, 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

Evidence before this study

No previous genome-wide association studies have investigated the genetic architecture of early outcomes after ischemic stroke.

Added Value of this study

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.

Implications of all available evidence

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.