Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke
Por:
Ibanez, L, Heitsch, L, Carrera, C, Farias, FHG, Del Aguila, JL, Dhar, R, Budde, J, Bergmann, K, Bradley, J, Harari, O, Phuah, CL, Lemmens, R, Souza, AAVO, Moniche, F, Cabezas-Juan, A, Arenillas, JF, Krupinksi, J, Cullell, N, Torres-Aguila, N, Muino, E, Carcel-Marquez, J, Marti-Fabregas, J, Delgado-Mederos, R, Marin-Bueno, R, Hornick, A, Vives-Bauza, C, Navarro, RD, Tur, S, Jimenez, C, Obach, V, Segura, T, Serrano-Heras, G, Chung, JW, Roquer, J, Soriano-Tarraga, C, Giralt-Steinhauer, E, Mola-Caminal, M, Pera, J, Lapicka-Bodzioch, K, Derbisz, J, Davalos, A, Lopez-Cancio, E, Munoz, L, Tatlisumak, T, Molina, C, Ribo, M, Bustamante, A, Sobrino, T, Castillo-Sanchez, J, Campos, F, Rodriguez-Castro, E, Arias-Rivas, S, Rodriguez-Yanez, M, Herbosa, C, Ford, AL, Gutierrez-Romero, A, Uribe-Pacheco, R, Arauz, A, Lopes-Cendes, I, Lowenkopf, T, Barboza, MA, Amini, H, Stamova, B, Ander, BP, Sharp, FR, Kim, GM, Bang, OY, Jimenez-Conde, J, Slowik, A, Stribian, D, Tsai, EA, Burkly, LC, Montaner, J, Fernandez-Cadenas, I, Lee, JM, Cruchaga, C
Publicada:
29 jul 2022
Ahead of Print:
1 feb 2022
Resumen:
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.
Ibanez et al. perform a multi-ancestry meta-analysis to investigate the genetic architecture of early stroke outcomes. Two of the eight genome-wide significant loci identified-ADAM23 and GRIA1-are involved in synaptic excitability, suggesting that excitotoxicity contributes to neurological instability after ischaemic stroke.
Filiaciones:
Ibanez, L:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Washington Univ, Sch Med, NeuroGen & Informat, St Louis, MO 63110 USA
Heitsch, L:
Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
Washington Univ, Sch Med, Dept Emergency Med, St Louis, MO 63110 USA
Carrera, C:
Univ Barcelona, Vall Hebron Univ Hosp, Stroke Unit, Barcelona 08035, Spain
Farias, FHG:
Washington Univ, Sch Med, NeuroGen & Informat, St Louis, MO 63110 USA
Del Aguila, JL:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Washington Univ, Sch Med, NeuroGen & Informat, St Louis, MO 63110 USA
Dhar, R:
Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
Budde, J:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Washington Univ, Sch Med, NeuroGen & Informat, St Louis, MO 63110 USA
Bergmann, K:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Washington Univ, Sch Med, NeuroGen & Informat, St Louis, MO 63110 USA
Bradley, J:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Washington Univ, Sch Med, NeuroGen & Informat, St Louis, MO 63110 USA
Harari, O:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Washington Univ, Sch Med, NeuroGen & Informat, St Louis, MO 63110 USA
Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA
Washington Univ, Sch Med, Charles F & Joanne Knight Alzheimer Dis Res Ctr, St Louis, MO 63110 USA
Phuah, CL:
Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
Lemmens, R:
Katholieke Univ Leuven, Dept Neurosci, Campus Gasthuisberg O&N2, BE-3000 Leuven, Belgium
Souza, AAVO:
Univ Campinas UNICAMP, Sch Med Sci, Dept Neurol, Cidade Univ, BR-13083887 Campinas, Brazil
Brazilian Inst Neurosci & Neurotechnol BRAINN, BR-13083887 Campinas, Brazil
Moniche, F:
Univ Seville, Hosp Virgen Rocio, Dept Neurol, Seville 41013, Spain
Cabezas-Juan, A:
Univ Seville, Hosp Virgen Rocio, Dept Neurol, Seville 41013, Spain
Univ Seville, Hosp Virgen Macarena, Seville 41009, Spain
Arenillas, JF:
Valladolid Univ, Hosp Clin Univ Valladolid, Dept Neurol, Valladolid 47003, Spain
Krupinksi, J:
Univ Barcelona, Mutua Terrassa Univ Hosp, Dept Neurol, Terrassa 08221, Spain
Univ Barcelona, Fundacio Docencia & Recerca Mutua Terrassa, Terrassa 08221, Spain
Cullell, N:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08041, Spain
Torres-Aguila, N:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08041, Spain
Muino, E:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08041, Spain
Carcel-Marquez, J:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08041, Spain
Marti-Fabregas, J:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08041, Spain
Delgado-Mederos, R:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08041, Spain
Marin-Bueno, R:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08041, Spain
Hornick, A:
Southern Illinois Healthcare Mem Hosp Carbondale, Dept Neurol, Carbondale, IL 62901 USA
Vives-Bauza, C:
Univ Illes Balears, Dept Biol, Palma De Mallorca 07122, Spain
Navarro, RD:
Univ Illes Balears, Hosp Univ Son Espases, Dept Neurol, Palma De Mallorca 07120, Spain
Tur, S:
Univ Illes Balears, Hosp Univ Son Espases, Dept Neurol, Palma De Mallorca 07120, Spain
Jimenez, C:
Univ Illes Balears, Hosp Univ Son Espases, Dept Neurol, Palma De Mallorca 07120, Spain
Obach, V:
Univ Barcelona, Hosp Clin Barcelona, Dept Neurol, Barcelona 08036, Spain
Segura, T:
Complejo Hosp Univ Albacete, Res Unit, Albacete 02008, Spain
Serrano-Heras, G:
Complejo Hosp Univ Albacete, Res Unit, Albacete 02008, Spain
Chung, JW:
Samsung Med Ctr, Dept Neurol, Seoul, South Korea
Roquer, J:
Inst Hosp Mar Invest Med, Neurovasc Res Grp, Barcelona 08003, Spain
Soriano-Tarraga, C:
Washington Univ, Sch Med, NeuroGen & Informat, St Louis, MO 63110 USA
Inst Hosp Mar Invest Med, Neurovasc Res Grp, Barcelona 08003, Spain
Giralt-Steinhauer, E:
Inst Hosp Mar Invest Med, Neurovasc Res Grp, Barcelona 08003, Spain
Mola-Caminal, M:
Inst Hosp Mar Invest Med, Neurovasc Res Grp, Barcelona 08003, Spain
Uppsala Univ, Dept Surg Sci, Orthoped, S-75185 Uppsala, Sweden
Pera, J:
Jagiellonian Univ, Dept Neurol, PL-31007 Krakow, Poland
Univ Autonoma Barcelona, Hosp Germans Trias & Pujol, Dept Neurol, Badalona 08916, Spain
Lapicka-Bodzioch, K:
Jagiellonian Univ, Dept Neurol, PL-31007 Krakow, Poland
Derbisz, J:
Jagiellonian Univ, Dept Neurol, PL-31007 Krakow, Poland
Lopez-Cancio, E:
Hosp Univ Cent Asturias, Dept Neurol, Oviedo, Spain
Munoz, L:
Univ Autonoma Barcelona, Hosp Germans Trias & Pujol, Dept Neurol, Badalona 08916, Spain
Tatlisumak, T:
Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Neurol, S-41345 Gothenburg, Sweden
Sahlgrenska Acad Univ Gothenburg, Inst Neurosci & Physiol, Dept Clin Neurosci, Gothenburg, Sweden
Molina, C:
Univ Barcelona, Vall Hebron Univ Hosp, Stroke Unit, Barcelona 08035, Spain
Ribo, M:
Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA
Bustamante, A:
Univ Autonoma Barcelona, Hosp Germans Trias & Pujol, Dept Neurol, Badalona 08916, Spain
Sobrino, T:
Hlth Res Inst Santiago de Compostela IDIS, Clin Neurosci Res Lab, Santiago de Compostela 15706, Spain
Castillo-Sanchez, J:
Hlth Res Inst Santiago de Compostela IDIS, Clin Neurosci Res Lab, Santiago de Compostela 15706, Spain
Campos, F:
Hlth Res Inst Santiago de Compostela IDIS, Clin Neurosci Res Lab, Santiago de Compostela 15706, Spain
Rodriguez-Castro, E:
Hlth Res Inst Santiago de Compostela IDIS, Clin Neurosci Res Lab, Santiago de Compostela 15706, Spain
Arias-Rivas, S:
Hlth Res Inst Santiago de Compostela IDIS, Clin Neurosci Res Lab, Santiago de Compostela 15706, Spain
Rodriguez-Yanez, M:
Hlth Res Inst Santiago de Compostela IDIS, Clin Neurosci Res Lab, Santiago de Compostela 15706, Spain
Ford, AL:
Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA
Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA
Gutierrez-Romero, A:
Inst Nacl Neurol & Neurocirurgia Mexico, Ciudad de Mexico 14269, Mexico
Uribe-Pacheco, R:
Inst Nacl Neurol & Neurocirurgia Mexico, Ciudad de Mexico 14269, Mexico
Arauz, A:
Inst Nacl Neurol & Neurocirurgia Mexico, Ciudad de Mexico 14269, Mexico
Lopes-Cendes, I:
Univ Campinas UNICAMP, Sch Med Sci, Dept Neurol, Cidade Univ, BR-13083887 Campinas, Brazil
Brazilian Inst Neurosci & Neurotechnol BRAINN, BR-13083887 Campinas, Brazil
Lowenkopf, T:
Providence St Vincent Med Ctr, Dept Neurol, Portland, OR 97225 USA
Barboza, MA:
Hosp Rafael A Calderon Guardia, Neurosci Dept, San Jose, Costa Rica
Amini, H:
Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA
Stamova, B:
Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA
Ander, BP:
Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA
Sharp, FR:
Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA
Stribian, D:
Univ Calif Davis, MIND Inst, Sacramento, CA 95817 USA
Tsai, EA:
Helsinki Univ Hosp, Dept Neurol, Helsinki 00290, Finland
Burkly, LC:
Biogen Inc, Translat Biol, Cambridge, MA 02142 USA
Montaner, J:
Univ Barcelona, Vall Hebron Univ Hosp, Stroke Unit, Barcelona 08035, Spain
Fernandez-Cadenas, I:
Univ Barcelona, Vall Hebron Univ Hosp, Stroke Unit, Barcelona 08035, Spain
Lee, JM:
Washington Univ, Sch Med, Dept Biomed Engn, St Louis, MO 63110 USA
Washington Univ, Sch Med, Stroke & Cerebrovasc Ctr, St Louis, MO 63110 USA
Cruchaga, C:
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Washington Univ, Sch Med, NeuroGen & Informat, St Louis, MO 63110 USA
Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA
Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA
Green Accepted, All Open Access; Green
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