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

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MARC

Ibanez, L.Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA.;Washington Univ, Sch Med, NeuroGen & Informat, St Louis, MO 63110 USA (author)

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

Article/chapterEnglish2022

Publisher, publication year, extent ...

2022-02-25
Oxford University Press (OUP),2022

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LIBRIS-ID:oai:gup.ub.gu.se/320688
https://gup.ub.gu.se/publication/320688URI
https://doi.org/10.1093/brain/awac080DOI
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-485993URI

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Language:English

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SwePubSwePub

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

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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.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Neurologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Neurology hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Medicinsk genetik hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Medical Genetics hsv//eng
ischaemic stroke
neuroprotection
genetics
NIHSS
spontaneous reperfusion
gene-expression
metaanalysis
annotation
disease
genome
adam23
lgi1
neuroprotection
severity
Neurosciences & Neurology
ischaemic stroke

Added entries (persons, corporate bodies, meetings, titles ...)

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 (author)
Carrera, C.Univ Barcelona, Vall Hebron Univ Hosp, Stroke Unit, Barcelona 08035, Spain,Biogen Inc, Translat Biol, Cambridge, MA 02142 USA (author)
Farias, F. H. G.Washington Univ, Sch Med, NeuroGen & Informat, St Louis, MO 63110 USA (author)
Del Aguila, J. L.Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA.;Washington Univ, Sch Med, NeuroGen & Informat, St Louis, MO 63110 USA (author)
Dhar, R.Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA (author)
Budde, J.Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA.;Washington Univ, Sch Med, NeuroGen & Informat, St Louis, MO 63110 USA (author)
Bergmann, K.Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA.;Washington Univ, Sch Med, NeuroGen & Informat, St Louis, MO 63110 USA (author)
Bradley, J.Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA.;Washington Univ, Sch Med, NeuroGen & Informat, St Louis, MO 63110 USA (author)
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 (author)
Phuah, C. L.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 (author)
Lemmens, R.Katholieke Univ Leuven, Dept Neurosci, Campus Gasthuisberg O&N2, BE-3000 Leuven, Belgium (author)
Souza, AavoUniv Campinas UNICAMP, Sch Med Sci, Dept Neurol, Cidade Univ, BR-13083887 Campinas, Brazil.;Brazilian Inst Neurosci & Neurotechnol BRAINN, BR-13083887 Campinas, Brazil (author)
Moniche, F.Univ Seville, Hosp Virgen Rocio, Dept Neurol, Seville 41013, Spain (author)
Cabezas-Juan, A.Univ Seville, Hosp Virgen Rocio, Dept Neurol, Seville 41013, Spain.;Univ Seville, Hosp Virgen Macarena, Seville 41009, Spain,Inst Nacl Neurol & Neurocirurgia Mexico, Ciudad de Mexico 14269, Mexico (author)
Arenillas, J. F.Valladolid Univ, Hosp Clin Univ Valladolid, Dept Neurol, Valladolid 47003, Spain (author)
Krupinksi, J.Univ Barcelona, Mutua Terrassa Univ Hosp, Dept Neurol, Terrassa 08221, Spain.;Univ Barcelona, Fundacio Docencia & Recerca Mutua Terrassa, Terrassa 08221, Spain (author)
Cullell, N.Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08041, Spain (author)
Torres-Aguila, N.Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08041, Spain (author)
Muino, E.Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08041, Spain (author)
Carcel-Marquez, J.Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08041, Spain,Univ Illes Balears, Hosp Univ Son Espases, Dept Neurol, Palma De Mallorca 07120, Spain (author)
Marti-Fabregas, J.Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08041, Spain (author)
Delgado-Mederos, R.Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08041, Spain (author)
Marin-Bueno, R.Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08041, Spain (author)
Hornick, A.Southern Illinois Healthcare Mem Hosp Carbondale, Dept Neurol, Carbondale, IL 62901 USA (author)
Vives-Bauza, C.Univ Illes Balears, Dept Biol, Palma De Mallorca 07122, Spain (author)
Navarro, R. D.Univ Illes Balears, Hosp Univ Son Espases, Dept Neurol, Palma De Mallorca 07120, Spain (author)
Tur, S.Univ Illes Balears, Hosp Univ Son Espases, Dept Neurol, Palma De Mallorca 07120, Spain (author)
Jimenez, C. (author)
Obach, V.Univ Barcelona, Hosp Clin Barcelona, Dept Neurol, Barcelona 08036, Spain (author)
Segura, T.Complejo Hosp Univ Albacete, Res Unit, Albacete 02008, Spain (author)
Serrano-Heras, G.Complejo Hosp Univ Albacete, Res Unit, Albacete 02008, Spain (author)
Chung, J. W.Samsung Med Ctr, Dept Neurol, Seoul, South Korea (author)
Roquer, J.Inst Hosp Mar Invest Med, Neurovasc Res Grp, Barcelona 08003, Spain (author)
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 (author)
Giralt-Steinhauer, E.Inst Hosp Mar Invest Med, Neurovasc Res Grp, Barcelona 08003, Spain (author)
Mola-Caminal, MarinaUppsala universitet,Ortopedi,Inst Hosp Mar Invest Med, Neurovasc Res Grp, Barcelona 08003, Spain(Swepub:uu)marmo445 (author)
Pera, J.Jagiellonian Univ, Dept Neurol, PL-31007 Krakow, Poland.;Univ Autonoma Barcelona, Hosp Germans Trias & Pujol, Dept Neurol, Badalona 08916, Spain (author)
Lapicka-Bodzioch, K.Jagiellonian Univ, Dept Neurol, PL-31007 Krakow, Poland (author)
Derbisz, J.Jagiellonian Univ, Dept Neurol, PL-31007 Krakow, Poland (author)
Davalos, A. (author)
Lopez-Cancio, E.Hosp Univ Cent Asturias, Dept Neurol, Oviedo, Spain (author)
Munoz, L.Univ Autonoma Barcelona, Hosp Germans Trias & Pujol, Dept Neurol, Badalona 08916, Spain (author)
Tatlisumak, TurgutGothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för klinisk neurovetenskap,Institute of Neuroscience and Physiology, Department of Clinical Neuroscience,Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Neurol, S-41345 Gothenburg, Sweden.;Sahlgrenska Acad Univ Gothenburg, Inst Neurosci & Physiol, Dept Clin Neurosci, Gothenburg, Sweden(Swepub:gu)xtatlt (author)
Molina, C.Univ Barcelona, Vall Hebron Univ Hosp, Stroke Unit, Barcelona 08035, Spain (author)
Ribo, M.Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA (author)
Bustamante, A.Univ Autonoma Barcelona, Hosp Germans Trias & Pujol, Dept Neurol, Badalona 08916, Spain (author)
Sobrino, T.Hlth Res Inst Santiago de Compostela IDIS, Clin Neurosci Res Lab, Santiago de Compostela 15706, Spain (author)
Castillo-Sanchez, J.Hlth Res Inst Santiago de Compostela IDIS, Clin Neurosci Res Lab, Santiago de Compostela 15706, Spain (author)
Campos, F.Hlth Res Inst Santiago de Compostela IDIS, Clin Neurosci Res Lab, Santiago de Compostela 15706, Spain (author)
Rodriguez-Castro, E.Hlth Res Inst Santiago de Compostela IDIS, Clin Neurosci Res Lab, Santiago de Compostela 15706, Spain (author)
Arias-Rivas, S.Hlth Res Inst Santiago de Compostela IDIS, Clin Neurosci Res Lab, Santiago de Compostela 15706, Spain (author)
Rodriguez-Yanez, M.Hlth Res Inst Santiago de Compostela IDIS, Clin Neurosci Res Lab, Santiago de Compostela 15706, Spain (author)
Herbosa, C. (author)
Ford, A. L.Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA.;Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA (author)
Gutierrez-Romero, A.Inst Nacl Neurol & Neurocirurgia Mexico, Ciudad de Mexico 14269, Mexico (author)
Uribe-Pacheco, R.Inst Nacl Neurol & Neurocirurgia Mexico, Ciudad de Mexico 14269, Mexico (author)
Arauz, A.Hosp Rafael A Calderon Guardia, Neurosci Dept, San Jose, Costa Rica,Helsinki Univ Hosp, Dept Neurol, Helsinki 00290, Finland (author)
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 (author)
Lowenkopf, T.Providence St Vincent Med Ctr, Dept Neurol, Portland, OR 97225 USA (author)
Barboza, M. A. (author)
Amini, H.Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA (author)
Stamova, B.Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA (author)
Ander, B. P.Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA (author)
Sharp, F. R.Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA (author)
Kim, G. M. (author)
Bang, O. Y. (author)
Jimenez-Conde, J. (author)
Slowik, A. (author)
Stribian, D.Univ Calif Davis, MIND Inst, Sacramento, CA 95817 USA (author)
Tsai, E. A. (author)
Burkly, L. C. (author)
Montaner, J.Univ Barcelona, Vall Hebron Univ Hosp, Stroke Unit, Barcelona 08035, Spain (author)
Fernandez-Cadenas, I.Univ Barcelona, Vall Hebron Univ Hosp, Stroke Unit, Barcelona 08035, Spain (author)
Lee, J. M.Washington Univ, Sch Med, Dept Biomed Engn, St Louis, MO 63110 USA.;Washington Univ, Sch Med, Stroke & Cerebrovasc Ctr, St Louis, MO 63110 USA (author)
Cruchaga, C. (author)
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA.;Washington Univ, Sch Med, NeuroGen & Informat, St Louis, MO 63110 USAWashington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA.;Washington Univ, Sch Med, Dept Emergency Med, St Louis, MO 63110 USA (creator_code:org_t)

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By the author/editor: Ibanez, L.; Heitsch, L.; Carrera, C.; Farias, F. H. G.; Del Aguila, J. L ...; Dhar, R.; show more...; Budde, J.; Bergmann, K.; Bradley, J.; Harari, O.; Phuah, C. L.; Lemmens, R.; Souza, Aavo; Moniche, F.; Cabezas-Juan, A.; Arenillas, J. F.; Krupinksi, J.; Cullell, N.; Torres-Aguila, N ...; Muino, E.; Carcel-Marquez, ...; Marti-Fabregas, ...; Delgado-Mederos, ...; Marin-Bueno, R.; Hornick, A.; Vives-Bauza, C.; Navarro, R. D.; Tur, S.; Jimenez, C.; Obach, V.; Segura, T.; Serrano-Heras, G ...; Chung, J. W.; Roquer, J.; Soriano-Tarraga, ...; Giralt-Steinhaue ...; Mola-Caminal, Ma ...; Pera, J.; Lapicka-Bodzioch ...; Derbisz, J.; Davalos, A.; Lopez-Cancio, E.; Munoz, L.; Tatlisumak, Turg ...; Molina, C.; Ribo, M.; Bustamante, A.; Sobrino, T.; Castillo-Sanchez ...; Campos, F.; Rodriguez-Castro ...; Arias-Rivas, S.; Rodriguez-Yanez, ...; Herbosa, C.; Ford, A. L.; Gutierrez-Romero ...; Uribe-Pacheco, R ...; Arauz, A.; Lopes-Cendes, I.; Lowenkopf, T.; Barboza, M. A.; Amini, H.; Stamova, B.; Ander, B. P.; Sharp, F. R.; Kim, G. M.; Bang, O. Y.; Jimenez-Conde, J ...; Slowik, A.; Stribian, D.; Tsai, E. A.; Burkly, L. C.; Montaner, J.; Fernandez-Cadena ...; Lee, J. M.; Cruchaga, C.; show less...

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