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

Laura Ibanez; Laura Heitsch; Caty Carrera; Fabiana H.G. Farias; Jorge L. Del Aguila; 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 Francisco Arenillas; Jerzy Krupinksi; Natalia Cullell; Nuria Torres-Aguila; Elena Muiño; Jara Cárcel-Márquez; Joan Marti-Fabregas; Raquel Delgado-Mederos; Rebeca Marin-Bueno; Alejandro Hornick; Cristofol Vives-Bauza; Rosa Diaz Navarro; Silvia Tur; Carmen Jimenez; Victor Obach; Tomas Segura; Gemma Serrano-Heras; Jong Won Chung; Jaume Roquer; Carol Soriano-Tarraga; Eva Giralt-Steinhauer; Marina Mola-Caminal; Joanna Pera; Katarzyna Lapicka-Bodzioch; Justyna Derbisz; Antoni Davalos; Elena Lopez-Cancio; Lucia Muñoz; Turgut Tatlisumak; Carlos Molina; Marc Ribo; Alejandro Bustamante; Tomas Sobrino; Jose Castillo-Sanchez; Francisco Campos; Emilio Rodriguez-Castro; Susana Arias-Rivas; Manuel Rodríguez-Yáñez; Christina Herbosa; Andria L. Ford; Alonso Gutierrez-Romero; Rodrigo Uribe-Pacheco; Antonio Arauz; Iscia Lopes-Cendes; Theodore Lowenkopf; Miguel A. Barboza; Hajar Amini; Boryana Stamova; Bradley P. Ander; Frank R. Sharp; Gyeong Moon Kim; Oh Young Bang; Jordi Jimenez-Conde; Agnieszka Slowik; Daniel Stribian; Ellen A. Tsai; Linda C. Burkly; Joan Montaner; Israel Fernandez-Cadenas; Jin Moo Lee; Carlos Cruchaga

doi:10.1093/brain/awac080

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

Laura Ibanez, Laura Heitsch, Caty Carrera, Fabiana H.G. Farias, Jorge L. Del Aguila, 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 Francisco Arenillas, Jerzy Krupinksi, Natalia Cullell, Nuria Torres-Aguila, Elena MuiñoJara Cárcel-Márquez, Joan Marti-Fabregas, Raquel Delgado-Mederos, Rebeca Marin-Bueno, Alejandro Hornick, Cristofol Vives-Bauza, Rosa Diaz Navarro, Silvia Tur, Carmen Jimenez, Victor Obach, Tomas Segura, Gemma Serrano-Heras, Jong Won Chung, Jaume Roquer, Carol Soriano-Tarraga, Eva Giralt-Steinhauer, Marina Mola-Caminal, Joanna Pera, Katarzyna Lapicka-Bodzioch, Justyna Derbisz, Antoni Davalos, Elena Lopez-Cancio, Lucia Muñoz, Turgut Tatlisumak, Carlos Molina, Marc Ribo, Alejandro Bustamante, Tomas Sobrino, Jose Castillo-Sanchez, Francisco Campos, Emilio Rodriguez-Castro, Susana Arias-Rivas, Manuel Rodríguez-Yáñez, Christina Herbosa, Andria L. Ford, Alonso Gutierrez-Romero, Rodrigo Uribe-Pacheco, Antonio Arauz, Iscia Lopes-Cendes, Theodore Lowenkopf, Miguel A. Barboza, Hajar Amini, Boryana Stamova, Bradley P. Ander, Frank R. Sharp, Gyeong Moon Kim, Oh Young Bang, Jordi Jimenez-Conde, Agnieszka Slowik, Daniel Stribian, Ellen A. Tsai, Linda C. Burkly, Joan Montaner, Israel Fernandez-Cadenas, Jin Moo Lee^*, Carlos Cruchaga^*

^*Corresponding author for this work

School of Biology

Research output: Contribution to journal › Article › peer-review

Abstract

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 6h of stroke onset and NIHSS at 24h.

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 24h 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.

Original language	English
Pages (from-to)	2394-2406
Number of pages	13
Journal	Brain
Volume	145
Issue number	7
Early online date	25 Feb 2022
DOIs	https://doi.org/10.1093/brain/awac080
Publication status	Published - 1 Jul 2022

Keywords

Genetics
Ischaemic stroke
Neuroprotection
NIHSS

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/brain/awac080

Ibanez_2022_Brain_Multi-ancestry-GWAS_AAM
Copyright © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. This work has been made available online in accordance with publisher policies or with permission. Permission for further reuse of this content should be sought from the publisher or the rights holder. This is the author created accepted manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://doi.org/10.1093/brain/awac080.
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Ibanez, L., Heitsch, L., Carrera, C., Farias, F. H. G., Del Aguila, J. L., Dhar, R., Budde, J., Bergmann, K., Bradley, J., Harari, O., Phuah, C. L., Lemmens, R., Souza, A. A. V. O., Moniche, F., Cabezas-Juan, A., Arenillas, J. F., Krupinksi, J., Cullell, N., Torres-Aguila, N., ... Cruchaga, C. (2022). Multi-Ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke. Brain, 145(7), 2394-2406. https://doi.org/10.1093/brain/awac080

@article{0d4ee852c7474642b6cf1de8e44b8482,

title = "Multi-Ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke",

abstract = "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 6h of stroke onset and NIHSS at 24h. 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 24h 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. ",

keywords = "Genetics, Ischaemic stroke, Neuroprotection, NIHSS",

author = "Laura Ibanez and Laura Heitsch and Caty Carrera and Farias, {Fabiana H.G.} and {Del Aguila}, {Jorge L.} and Rajat Dhar and John Budde and Kristy Bergmann and Joseph Bradley and Oscar Harari and Phuah, {Chia Ling} and Robin Lemmens and Souza, {Alessandro A.Viana Oliveira} and Francisco Moniche and Antonio Cabezas-Juan and Arenillas, {Juan Francisco} and Jerzy Krupinksi and Natalia Cullell and Nuria Torres-Aguila and Elena Mui{\~n}o and Jara C{\'a}rcel-M{\'a}rquez and Joan Marti-Fabregas and Raquel Delgado-Mederos and Rebeca Marin-Bueno and Alejandro Hornick and Cristofol Vives-Bauza and Navarro, {Rosa Diaz} and Silvia Tur and Carmen Jimenez and Victor Obach and Tomas Segura and Gemma Serrano-Heras and Chung, {Jong Won} and Jaume Roquer and Carol Soriano-Tarraga and Eva Giralt-Steinhauer and Marina Mola-Caminal and Joanna Pera and Katarzyna Lapicka-Bodzioch and Justyna Derbisz and Antoni Davalos and Elena Lopez-Cancio and Lucia Mu{\~n}oz and Turgut Tatlisumak and Carlos Molina and Marc Ribo and Alejandro Bustamante and Tomas Sobrino and Jose Castillo-Sanchez and Francisco Campos and Emilio Rodriguez-Castro and Susana Arias-Rivas and Manuel Rodr{\'i}guez-Y{\'a}{\~n}ez and Christina Herbosa and Ford, {Andria L.} and Alonso Gutierrez-Romero and Rodrigo Uribe-Pacheco and Antonio Arauz and Iscia Lopes-Cendes and Theodore Lowenkopf and Barboza, {Miguel A.} and Hajar Amini and Boryana Stamova and Ander, {Bradley P.} and Sharp, {Frank R.} and {Moon Kim}, Gyeong and Bang, {Oh Young} and Jordi Jimenez-Conde and Agnieszka Slowik and Daniel Stribian and Tsai, {Ellen A.} and Burkly, {Linda C.} and Joan Montaner and Israel Fernandez-Cadenas and Lee, {Jin Moo} and Carlos Cruchaga",

note = "Funding: This work was supported by grants from the Emergency Medicine Foundation Career Development Grant; AHA Mentored Clinical & Population Research Award (14CRP18860027); NIH/NINDS-R01-NS085419 (C.C., J.M.L.); NIH/NINDS-R37-NS107230, NIH/NINDS U24-NS107230 (J.M.L.); NIH/NINDS-K23-NS099487 (L.H.); NIH/NIA-K99-AG062723 (L.I.); Barnes-Jewish Hospital Foundation (J.M.L.); Biogen (C.C., J.M.L.); Bright Focus Foundation, US Department of Defense, Helsinki University Central Hospital; Finnish Medical Foundation; Finland government subsidiary funds; Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III (grants {\textquoteleft}Registro BASICMAR{\textquoteright} Funding for Research in Health (PI051737), {\textquoteleft}GWALA project{\textquoteright} from Fondos de Investigaci{\'o}n Sanitaria ISC III (PI10/02064, PI12/01238 and PI15/00451), JR18/00004); Fondos FEDER/EDRF Red de Investigaci{\'o}n Cardiovascular (RD12/0042/0020); Fundaci{\'o} la Marat{\'o} TV3; Genestroke Consortium (76/C/2011); Recercaixa{\textquoteright}13 (JJ086116). Tom{\'a}s Sobrino (CPII17/00027), Francisco Campos (CPII19/00020) and Israel Fernandez are supported by Miguel Servet II Program from Instituto de Salud Carlos III and Fondos FEDER. I.F. is also supported by Maestro project (PI18/01338) and Pre-test project (PMP15/00022) from Instituto de Salud Carlos III and Fondos Feder, Agaur; and Epigenesis project from Marat{\'o} TV3 Foundation. J.C., J.M., A.D., J.M.-F., J.A. and I.F. are supported by Invictus plus Network (RD16/0019) from Instituto de Salud Carlos III and Fondos Feder. Funda{\c c}{\~a}o de Amparo {\`a} Pesquisa do Estado de S{\~a}o Paulo (FAPESP-2013/07559-3) (I.L.-C.), Sigrid Juselius Foundation. The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html. B.S., B.A. and F.S. are supported by NIH awards NS097000, NS101718, NS075035, NS079153 and NS106950.",

year = "2022",

month = jul,

day = "1",

doi = "10.1093/brain/awac080",

language = "English",

volume = "145",

pages = "2394--2406",

journal = "Brain",

issn = "0006-8950",

publisher = "Oxford University Press",

number = "7",

}

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, Muiño, E, Cárcel-Márquez, 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, Muñoz, L, Tatlisumak, T, Molina, C, Ribo, M, Bustamante, A, Sobrino, T, Castillo-Sanchez, J, Campos, F, Rodriguez-Castro, E, Arias-Rivas, S, Rodríguez-Yáñez, 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, Moon Kim, G, Bang, OY, Jimenez-Conde, J, Slowik, A, Stribian, D, Tsai, EA, Burkly, LC, Montaner, J, Fernandez-Cadenas, I, Lee, JM & Cruchaga, C 2022, 'Multi-Ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke', Brain, vol. 145, no. 7, pp. 2394-2406. https://doi.org/10.1093/brain/awac080

TY - JOUR

T1 - Multi-Ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke

AU - Ibanez, Laura

AU - Heitsch, Laura

AU - Carrera, Caty

AU - Farias, Fabiana H.G.

AU - Del Aguila, Jorge L.

AU - Dhar, Rajat

AU - Budde, John

AU - Bergmann, Kristy

AU - Bradley, Joseph

AU - Harari, Oscar

AU - Phuah, Chia Ling

AU - Lemmens, Robin

AU - Souza, Alessandro A.Viana Oliveira

AU - Moniche, Francisco

AU - Cabezas-Juan, Antonio

AU - Arenillas, Juan Francisco

AU - Krupinksi, Jerzy

AU - Cullell, Natalia

AU - Torres-Aguila, Nuria

AU - Muiño, Elena

AU - Cárcel-Márquez, Jara

AU - Marti-Fabregas, Joan

AU - Delgado-Mederos, Raquel

AU - Marin-Bueno, Rebeca

AU - Hornick, Alejandro

AU - Vives-Bauza, Cristofol

AU - Navarro, Rosa Diaz

AU - Tur, Silvia

AU - Jimenez, Carmen

AU - Obach, Victor

AU - Segura, Tomas

AU - Serrano-Heras, Gemma

AU - Chung, Jong Won

AU - Roquer, Jaume

AU - Soriano-Tarraga, Carol

AU - Giralt-Steinhauer, Eva

AU - Mola-Caminal, Marina

AU - Pera, Joanna

AU - Lapicka-Bodzioch, Katarzyna

AU - Derbisz, Justyna

AU - Davalos, Antoni

AU - Lopez-Cancio, Elena

AU - Muñoz, Lucia

AU - Tatlisumak, Turgut

AU - Molina, Carlos

AU - Ribo, Marc

AU - Bustamante, Alejandro

AU - Sobrino, Tomas

AU - Castillo-Sanchez, Jose

AU - Campos, Francisco

AU - Rodriguez-Castro, Emilio

AU - Arias-Rivas, Susana

AU - Rodríguez-Yáñez, Manuel

AU - Herbosa, Christina

AU - Ford, Andria L.

AU - Gutierrez-Romero, Alonso

AU - Uribe-Pacheco, Rodrigo

AU - Arauz, Antonio

AU - Lopes-Cendes, Iscia

AU - Lowenkopf, Theodore

AU - Barboza, Miguel A.

AU - Amini, Hajar

AU - Stamova, Boryana

AU - Ander, Bradley P.

AU - Sharp, Frank R.

AU - Moon Kim, Gyeong

AU - Bang, Oh Young

AU - Jimenez-Conde, Jordi

AU - Slowik, Agnieszka

AU - Stribian, Daniel

AU - Tsai, Ellen A.

AU - Burkly, Linda C.

AU - Montaner, Joan

AU - Fernandez-Cadenas, Israel

AU - Lee, Jin Moo

AU - Cruchaga, Carlos

N1 - Funding: This work was supported by grants from the Emergency Medicine Foundation Career Development Grant; AHA Mentored Clinical & Population Research Award (14CRP18860027); NIH/NINDS-R01-NS085419 (C.C., J.M.L.); NIH/NINDS-R37-NS107230, NIH/NINDS U24-NS107230 (J.M.L.); NIH/NINDS-K23-NS099487 (L.H.); NIH/NIA-K99-AG062723 (L.I.); Barnes-Jewish Hospital Foundation (J.M.L.); Biogen (C.C., J.M.L.); Bright Focus Foundation, US Department of Defense, Helsinki University Central Hospital; Finnish Medical Foundation; Finland government subsidiary funds; Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III (grants ‘Registro BASICMAR’ Funding for Research in Health (PI051737), ‘GWALA project’ from Fondos de Investigación Sanitaria ISC III (PI10/02064, PI12/01238 and PI15/00451), JR18/00004); Fondos FEDER/EDRF Red de Investigación Cardiovascular (RD12/0042/0020); Fundació la Marató TV3; Genestroke Consortium (76/C/2011); Recercaixa’13 (JJ086116). Tomás Sobrino (CPII17/00027), Francisco Campos (CPII19/00020) and Israel Fernandez are supported by Miguel Servet II Program from Instituto de Salud Carlos III and Fondos FEDER. I.F. is also supported by Maestro project (PI18/01338) and Pre-test project (PMP15/00022) from Instituto de Salud Carlos III and Fondos Feder, Agaur; and Epigenesis project from Marató TV3 Foundation. J.C., J.M., A.D., J.M.-F., J.A. and I.F. are supported by Invictus plus Network (RD16/0019) from Instituto de Salud Carlos III and Fondos Feder. Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP-2013/07559-3) (I.L.-C.), Sigrid Juselius Foundation. The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html. B.S., B.A. and F.S. are supported by NIH awards NS097000, NS101718, NS075035, NS079153 and NS106950.

PY - 2022/7/1

Y1 - 2022/7/1

N2 - 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 6h of stroke onset and NIHSS at 24h. 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 24h 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.

AB - 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 6h of stroke onset and NIHSS at 24h. 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 24h 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.

KW - Genetics

KW - Ischaemic stroke

KW - Neuroprotection

KW - NIHSS

U2 - 10.1093/brain/awac080

DO - 10.1093/brain/awac080

M3 - Article

C2 - 35213696

AN - SCOPUS:85135708734

SN - 0006-8950

VL - 145

SP - 2394

EP - 2406

JO - Brain

JF - Brain

IS - 7

ER -

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

Abstract

Keywords

UN SDGs

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