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

Autor: 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
Přispěvatelé: University of St Andrews. School of Biology, HUS Neurocenter, Neurologian yksikkö
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: BRAIN
r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname
Brain : a journal of neurology, vol 145, iss 7
Brain
r-IGTP. Repositorio Institucional de Producción Científica del Instituto de Investigación Germans Trias i Pujol
ISSN: 0006-8950
1460-2156
Popis: 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. 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. Postprint
Databáze: OpenAIRE
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