Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke-Reference-Cited by-同舟云学术

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

Published:2022-02-25 Issue:7 Volume:145 Page:2394-2406
ISSN:0006-8950
Container-title:Brain
language:en
Short-container-title:

Author:

Ibanez Laura¹²^ORCID,Heitsch Laura³⁴,Carrera Caty⁵,Farias Fabiana H G¹²,Del Aguila Jorge L¹²,Dhar Rajat³,Budde John¹²,Bergmann Kristy¹²,Bradley Joseph¹²,Harari Oscar¹²⁶⁷,Phuah Chia Ling³^ORCID,Lemmens Robin⁸^ORCID,Viana Oliveira Souza Alessandro A⁹¹⁰,Moniche Francisco¹¹^ORCID,Cabezas-Juan Antonio¹¹¹²,Arenillas Juan Francisco¹³,Krupinksi Jerzy¹⁴¹⁵,Cullell Natalia¹⁵¹⁶,Torres-Aguila Nuria¹⁵¹⁶^ORCID,Muiño Elena¹⁶,Cárcel-Márquez Jara¹⁶,Marti-Fabregas Joan¹⁶^ORCID,Delgado-Mederos Raquel¹⁶,Marin-Bueno Rebeca¹⁶,Hornick Alejandro¹⁷,Vives-Bauza Cristofol¹⁸,Navarro Rosa Diaz¹⁹,Tur Silvia¹⁹,Jimenez Carmen¹⁹,Obach Victor²⁰,Segura Tomas²¹,Serrano-Heras Gemma²¹,Chung Jong Won²²,Roquer Jaume²³,Soriano-Tarraga Carol¹²²³^ORCID,Giralt-Steinhauer Eva²³,Mola-Caminal Marina²³²⁴,Pera Joanna²⁵,Lapicka-Bodzioch Katarzyna²⁵,Derbisz Justyna²⁵,Davalos Antoni²⁶,Lopez-Cancio Elena²⁷,Muñoz Lucia²⁶,Tatlisumak Turgut²⁸²⁹,Molina Carlos⁵,Ribo Marc⁵,Bustamante Alejandro²⁶,Sobrino Tomas³⁰,Castillo-Sanchez Jose³⁰,Campos Francisco³⁰,Rodriguez-Castro Emilio³⁰,Arias-Rivas Susana³⁰,Rodríguez-Yáñez Manuel³⁰,Herbosa Christina³,Ford Andria L³⁶³¹^ORCID,Gutierrez-Romero Alonso³²,Uribe-Pacheco Rodrigo³²,Arauz Antonio³²,Lopes-Cendes Iscia⁹¹⁰,Lowenkopf Theodore³³,Barboza Miguel A³⁴,Amini Hajar³⁵,Stamova Boryana³⁵,Ander Bradley P³⁵,Sharp Frank R³⁵,Kim Gyeong Moon²²,Bang Oh Young²²,Jimenez-Conde Jordi²³,Slowik Agnieszka²⁵,Stribian Daniel³⁶^ORCID,Tsai Ellen A³⁷,Burkly Linda C³⁸,Montaner Joan⁵¹¹¹²,Fernandez-Cadenas Israel⁵¹⁶,Lee Jin Moo³⁶³¹³⁹⁴⁰,Cruchaga Carlos¹²³⁶⁷⁴¹

Affiliation:

1. Department of Psychiatry, School of Medicine, Washington University , Saint Louis 63110, MO , USA

2. NeuroGenomics and Informatics, School of Medicine, Washington University , Saint Louis 63110, MO , USA

3. Department of Neurology, School of Medicine, Washington University , Saint Louis 63110, MO , USA

4. Department of Emergency Medicine, School of Medicine, Washington University , Saint Louis 63110, MO , USA

5. Stroke Unit, Vall d’Hebron University Hospital, Universitat de Barcelona , Barcelona 08035 , Spain

6. Hope Center for Neurological Disorders, School of Medicine, Washington University , Saint Louis 63110, MO , USA

7. The Charles F. and Joanne Knight Alzheimer Disease Research Center, School of Medicine, Washington University , Saint Louis 63110, MO , USA

8. Department of Neuroscience, Katholieke Universiteit Leuven , Campus Gasthuisberg O&N2, Leuven BE-3000 , Belgium

9. Department of Neurology, School of Medical Sciences, University of Campinas (UNICAMP), Cidade Universitaria , Campinas 13083-887 , Brazil

10. Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), R. Tessalia Viera de Camargo , Campinas 13083-887 , Brazil

11. Department of Neurology, Hospital Virgen del Rocio, University of Seville , Seville 41013 , Spain

12. Hospital Virgen de la Macarena, University of Seville , Seville 41009 , Spain

13. Department of Neurology, Hospital Clinico Universitario Valladolid, Valladolid University , Valladolid 47003 , Spain

14. Department of Neurology, Mutua Terrassa University Hospital, Universitat de Barcelona , Terrassa 08221 , Spain

15. Fundacio Docencia i Recerca Mutua Terrassa, Universitat de Barcelona , Terrassa 08221 , Spain

16. Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona , Barcelona 08041 , Spain

17. Department of Neurology, Southern Illinois Healthcare Memorial Hospital of Carbondale , Carbondale 62901, IL , USA

18. Department of Biology, Universitat de les Illes Balears , Palma 07122 , Spain

19. Department of Neurology, Hospital Universitari Son Espases, Universitat de les Illes Balears , Palma 07120 , Spain

20. Department of Neurology, Hospital Clinic de Barcelona, Universitat de Barcelona , Barcelona 08036 , Spain

21. Research Unit, Complejo Hospitalario Universitario de Albacete, Albacete 02008 , Spain

22. Department of Neurology, Samsung Medical Center , Seoul , South Korea

23. Neurovascular Research Group, Institut Hospital del Mar de Investigacions Mediques , Barcelona 08003 , Spain

24. Department of Surgical Sciences, Orthopedics, Uppsala University , Uppsala 75185 , Sweden

25. Department of Neurology, Jagiellonian University , Krakow 31-007 , Poland

26. Department of Neurology, Hospital Germans Trias i Pujol, Universitat Autonoma de Barcelona , Badalona 08916 , Spain

27. Department of Neurology, Hospital Universitario Central de Asturias , Oviedo , Spain

28. Department of Neurology, Sahlgrenska University Hospital, University of Gothenburg , Gothenburg 413 45 , Sweden

29. Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg , Gothenburg , Sweden

30. Clinical Neurosciences Research Laboratory, Health Research Institute of Santiago de Compostela (IDIS) , Santiago de Compostela 15706 , Spain

31. Department of Radiology, School of Medicine, Washington University , Saint Louis 63110, MO , USA

32. Instituto Nacional de Neurologia y Neurocirurgia de Mexico , Ciudad de Mexico 14269 , Mexico

33. Department of Neurology, Providence St. Vincent Medical Center , Portland 97225, OR , USA

34. Neurosciences Department, Hospital Rafael A. Calderon Guardia , Aranjuez, San José , Costa Rica

35. Department of Neurology and MIND Institute, University of California at Davis , Sacramento 95817, CA , USA

36. Department of Neurology, Helsinki University Hospital , Helsinki 00290 , Finland

37. Translational Biology, Biogen, Inc. , Cambridge 02142, MA , USA

38. Genetics and Neurodevelopmental Disease Research Unit, Biogen, Inc. , Cambridge 02142, MA , USA

39. Department of Biomedical Engineering, School of Medicine, Washington University , Saint Louis 63110, MO , USA

40. Stroke and Cerebrovascular Center, School of Medicine, Washington University , Saint Louis 63110, MO , USA

41. Department of Genetics, School of Medicine, Washington University , Saint Louis 63110, MO , USA

Abstract

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 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.

Funder

Emergency Medicine Foundation

AHA Mentored Clinical & Population Research Award

NINDS

NIA

Barnes-Jewish Hospital Foundation

Biogen

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

Fondos de Investigación Sanitaria ISC III

Fondos FEDER/EDRF Red de Investigación Cardiovascular

Fundació la Marató TV3

Genestroke Consortium

Recercaixa’13

Tomás Sobrino

Francisco Campos

Fondos FEDER

Pre-test project

Marató TV3 Foundation

Invictus plus Network

Fundação de Amparo à Pesquisa do Estado de São Paulo

Sigrid Juselius Foundation

NIH

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

Link

https://academic.oup.com/brain/advance-article-pdf/doi/10.1093/brain/awac080/44814226/awac080.pdf

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