Genome-wide association meta-analysis of functional outcome after ischemic stroke
Söderholm, Martin (Skåne University Hospital (Suècia))
Pedersen, Annie (Department of Clinical Neuroscience. Institute of Neuroscience and Physiology. Sahlgrenska Academy. University of Gothenburg)
Lorentzen, Erik (Sahlgrenska University Hospital (Suècia))
Stanne, Tara M. (Institute of Biomedicine)
Bevan, Steve (Bioinformatics Core Facility. University of Gothenburg)
Olsson, Maja (Institute of Biomedicine)
Cole, John W.
Fernandez-Cadenas, Israel (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Hankey, Graeme J. (Medical School. The University of Western Australia, Perth; Department of Neurology)
Jimenez-Conde, Jordi (Institut Hospital del Mar d'Investigacions Mèdiques)
Jood, Katarina (Department of Clinical Genetics and Genomics)
Lee, Jin-Moo (Department of Neurology. Washington University School of Medicine, St. Louis, MO)
Lemmens, Robin (University Hospitals Leuven (Bèlgica))
Levi, Christopher R (School of Medicine and Public Health)
Mitchell, Braxton D. (Priority Research Centre for Stroke and Traumatic Brain Injury. University of Newcastle)
Norrving, Bo (Skåne University Hospital (Suècia))
Rannikmäe, Kristiina (University of Maryland. Department of Medicine)
Rost, Natalia S. (Geriatric Research. Education. and Clinical Center. Veterans Affairs Medical Center)
Rosand, Jonathan (Massachusetts General Hospital (Boston))
Rothwell, Peter M. (Broad Institute of MIT and Harvard)
Scott, Rodney (University of Virginia. Departments of Neurology and Health Evaluation Sciences)
Strbian, Daniel (Massachusetts General Hospital (Boston))
Sturm, Jonathan W. (VIB. Center for Brain and Disease Research)
Sudlow, Cathie (University of Maryland. Department of Medicine)
Traylor, Matthew (University of Oxford. Nuffield Department of Clinical Neurosciences.)
Thijs, Vincent (University of Cambridge. Department of ClinicalNeurosciences)
Tatlisumak, Turgut (Stroke Division. Florey Institute for Neuroscience and Mental Health. University of Melbourne)
Woo, Daniel (Austin Health. Department of Neurology)
Worrall, Bradford B. (University of Cincinnati. Department of Neurology and Rehabilitation)
Maguire, Jane M. (HunterMedical Research Centre. PRC Stroke and Brain Injury)
Lindgren, Arne (Skåne University Hospital (Suècia))
Jern, Christina (University of Lincoln. School of Life Sciences)
Universitat Autònoma de Barcelona

Data:	2019
Resum:	ObjectiveTo discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study. MethodsThe study comprised 6,165 patients with ischemic stroke from 12 studies in Europe, the United States, and Australia included in the GISCOME (Genetics of Ischaemic Stroke Functional Outcome) network. The primary outcome was modified Rankin Scale score after 60 to 190 days, evaluated as 2 dichotomous variables (0-2 vs 3-6 and 0-1 vs 2-6) and subsequently as an ordinal variable. GWA analyses were performed in each study independently and results were meta-analyzed. Analyses were adjusted for age, sex, stroke severity (baseline NIH Stroke Scale score), and ancestry. The significance level was p < 5 × 10. ResultsWe identified one genetic variant associated with functional outcome with genome-wide significance (modified Rankin Scale scores 0-2 vs 3-6, p = 5. 3 × 10). This intronic variant (rs1842681) in the LOC105372028 gene is a previously reported trans-Expression quantitative trait locus for PPP1R21, which encodes a regulatory subunit of protein phosphatase 1. This ubiquitous phosphatase is implicated in brain functions such as brain plasticity. Several variants detected in this study demonstrated suggestive association with outcome (p < 10), some of which are within or near genes with experimental evidence of influence on ischemic stroke volume and/or brain recovery (e. g. , NTN4, TEK, and PTCH1). ConclusionsIn this large GWA study on functional outcome after ischemic stroke, we report one significant variant and several variants with suggestive association to outcome 3 months after stroke onset with plausible mechanistic links to poststroke recovery. Future replication studies and exploration of potential functional mechanisms for identified genetic variants are warranted.
Nota:	Altres ajuts: The Stroke Genetics Network (SiGN) study was funded by a cooperative agreement grant from the US National Institute of Neurological Disorders and Stroke (NINDS), NIH (U01 NS069208 and R01 NS100178). SAHLSIS was supported by the Swedish Heart and Lung Foundation (HLF-20160316), the Swedish Research Council (K2014-64X-14605-12-5), the Swedish Stroke Association, the Swedish state (under the "Avtal om Läkarutbildning och Medicinsk Forskning, ALF") (ALFGBG-720081). Australian Stroke Genetics Collaboration study was supported by the National Health and Medical Research Council, Australia. Stroke Pharmacogenomics and Genetics group was supported by Invictus plus network, Generation project, and Miguel Servet programme from Instituto de Salud Carlos III, GODs project and Epigenesis project from Marató de TV3 Foundation and Agaur from Generalitat de Catalunya Government. Arne Lindgren was supported by the Swedish Heart and Lung Foundation, Region Skåne, Skåne University Hospital, the Freemasons Lodge of Instruction EOS in Lund, Lund University, the Foundation of Färs & Frosta-one of Spar-banken Skåne's ownership Foundations, and the Swedish Stroke Association. Martin Söderholm was supported by grants from the Swedish Stroke Association, the Foundation of Färs & Frosta-one of Sparbanken Skåne's ownership Foundations, and the Swedish government (under the "Avtal om Läkarutbildning och Medicinsk Forskning, ALF"). Annie Pedersen was supported by grants from the Swedish government (under the "Avtal om Läkarutbildning och Medi-cinsk Forskning, ALF") and the Gothenburg Foundation for Neurological Research. Natalia Rost was in part supported by NIH-NINDS (R01NS086905 and R01NS082285). Daniel Strbian was supported by the Finnish Subsidiary Governmental Fund (VTR). The authors thank NINDS for funding the genotyping of patients included in the SiGN study (U01 NS069208 and R01 NS100178) and Sólveig Grétarsdóttir for genotyping a subsample of the SAHLSIS cohort.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Neurology, Vol. 92 Núm. 12 (19 2019) , p. E1271-E1283, ISSN 1526-632X

DOI: 10.1212/WNL.0000000000007138
PMID: 30796134

13 p, 1.4 MB

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