Genome-wide association meta-analysis of functional outcome after ischemic stroke

Söderholm, M; Pedersen, A; Lorentzen, E; Stanne, TM; Bevan, S; Olsson, M; Cole, JW; Fernandez-Cadenas, I; Hankey, GJ; Jimenez-Conde, J; Jood, K; Lee, JM; Lemmens, R; Levi, C; Mitchell, BD; Norrving, B; Rannikmäe, K; Rost, NS; Rosand, J; Rothwell, PM; Scott, R; Strbian, D; Sturm, JW; Sudlow, C; Traylor, M; Thijs, V; Tatlisumak, T; Woo, D; Worrall, BB; Maguire, JM; Lindgren, A; Jern, C

Genome-wide association meta-analysis of functional outcome after ischemic stroke

Söderholm, M Pedersen, A Lorentzen, E Stanne, TM Bevan, S Olsson, M Cole, JW Fernandez-Cadenas, I Hankey, GJ Jimenez-Conde, J Jood, K Lee, JM Lemmens, R Levi, C

Mitchell, BD Norrving, B Rannikmäe, K Rost, NS Rosand, J Rothwell, PM Scott, R Strbian, D Sturm, JW Sudlow, C Traylor, M Thijs, V Tatlisumak, T Woo, D Worrall, BB Maguire, JM

Lindgren, A Jern, C

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Publication Type:: Journal Article
Citation:: Neurology, 2019, 92 (12), pp. E1271 - E1283
Issue Date:: 2019-03-19

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Field	Value	Language
dc.contributor.author	Söderholm, M	en_US
dc.contributor.author	Pedersen, A	en_US
dc.contributor.author	Lorentzen, E	en_US
dc.contributor.author	Stanne, TM	en_US
dc.contributor.author	Bevan, S	en_US
dc.contributor.author	Olsson, M	en_US
dc.contributor.author	Cole, JW	en_US
dc.contributor.author	Fernandez-Cadenas, I	en_US
dc.contributor.author	Hankey, GJ	en_US
dc.contributor.author	Jimenez-Conde, J	en_US
dc.contributor.author	Jood, K	en_US
dc.contributor.author	Lee, JM	en_US
dc.contributor.author	Lemmens, R	en_US
dc.contributor.author	Levi, C https://orcid.org/0000-0002-9474-796X	en_US
dc.contributor.author	Mitchell, BD	en_US
dc.contributor.author	Norrving, B	en_US
dc.contributor.author	Rannikmäe, K	en_US
dc.contributor.author	Rost, NS	en_US
dc.contributor.author	Rosand, J	en_US
dc.contributor.author	Rothwell, PM	en_US
dc.contributor.author	Scott, R	en_US
dc.contributor.author	Strbian, D	en_US
dc.contributor.author	Sturm, JW	en_US
dc.contributor.author	Sudlow, C	en_US
dc.contributor.author	Traylor, M	en_US
dc.contributor.author	Thijs, V	en_US
dc.contributor.author	Tatlisumak, T	en_US
dc.contributor.author	Woo, D	en_US
dc.contributor.author	Worrall, BB	en_US
dc.contributor.author	Maguire, JM https://orcid.org/0000-0001-5722-8311	en_US
dc.contributor.author	Lindgren, A	en_US
dc.contributor.author	Jern, C	en_US
dc.date.available	2018-11-09	en_US
dc.date.issued	2019-03-19	en_US
dc.identifier.citation	Neurology, 2019, 92 (12), pp. E1271 - E1283	en_US
dc.identifier.issn	0028-3878	en_US
dc.identifier.uri	http://hdl.handle.net/10453/135373
dc.description.abstract	© American Academy of Neurology. 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 × 10-8.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 × 10-9). 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 < 10-5), 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.	en_US
dc.relation.ispartof	Neurology	en_US
dc.relation.isbasedon	10.1212/WNL.0000000000007138	en_US
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.classification	Neurology & Neurosurgery	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Brain Ischemia	en_US
dc.subject.mesh	Recovery of Function	en_US
dc.subject.mesh	Stroke	en_US
dc.subject.mesh	Genome-Wide Association Study	en_US
dc.title	Genome-wide association meta-analysis of functional outcome after ischemic stroke	en_US
dc.type	Journal Article
utslib.citation.volume	12	en_US
utslib.citation.volume	92	en_US
utslib.for	0604 Genetics	en_US
utslib.for	1102 Cardiorespiratory Medicine and Haematology	en_US
utslib.for	1103 Clinical Sciences	en_US
utslib.for	1109 Neurosciences	en_US
utslib.for	1702 Cognitive Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/Nursing
utslib.copyright.status	open_access	*
pubs.issue	12	en_US
pubs.publication-status	Published	en_US
pubs.volume	92	en_US

Abstract:

© American Academy of Neurology. 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 × 10-8.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 × 10-9). 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 < 10-5), 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.

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http://hdl.handle.net/10453/135373