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

Martin Söderholm; Annie Pedersen; Erik Lorentzen; Tara M. Stanne; Steve Bevan; Maja Olsson; John W. Cole; Israel Fernandez-Cadenas; Graeme J. Hankey; Jordi Jimenez-Conde; Katarina Jood; Jin Moo Lee; Robin Lemmens; Christopher Levi; Braxton D. Mitchell; Bo Norrving; Kristiina Rannikmäe; Natalia S. Rost; Jonathan Rosand; Peter M. Rothwell; Rodney Scott; Daniel Strbian; Jonathan W. Sturm; Cathie Sudlow; Matthew Traylor; Vincent Thijs; Turgut Tatlisumak; Daniel Woo; Bradford B. Worrall; Jane M. Maguire; Arne Lindgren; Christina Jern

doi:10.1212/WNL.0000000000007138

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

Martin Söderholm
, Annie Pedersen
, Erik Lorentzen
, Tara M. Stanne
, Steve Bevan
, Maja Olsson
, John W. Cole
, Israel Fernandez-Cadenas
, Graeme J. Hankey
, Jordi Jimenez-Conde
, Katarina Jood
, Jin Moo Lee
, Robin Lemmens
, Christopher Levi
, Braxton D. Mitchell
, Bo Norrving
, Kristiina Rannikmäe
, Natalia S. Rost
, Jonathan Rosand
, Peter M. Rothwell

Rodney Scott, Daniel Strbian, Jonathan W. Sturm, Cathie Sudlow, Matthew Traylor, Vincent Thijs, Turgut Tatlisumak, Daniel Woo, Bradford B. Worrall, Jane M. Maguire, Arne Lindgren, Christina Jern

Neurology

University at Buffalo

Lund University
Institute of Biomedicine
University of Gothenburg
Sahlgrenska University Hospital
University of Maryland, Baltimore
Hospital de la Sant Pau
Autonomous University of Barcelona
University of Western Australia
Hospital del Mar
Washington University St. Louis
KU Leuven
Flanders Institute for Biotechnology
School of Medicine and Public Health
Hunter Medical Research Institute, Australia
University of Newcastle
Department of Veterans Affairs
University of Edinburgh
Massachusetts General Hospital
The Broad Institute of MIT and Harvard
University of Virginia
University of Oxford
Helsinki University Hospital
University of Cambridge
University of Melbourne
University of Cincinnati
University of Technology Sydney
PRC Stroke and Brain Injury
University of Lincoln

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

140 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	E1271-E1283
Journal	Neurology
Volume	92
Issue number	12
DOIs	https://doi.org/10.1212/WNL.0000000000007138
State	Published - Mar 19 2019

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Söderholm, M., Pedersen, A., Lorentzen, E., Stanne, T. M., Bevan, S., Olsson, M., Cole, J. W., Fernandez-Cadenas, I., Hankey, G. J., Jimenez-Conde, J., Jood, K., Lee, J. M., Lemmens, R., Levi, C., Mitchell, B. D., Norrving, B., Rannikmäe, K., Rost, N. S., Rosand, J., ... Jern, C. (2019). Genome-wide association meta-analysis of functional outcome after ischemic stroke. Neurology, 92(12), E1271-E1283. https://doi.org/10.1212/WNL.0000000000007138

@article{90f323e7cebc47c4b26470af39729e03,

title = "Genome-wide association meta-analysis of functional outcome after ischemic stroke",

abstract = "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.",

author = "Martin S{\"o}derholm and Annie Pedersen and Erik Lorentzen and Stanne, \{Tara M.\} and Steve Bevan and Maja Olsson and Cole, \{John W.\} and Israel Fernandez-Cadenas and Hankey, \{Graeme J.\} and Jordi Jimenez-Conde and Katarina Jood and Lee, \{Jin Moo\} and Robin Lemmens and Christopher Levi and Mitchell, \{Braxton D.\} and Bo Norrving and Kristiina Rannikm{\"a}e and Rost, \{Natalia S.\} and Jonathan Rosand and Rothwell, \{Peter M.\} and Rodney Scott and Daniel Strbian and Sturm, \{Jonathan W.\} and Cathie Sudlow and Matthew Traylor and Vincent Thijs and Turgut Tatlisumak and Daniel Woo and Worrall, \{Bradford B.\} and Maguire, \{Jane M.\} and Arne Lindgren and Christina Jern",

note = "Publisher Copyright: {\textcopyright} American Academy of Neurology.",

year = "2019",

month = mar,

day = "19",

doi = "10.1212/WNL.0000000000007138",

language = "English",

volume = "92",

pages = "E1271--E1283",

journal = "Neurology",

issn = "0028-3878",

publisher = "Lippincott Williams and Wilkins",

number = "12",

}

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 2019, 'Genome-wide association meta-analysis of functional outcome after ischemic stroke', Neurology, vol. 92, no. 12, pp. E1271-E1283. https://doi.org/10.1212/WNL.0000000000007138

TY - JOUR

T1 - Genome-wide association meta-analysis of functional outcome after ischemic stroke

AU - Söderholm, Martin

AU - Pedersen, Annie

AU - Lorentzen, Erik

AU - Stanne, Tara M.

AU - Bevan, Steve

AU - Olsson, Maja

AU - Cole, John W.

AU - Fernandez-Cadenas, Israel

AU - Hankey, Graeme J.

AU - Jimenez-Conde, Jordi

AU - Jood, Katarina

AU - Lee, Jin Moo

AU - Lemmens, Robin

AU - Levi, Christopher

AU - Mitchell, Braxton D.

AU - Norrving, Bo

AU - Rannikmäe, Kristiina

AU - Rost, Natalia S.

AU - Rosand, Jonathan

AU - Rothwell, Peter M.

AU - Scott, Rodney

AU - Strbian, Daniel

AU - Sturm, Jonathan W.

AU - Sudlow, Cathie

AU - Traylor, Matthew

AU - Thijs, Vincent

AU - Tatlisumak, Turgut

AU - Woo, Daniel

AU - Worrall, Bradford B.

AU - Maguire, Jane M.

AU - Lindgren, Arne

AU - Jern, Christina

PY - 2019/3/19

Y1 - 2019/3/19

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85062685902

U2 - 10.1212/WNL.0000000000007138

DO - 10.1212/WNL.0000000000007138

M3 - Article

C2 - 30796134

SN - 0028-3878

VL - 92

SP - E1271-E1283

JO - Neurology

JF - Neurology

IS - 12

ER -

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

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