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

Söderholm, Martin LU ; Pedersen, Annie ; Lorentzen, Erik ; Stanne, Tara M. ; Bevan, Steve ; Olsson, Maja ; Cole, John W. ; Fernandez-Cadenas, Israel ; Hankey, Graeme J. and Jimenez-Conde, Jordi , et al. (2019) In Neurology 92(12). p.1271-1283
Abstract

OBJECTIVE: To discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study. METHODS: The 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 ×... (More)

OBJECTIVE: To discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study. METHODS: The 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. RESULTS: We 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). CONCLUSIONS: In 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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published
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Neurology
volume
92
issue
12
pages
1271 - 1283
publisher
American Academy of Neurology
external identifiers
  • pmid:30796134
  • scopus:85062685902
ISSN
1526-632X
DOI
10.1212/WNL.0000000000007138
language
English
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yes
id
dc82c1c5-38e2-4468-99ed-a261e61c871d
alternative location
https://europepmc.org/articles/pmc6511098
date added to LUP
2019-07-01 09:09:55
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2019-12-03 02:15:30
@article{dc82c1c5-38e2-4468-99ed-a261e61c871d,
  abstract     = {<p>OBJECTIVE: To discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study. METHODS: The 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 &lt; 5 × 10-8. RESULTS: We 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 &lt; 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). CONCLUSIONS: In 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.</p>},
  author       = {Söderholm, Martin and Pedersen, Annie and Lorentzen, Erik and Stanne, Tara M. and Bevan, Steve and Olsson, Maja and Cole, John W. and Fernandez-Cadenas, Israel and Hankey, Graeme J. and Jimenez-Conde, Jordi and Jood, Katarina and Lee, Jin Moo and Lemmens, Robin and Levi, Christopher and Mitchell, Braxton D. and Norrving, Bo and Rannikmäe, Kristiina and Rost, Natalia S. and Rosand, Jonathan and Rothwell, Peter M. and Scott, Rodney and Strbian, Daniel and Sturm, Jonathan W. and Sudlow, Cathie and Traylor, Matthew and Thijs, Vincent and Tatlisumak, Turgut and Woo, Daniel and Worrall, Bradford B. and Maguire, Jane M. and Lindgren, Arne and Jern, Christina},
  issn         = {1526-632X},
  language     = {eng},
  month        = {03},
  number       = {12},
  pages        = {1271--1283},
  publisher    = {American Academy of Neurology},
  series       = {Neurology},
  title        = {Genome-wide association meta-analysis of functional outcome after ischemic stroke},
  url          = {http://dx.doi.org/10.1212/WNL.0000000000007138},
  doi          = {10.1212/WNL.0000000000007138},
  volume       = {92},
  year         = {2019},
}