TY - JOUR
T1 - Genome-wide association meta-analysis of functional outcome after ischemic stroke
AU - Int Stroke Genetics Consortium
AU - NINDS-SiGN Consortium
AU - Genetics Ischaemic Stroke Funct
AU - Soderholm, 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 - Rannikmaee, 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 - 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 x 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 x 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.
AB - 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 x 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 x 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.
KW - NEURONAL DIFFERENTIATION
KW - SOD1 EXPRESSION
KW - GENETIC-FACTORS
KW - TIE2 RECEPTOR
KW - ANGIOPOIETIN-1
KW - IDENTIFICATION
KW - NETRIN-4
KW - RECOVERY
KW - GENOTYPE
KW - DAMAGE
U2 - 10.1212/WNL.0000000000007138
DO - 10.1212/WNL.0000000000007138
M3 - Article
C2 - 30796134
VL - 92
SP - e1271-e1283
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 12
ER -