Genome-wide association meta-analysis of functional outcome after ischemic stroke
Por:
Soderholm, 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, Rannikmae, 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, Int Stroke Genetics Consortium, NINDS-SIGN Consortium, Genetics Ischaemic Stroke Funct
Publicada:
19 mar 2019
Resumen:
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.
Filiaciones:
Soderholm, M:
Lund Univ, Dept Clin Sci Malmo, Lund, Sweden
Skane Univ Hosp, Dept Neurol & Rehabil Med, Lund, Sweden
Skane Univ Hosp, Dept Neurol & Rehabil Med, Malmo, Sweden
Pedersen, A:
Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Gothenburg, Sweden
Sahlgrens Univ Hosp, Dept Clin Genet & Genom, Gothenburg, Sweden
Lorentzen, E:
Univ Gothenburg, Bioinformat Core Facil, Gothenburg, Sweden
Stanne, TM:
Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Gothenburg, Sweden
Bevan, S:
Univ Lincoln, Sch Life Sci, Lincoln, England
Olsson, M:
Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Gothenburg, Sweden
Fernandez-Cadenas, I:
Hosp Santa Creu & Sant Pau, Stroke Pharmacogen & Genet, Inst Invest Biomed St Pau, Barcelona, Spain
Univ Autonoma Barcelona, Vall dHebron Hosp, Neurol Dept, Neurovasc Res Lab, Barcelona, Spain
Univ Autonoma Barcelona, Vall dHebron Hosp, Med Dept, Neurovasc Res Lab, Barcelona, Spain
Univ Autonoma Barcelona, Vall dHebron Hosp, Neurol Dept, Neurovasc Unit, Barcelona, Spain
Univ Autonoma Barcelona, Vall dHebron Hosp, Med Dept, Neurovasc Unit, Barcelona, Spain
Hankey, GJ:
Univ Western Australia, Med Sch, Perth, WA, Australia
Jimenez-Conde, J:
Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA
Baltimore VAMC, Baltimore, MD 21201 USA
Inst Hosp Mar Invest Med IMIM, Dept Neurol, Barcelona, Spain
Univ Autonoma Barcelona, Barcelona, Spain
Jood, K:
Univ Gothenburg, Sahlgrenska Acad, Dept Clin Neurosci, Inst Neurosci & Physiol, Gothenburg, Sweden
Sahlgrens Univ Hosp, Dept Neurol, Gothenburg, Sweden
Lee, JM:
Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
Lemmens, R:
Univ Leuven, KU Leuven, Dept Neurosci, Expt Neurol, Leuven, Belgium
VIB, Ctr Brain & Dis Res, Lab Neurobiol, Leuven, Belgium
Univ Hosp Leuven, Dept Neurol, Leuven, Belgium
Levi, C:
Univ Newcastle, Sch Med & Publ Hlth, Newcastle, NSW, Australia
Univ Newcastle, Hunter Med Res Inst, Newcastle, NSW, Australia
Univ Newcastle, Prior Res Ctr Stroke & Traumat Brain Injury, Newcastle, NSW, Australia
Mitchell, BD:
Univ Maryland, Dept Med, Baltimore, MD 21201 USA
Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Baltimore, MD USA
Norrving, B:
Lund Univ, Dept Clin Sci Lund, Neurol, Lund, Sweden
Skane Univ Hosp, Dept Neurol & Rehabil Med, Lund, Sweden
Skane Univ Hosp, Dept Neurol & Rehabil Med, Malmo, Sweden
Rannikmae, K:
Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland
Rost, NS:
Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA 02115 USA
Rosand, J:
Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA 02115 USA
Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA
Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA
Rothwell, PM:
Univ Oxford, Nuffield Dept Clin Neurosci, Stroke Prevent Res Unit, Oxford, England
Scott, R:
Univ Newcastle, Sch Med & Publ Hlth, Newcastle, NSW, Australia
Univ Newcastle, Hunter Med Res Inst, Newcastle, NSW, Australia
Strbian, D:
Helsinki Univ Hosp, Dept Neurol, Helsinki, Finland
Sturm, JW:
Univ Newcastle, Sch Med & Publ Hlth, Newcastle, NSW, Australia
Sudlow, C:
Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland
Traylor, M:
Univ Cambridge, Dept Clin Neurosci, Cambridge, England
Thijs, V:
Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Stroke Div, Heidelberg, Vic, Australia
Austin Hlth, Dept Neurol, Heidelberg, Vic, Australia
Tatlisumak, T:
Univ Gothenburg, Sahlgrenska Acad, Dept Clin Neurosci, Inst Neurosci & Physiol, Gothenburg, Sweden
Helsinki Univ Hosp, Dept Neurol, Helsinki, Finland
Woo, D:
Univ Cincinnati, Coll Med, Dept Neurol & Rehabil, Cincinnati, OH USA
Worrall, BB:
Univ Virginia, Dept Neurol Sci, Charlottesville, VA USA
Univ Virginia, Dept Hlth Evaluat Sci, Charlottesville, VA USA
Maguire, JM:
Univ Technol Sydney, Fac Hlth, Sydney, NSW, Australia
PRC Stroke & Brain Injury, Hunter Med Res Ctr, Newcastle, NSW, Australia
Lindgren, A:
Lund Univ, Dept Clin Sci Lund, Neurol, Lund, Sweden
Skane Univ Hosp, Dept Neurol & Rehabil Med, Lund, Sweden
Skane Univ Hosp, Dept Neurol & Rehabil Med, Malmo, Sweden
Jern, C:
Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Gothenburg, Sweden
Sahlgrens Univ Hosp, Dept Clin Genet & Genom, Gothenburg, Sweden
Green Published, Hybrid Gold
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