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Circ Res. 2019 Jan 4;124(1):114-120. doi: 10.1161/CIRCRESAHA.118.313533.

PATJ Low Frequency Variants Are Associated With Worse Ischemic Stroke Functional Outcome.

Author information

1
From the Department of Neurology, Neurovascular Research Group, Hospital del Mar Medical Research Institute, Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra (M.M.-C., C.S.-T., E.G.-S., A.R.-C., A.O., E.C.-G., R.M.V.-H., J.R., J.J.-C.).
2
Department of Genetics, Universitat de Barcelona (M.M.-C.).
3
Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (C.C., M.H.-G., M.S., P.D., A.B., T.G.-B., M.M., J.M., I.F.-C.), Universitat Autònoma de Barcelona.
4
Department of Neurology (R.M.D.-N., S.T., C.J.), Son Espases University Hospital, Institut d'Investigació Sanitària de Les Illes Balears, Palma de Mallorca.
5
Research Unit (A.M.-D., C.V.-B.), Son Espases University Hospital, Institut d'Investigació Sanitària de Les Illes Balears, Palma de Mallorca.
6
Stroke Pharmacogenomics and Genetics Group, Fundació Docència i Recerca Mútua Terrassa (N.C., N.P.T.-A., E.M., I.F.-C.).
7
Neurology Service, A Coruña University Hospital and Biomedical Research Institute, La Coruña (M.C.).
8
Department of Neurology, Doctor Josep Trueta University Hospital, Girona Institute of Biomedical Investigation (J.S.).
9
Stroke Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona (J.M.-F.S.).
10
Department of Neurology (T.S.), Complejo Hospitalario Universitario de Albacete.
11
Research Unit (G.S.-H.), Complejo Hospitalario Universitario de Albacete.
12
Department of Neurology, Hospital Clínic i Provincial de Barcelona (V.O.).
13
Stroke Unit, Department of Neurology, Hospital Universitari Vall d'Hebron, Barcelona (M.R., C.A.M., J.A.-S.).
14
Department of Neurology, Hospital de Mataró (E.P.).
15
Department of Neurology, Hospital de Basurto, Bilbao (M.F.).
16
Department of Neurology, Hospital de Bellvitge, Hospitalet de Llobregat (M.A.F.).
17
Department of Neurology, J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (J.R., N.S.R.).
18
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA (J.R., C.G.-F.).
19
Center for Genomic Medicine, Massachusetts General Hospital, Boston (J.R., C.G.F.).
20
Department of Neurology (J.-M.L., L.H., L.I., C.C., C.-L.P.), Washington University School of Medicine, St. Louis, MO.
21
The Division of Emergency Medicine (L.H.), Washington University School of Medicine, St. Louis, MO.
22
Department of Neurosciences, Experimental Neurology, KU Leuven - University of Leuven, Belgium (R.L.).
23
Laboratory of Neurobiology, VIB, Center for Brain & Disease Research, Leuven (R.L.).
24
Department of Neurology, University Hospitals Leuven (R.L.).
25
Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, Australia (V.T.).
26
Department of Neurology, Austin Health, Heidelberg, Australia (V.T.).
27
Clinical Sciences Lund, Neurology, Lund University, Sweden (A.L.).
28
Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden (A.L.).
29
Faculty of Health, University of Technology, Sidney (J. Maguire).
30
Priority Research Centre for Stroke and Brain Injury, Hunter Medical Research Institute, University of Newcastle, Australia (J. Maguire).
31
Division of Clinical Brain Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, United Kingdom (K.R., C.L.S.).
32
Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg (C.J., T.M.S.).
33
Bioinformatics Core Facility, University of Gothenburg (E.L.).
34
Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol (L.M.-N., A.D.), Universitat Autònoma de Barcelona.
35
Stroke Unit, Hospital Universitario Central de Asturias (HUCA), Oviedo (E.L.-C.).
36
Neurology and Department of Public Health Sciences, University of Virginia, Charlottesville (B.B.W.).
37
Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, OH (D.W.).
38
Department of Neurology, University of Maryland School of Medicine and Baltimore VAMC, MD (S.J.K.).
39
Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, MD (B.D.M.).
40
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD (B.D.M.).
41
Neurovascular Research Laboratory, Institute of Biomedicine of Seville, Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla (J. Montaner).
42
Department of Neurology, Hospital Universitario Virgen Macarena, Sevilla (J. Montaner).
43
Neurology Unit, Neuroscience Department, Mútua de Terrassa Hospital (J.K.).
44
Research Department, Sidra Medicine, Doha, Qatar (X.E.).
45
Genomics Unit, Dexeus Woman's Health, Barcelona (X.E.).
46
Centre for Genomic Regulation, Barcelona (R.R.).
47
Stroke Pharmacogenomics and Genetics Group, Institut de Recerca Hospital de la Santa Creu i Sant Pau, Barcelona (I.F.-C.).

Abstract

RATIONALE:

Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome.

OBJECTIVE:

Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date.

METHODS AND RESULTS:

A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P=1.70×10-9).

CONCLUSIONS:

Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.

KEYWORDS:

allele; genetic loci; genetic variant; genome-wide association study; ischemic stroke

Comment in

PMID:
30582445
PMCID:
PMC6501820
[Available on 2020-01-04]
DOI:
10.1161/CIRCRESAHA.118.313533
[Indexed for MEDLINE]

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