Meta-Analysis

. 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

Marina Mola-Caminal^{1

2}, Caty Carrera³, Carolina Soriano-Tárraga¹, Eva Giralt-Steinhauer¹, Rosa M Díaz-Navarro⁴, Sílvia Tur⁴, Carmen Jiménez⁴, Aina Medina-Dols⁵, Natàlia Cullell⁶, Nuria P Torres-Aguila⁶, Elena Muiño⁶, Ana Rodríguez-Campello¹, Angel Ois¹, Elisa Cuadrado-Godia¹, Rosa M Vivanco-Hidalgo¹, Mar Hernandez-Guillamon³, Montse Solé³, Pilar Delgado³, Alejandro Bustamante³, Teresa García-Berrocoso³, Maite Mendióroz³, Mar Castellanos⁷, Joaquín Serena⁸, Joan Martí-Fàbregas⁹, Tomás Segura¹⁰, Gemma Serrano-Heras¹¹, Victor Obach¹², Marc Ribó¹³, Carlos A Molina¹³, José Alvarez-Sabín¹³, Ernest Palomeras¹⁴, Mar Freijo¹⁵, Maria A Font¹⁶, Jonathan Rosand¹, Natalia S Rost¹⁷, Cristina Gallego-Fabrega^{18

19}, Jin-Moo Lee²⁰, Laura Heitsch^{20

21}, Laura Ibanez²⁰, Carlos Cruchaga²⁰, Chia-Ling Phuah²⁰, Robin Lemmens^{22

23

24}, Vincent Thijs^{25

26}, Arne Lindgren^{27

28}, Jane Maguire^{29

30}, Kristiina Rannikmae³¹, Catherine L Sudlow³¹, Christina Jern³², Tara M Stanne³², Erik Lorentzen³³, Lucía Muñoz-Narbona³⁴, Antonio Dávalos³⁴, Elena López-Cancio³⁵, Bradford B Worrall³⁶, Daniel Woo³⁷, Steven J Kittner³⁸, Braxton D Mitchell^{39

40}, Joan Montaner^{3

41

42}, Jaume Roquer^{17

18

19}, Jurek Krupinski⁴³, Xavier Estivill^{44

45}, Raquel Rabionet⁴⁶, Cristòfol Vives-Bauzá⁵, Israel Fernández-Cadenas^{3

6

47}, Jordi Jiménez-Conde¹

Affiliations

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.).

PMID: 30582445
PMCID: PMC6501820
DOI: 10.1161/CIRCRESAHA.118.313533

Meta-Analysis

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

Marina Mola-Caminal et al. Circ Res. 2019.

. 2019 Jan 4;124(1):114-120.

doi: 10.1161/CIRCRESAHA.118.313533.

Authors

Affiliations

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.).

PMID: 30582445
PMCID: PMC6501820
DOI: 10.1161/CIRCRESAHA.118.313533

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.

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Figures

**Figure 1:. Manhattan plot (A) and Q-Q Plot (B) of the discovery results.**
Association testing was performed using a lineal regression model adjusted for the first two PCs, sex, age, smoking, stroke subtype, and discharge NIHSS. The red line shows p=1×10⁻⁵ and the blue line the GWAS significance threshold (p=5×10⁻⁸) (A). The X-axis is the expected −log₁₀ p under the null hypothesis and lambda is the observed median χ² test statistic divided by the median expected χ² test statistic under the null hypothesis (B).

**Figure 2:. Forest plot (A) and regional association plot (B) for rs76221407 in the *open* joint-analysis.**
Plot of the effect size of the association with 3-month mRS across the 12 cohorts (*open* joint-analysis) (A). Association of rs76221407 and other SNPs in the region was plotted with −log₁₀ p-values (left y-axis), the estimated local recombination rate in blue (right y-axis). The signals are distinguished by color and shape. Linkage disequilibrium (r²) of nearby SNPs is shown by color gradient (B). CI, Confidence Interval; cM, centimorgan; Mb, Megabase; INADL, Inactivation-No-Afterpotential D-Like (PATJ gene); L1TD1, LINE1 Type Transposase Domain Containing 1; KANK4, KN Motif And Ankyrin Repeat Domains 4; chr1, chromosome 1.

**Figure 3:. Distribution of 3-month mRS score in the *stringent* joint-analysis.**
*Joining in the same category the mRS values 5–6 and in the same group the G allele carriers (heterozygous and homozygous) is uniquely suited for facilitating the visualization of this figure, although the analyses are done without joining these categories.

See this image and copyright information in PMC

Comment in

Genetics of Recovery After Stroke.
Kessler T, Schunkert H. Kessler T, et al. Circ Res. 2019 Jan 4;124(1):18-20. doi: 10.1161/CIRCRESAHA.118.314269. Circ Res. 2019. PMID: 30605410 No abstract available.

References

1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart Disease and Stroke Statistics−−2015 Update: A Report From the American Heart Association. Circulation 2015; 131:e535. - PubMed
1. World Health Organization. The top 10 causes of death. May 2014. http://www.who.int/mediacentre/factsheets/fs310/en/ (accessed June 11, 2017).
1. Feigin VL, Lawes CMM, Bennett DA, Anderson CS. Stroke epidemiology: A review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol 2003; 2:43–53. - PubMed
1. Mahar M, Cavalli V. Intrinsic mechanisms of neuronal axon regeneration. Nat Rev Neurosci 2018; 19:10–3. - PMC - PubMed
1. Roquer J, Ois A, Rodriguez-Campello A, Gomis M, Munteis E, Jimenez-Conde J, Cuadrado-Godia E, Martinez-Rodriguez JE. Atherosclerotic burden and early mortality in acute ischemic stroke. Arch Neurol 2007; 64:699–704. - PubMed

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

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

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