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Originally Published 15 October 2018
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PATJ Low Frequency Variants Are Associated With Worse Ischemic Stroke Functional Outcome: A Genome-Wide Meta-Analysis

Marina Mola-Caminal [email protected], Caty Carrera, Carolina Soriano-Tárraga, Eva Giralt-Steinhauer, Rosa M. Díaz-Navarro, Sílvia Tur, Carmen Jiménez, … Show All … , Aina Medina-Dols, Natàlia Cullell, Nuria P. Torres-Aguila, Elena Muiño, Ana Rodríguez-Campello, Angel Ois, Elisa Cuadrado-Godia, Rosa M. Vivanco-Hidalgo, Mar Hernandez-Guillamon, Montse Solé, Pilar Delgado, Alejandro Bustamante, Teresa García-Berrocoso, Maite Mendióroz, Mar Castellanos, Joaquín Serena, Joan Martí-Fàbregas, Tomás Segura, Gemma Serrano-Heras, Victor Obach, Marc Ribó, Carlos A. Molina, José Alvarez-Sabín, Ernest Palomeras, Mar Freijo, Maria A. Font, Jonathan Rosand, Natalia S. Rost, Cristina Gallego-Fabrega, Jin-Moo Lee, Laura Heitsch, Laura Ibanez, Carlos Cruchaga, Chia-Ling Phuah, Robin Lemmens, Vincent Thijs, Arne Lindgren, Jane Maguire, Kristiina Rannikmae, Catherine L. Sudlow, Christina Jern, Tara M. Stanne, Erik Lorentzen, Lucía Muñoz-Narbona, Antonio Dávalos, Elena López-Cancio, Bradford B. Worrall, Daniel Woo, Steven J. Kittner, Braxton D. Mitchell, Joan Montaner, Jaume Roquer, Jurek Krupinski, Xavier Estivill, Raquel Rabionet, Cristòfol Vives-Bauzá, Israel Fernández-Cadenas [email protected], and Jordi Jiménez-Conde [email protected]Author Info & Affiliations
Circulation Research
Volume 124, Number 1
https://doi.org/10.1161/CIRCRESAHA.118.313533
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VIEW EDITORIAL:Genetics of Recovery After Stroke

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.

Introduction

Ischemic stroke (IS) is the leading cause of adult disability1 and the second cause of death worldwide.2 Approximately 15 million people per year have a stroke, 5 million results in long-term disability.3 More than a thousand potential targets for neuronal recovery have been identified,4 although few have been tested in clinical trials. As no trials had positive results it is of high priority to find new drug targets for clinical practice.
Editorial, see p 18
In This Issue, see p 2
Meet the First Author, see p 3
Functional outcome after IS varies between individuals irrespective of clinical factors as initial stroke severity, stroke subtype, and vascular risk factors.5 Multiple metabolic pathways are important in the response to cerebral ischemic damage and their activity may be modulated by variation in the genes of the involved components. New synaptic connections have been observed in areas surrounding a cerebral infarct within days after a stroke and this response is correlated with functional recovery.6
It is reasonable to presume that genetic variation may influence stroke recovery.7 Candidate-gene studies reported the association between several genes and disability after stroke, but no locus has been found through a hypothesis-free genome-wide approach and most of the reported candidates failed to replicate in other cohorts.8
Genome-wide association studies (GWASs) have identified multiple single nucleotide polymorphisms (SNPs) contributing with a small effect to the risk of complex diseases, and different genes have arisen as potential therapeutic targets to reduce the risk of stroke.9,10 Studying the genetic component of stroke outcome is of great scientific interest but requires very accurate phenotyping and proper attention to potentially confounding factors that may hide the true genetic contribution.
We aimed to find the genetics influencing the stroke recovery process in a dataset of first-ever IS patients, using highly accurate phenotyping and producing the largest GWAS in stroke mid-term functional outcome to date to identify new potential drug targets.

Methods

The data that support the findings of this study are available from the corresponding author upon reasonable request.
Detailed Methods are provided in the online-only Data Supplement.

Study Design

We conducted a 2-phase analysis; discovery-replication and joint association of IS cases. The discovery consisted of a meta-analysis of 4 GWAS. The replication was performed as an in silico analysis of the top SNPs (P<1×10−5) identified in the discovery. Two final joint meta-analyses according to open or stringent criteria were performed. The open joint meta-analysis (n=2482) included 4 discovery and 8 replication cohorts and the stringent joint meta-analysis (n=1791) 4 discovery and 3 replication cohorts. This joint approach has proved to be more efficient than discovery-replication alone in increasing the statistical power.11 A gene-based burden test was conducted.

Study Sample

European ancestry patients with a diagnosis of IS according to World Health Organization criteria were selected from the Spanish Stroke Genetics Consortium (GeneStroke) and the International Stroke Genetics Consortium.

Genome-Wide Association Study

After GWAS quality controls and imputation, association analyses with 3-month modified Rankin Scale (mRS) were performed using an additive model and a multivariate linear regression. The common variants between the individual GWAS were joined into weighted z-score meta-analyses for 3-month mRS. All the SNPs with P<5×10−8 were considered statistically significant for a genome-wide approach.

Results

Genome-Wide Association Study

GWAS—Discovery Phase

We meta-analyzed 4 individual GWAS with 1225 individuals and 4 480 015 SNPs in the discovery phase. In the bivariate analysis (Table II in the online-only Data Supplement), 3-month mRS showed association with age at stroke onset, sex, smoking status, stroke subtype by Trial of Org 10172 in acute stroke treatment,12 and discharge National Institutes of Health Stroke Scale. The results include 79 variants in 18 independent (r2<0·001) genomic regions associated with impaired 3-month mRS at P<1×10−5 (Figure 1; Table III in the online-only Data Supplement), selected for replication. Global genomic inflation was λ=1032. Best evidence was for 3 SNPs in PATJ (Pals1-associated tight junction) on chromosome 1 exceeding P<5×10−8: rs76221407 (P=1.087×10−8, β=0.42); rs150862264 (P=1.539×10−8, β=0.41); and rs182008837 (P=1.825×10−8, β=0.40). The top variant was imputed with r2=89.9% and imputation certainty=99.2%.
Figure 1. Manhattan plot and Q-Q plot of the discovery results. Association testing was performed using a linear regression model adjusted for the first 2 PCs, sex, age, smoking, stroke subtype, and discharge National Institutes of Health Stroke Scale (NIHSS). The red line shows P=1×10−5 and the blue line the genome-wide association study (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).

GWAS—Replication Phase

The SNPs selected for replication were analyzed in 8 cohorts (Table IV in the online-only Data Supplement). The stringent replication meta-analysis with 3 cohorts that strictly fulfill our selection criteria showed 5 SNPs in PATJ nominally associated with 3-month mRS (P<0.05), including the 3 top SNPs from the discovery (Table V in the online-only Data Supplement). The effect size in the replication is slightly lower than in the discovery, indicating widespread consistency of results among the cohorts.

GWAS—Joint

A stringent joint meta-analysis was performed with the 4 discovery and the 3 stringent replication cohorts (1791 individuals). The analysis revealed strong genetic association between 18 low-frequency SNPs in PATJ and worse 3-month mRS (Table). The most striking SNP was rs76221407 (P=1.72×10−9, β=0.40), as shown in the forest plot (Figure IV in the online-only Data Supplement), driven by a variant with low frequency (3%) in our European ancestry cohorts (which is consistent with 1 kg data). Figure 2 shows the percentage of patients per group of 3-month mRS depending on the presence of the risk allele.
Table. Intronic Variants in PATJ Associated With 3-Mo mRS at P<5×10−8 in the Stringent Joint Analysis
SNPPositionGeneSNP TypeMAMAFββ (80% power)SEP Value
rs762214071:62131826PATJintronicG0.030.400.440.071.72×10−9
rs1508622641:62132045PATJintronicC0.030.400.440.071.76×10−9
rs1820088371:62107102PATJintronicC0.030.390.430.072.93×10−9
rs1173359781:62140649PATJintronicT0.020.460.540.081.96×10−8
rs1379996921:62092932PATJintronicA0.030.360.430.072.98×10−8
rs757179581:62141064PATJintronicA0.020.470.550.083.71×10−8
rs75467441:62141462PATJintronicA0.020.470.550.083.71×10−8
rs75139821:62141944PATJintronicC0.020.470.550.083.72×10−8
rs171231331:62142178PATJintronicA0.020.470.550.083.72×10−8
rs75141071:62142096PATJintronicC0.020.470.550.083.72×10−8
rs1414792961:62140561PATJintronicG0.020.470.550.083.77×10−8
rs118058021:62142912PATJintronicC0.020.470.550.083.78×10−8
rs101575041:62140248PATJintronicG0.020.470.550.083.80×10−8
rs744690181:62144275PATJintronicT0.020.470.560.083.86×10−8
rs770075851:62144350PATJintronicA0.020.470.560.083.88×10−8
rs118066561:62144566PATJintronicC0.020.470.560.083.88×10−8
rs75425981:62145477PATJintronicT0.020.470.560.083.95×10−8
rs1181681811:62141702PATJintronicA0.020.470.560.093.98×10−8
β, β-value for the association; β (80% power), β that could be detected as statistically significant under 80% power; Position, chromosome: genomic coordinates according to human genome reference version 19 (build GRCh38/hg38). MA indicates minor allele; MAF, minor allele frequency; and SNP, single nucleotide polymorphism.
Figure 2. Distribution of 3-mo 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.
An open joint meta-analysis was performed with all 12 cohorts (2482 individuals) independently of meeting criteria for stringent analysis. Results revealed less significant P values than the stringent analysis (rs76221407, P=1.3×10−8, β=0.37; Figure 3; Table VI and Figure V in the online-only Data Supplement). The percentage of the phenotypic variation in 3-month mRS accounted by the lead SNP is 0.27% in the whole sample (12 cohorts).
Figure 3. Forest plot and regional association plot for rs76221407 in the open joint-analysis. Plot of the effect size of the association with 3-mo mRS across the 12 cohorts (open joint-analysis; A). Association of rs76221407 and other single nucleotide polymorphisms (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). chr1 indicates chromosome 1; CI, confidence interval; cM, centimorgan; INADL, inactivation-no-afterpotential D-like (PATJ gene); KANK4, KN motif and ankyrin repeat domains 4; L1TD1, LINE1 type transposase domain-containing 1; and Mb, megabase.
The same analyses through an ordinal regression showed loss of statistical power (stringent, P=3.60×10−5; open, P=4.33×10−5). Evidence of the robustness of the genetic association presented in this work is clearly shown in Figure 3, where the top SNP has a consistent effect direction in 11 out of 12 cohorts.

Gene-Based Study

The gene-based association test revealed the PATJ gene as significantly associated with 3-month mRS. The 4.48 million genetic variants from the discovery GWAS were clustered in 23 972 genes, of which the only significant gene was PATJ (P=1.99×10−6) (Table VII in the online-only Data Supplement). Significance threshold was set at P<0.05/23 972=2.086×10−6.

Discussion

We report the first genetic findings in IS outcome using a GWAS. Our results show a novel association between low-frequency genetic variants in PATJ gene and worse IS functional outcome measured with 3-month mRS. Genetic studies on IS outcome had previously focused on candidate loci (see Lindgren and Maguire).7 However, findings had shown contradictory results and failed in consistent replications.8 We performed a meta-analysis of 12 independent cohorts within the International Stroke Genetics Consortium, applying open and stringent criteria. Several low-frequency variants in PATJ were significantly associated with worse functional outcome at 3 months. The lead variant, rs76221407, presents a consistent effect direction in 11 of 12 cohorts, providing convincing evidence of its robust genetic association with stroke outcome. The SNP is located in an intronic region of PATJ and shows linkage disequilibrium with 17 other variants found through the stringent joint meta-analysis (r2>0.3, in 1000 Genomes Project for European ancestry individuals). The fact that the variants are intronic may suggest that its effect on protein synthesis is carried out through the regulation of gene expression, similar to other common variants identified by GWAS that are linked to diseases by their modulation of the activity of DNA regulatory elements.13 No previously established risk locus for stroke10 has been related to stroke outcome in this work. Considering our restrictive inclusion criteria, which widely differ from the case/control studies, it is reasonable that we do not find overlaps in the top SNPs. None of our significant variants have been associated with another phenotype yet, although other PATJ polymorphisms have been related to sleep disturbance14 and obesity-related traits.15
The results show a positive effect (β=0.4) for the G allele of rs76221407, indicating that an increase of 0.4 points in the mRS score is attributed to each copy of G allele (GG>GA>AA). This means that G allele is related to poor functional outcome at 3-month. The results from the gene-based test also revealed significance for this locus (P=1.99×10−6) pointing out PATJ as a hot region of accumulated contributing variants. Although our PATJ SNPs are low frequency (≈3%), the power of the association is strong enough to persist in the replication, evidencing the consistency of the results presented and the suitability of this gene as a therapeutic target.
PATJ, also known as INADL (inactivation-no-afterpotential D-like), localized at tight junctions and at the apical membrane of epithelial cells, encodes a protein with 7 PDZ domains, interaction modules that regulate multiple biological processes like ion channel signaling and transport.
To study the genetic component of a complex trait as IS functional outcome, it is key to be precise in characterizing the phenotype. The exclusion of posterior and lacunar strokes was considered necessary because these locations show a poor correlation between infarct size and clinical symptoms, and thus functional outcome.16 A small lesion can be asymptomatic or show very severe symptoms with great disability depending on a variation of just few millimeters in its location. In these cases, recovery processes and tissue regeneration mechanisms could be masked by this random location effect.
Minor strokes (initial National Institutes of Health Stroke Scale ≤4) and individuals with a dependent status previous to the stroke event (mRS score of >2) were also excluded. This was done to permit the analyses of an equivalent recovery process, without taking into consideration the degree of disability before stroke or those patients with only minimal damage to be recovered. In both cases, it would be difficult to evaluate the significance of recovery at 3-month. The achievement of a highly homogeneous sample was one of the main priorities during the study design. This led to the performance of 2 types of joint meta-analyses. The more permissive inclusion criteria of the open analysis led to a larger sample size (1.5× greater) but less significant results compared with the stringent analysis. The reduction of phenotypic heterogeneity by properly defining the study cohort increases statistical power.17 While the phenotypic homogeneity of the sample is the main strength of our study, it also limited the sample size, as very few cohorts worldwide have the complete data needed for the stringent analysis8 and this may prevent the discovery of other loci. However, our work demonstrates the value of prioritizing homogeneity and phenotyping accuracy over a larger sample size. The mRS, the most widely used scale in stroke patients to assess functional outcome, has only 7 categories but it offers the advantages of being easy to apply and having good inter-observer reproducibility.18 Analyzing the mRS score as a continuous instead of an ordinal value,19 according to Rhemtulla et al,20 is the preferable choice for ordinal data with >4 categories in contrast to robust categorical methodology, and the statistical power is improved.
This project generated extensive genotyping and phenotyping of individual-level data that can help to disentangle the genetic architecture of the stroke recovery process. The use of whole exome or genome sequencing would provide information about rare variants, which may account for a greater proportion of the stroke outcome’s genetic component than common variants. Additional functional studies are warranted to establish whether PATJ can reveal biological pathways that could be novel therapeutic targets to improve post-IS rehabilitation strategies.

Novelty and Significance

VIEW EDITORIAL:Genetics of Recovery After Stroke

What Is Known?

•
Disability because of stroke has a significant impact on public health as it affects the quality of life of both—the patients and the caregivers.
•
Irrespective of clinical factors, functional recovery after ischemic stroke (IS) varies widely among individuals.
•
Variability in functional outcome has been attributed, in part, to genetic factors, but to date, no locus has been consistently associated with stroke outcome.

What New Information Does This Article Contribute?

•
Genetic variants in PATJ gene are associated with IS functional outcome at 3 months.
•
Association of PATJ gene variants with IS functional outcome was discovered through a meta-analysis of genome-wide association studies and was validated in a multiple-cohort replication study.
Cerebrovascular disease is the leading cause of adult disability. Mid-term functional recovery after stroke varies significantly among individuals, independent of infarct size, stroke subtype, vascular risk factors, or clinical status after acute treatment. Identifying genetic factors that contribute to this variability requires a hypothesis-free, comprehensive genotyping approach, such as genome-wide association studies, as well as accurate phenotyping to identify confounding factors that may obscure the genetic effects. Using a restrictive inclusion criteria to obtain a less heterogeneous patient population, in a multi-cohort genome-wide association studies we found that PATJ gene variants were associated with functional outcomes in patients with IS. The accumulation of risk alleles in the PATJ gene was associated with a worse functional outcome at 3-month after IS. This evidence for a genetic contribution to mid-term stroke prognosis provides a new platform for understanding the mechanisms that determine functional recovery after stroke, and may also help in better prediction of functional outcomes after IS.

Footnote

Nonstandard Abbreviations and Acronyms

GWAS
genome-wide association study
IS
ischemic stroke
mRS
modified Rankin Scale
SNPs
single nucleotide polymorphisms

Supplemental Material

File (313533_online.pdf)
File (circres_circres-2018-313533_supp1.pdf)

Appendix

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.); Department of Genetics, Universitat de Barcelona (M.M.-C.); 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.), and Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol (L.M.-N., A.D.), Universitat Autònoma de Barcelona; Department of Neurology (R.M.D.-N., S.T., C.J.), and Research Unit (A.M.-D., C.V.-B.), Son Espases University Hospital, Institut d’Investigació Sanitària de Les Illes Balears, Palma de Mallorca; Stroke Pharmacogenomics and Genetics Group, Fundació Docència i Recerca Mútua Terrassa (N.C., N.P.T.-A., E.M., I.F.-C.); Neurology Service, A Coruña University Hospital and Biomedical Research Institute, La Coruña (M.C.); Department of Neurology, Doctor Josep Trueta University Hospital, Girona Institute of Biomedical Investigation (J.S.); Stroke Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona (J.M.-F.S.); Department of Neurology (T.S.), and Research Unit (G.S.-H.), Complejo Hospitalario Universitario de Albacete; Department of Neurology, Hospital Clínic i Provincial de Barcelona (V.O.); Stroke Unit, Department of Neurology, Hospital Universitari Vall d’Hebron, Barcelona (M.R., C.A.M., J.A.-S.); Department of Neurology, Hospital de Mataró (E.P.); Department of Neurology, Hospital de Basurto, Bilbao (M.F.); Department of Neurology, Hospital de Bellvitge, Hospitalet de Llobregat (M.A.F.); Department of Neurology, J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (J.R., N.S.R.); Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA (J.R., C.G.-F.), Center for Genomic Medicine, Massachusetts General Hospital, Boston (J.R., C.G.F.); Department of Neurology (J.-M.L., L.H., L.I., C.C., C.-L.P.), and The Division of Emergency Medicine (L.H.), Washington University School of Medicine, St. Louis, MO; Department of Neurosciences, Experimental Neurology, KU Leuven - University of Leuven, Belgium (R.L.); Laboratory of Neurobiology, VIB, Center for Brain & Disease Research, Leuven (R.L.); Department of Neurology, University Hospitals Leuven (R.L.); Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, Australia (V.T.); Department of Neurology, Austin Health, Heidelberg, Australia (V.T.); Clinical Sciences Lund, Neurology, Lund University, Sweden (A.L.); Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden (A.L.); Faculty of Health, University of Technology, Sidney (J. Maguire); Priority Research Centre for Stroke and Brain Injury, Hunter Medical Research Institute, University of Newcastle, Australia (J. Maguire); Division of Clinical Brain Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, United Kingdom (K.R., C.L.S.); Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg (C.J., T.M.S.); Bioinformatics Core Facility, University of Gothenburg (E.L.); Stroke Unit, Hospital Universitario Central de Asturias (HUCA), Oviedo (E.L.-C.); Neurology and Department of Public Health Sciences, University of Virginia, Charlottesville (B.B.W.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, OH (D.W.), Department of Neurology, University of Maryland School of Medicine and Baltimore VAMC, MD (S.J.K.);Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, MD (B.D.M.); Department of Medicine, University of Maryland School of Medicine, Baltimore, MD (B.D.M.); Neurovascular Research Laboratory, Institute of Biomedicine of Seville, Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla (J. Montaner); Department of Neurology, Hospital Universitario Virgen Macarena, Sevilla (J. Montaner); Neurology Unit, Neuroscience Department, Mútua de Terrassa Hospital (J.K.), Research Department, Sidra Medicine, Doha, Qatar (X.E.); Genomics Unit, Dexeus Woman’s Health, Barcelona (X.E.); Centre for Genomic Regulation, Barcelona (R.R.); and Stroke Pharmacogenomics and Genetics Group, Institut de Recerca Hospital de la Santa Creu i Sant Pau, Barcelona (I.F.-C.).

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Published In

Go to Circulation Research
Circulation Research
Volume 124 • Number 1 • 4 January 2019
Pages: 114 - 120
PubMed: 30582445

Copyright

© 2018 American Heart Association, Inc.

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Published online: 15 October 2018
Published in print: 4 January 2019

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Keywords

  1. allele
  2. genetic loci
  3. genetic variant
  4. genome-wide association study
  5. ischemic stroke

Subjects

  1. Genetic, Association Studies
  2. Ischemic Stroke
  3. Neurogenesis
  4. Vascular Disease

Authors

Affiliations

Marina Mola-Caminal [email protected]
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.)
Department of Genetics, Universitat de Barcelona (M.M.-C.)
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Caty Carrera
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
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Carolina Soriano-Tárraga
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.)
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Eva Giralt-Steinhauer
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.)
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Rosa M. Díaz-Navarro
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
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Sílvia Tur
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
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Carmen Jiménez
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
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Aina Medina-Dols
Research Unit (A.M.-D., C.V.-B.), Son Espases University Hospital, Institut d’Investigació Sanitària de Les Illes Balears, Palma de Mallorca
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Natàlia Cullell
Stroke Pharmacogenomics and Genetics Group, Fundació Docència i Recerca Mútua Terrassa (N.C., N.P.T.-A., E.M., I.F.-C.)
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Nuria P. Torres-Aguila
Stroke Pharmacogenomics and Genetics Group, Fundació Docència i Recerca Mútua Terrassa (N.C., N.P.T.-A., E.M., I.F.-C.)
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Elena Muiño
Stroke Pharmacogenomics and Genetics Group, Fundació Docència i Recerca Mútua Terrassa (N.C., N.P.T.-A., E.M., I.F.-C.)
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Ana Rodríguez-Campello
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.)
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Angel Ois
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.)
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Elisa Cuadrado-Godia
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.)
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Rosa M. Vivanco-Hidalgo
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.)
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Mar Hernandez-Guillamon
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
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Montse Solé
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
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Pilar Delgado
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
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Alejandro Bustamante
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
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Teresa García-Berrocoso
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
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Maite Mendióroz
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
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Mar Castellanos
Neurology Service, A Coruña University Hospital and Biomedical Research Institute, La Coruña (M.C.)
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Joaquín Serena
Department of Neurology, Doctor Josep Trueta University Hospital, Girona Institute of Biomedical Investigation (J.S.)
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Joan Martí-Fàbregas
Stroke Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona (J.M.-F.S.)
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Tomás Segura
Department of Neurology (T.S.), Complejo Hospitalario Universitario de Albacete
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Gemma Serrano-Heras
Research Unit (G.S.-H.), Complejo Hospitalario Universitario de Albacete
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Victor Obach
Department of Neurology, Hospital Clínic i Provincial de Barcelona (V.O.)
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Marc Ribó
Stroke Unit, Department of Neurology, Hospital Universitari Vall d’Hebron, Barcelona (M.R., C.A.M., J.A.-S.)
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Carlos A. Molina
Stroke Unit, Department of Neurology, Hospital Universitari Vall d’Hebron, Barcelona (M.R., C.A.M., J.A.-S.)
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José Alvarez-Sabín
Stroke Unit, Department of Neurology, Hospital Universitari Vall d’Hebron, Barcelona (M.R., C.A.M., J.A.-S.)
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Ernest Palomeras
Department of Neurology, Hospital de Mataró (E.P.)
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Mar Freijo
Department of Neurology, Hospital de Basurto, Bilbao (M.F.)
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Maria A. Font
Department of Neurology, Hospital de Bellvitge, Hospitalet de Llobregat (M.A.F.)
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Jonathan Rosand
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.)
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Natalia S. Rost
Department of Neurology, J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (J.R., N.S.R.)
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Cristina Gallego-Fabrega
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA (J.R., C.G.-F.)
Center for Genomic Medicine, Massachusetts General Hospital, Boston (J.R., C.G.F.)
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Jin-Moo Lee
Department of Neurology (J.-M.L., L.H., L.I., C.C., C.-L.P.), Washington University School of Medicine, St. Louis, MO
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Laura Heitsch
Department of Neurology (J.-M.L., L.H., L.I., C.C., C.-L.P.), Washington University School of Medicine, St. Louis, MO
The Division of Emergency Medicine (L.H.), Washington University School of Medicine, St. Louis, MO
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Laura Ibanez
Department of Neurology (J.-M.L., L.H., L.I., C.C., C.-L.P.), Washington University School of Medicine, St. Louis, MO
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Carlos Cruchaga
Department of Neurology (J.-M.L., L.H., L.I., C.C., C.-L.P.), Washington University School of Medicine, St. Louis, MO
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Chia-Ling Phuah
Department of Neurology (J.-M.L., L.H., L.I., C.C., C.-L.P.), Washington University School of Medicine, St. Louis, MO
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Robin Lemmens
Department of Neurosciences, Experimental Neurology, KU Leuven - University of Leuven, Belgium (R.L.)
Laboratory of Neurobiology, VIB, Center for Brain & Disease Research, Leuven (R.L.)
Department of Neurology, University Hospitals Leuven (R.L.)
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Vincent Thijs
Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, Australia (V.T.)
Department of Neurology, Austin Health, Heidelberg, Australia (V.T.)
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Arne Lindgren
Clinical Sciences Lund, Neurology, Lund University, Sweden (A.L.)
Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden (A.L.)
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Jane Maguire
Faculty of Health, University of Technology, Sidney (J. Maguire)
Priority Research Centre for Stroke and Brain Injury, Hunter Medical Research Institute, University of Newcastle, Australia (J. Maguire)
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Kristiina Rannikmae
Division of Clinical Brain Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, United Kingdom (K.R., C.L.S.)
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Catherine L. Sudlow
Division of Clinical Brain Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, United Kingdom (K.R., C.L.S.)
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Christina Jern
Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg (C.J., T.M.S.)
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Tara M. Stanne
Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg (C.J., T.M.S.)
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Erik Lorentzen
Bioinformatics Core Facility, University of Gothenburg (E.L.)
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Lucía Muñoz-Narbona
Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol (L.M.-N., A.D.), Universitat Autònoma de Barcelona
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Antonio Dávalos
Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol (L.M.-N., A.D.), Universitat Autònoma de Barcelona
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Elena López-Cancio
Stroke Unit, Hospital Universitario Central de Asturias (HUCA), Oviedo (E.L.-C.)
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Bradford B. Worrall
Neurology and Department of Public Health Sciences, University of Virginia, Charlottesville (B.B.W.)
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Daniel Woo
Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, OH (D.W.)
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Steven J. Kittner
Department of Neurology, University of Maryland School of Medicine and Baltimore VAMC, MD (S.J.K.)
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Braxton D. Mitchell
Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, MD (B.D.M.)
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD (B.D.M.)
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Joan Montaner
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
Neurovascular Research Laboratory, Institute of Biomedicine of Seville, Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla (J. Montaner)
Department of Neurology, Hospital Universitario Virgen Macarena, Sevilla (J. Montaner)
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Jaume Roquer
Department of Neurology, J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (J.R., N.S.R.)
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA (J.R., C.G.-F.)
Center for Genomic Medicine, Massachusetts General Hospital, Boston (J.R., C.G.F.)
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Jurek Krupinski
Neurology Unit, Neuroscience Department, Mútua de Terrassa Hospital (J.K.)
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Xavier Estivill
Research Department, Sidra Medicine, Doha, Qatar (X.E.)
Genomics Unit, Dexeus Woman’s Health, Barcelona (X.E.)
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Raquel Rabionet
Centre for Genomic Regulation, Barcelona (R.R.)
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Cristòfol Vives-Bauzá
Research Unit (A.M.-D., C.V.-B.), Son Espases University Hospital, Institut d’Investigació Sanitària de Les Illes Balears, Palma de Mallorca
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Israel Fernández-Cadenas [email protected]
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
Stroke Pharmacogenomics and Genetics Group, Fundació Docència i Recerca Mútua Terrassa (N.C., N.P.T.-A., E.M., I.F.-C.)
Stroke Pharmacogenomics and Genetics Group, Institut de Recerca Hospital de la Santa Creu i Sant Pau, Barcelona (I.F.-C.).
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Jordi Jiménez-Conde [email protected]
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.)
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Notes

In September 2018, the average time from submission to first decision for all original research papers submitted to Circulation Research was 14.06 days.
The full list of affiliations is available in the Appendix.
This study was supported by Genetic Contribution to Functional Outcome and Disability After Stroke (GODS) Project, NINDS Stroke Genetics Network (SiGN), International Stroke Genetics Consortium (ISGC), and GeneStroke Consortium
*
These authors contributed equally.
The online-only Data Supplement is available with this article at Supplemental Material.
Correspondence to Jordi Jiménez-Conde, MD, PhD, Hospital del Mar Medical Research Institute, Room 162, Doctor Aiguader 88, 08003 Barcelona, Spain, Email [email protected]
Israel Fernández-Cadenas, PhD, Sant Pau Institute of Research, Sant Antoni Mª Claret 167, 08025 Barcelona, Spain, Email [email protected]
Marina Mola-Caminal, PhD, Hospital del Mar Medical Research Institute, Room 157, Doctor Aiguader 88, 08003 Barcelona, Spain. Email [email protected]

Disclosures

None.

Sources of Funding

Genetic contribution to functional outcome and disability after stroke (GODS) project, Fundació Marató-TV3 Grant 2011 (76/C/2011), Recercaixa’13; Generación Project, Instituto de Salud Carlos III; GENISIS (Genetics of Early Neurological InStability After Ischemic Stroke) project, National Institutes of Health (NIH); National Institute of Neurological Disorders and Stroke Stroke Genetics Network (SiGN) Project, NIH. See information about funding for each cohort in the online-only Data Supplement (p 20).

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