Letter | Published:

Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection

Nature Genetics volume 47, pages 7883 (2015) | Download Citation

Abstract

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year)1. Minor cervical traumas, infection, migraine and hypertension are putative risk factors1,2,3, and inverse associations with obesity and hypercholesterolemia are described3,4. No confirmed genetic susceptibility factors have been identified using candidate gene approaches5. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69–0.82; P = 4.46 × 10−10), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10−3; combined P = 1.00 × 10−11). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction6,7,8,9. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.

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Acknowledgements

The authors thank the staff and participants of all CADISP centers for their important contributions. The CADISP study has been supported by INSERM, Lille 2 University, Institut Pasteur de Lille and Lille University Hospital and received funding from the European Regional Development Fund (FEDER funds) and Région Nord-Pas-de-Calais in the framework of Contrat de Projets Etat-Region 2007–2013 Région Nord-Pas-de-Calais (grant 09120030), Centre National de Génotypage, the Emil Aaltonen Foundation, the Paavo Ilmari Ahvenainen Foundation, the Helsinki University Central Hospital Research Fund, the Helsinki University Medical Foundation, the Päivikki and Sakari Sohlberg Foundation, the Aarne Koskelo Foundation, the Maire Taponen Foundation, the Aarne and Aili Turunen Foundation, the Lilly Foundation, the Alfred Kordelin Foundation, the Finnish Medical Foundation, the Orion Farmos Research Foundation, the Maud Kuistila Foundation, the Finnish Brain Foundation, the Biomedicum Helsinki Foundation, Projet Hospitalier de Recherche Clinique Régional, Fondation de France, Génopôle de Lille, Adrinord, the Basel Stroke Funds, the Käthe-Zingg-Schwichtenberg-Fonds of the Swiss Academy of Medical Sciences and the Swiss Heart Foundation.

L.H.B., S.T.E. and P.A.L. were supported, in part, by a grant from the Swiss National Science Foundation (33CM30-124119). S.D. is supported by a Chair of Excellence from the French National Research Agency (ANR). S.D. and M.D. are supported by a grant from the Leducq Foundation. M.D. is supported by the Vascular Dementia Research Foundation. I.F.-C. is supported by the Miguel Servet programme (CP12/03298) from the Spanish Ministry of Health (Instituto de Salud Carlos III). G.K. is a member of the Deutsche Forschungsgemeinschaft Cluster of Excellence 'Inflammation at Interfaces'. P.S. is supported by a Department of Health (UK) senior fellowship. A.M.S. is supported by the American Heart Association/American Stroke Association National Clinical Research Program (AHA 3CRP14140001). V.T. is supported by Fonds Wetenschappelijk Onderzoek Flanders.

More detailed acknowledgments can be found in the Supplementary Note.

Author information

Author notes

    • Didier Leys
    • , Philippe Amouyel
    •  & Jean Dallongeville

    These authors contributed equally to this work.

Affiliations

  1. INSERM U744, Lille, France.

    • Stéphanie Debette
    • , Philippe Amouyel
    •  & Jean Dallongeville
  2. Institut Pasteur de Lille, Lille, France.

    • Stéphanie Debette
    • , Philippe Amouyel
    •  & Jean Dallongeville
  3. Université Lille Nord de France, Lille, France.

    • Stéphanie Debette
    • , Didier Leys
    • , Philippe Amouyel
    •  & Jean Dallongeville
  4. Lille University Hospital, Lille, France.

    • Stéphanie Debette
    • , Didier Leys
    •  & Philippe Amouyel
  5. Department of Neurology, Equipe d'accueil 1046, Lille, France.

    • Stéphanie Debette
    •  & Didier Leys
  6. INSERM U897, University of Bordeaux, Bordeaux, France.

    • Stéphanie Debette
    • , Ganesh Chauhan
    • , Christiane Wolf
    •  & Didier Leys
  7. Centre National de Génotypage, Evry, France.

    • Yoichiro Kamatani
    • , Diana Zelenika
    •  & Mark Lathrop
  8. Fondation Jean Dausset, Centre d'Etude du Polymorphisme Humain (CEPH), Paris, France.

    • Yoichiro Kamatani
    •  & Mark Lathrop
  9. Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.

    • Yoichiro Kamatani
  10. Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.

    • Tiina M Metso
    • , Antti J Metso
    •  & Turgut Tatlisumak
  11. Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.

    • Manja Kloss
    • , Inge Werner
    •  & Christoph Lichy
  12. Department of Neurology, Basel University Hospital, Basel, Switzerland.

    • Stefan T Engelter
    • , Leo H Bonati
    •  & Philippe A Lyrer
  13. Department of Clinical and Experimental Sciences, Neurology Clinic, Brescia University Hospital, Brescia, Italy.

    • Alessandro Pezzini
    •  & Alessandro Padovani
  14. Department of Neurology, Leuven University Hospital, Leuven, Belgium.

    • Vincent Thijs
  15. Vesalius Research Center, VIB, Leuven, Belgium.

    • Vincent Thijs
  16. Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

    • Hugh S Markus
  17. Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilians Universität, Munich, Germany.

    • Martin Dichgans
    •  & Andreas Gschwendtner
  18. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

    • Martin Dichgans
    •  & Andreas Gschwendtner
  19. Department of Statistical Genetics, Max Planck Institute for Psychiatry, Munich, Germany.

    • Christiane Wolf
  20. Department of Neurology, University Hospital of Münster, Münster, Germany.

    • Ralf Dittrich
    •  & Erich-Bernd Ringelstein
  21. Department of Neurology, University Hospital of Sainte-Anne, Paris, France.

    • Emmanuel Touzé
  22. Department of Neurology, University Hospital of Caen, Caen, France.

    • Emmanuel Touzé
  23. Department of Neurology, University of Virginia, Charlottesville, Virginia, USA.

    • Andrew M Southerland
    •  & Bradford B Worrall
  24. Urgences Cérébro-Vasculaire, Assistance Publique–Hôpitaux de Paris Salpêtrière Urgences Cérébro-Vasculaires and Université Pierre et Marie Curie Paris Paris VI Université, Paris, France.

    • Yves Samson
  25. Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, Belgium.

    • Shérine Abboud
  26. Department of Neurology, Dijon University Hospital, Dijon, France.

    • Yannick Béjot
  27. Stroke Unit, University of Perugia Santa Maria della Misericordia Hospital, Sant'Andrea delle Fratte, Perugia, Italy.

    • Valeria Caso
  28. Division of Cardiovascular Medicine, University of Perugia Santa Maria della Misericordia Hospital, Sant'Andrea delle Fratte, Perugia, Italy.

    • Valeria Caso
  29. Department of Cerebrovascular Diseases, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta, Milan, Italy.

    • Anna Bersano
    •  & Giorgio B Boncoraglio
  30. Department of Neurology, Milan, San Raffaele University Hospital, Milan, Italy.

    • Maria Sessa
  31. Maryland Stroke Center, Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • John Cole
    •  & Yu-Ching Cheng
  32. Department of Neurology, Amiens University Hospital, Amiens, France.

    • Chantal Lamy
  33. Department of Neurology, Besançon University Hospital, Besançon, France.

    • Elisabeth Medeiros
  34. Department of Neurology, University of Milano Bicocca, San Gerardo Hospital, Monza, Italy.

    • Simone Beretta
  35. Department of Neurology, Klinikum Ludwigshafen, Ludwigshafen, Germany.

    • Armin J Grau
  36. Department of Neurology, Lausanne University Hospital, Lausanne, Switzerland.

    • Patrik Michel
  37. Division of Vascular Neurology, Department of Neurology, University of Utah, Salt Lake City, Utah, USA.

    • Jennifer J Majersik
  38. Institute of Cardiovascular Research Royal Holloway University of London (ICR2UL), London, UK.

    • Pankaj Sharma
  39. Ashford and St Peter's Hospitals, London, UK.

    • Pankaj Sharma
  40. Research Center of Neurology, Russian Academy of Medical Sciences, Moscow, Russia.

    • Ludmila Kalashnikova
    • , Maria Nazarova
    •  & Larisa Dobrynina
  41. Centre for Cognition and Decision Making, Higher School of Economics, Moscow, Russia.

    • Maria Nazarova
  42. Center for Neurological Vascular Diagnostics, Munich, Germany.

    • Eva Bartels
  43. Department of Neurology, Nantes University Hospital, Nantes, France.

    • Benoit Guillon
  44. Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

    • Evita G van den Herik
    •  & M Arfan Ikram
  45. Stroke Pharmacogenomics and Genetics, Fundació Docència i Recerca MutuaTerrassa, Terrassa, Spain.

    • Israel Fernandez-Cadenas
  46. Laboratorio Neurovascular, Institut de Recerca, Hospital Vall d'Hebron, Barcelona, Spain.

    • Israel Fernandez-Cadenas
  47. Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

    • Katarina Jood
  48. Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.

    • Michael A Nalls
  49. Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.

    • Frank-Erik De Leeuw
    •  & Christina Jern
  50. Department of Rehabilitation, Schmieder Klinik, Heidelberg, Germany.

    • Tobias Brandt
  51. Institute of Epidemiology, Helmholtz Center Munich, Neuherberg, Germany.

    • Heinz-Erich Wichmann
  52. Institute of Genetic Epidemiology, Helmholtz Center Munich, Neuherberg, Germany.

    • Christian Gieger
  53. National Heart, Lung, and Blood Institute's Framingham Heart Study Cardiovascular Epidemiology and Human Genomics Branch, Framingham, Massachusetts, USA.

    • Andrew D Johnson
  54. Department of Neurology, Rostock University Hospital, Rostock, Germany.

    • Thomas Böttcher
    •  & Arndt Rolfs
  55. Department of Clinical and Experimental Sciences, Clinica Medica, Brescia University Hospital, Brescia, Italy.

    • Maurizio Castellano
  56. Department of Epidemiology and Public Health, EA 3430, Strasbourg University, Strasbourg, France.

    • Dominique Arveiler
  57. Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

    • M Arfan Ikram
    •  & Monique M B Breteler
  58. Department of Radiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

    • M Arfan Ikram
  59. Netherlands Consortium for Healthy Aging, Leiden, the Netherlands.

    • M Arfan Ikram
  60. Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

    • Monique M B Breteler
  61. Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, USA.

    • James F Meschia
  62. Institute of Experimental Medicine, University of Kiel, Kiel, Germany.

    • Gregor Kuhlenbäumer
  63. Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA.

    • Bradford B Worrall
  64. Génome Québec, McGill University, Montreal, Quebec, Canada.

    • Mark Lathrop

Consortia

  1. International Stroke Genetics Consortium

    A list of contributing members appears in the Supplementary Note.

  2. the CADISP group

    A list of members and affiliations appears in the Supplementary Note.

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Contributions

Study conception and design were performed by S.D., Y.K., M.L., D.L., P.A. and J.D. Acquisition of data was carried out by S.D., T.M.M., M.K., S.T.E., A. Pezzini, V.T., H.S.M., M.D., R.D., E.T., A.M.S., Y.S., S.A., Y.B., V.C., A.B., A.G., M.S., J.C., C. Lamy, E.M., S.B., L.H.B., A.J.G., P.M., J.J.M., P.S., E.B., B.G., E.G.v.d.H., I.F.-C., K.J., I.W., M.A.N., F.-E.D.L., C.J., Y.-C.C., A.J.M., C. Lichy, L.D., L.K., M.N., P.A.L., T. Brandt, G.B.B., H.-E.W., C.G., T. Böttcher, M.C., D.A., M.A.I., M.M.B.B., A. Padovani, J.F.M., G.K., A.R., B.B.W., E.-B.R., D.Z., T.T., M.L., D.L., P.A. and J.D. Statistical analysis and interpretation of the data were performed by S.D., Y.K., C.W., Y.-C.C., G.C., M.L., P.A. and J.D. The manuscript was drafted by S.D., Y.K., M.L., P.A. and J.D. Critical revision of the manuscript was performed by S.D., Y.K., T.M.M., S.T.E., C.W., M.L., P.A., J.D., A. Pezzini, V.T., H.S.M., E.T., A.M.S., J.C., J.J.M., P.S., I.F.-C., A.J.M., P.A.L., M.A.I., D.Z., T.T., M.L., D.L., P.A. and J.D. Annotation for expression quantitative trait loci was performed by A.D.J. Funding was obtained by S.D., S.T.E., A. Pezzini, V.T., H.S.M., M.D., S.B., A.J.G., P.M., J.J.M., P.S., B.G., F.-E.D.L., C.J., P.A.L., G.B.B., H.-E.W., M.C., D.A., M.M.B.B., J.F.M., A.R., B.B.W., E.-B.R., D.Z., T.T., M.L., D.L., P.A. and J.D.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Stéphanie Debette.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–8, Supplementary Tables 1–22 and Supplementary Note

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DOI

https://doi.org/10.1038/ng.3154

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