Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection
Open accessAbstract
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). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. 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 infarction. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.
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The PHACTR1 region at 6p24 is linked by genome-wide studies to five vascular conditions: high blood pressure, fibromuscular dysplasia, cervical artery dissection, migraine, and coronary heart disease.
“Genome-wide association studies (GWASs) implicate the PHACTR1 locus (6p24) in risk for five vascular diseases, including coronary artery disease, migraine headache, cervical artery dissection, fibro-muscular dysplasia, and hypertension.”
From A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression (2017) · cites this paper as Debette et al., 2015
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- Authors
- International Stroke Genetics Consortium, Debette, S., the CADISP group, Kamatani, Y., Metso, T. M., Kloss, M., Chauhan, G., Engelter, S. T., Pezzini, A., Thijs, V., Markus, H. S., Dichgans, M., Wolf, C., Dittrich, R., Touzé, E., Southerland, A. M., Samson, Y., Abboud, S., Béjot, Y., Caso, V., Bersano, A., Gschwendtner, A., Sessa, M., Cole, J., Lamy, C., Medeiros, E., Beretta, S., Bonati, L. H., Grau, A. J., Michel, P., Majersik, J. J., Sharma, P., Kalashnikova, L., Nazarova, M., Dobrynina, L., Bartels, E., Guillon, B., van den Herik, E. G., Fernandez-Cadenas, I., Jood, K., Nalls, M. A., De Leeuw, F.-E., Jern, C., Cheng, Y.-C., Werner, I., Metso, A. J., Lichy, C., Lyrer, P. A., Brandt, T., Boncoraglio, G. B., Wichmann, H.-E., Gieger, C., Johnson, A. D., Böttcher, T., Castellano, M., Arveiler, D., Ikram, M. A., Breteler, M. M. B., Padovani, A., Meschia, J. F., Kuhlenbäumer, G., Rolfs, A., Worrall, B. B., Ringelstein, E.-B., Zelenika, D., Tatlisumak, T., Lathrop, M., Leys, D., Amouyel, P., & Dallongeville, J.
- Affiliations
- Université de Bordeaux (FR)
- RIKEN Center for Integrative Medical Sciences (JP)
- Helsinki University Hospital (FI)
- University Hospital Heidelberg (DE)
- University Hospital of Basel (CH)
- Universitair Ziekenhuis Leuven (BE)
- University of Cambridge (GB)
- Munich Cluster for Systems Neurology (DE)
- University Hospital Münster (DE)
- Centre Hospitalier Sainte-Anne (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Université Libre de Bruxelles (BE)
- University of Perugia (IT)
- University of Maryland, Baltimore (US)
- Centre Hospitalier Universitaire de Besançon (FR)
- Centre Hospitalier Universitaire Vaudois (CH)
- University of Utah (US)
- Russian Academy of Sciences (RU)
- National Research University Higher School of Economics (RU)
- Erasmus MC (NL)
- National Institutes of Health (US)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Helmholtz Munich (DE)
- Framingham Heart Study (US)
- Universitätsmedizin Rostock (DE)
- University of Brescia (IT)
- German Center for Neurodegenerative Diseases (DE)
- Mayo Clinic (US)
- Mayo Clinic in Florida (US)
- Christian-Albrechts-Universität zu Kiel (DE)
- University of Münster (DE)
- Université de Lille (FR)
- Inserm (FR)
- Corresponding author
- Debette, Stéphanie
- ORCID
- Debette, Stéphanie
- Metso, Tiina M
- Chauhan, Ganesh
- Engelter, Stefan T
- Pezzini, Alessandro
- Thijs, Vincent
- Markus, Hugh S
- Dichgans, Martin
- Wolf, Christiane
- Dittrich, Ralf
- Touzé, Emmanuel
- Southerland, Andrew M
- Samson, Yves
- Béjot, Yannick
- Caso, Valeria
- Bersano, Anna
- Sessa, Maria
- Lamy, Chantal
- Beretta, Simone
- Bonati, Leo H
- Grau, Armin J
- Michel, Patrik
- Majersik, Jennifer J
- Sharma, Pankaj
- Nazarova, Maria
- Bartels, Eva
- Guillon, Benoit
- Jood, Katarina
- Jern, Christina
- Werner, Inge
- Lyrer, Philippe A
- Brandt, Tobias
- Boncoraglio, Giorgio B
- Wichmann, Heinz-Erich
- Gieger, Christian
- Johnson, Andrew D
- Castellano, Maurizio
- Ikram, M Arfan
- Breteler, Monique M B
- Padovani, Alessandro
- Meschia, James F
- Kuhlenbäumer, Gregor
- Worrall, Bradford B
- Tatlisumak, Turgut
- Lathrop, Mark
- Leys, Didier
- Amouyel, Philippe
- Venue
- Nature Genetics
- Published
- 2014-11-24
- Volume
- 47
- Issue
- 1
- Pages
- 78-83
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5824623
- OpenAlex
- W1988886385
- Cited by
- 231
- References
- 57
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 17 · 2023: 12 · 2022: 20 · 2021: 28 · 2020: 24 · 2019: 23 · 2018: 30 · 2017: 23 · 2016: 28 · 2015: 7
- FWCI
- 15.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- PubMed Central (acceptedVersion)
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- BOA (University of Milano-Bicocca) (submittedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
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- Radboud Repository (Radboud University) (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion)
- Funders
- National Science Foundation
- American Heart Association
- Eli Lilly and Company
- American Stroke Association
- Helsingin ja Uudenmaan Sairaanhoitopiiri
- Suomen Lääketieteen Säätiö
- Alfred Kordelinin Säätiö
- Maud Kuistilan Muistosäätiö
- Aarne Koskelon Säätiö
- Deutsche Forschungsgemeinschaft
- Agence Nationale de la Recherche
- Fondation Leducq
- Institut National de la Santé et de la Recherche Médicale
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (124119)
- Fonds Wetenschappelijk Onderzoek
- Biomedicum Helsinki-säätiö
- Päivikki ja Sakari Sohlbergin Säätiö
- Schweizerische Herzstiftung
- Fondation de France
- Emil Aaltosen Säätiö
- Aarne ja Aili Turusen Säätiö
- Schweizerische Akademie der Medizinischen Wissenschaften
- Exzellenzclusters Entzündungsforschung
- Vlaamse regering
- Centre hospitalier régional universitaire de Lille
- Stiftung zur Erforschung der Vaskulären Demenz
- National Institutes of Health (Z99 AG999999)
- Instituto de Salud Carlos III (CP12/03298)
- European Regional Development Fund (2007 – 2013)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cerebrovascular and Carotid Artery Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
- Keywords
- cervical artery dissection, PHACTR1, genetic susceptibility, ischemic stroke in young adults, migraine, myocardial infarction, pleiotropy, carotid artery, vertebral artery, genome-wide association study
- MeSH terms
- Adult, Alleles, Brain Ischemia, Female, Finland, Follow-Up Studies, Humans, Hypercholesterolemia, Hypertension, Male, Microfilament Proteins, Middle Aged, Migraine Disorders, Myocardial Infarction, Obesity, Risk Factors, Odds Ratio, Genetic Predisposition to Disease, Carotid Artery, Internal, Dissection, Vertebral Artery Dissection, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Pleiotropy
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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