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.
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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.
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Debette, S., Kamatani, Y., Metso, T. et al. Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection. Nat Genet 47, 78–83 (2015). https://doi.org/10.1038/ng.3154
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DOI: https://doi.org/10.1038/ng.3154
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