Abstract
Stroke is the world's third leading cause of death. One cause of stroke, intracranial aneurysm, affects ∼2% of the population and accounts for 500,000 hemorrhagic strokes annually in mid-life (median age 50), most often resulting in death or severe neurological impairment1. The pathogenesis of intracranial aneurysm is unknown, and because catastrophic hemorrhage is commonly the first sign of disease, early identification is essential. We carried out a multistage genome-wide association study (GWAS) of Finnish, Dutch and Japanese cohorts including over 2,100 intracranial aneurysm cases and 8,000 controls. Genome-wide genotyping of the European cohorts and replication studies in the Japanese cohort identified common SNPs on chromosomes 2q, 8q and 9p that show significant association with intracranial aneurysm with odds ratios 1.24–1.36. The loci on 2q and 8q are new, whereas the 9p locus was previously found to be associated with arterial diseases, including intracranial aneurysm2,3,4,5. Associated SNPs on 8q likely act via SOX17, which is required for formation and maintenance of endothelial cells6,7,8, suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role9. These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm.
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Acknowledgements
We are grateful to the participants who made this study possible. We thank A. Chamberlain, O. Törnwall, M. Alalahti, K. Helin, S. Malin and J. Budzinack for their technical help. This study was supported by the Yale Center for Human Genetics and Genomics and the Yale Program on Neurogenetics, the US National Institutes of Health grants R01NS057756 (M.G.) and U24 NS051869 (S.M.) and the Howard Hughes Medical Institute (R.P.L.). C.E.M. and M.W.S. are supported by a gift from the Lawrence Family and Y.M.R. by the Dr E. Dekker program of The Netherlands Heart Foundation (2005T014). K.Y. and I.I. were supported by the Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation.
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Cohort ascertainment, characterization and DNA preparation: M.N., E.G., A.L., A.P., J.Ö. and J.H. (Helsinki); M.v.u.z.F., A.R., T.K., J.R., A.P. and J.E.J. (Kuopio); Y.M.R., L.H.v.d.B., C.W. and G.J.E.R. (Utrecht); C.M.v.D. and M.M.B.B. (Rotterdam) and A.T., A.H., H.K. and I.I. (Japan). Genotyping: K.B., Y.B., L.K., Z.A., S.R., R.P.L., M.G. and S.M. Study design and analysis plan: R.P.L. and M.G. Data management and informatics: C.E.M., K.B., M.W.S. and M.G. Statistical analysis: K.Y., K.B., I.I., M.C., R.P.L. and M.G. Writing team: K.B., K.Y., M.W.S., M.G. and R.P.L.
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Supplementary Methods, Supplementary Tables 1–6 and Supplementary Figure 1 (PDF 374 kb)
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Bilguvar, K., Yasuno, K., Niemelä, M. et al. Susceptibility loci for intracranial aneurysm in European and Japanese populations. Nat Genet 40, 1472–1477 (2008). https://doi.org/10.1038/ng.240
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DOI: https://doi.org/10.1038/ng.240
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