Abstract
Saccular intracranial aneurysms are balloon-like dilations of the intracranial arterial wall; their hemorrhage commonly results in severe neurologic impairment and death. We report a second genome-wide association study with discovery and replication cohorts from Europe and Japan comprising 5,891 cases and 14,181 controls with ∼832,000 genotyped and imputed SNPs across discovery cohorts. We identified three new loci showing strong evidence for association with intracranial aneurysms in the combined dataset, including intervals near RBBP8 on 18q11.2 (odds ratio (OR) = 1.22, P = 1.1 × 10−12), STARD13-KL on 13q13.1 (OR = 1.20, P = 2.5 × 10−9) and a gene-rich region on 10q24.32 (OR = 1.29, P = 1.2 × 10−9). We also confirmed prior associations near SOX17 (8q11.23–q12.1; OR = 1.28, P = 1.3 × 10−12) and CDKN2A-CDKN2B (9p21.3; OR = 1.31, P = 1.5 × 10−22). It is noteworthy that several putative risk genes play a role in cell-cycle progression, potentially affecting the proliferation and senescence of progenitor-cell populations that are responsible for vascular formation and repair.
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Acknowledgements
We are grateful to the participants who made this study possible. We thank A. Chamberlain, B. Meseck-Selchow and members of the Keck Foundation Biotechnology Resource Laboratory 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 (NIH) grants R01NS057756 (M.G.) and U24 NS051869 (S.M.) and the Howard Hughes Medical Institute (R.P.L.). This study is partially funded by the European Commission under the 6th Framework Programme through the @neurIST (www.aneurist.org) project under contract no. FP6-IST-2004-027703. The Frankfurt case cohort collection was supported by Bundesministerium für Bildung und Forschung (01GI9907), Utrecht Control cohort by the Prinses Beatrix Fonds and the Adessium foundation (L.H.v.d.B.). S.M. was supported in part by the Clinical and Translational Science Award UL1 RR024139, National Center for Research Resources, NIH. We would also like to acknowledge the use of Yale University Biomedical High Performance Computing Center (NIH grant: RR19895).
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Study Cohorts: ascertainment, characterization and DNA preparation: M.N., M.v.u.z.F., E.G., J.E.J., J.H. and A.P. (Finnish case-control); Y.M.R. and G.J.E.R. (NL cases); P.B., T.D., J. Blasco, G.Z., P.S., R.R., T.S., C.M.F., P.S., A.F.F., V.E., M.C.J.M.S., P.L., J. Byrne, J.M. and D.R. (@neurIST case series); B.K., G.A., M.S., D.K., F.W., A.O., B.S., C.S., J. Beck, F.R., C.R., D.B., C.G., E.I.S., B.M., A.R. and H.S. (DE case series); A.T., A.H., H.K. and I.I. (JP1); S.-K.L., H.Z. and Y.N. (JP2). Control Cohorts: A.A., L.P. and A.P. (Health2000); A.A., L.P. and A.P. (NFBC1966); C.M.v.D. and M.M.B.B. (Rotterdam Study); L.H.v.d.B. and C.W. (Utrecht); T.I. and H.E.W. (KORA-gen); S.S. (PopGen). Genotyping: K.B., Z.A., N.N., A.K.O., E.G., S.M., R.P.L. and M.G. (Yale); C. Perret, C. Proust and F.C. (Aneurist); S.-K.L., H.Z. and Y.N. (JP2). Data management and informatics: K.Y., K.B., Z.A., N.N. and M.G. (Yale); S.-K.L., H.Z. and Y.N. (JP2 cohort); Statistical analysis: K.Y. and M.G. Writing team: K.Y., K.B., M.W.S., R.P.L. and M.G. Study design and analysis plan: K.Y., R.P.L. and M.G.
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Yasuno, K., Bilguvar, K., Bijlenga, P. et al. Genome-wide association study of intracranial aneurysm identifies three new risk loci. Nat Genet 42, 420–425 (2010). https://doi.org/10.1038/ng.563
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DOI: https://doi.org/10.1038/ng.563
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