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.

Author information

Affiliations

  1. Departments of Neurosurgery, Neurobiology, Yale Center for Human Genetics and Genomics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.

    • Kaya Bilguvar
    • , Emília Gaál
    • , Yasar Bayri
    • , Luis Kolb
    • , Zulfikar Arlier
    •  & Murat Günel
  2. Genetics, Yale Program on Neurogenetics, Yale Center for Human Genetics and Genomics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.

    • Kaya Bilguvar
    • , Christopher E Mason
    • , Murim Choi
    • , Emília Gaál
    • , Yasar Bayri
    • , Luis Kolb
    • , Zulfikar Arlier
    • , Matthew W State
    • , Richard P Lifton
    •  & Murat Günel
  3. Division of Molecular Life Science, School of Medicine, Tokai University, Shimokasuya 143, Isehara, Kanagawa 259-1193, Japan.

    • Katsuhito Yasuno
    • , Atsushi Tajima
    •  & Ituro Inoue
  4. Department of Neurosurgery, Helsinki University Central Hospital, Helsinki, P.O. Box 266, FI-00029 HUS, Finland.

    • Mika Niemelä
    • , Emília Gaál
    • , Aki Laakso
    •  & Juha Hernesniemi
  5. Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.

    • Ynte M Ruigrok
    • , Leonard H van den Berg
    •  & Gabriel J E Rinkel
  6. Department of Neurosurgery, Kuopio University Hospital, Kuopio FI-70211, Finland.

    • Mikael von und zu Fraunberg
    • , Antti Ronkainen
    • , Timo Koivisto
    • , Jaakko Rinne
    •  & Juha E Jääskeläinen
  7. Genetic Epidemiology Unit, Department of Epidemiology and Biostatistics and Department of Clinical Genetics, Erasmus Medical Center, 2040, 3000 CA Rotterdam, The Netherlands.

    • Cornelia M van Duijn
    •  & Monique M B Breteler
  8. Keck Foundation Biotechnology Resource Laboratory, Yale University, 300 George Street, New Haven, Connecticut 06510, USA.

    • Shrikant Mane
    •  & Sudhakar Ravuri
  9. Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA.

    • Christopher E Mason
    •  & Matthew W State
  10. Department of Public Health, School of Medicine, Chiba University, Chiba 260-8670, Japan.

    • Akira Hata
  11. Department of Neurosurgery, Medical Center East, Tokyo Women's University, Tokyo 116-8567, Japan.

    • Hidetoshi Kasuya
  12. Department of Neurosurgery, Tampere University Hospital, 33521 Tampere, Finland.

    • Juha Öhman
  13. Complex Genetics Section, Department of Biomedical Genetics, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands.

    • Cisca Wijmenga
  14. Department of Genetics, University Medical Center Groningen and University of Groningen, 9700 RR Groningen, The Netherlands.

    • Cisca Wijmenga
  15. Biomedicum Helsinki, Research Program in Molecular Medicine, University of Helsinki, 00290 Helsinki, Finland.

    • Aarno Palotie
  16. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.

    • Aarno Palotie
  17. Howard Hughes Medical Institute and Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.

    • Richard P Lifton

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Contributions

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.

Corresponding authors

Correspondence to Richard P Lifton or Murat Günel.

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DOI

https://doi.org/10.1038/ng.240

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