Letter abstract
Nature Genetics 40, 1472 - 1477 (2008)
Published online: 9 November 2008 | doi:10.1038/ng.240
Susceptibility loci for intracranial aneurysm in European and Japanese populations
Kaya Bilguvar1,2, Katsuhito Yasuno3, Mika Niemelä4, Ynte M Ruigrok5, Mikael von und zu Fraunberg6, Cornelia M van Duijn7, Leonard H van den Berg5, Shrikant Mane8, Christopher E Mason2,9, Murim Choi2, Emília Gaál1,2,4, Yasar Bayri1,2, Luis Kolb1,2, Zulfikar Arlier1,2, Sudhakar Ravuri8, Antti Ronkainen6, Atsushi Tajima3, Aki Laakso4, Akira Hata10, Hidetoshi Kasuya11, Timo Koivisto6, Jaakko Rinne6, Juha Öhman12, Monique M B Breteler7, Cisca Wijmenga13,14, Matthew W State2,9, Gabriel J E Rinkel5, Juha Hernesniemi4, Juha E Jääskeläinen6, Aarno Palotie15,16, Ituro Inoue3, Richard P Lifton2,17 & Murat Günel1,2
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.
- Departments of Neurosurgery, Neurobiology, Yale Center for Human Genetics and Genomics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
- Genetics, Yale Program on Neurogenetics, Yale Center for Human Genetics and Genomics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
- Division of Molecular Life Science, School of Medicine, Tokai University, Shimokasuya 143, Isehara, Kanagawa 259-1193, Japan.
- Department of Neurosurgery, Helsinki University Central Hospital, Helsinki, P.O. Box 266, FI-00029 HUS, Finland.
- Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
- Department of Neurosurgery, Kuopio University Hospital, Kuopio FI-70211, Finland.
- Genetic Epidemiology Unit, Department of Epidemiology and Biostatistics and Department of Clinical Genetics, Erasmus Medical Center, 2040, 3000 CA Rotterdam, The Netherlands.
- Keck Foundation Biotechnology Resource Laboratory, Yale University, 300 George Street, New Haven, Connecticut 06510, USA.
- Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
- Department of Public Health, School of Medicine, Chiba University, Chiba 260-8670, Japan.
- Department of Neurosurgery, Medical Center East, Tokyo Women's University, Tokyo 116-8567, Japan.
- Department of Neurosurgery, Tampere University Hospital, 33521 Tampere, Finland.
- Complex Genetics Section, Department of Biomedical Genetics, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands.
- Department of Genetics, University Medical Center Groningen and University of Groningen, 9700 RR Groningen, The Netherlands.
- Biomedicum Helsinki, Research Program in Molecular Medicine, University of Helsinki, 00290 Helsinki, Finland.
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
- Howard Hughes Medical Institute and Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Correspondence to: Richard P Lifton2,17 e-mail: richard.lifton@yale.edu
Correspondence to: Murat Günel1,2 e-mail: murat.gunel@yale.edu
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