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Stroke is the world's third leading cause of death. One cause of stroke, intracranial aneurysm, affects approximately 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 impairment. 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 aneurysm. Associated SNPs on 8q likely act via SOX17, which is required for formation and maintenance of endothelial cells, suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role. These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm.

Original publication

DOI

10.1038/ng.240

Type

Journal article

Journal

Nature genetics

Publication Date

12/2008

Volume

40

Pages

1472 - 1477

Addresses

Department of Neurosurgery, Neurobiology, Yale Center for Human Genetics and Genomics, Yale University School of Medicine, New Haven, CT 06510, USA.

Keywords

Chromosomes, Human, Pair 2, Chromosomes, Human, Pair 8, Chromosomes, Human, Pair 9, Humans, Intracranial Aneurysm, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Asian Continental Ancestry Group, European Continental Ancestry Group, Genome-Wide Association Study