Date of Award

9-28-2010

Document Type

Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Murat Gunel

Second Advisor

Anne Williamson

Abstract

The rupture of intracranial aneurysm (IA) causes a form of hemorrhagic stroke with extremely high morbidity and mortality. While IA is a common disease, affecting up to five percent of the population, only a fraction of IA patients will develop subarachnoid hemorrhage (SAH) secondary to rupture. SAH carries the highest mortality of all types of stroke, with nearly 50 percent of individuals not surviving one month after the initial event. Despite clinical advances in the treatment of IA, the poor prognosis of SAH highlights the importance of early detection and treatment. While there are several known environmental risk factors associated with IA, a genetic contribution to the disease has long been suspected. We hypothesize that both rare and common variants in the human genome play a role in predisposing an individual to the formation and rupture of IA. To study the common variants, our group conducted a multistage genome-wide association study European and Japanese cohorts including over 5,800 IA cases and 14,000 matched controls. The discovery phase in the European cohorts and subsequent replication study in the Japanese cohort identified loci on chromosomes 8q, 9p, 10q, 13q, and 18q with significant association with IA. These regions carried odds ratios of 1.20-1.31 and collectively account for nearly 5% of the genetic risk of developing IA. The loci on 10q, 13q, and 18q represent novel findings, while the regions on 8q and 9p have been previously associated with IA in a previous GWAS. The locus on 8q displayed the strongest evidence of association. The nearby gene, SOX17, has a role in fetal and neonatal hematopoietic stem cells and expression in adult endothelial cells. Of the newly-identified loci, RBBP8 on 18q and STARD13 on 13q are also of particular interest because of roles in cell cycle regulation and endothelial cell attachment and migration, respectively.

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