Date of Award


Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Murat Gunel MD


Introduction: Intracranial aneurysms (IA) are a common neurological problem, the rupture of which frequently constitutes a catastrophic neurological event. While the pathogenesis is largely unknown, it is believed that both genetic and environmental factors work in concert to some degree within patients. Our goal was to take a comprehensive approach to understanding the pathogenesis of IA by identifying factors leading to the formation, growth and rupture of IA. Methods: Since 1994, we have recruited patients and families with IA into the Yale Brain Aneurysm Database. Information regarding aneurysm characteristics (size, location, number), patient characteristics (age, medical, and social history), and family history were recorded. We analyzed this database for environmental factors associated with aneurysmal rupture. Within the same database, we identified and analyzed kindreds with a high IA incidence and penetrance using genome-wide linkage analysis. Collaborations with other centers provided additional kindreds to analyze and confirm our results. Results: Analysis of our database revealed hypertensive patients with IA ≤ 7mm were 2.6 times more likely to rupture (p = .01, 95% CI: 1.21, 5.53) than normotensive patients. Posterior circulation aneurysms were 3.5 times more likely to rupture than anterior circulation aneurysms (p = .048, 95% CI: 0.95, 19.4). Further, genome-wide linkage analysis revealed significant linkage to a single locus, with a lod score of 4.2 at 1p34-36. Conclusions: We identified hypertension, young age, and posterior circulation as significant risk factors for rupture among patients with small aneurysms (≤ 7mm). Additionally, we are the first to map the gene responsible for IA to chromosome 1p34-26.