424 - Genetics of Intracranial Aneurysms

Abstract

Intracranial aneurysms (IAs) are focal, pathologic dilations in major brain arteries that affect 3% to 5% of the world population. IA rupture generally occurs without any warning signs. Though it is rare, IAs underlie 80% of all cases of subarachnoid hemorrhage (SAH), which in turn accounts for 5% to 10% of all strokes in the United States. Approximately one in four individuals who experience SAH die suddenly, often before hospital admission. The 1-month mortality rate among admitted patients is 22% to 42%, whereas only 63% of survivors return to work. Compared with other stroke types, aneurysmal SAH (from IA rupture) tends to affect younger individuals, thereby leading to a greater loss of productive life. Thus elucidating IA pathophysiology and the complex genetic architecture is critical to reduce mortality and morbidity associated with IA rupture. A genetic risk for IA formation and rupture has been suspected since the 1960s with a report of four families having at least two members with IAs. Genome-wide association studies have identified genomic regions and pathways that are associated with IA formation. Recent advances in sequencing technology have helped elucidate familial IA susceptibility genes and somatic alterations in IA tissue. Identification of genetic risk factors for IA formation has the potential to provide unique insights into IA pathophysiology and novel diagnostic and therapeutic entry points.