Genetics of intracranial aneurysms

Despite advances in the treatment of intracranial aneurysms (IA) in recent years, the overall outcome of patients with aneurysmal subarachnoid hemorrhage has shown only modest improvement. Given this poor prognosis, diagnosis of IA before rupture is of paramount importance. Currently, there are no reliable methods other than screening imaging studies of high-risk individuals to diagnose asymptomatic patients. Multiple levels of evidence suggest that environmental factors acting in concert with genetic susceptibilities lead to the formation, growth, and rupture of aneurysms in these patients. Epidemiological studies have already identified aneurysm-specific risk factors such as size and location, as well as patient-specific risk factors, such as age, sex, and presence of medical comorbidities, such as hypertension. In addition, exposure to certain environmental factors such as smoking have been shown to be important in the formation of IA. Furthermore, substantial evidence proves that certain loci contribute genetically to IA pathogenesis. Genome-wide linkage studies using relative pairs or rare families that are affected with the Mendelian forms of IA have already shown genetic heterogeneity of IA, suggesting that multiple genes, alone or in combination, are important in the disease pathophysiology. The linkage results, along with association studies, will ultimately lead to the identification of IA susceptibility genes. Identification of the genes important in IA pathogenesis will not only provide novel insights into the primary determinants of IA, but will also result in new opportunities for early diagnosis in the preclinical setting. Ultimately, novel therapeutic strategies based on biology will be developed, which will target these newly elucidated genetic susceptibilities.