Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ethnic, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells using gene mapping and heritability enrichment. Drug target enrichment shows pleiotropy between intracranial aneurysms and anti-epileptic and sex hormone drugs,

Background and Purpose-The morbidity and mortality of subarachnoid hemorrhage (SAH) are high, and established risk factors are scarce. We prospectively assessed the association of blood pressure, smoking, and body mass with the risk of aneurysmal SAH. Methods-All residents Ն20 years were invited to the Nord-Trøndelag Health (HUNT) Study (1984Study ( to 1986 and 74 977 (88.1%) attended. The study included standardized measurements of blood pressure, body weight and height, and self-administered questionnaires. Participants who later had aneurysmal SAH (nϭ132) were identified, and hazard ratios (HRs), adjusted for age and sex, were estimated using Cox regression analysis. Results-The crude annual incidence of aneurysmal SAH was 9.9 per 100 000 people; the incidence was almost twice as high in women as in men (12.9 versus 6.8, Pϭ0.001). Systolic blood pressure was positively associated with risk (P for trendϭ0.001). Compared with the reference (Ͻ130 mm Hg), the adjusted HR in people with systolic blood pressure of 130 to 139 mm Hg was 2.3 (95% CI, 1.4 to 3.8) and for systolic blood pressure Ͼ170 mm Hg, the HR was 3.3 (95% CI, 1.7 to 6.3). Diastolic pressure showed similar positive associations. Compared with never smokers, former (HR, 2.7; 95% CI, 1.4 to 5.1) and current (HR, 6.1; 95% CI, 3.6 to 10.4) smokers had substantially higher risk. Compared with normal weight (body mass index, 18.5 to 24.9 kg/m

The slight increase in incidence of aSAH over time may be explained by differences in diagnostic procedures. Case fatality remained stable during 23 years of follow-up.