Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of 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, effect of anti-epileptics on vascular tension and blood pressure will enhance our understanding of the disease-causing mechanisms. Furthermore, this could help to identify methods of intracranial aneurysm prevention using anti-epileptics or related drugs. In conclusion, we performed a GWAS meta-analysis of intracranial aneurysms, identifying 11 new risk loci, confirming 6 previously identified risk loci, and explaining over half of the heritability of intracranial aneurysms. We found strong evidence for a polygenic architecture. Through gene-mapping and heritability enrichment methods, we discovered a possible role for endothelial cells in intracranial aneurysm development. We showed that the genetic architecture of unruptured and ruptured aneurysms are very similar. The well-known clinical risk factors, smoking and hypertension, were identified as main genetic drivers of intracranial aneurysms. These risk factors also explained most of the similarity to other stroke types, IS and deep ICH, which could open a window for clinical prevention. We also found pleiotropic effects between intracranial aneurysms and anti-epileptic drugs, which require further investigation to understand the shared mechanisms of intracranial aneurysms and epilepsy. Our findings represent a major advance in understanding the pathogenesis of intracranial aneurysms and an important step towards the development of effective genetic risk prediction and prevention of intracranial aneurysm development and subsequent aSAH in the future.