Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors.
Bakker MK., van der Spek RAA., van Rheenen W., Morel S., Bourcier R., Hostettler IC., Alg VS., van Eijk KR., Koido M., Akiyama M., Terao C., Matsuda K., Walters RG., Lin K., Li L., Millwood IY., Chen Z., Rouleau GA., Zhou S., Rannikmäe K., Sudlow CLM., Houlden H., van den Berg LH., Dina C., Naggara O., Gentric J-C., Shotar E., Eugène F., Desal H., Winsvold BS., Børte S., Johnsen MB., Brumpton BM., Sandvei MS., Willer CJ., Hveem K., Zwart J-A., Verschuren WMM., Friedrich CM., Hirsch S., Schilling S., Dauvillier J., Martin O., HUNT All-In Stroke None., China Kadoorie Biobank Collaborative Group None., BioBank Japan Project Consortium None., ICAN Study Group None., CADISP Group None., Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study investigators None., International Stroke Genetics Consortium (ISGC) None., Jones GT., Bown MJ., Ko NU., Kim H., Coleman JRI., Breen G., Zaroff JG., Klijn CJM., Malik R., Dichgans M., Sargurupremraj M., Tatlisumak T., Amouyel P., Debette S., Rinkel GJE., Worrall BB., Pera J., Slowik A., Gaál-Paavola EI., Niemelä M., Jääskeläinen JE., von Und Zu Fraunberg M., Lindgren A., Broderick JP., Werring DJ., Woo D., Redon R., Bijlenga P., Kamatani Y., Veldink JH., Ruigrok YM.
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-ancestry, 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 by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.