Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors
Disease areas:
brain
heart and blood vessels
Last updated:
Author(s):
Mark K. Bakker, Rick A. A. van der Spek, Wouter van Rheenen, Sandrine Morel, Romain Bourcier, Isabel C. Hostettler, Varinder S. Alg, Kristel R. van Eijk, Masaru Koido, Masato Akiyama, Chikashi Terao, Koichi Matsuda, Robin G. Walters, Kuang Lin, Liming Li, Iona Y. Millwood, Zhengming Chen, Guy A. Rouleau, Sirui Zhou, Kristiina Rannikmäe, Cathie L. M. Sudlow, Henry Houlden, Leonard H. van den Berg, Christian Dina, Olivier Naggara, Jean-Christophe Gentric, Eimad Shotar, François Eugène, Hubert Desal, Bendik S. Winsvold, Sigrid Børte, Marianne Bakke Johnsen, Ben M. Brumpton, Marie Søfteland Sandvei, Cristen J. Willer, Kristian Hveem, John-Anker Zwart, W. M. Monique Verschuren, Christoph M. Friedrich, Sven Hirsch, Sabine Schilling, Jérôme Dauvillier, Olivier Martin, Gregory T. Jones, Matthew J. Bown, Nerissa U. Ko, Helen Kim, Jonathan R. I. Coleman, Gerome Breen, Jonathan G. Zaroff, Catharina J. M. Klijn, Rainer Malik, Martin Dichgans, Muralidharan Sargurupremraj, Turgut Tatlisumak, Philippe Amouyel, Stéphanie Debette, Gabriel J. E. Rinkel, Bradford B. Worrall, Joanna Pera, Agnieszka Slowik, Emília I. Gaál-Paavola, Mika Niemelä, Juha E. Jääskeläinen, Mikael von Und Zu Fraunberg, Antti Lindgren, Joseph P. Broderick, David J. Werring, Daniel Woo, Richard Redon, Philippe Bijlenga, Yoichiro Kamatani, Jan H. Veldink, Ynte M. Ruigrok
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.
Stroke is the second commonest case of death worldwide and a major global cause of severe disability. The three main pathological types (ischaemic stroke, intracerebral…
