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

Publication

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

Journal Paper/Review - Nov 16, 2020

Ruigrok Ynte M, Sargurupremraj Muralidharan, Dichgans Martin, Malik Rainer, Klijn Catharina J M, Zaroff Jonathan G, Breen Gerome, Coleman Jonathan R I, Kim Helen, Ko NeriU, Bown Matthew, Jones Gregory T, Martin Olivier, Dauvillier Jerome, Schilling Sabine, Hirsch Sven, Tatlisumak Turgut, Amouyel Philippe, Debette Stephanie, Veldink Jan H, Kamatani Yoichiro, Bijlenga Philippe, Redon Richard, Woo Daniel, Werring David J, Broderick Joseph P, Lindgren Antti, von Und Zu Fraunberg Mikael, Jaaskelainen Juha E, Niemelä Mika, Gaal-Paavola Emilia I, Slowik Agnieszka, Pera Joanna, Worrall Bradford B, Rinkel Gabriel J E, Friedrich Christoph M, Verschuren W M Monique, Zwart John-Anker, Chen Zhengming, Millwood Iona Y, Liang Liming, Lin Kuang, Walters Robin G, Matsuda Koichi, Terao Chikashi, Akiyama Masato, Koido Masaru, van Eijk Kristel R, Alg Varinder S, Hostettler Isabel, Bourcier Romain, Morel Sandrine, van Rheenen Wouter, van der Spek Rick A A, Rouleau Guy A, Zhou Sirui, Rannikmäe Kristiina, Hveem Kristian, Willer Cristen J, Sandvei Marie Søfteland, Brumpton Ben M, Johnsen Marianne Bakke, Børte Sigrid, Winsvold Bendik S, Desal Hubert, Eugène François, Shotar Eimad, Gentric Jean-Christophe, Naggara Olivier, Dina Christian, van den Berg Leonard H, Houlden Henry, Sudlow Cathie L M, Bakker Mark K

Citation

Ruigrok Y, Sargurupremraj M, Dichgans M, Malik R, Klijn C, Zaroff J, Breen G, Coleman J, Kim H, Ko N, Bown M, Jones G, Martin O, Dauvillier J, Schilling S, Hirsch S, Tatlisumak T, Amouyel P, Debette S, Veldink J, Kamatani Y, Bijlenga P, Redon R, Woo D, Werring D, Broderick J, Lindgren A, von Und Zu Fraunberg M, Jaaskelainen J, Niemelä M, Gaal-Paavola E, Slowik A, Pera J, Worrall B, Rinkel G, Friedrich C, Verschuren W, Zwart J, Chen Z, Millwood I, Liang L, Lin K, Walters R, Matsuda K, Terao C, Akiyama M, Koido M, van Eijk K, Alg V, Hostettler I, Bourcier R, Morel S, van Rheenen W, van der Spek R, Rouleau G, Zhou S, Rannikmäe K, Hveem K, Willer C, Sandvei M, Brumpton B, Johnsen M, Børte S, Winsvold B, Desal H, Eugène F, Shotar E, Gentric J, Naggara O, Dina C, van den Berg L, Houlden H, Sudlow C, Bakker M. Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors. Nat Genet 2020; 52:1303-1313.

Type

Journal Paper/Review (English)

Journal

Nat Genet 2020; 52

Publication Date

Nov 16, 2020

Issn Electronic

1546-1718

Pages

1303-1313

Brief description/objective

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.