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

ABSTRACT: 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.

SUBMITTER: Bakker MK 

PROVIDER: S-EPMC7116530 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Bakker Mark K MK   van der Spek Rick A A RAA   van Rheenen Wouter W   Morel Sandrine S   Bourcier Romain R   Hostettler Isabel C IC   Alg Varinder S VS   van Eijk Kristel R KR   Koido Masaru M   Akiyama Masato M   Terao Chikashi C   Matsuda Koichi K   Walters Robin G RG   Lin Kuang K   Li Liming L   Millwood Iona Y IY   Chen Zhengming Z   Rouleau Guy A GA   Zhou Sirui S   Rannikmäe Kristiina K   Sudlow Cathie L M CLM   Houlden Henry H   van den Berg Leonard H LH   Dina Christian C   Naggara Olivier O   Gentric Jean-Christophe JC   Shotar Eimad E   Eugène François F   Desal Hubert H   Winsvold Bendik S BS   Børte Sigrid S   Johnsen Marianne Bakke MB   Brumpton Ben M BM   Sandvei Marie Søfteland MS   Willer Cristen J CJ   Hveem Kristian K   Zwart John-Anker JA   Verschuren W M Monique WMM   Friedrich Christoph M CM   Hirsch Sven S   Schilling Sabine S   Dauvillier Jérôme J   Martin Olivier O   Jones Gregory T GT   Bown Matthew J MJ   Ko Nerissa U NU   Kim Helen H   Coleman Jonathan R I JRI   Breen Gerome G   Zaroff Jonathan G JG   Klijn Catharina J M CJM   Malik Rainer R   Dichgans Martin M   Sargurupremraj Muralidharan M   Tatlisumak Turgut T   Amouyel Philippe P   Debette Stéphanie S   Rinkel Gabriel J E GJE   Worrall Bradford B BB   Pera Joanna J   Slowik Agnieszka A   Gaál-Paavola Emília I EI   Niemelä Mika M   Jääskeläinen Juha E JE   von Und Zu Fraunberg Mikael M   Lindgren Antti A   Broderick Joseph P JP   Werring David J DJ   Woo Daniel D   Redon Richard R   Bijlenga Philippe P   Kamatani Yoichiro Y   Veldink Jan H JH   Ruigrok Ynte M YM  

Nature genetics 20201116 12

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 a  ...[more]

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