TY - JOUR
T1 - Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors
AU - HUNT All-In Stroke
AU - China Kadoorie Biobank Collaborative Group
AU - BioBank Japan Project Consortium
AU - The ICAN Study Group
AU - CADISP Group
AU - Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study investigators
AU - International Stroke Genetics Consortium (ISGC)
AU - Bakker, Mark K.
AU - van der Spek, Rick A.A.
AU - van Rheenen, Wouter
AU - Morel, Sandrine
AU - Bourcier, Romain
AU - Hostettler, Isabel C.
AU - Alg, Varinder S.
AU - van Eijk, Kristel R.
AU - Koido, Masaru
AU - Akiyama, Masato
AU - Terao, Chikashi
AU - Matsuda, Koichi
AU - Walters, Robin G.
AU - Lin, Kuang
AU - Li, Liming
AU - Millwood, Iona Y.
AU - Chen, Zhengming
AU - Rouleau, Guy A.
AU - Zhou, Sirui
AU - Rannikmäe, Kristiina
AU - Sudlow, Cathie L.M.
AU - Houlden, Henry
AU - van den Berg, Leonard H.
AU - Dina, Christian
AU - Naggara, Olivier
AU - Gentric, Jean Christophe
AU - Shotar, Eimad
AU - Eugène, François
AU - Desal, Hubert
AU - Winsvold, Bendik S.
AU - Børte, Sigrid
AU - Johnsen, Marianne Bakke
AU - Brumpton, Ben M.
AU - Sandvei, Marie Søfteland
AU - Willer, Cristen J.
AU - Hveem, Kristian
AU - Zwart, John Anker
AU - Verschuren, W. M.Monique
AU - Friedrich, Christoph M.
AU - Hirsch, Sven
AU - Schilling, Sabine
AU - Dauvillier, Jérôme
AU - Martin, Olivier
AU - Bian, Zheng
AU - Chen, Junshi
AU - Chen, Yiping
AU - Clarke, Robert
AU - Collins, Rory
AU - Guo, Yu
AU - Sargurupremraj, Muralidharan
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41588-020-00725-7
DO - 10.1038/s41588-020-00725-7
M3 - Article
C2 - 33199917
AN - SCOPUS:85096147340
SN - 1061-4036
VL - 52
SP - 1303
EP - 1313
JO - Nature Genetics
JF - Nature Genetics
IS - 12
ER -