抄録
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.
| 本文言語 | 英語 |
|---|---|
| ページ（範囲） | 1303-1313 |
| ページ数 | 11 |
| ジャーナル | Nature genetics |
| 巻 | 52 |
| 号 | 12 |
| DOI | |
| 出版ステータス | 出版済み - 12月 2020 |
| 外部発表 | はい |
!!!All Science Journal Classification (ASJC) codes
- 遺伝学
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Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors. / HUNT All-In Stroke; China Kadoorie Biobank Collaborative Group; BioBank Japan Project Consortium その他.
In: Nature genetics, Vol. 52, No. 12, 12.2020, p. 1303-1313.研究成果: ジャーナルへの寄稿 › 学術誌 › 査読
}
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 - Han, Xiao
N1 - Funding Information: This research has been conducted using the UK Biobank Resource under application no. 2532. We thank R. McLaughlin for the advice on population-based heritability analysis. We thank M. Gunel and K. Yasuno for their help with genotyping DNA samples of the Utrecht 1, Finland and @neurIST cohorts. We thank the staff and participants of all CADISP centers for their important contributions. We acknowledge the contribution of participants, project staff, and the China National Center for Disease Control and Prevention (CDC) and its regional offices to the CKB. China’s National Health Insurance provided electronic linkage to all hospital treatments. We thank K. Jebsen for genotyping quality control and imputation of the HUNT Study. For providing clinical information and biological samples collected during the @neurIST project, we thank J. Macho, T. Dóczi, J. Byrne, P. Summers, R. Risselada, M. Sturkenboom, U. Patel, S. Coley, A. Waterworth, D. Rüfenacht, C. Proust and F. Cambien. We acknowledge the support from the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation, CVON2015-08 ERASE. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant no. 852173). This project has received funding from the ERC under the European Union’s Horizon 2020 research and innovation program (grant no. 772376—EScORIAL). The BBJ project was supported by the Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government, and the Japan Agency for Medical Research and Development (19km0605001). The CADISP study has been supported by INSERM, Lille 2 University, Institut Pasteur de Lille and Lille University Hospital, and received funding from the European Regional Development Fund (FEDER funds) and Région Nord-Pas-de-Calais in the framework of Contrat de Projets Etat-Region 2007–2013 Région Nord-Pas-de-Calais (grant no. 09120030), Centre National de Génotypage, the Emil Aaltonen Foundation, the Paavo Ilmari Ahvenainen Foundation, the Helsinki University Central Hospital Research Fund, the Helsinki University Medical Foundation, the Päivikki and Sakari Sohlberg Foundation, the Aarne Koskelo Foundation, the Maire Taponen Foundation, the Aarne and Aili Turunen Foundation, the Lilly Foundation, the Alfred Kordelin Foundation, the Finnish Medical Foundation, the Orion Farmos Research Foundation, the Maud Kuistila Foundation, the Finnish Brain Foundation, the Biomedicum Helsinki Foundation, Projet Hospitalier de Recherche Clinique Régional, Fondation de France, Génopôle de Lille, Adrinord, the Basel Stroke Funds, and the Käthe-Zingg-Schwichtenberg-Fonds of the Swiss Academy of Medical Sciences and the Swiss Heart Foundation. S.D. received funding from the French National Funding Agency (ANR), and the ERC under the European Union’s Horizon 2020 research and innovation program (grant no. 640643). J.P. was supported by a Jagiellonian University Medical College (grant no. K/ZDS/001456). CKB was supported as follows: baseline survey and first re-survey: Hong Kong Kadoorie Charitable Foundation; long-term follow-up: UK Wellcome Trust (grant nos. 202922/Z/16/Z, 104085/Z/14/Z, 088158/Z/09/Z), National Natural Science Foundation of China (grant nos. 81390540, 81390541, 81390544) and National Key Research and Development Program of China (grant nos. 2016YFC 0900500, 0900501, 0900504, 1303904). DNA extraction and genotyping: GlaxoSmithKline, UK Medical Research Council (grant nos. MC_PC_13049, MC-PC-14135). Core funding to the Clinical Trial Service Unit and Epidemiological Studies Unit at Oxford University was provided by the British Heart Foundation, UK Medical Research Council and Cancer Research UK. S.Z. and G.A.R. received funding from the Canadian Institutes of Health Research (CIHR). This project has received funding from the European Union’s Horizon 2020 research and innovation program (no. 666881), SVDs@target (to M.D.) and CoSTREAM (Common Mechanisms and Pathways in Stroke and Alzheimer’s Disease; grant no. 667375, to M.D.); the DFG (Deutsche Forschungsgemeinschaft) as part of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and the CRC 1123 (B3, to M.D.); the Corona Foundation (to M.D.); the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain, to M.D.); the e:Med program (e:AtheroSysMed, to M.D.); and the FP7/2007-2103 European Union project CVgenes@ target (grant no. Health-F2-2013-601456, to M.D.). K.R. is funded by the Health Data Research UK (HDRUK) fellowship MR/S004130/1. C.L.M.S. was funded by the UK Biobank, HDRUK and Scottish Funding Council. I.C.H. received funding from the Alzheimer Research UK and Dunhill Medical Trust Foundation. J.P.B. and D.W. were supported by National Institutes of Health (NIH) funding. D.J.W. and V.S.A. received funding support from the Stroke Association. D.J.W. and H.H. received funding for genotyping from the NIHR University College London Hospitals Biomedical Research Center. The Nord-Trøndelag Health Study (HUNT Study) is a collaboration by the HUNT Research Center, Faculty of Medicine at the Norwegian University of Science and Technology (NTNU), the Norwegian Institute of Public Health and the Nord-Trøndelag County Council. The genotyping was financed by the NIH, University of Michigan, the Norwegian Research Council and Central Norway Regional Health Authority and the Faculty of Medicine and Health Sciences, NTNU. P.B. and C.M.F. were supported by EU commission FP6—IST – 027703 @neurIST-Integrated biomedical informatics for the management of cerebral aneurysms. P.B., S.M., S.H., S.S., J.D. and O.M. were supported by the grant (no. MRD 2014/261) from the Swiss SystemsX.ch initiative and evaluated by the Swiss National Science Foundation (AneuX project). 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.
UR - http://www.scopus.com/inward/record.url?scp=85096147340&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85096147340&partnerID=8YFLogxK
U2 - 10.1038/s41588-020-00725-7
DO - 10.1038/s41588-020-00725-7
M3 - Article
C2 - 33199917
AN - SCOPUS:85096147340
VL - 52
SP - 1303
EP - 1313
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 12
ER -