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

An Author Correction to this article was published on 22 December 2020

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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.

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Fig. 1: GWAS meta-analysis association results.
Fig. 2: Heritability and functional enrichment analyses.
Fig. 3: Cross-trait analyses.

Data availability

Summary statistics for stages 1 and 2 GWAS meta-analyses, the SAH-only and uIA-only GWAS, and a meta-analysis consisting of just East Asian samples, including effective sample size per SNP, can be accessed through Figshare (https://doi.org/10.6084/m9.figshare.11303372) and through the Cerebrovascular Disease Knowledge Portal (http://www.cerebrovascularportal.org). Detailed information on access to publicly available data is given in the Nature Research Reporting Summary.

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  • 22 December 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

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). We are grateful to the GenoBiRD core facility (Biogenouest), the Clinical Investigation Center (INSERM CIC1413) and the Center of Biological Resources in Nantes (BB-0033-00040; CHU Nantes, France) for their assistance in managing and genotyping the ICAN and PREGO biobanks. R.R. was supported by the French Regional Council of Pays-de-la-Loire (VaCaRMe program) and the Agence Nationale de la Recherche (ANR-15-CE17-0008-01 to G.L). H.D. and R.B. were supported by the French Ministry of Health (Clinical trial NCT02848495 to H.D.), the Genavie Foundation, the Société Française de Radiologie and the Société Française de Neuroradiologie.

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J.H.V. and Y.M.R. contributed equally to this study. M.K.B., Y.M.R. and J.H.V. wrote the manuscript. Y.M.R. and J.H.V. supervised the project. I.C.H., S.D., B.B.W., J.P., A.S., E.I.G.-P., M.N., J.E.J., M.v.U.Z.F., A.L., J.P.B., D.J.W., D.W., R.R., P.B., Y.K., J.H.V. and Y.M.R. designed the study. M.K.B., R.A.A.v.d.S. and W.v.R. performed the association analyses and scripts. M.K.B., R.A.A.v.d.S. and W.v.R. performed the functional analyses and scripts. S.M., R.B., C.M.F., S.H., S.S., J.D., O.M. and P.B. prepared the phenotypes. R.A.A.v.d.S. and K.R.v.E. provided technical assistance. M.K.B., Y.M.R., G.J.E.R., J.H.V., L.H.v.d.B., P.B., S.M., E.I.G.-P., M.N., J.P., A.S., J.E.E., M.v.U.Z.F., A.L., G.A.R., S.Z., N.U.K., R.M., K.R., C.L.M.S., D.J.W., I.C.H., H.H., V.S.A., J.P.B., D.W., R.R., R.B., C.D., O.N., J.-C.G., E.S., F.E., H.D. and W.M.M.V. contributed the phenotypes and genotypes. Y.K., M.K., M.A., C.T., K.M. (BBJ), R.G.W., K.L., L.L., I.Y.M., Z.C. (CKB), B.S.W., S.B., M.B.J., B.M.B., M.S.S., C.J.W., K.H., J.-A.Z. (HUNT), M.J.B., G.T.J. (AAA), H.K., J.G.Z., C.J.M.K., N.U.K. (AVM), D.W. (ICH), R.M., M.D. (IS), S.D., T.T., M.S. and P.A. (cervical artery dissection) summarized the statistical contributions. J.R.I.C. and G.B. performed drug-target and MAGMA pathway enrichment analyses. D.J.W. critiqued the output for important intellectual content.

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Correspondence to Mark K. Bakker or Ynte M. Ruigrok.

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When this study was conducted, C.L.M.S. was chief scientist for the UK Biobank study.

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Bakker, M.K., van der Spek, R.A.A., van Rheenen, W. et al. Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors. Nat Genet 52, 1303–1313 (2020). https://doi.org/10.1038/s41588-020-00725-7

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