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

doi:10.1038/s41588-020-00725-7

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

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Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1303-1313
Number of pages	11
Journal	Nature Genetics
Volume	52
Issue number	12
DOIs	https://doi.org/10.1038/s41588-020-00725-7
Publication status	Published - Dec 2020

Keywords

Asian Continental Ancestry Group/genetics
Blood Pressure/genetics
Case-Control Studies
Endothelial Cells/pathology
European Continental Ancestry Group/genetics
Genetic Predisposition to Disease/genetics
Genome-Wide Association Study
Humans
Hypertension/genetics
Intracranial Aneurysm/genetics
Polymorphism, Single Nucleotide/genetics
Risk Factors
Smoking/adverse effects
Subarachnoid Hemorrhage/genetics

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10.1038/s41588-020-00725-7

Cite this

@article{687262fc30ed4b8cbdba218605ffb8cd,

title = "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.",

keywords = "Asian Continental Ancestry Group/genetics, Blood Pressure/genetics, Case-Control Studies, Endothelial Cells/pathology, European Continental Ancestry Group/genetics, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study, Humans, Hypertension/genetics, Intracranial Aneurysm/genetics, Polymorphism, Single Nucleotide/genetics, Risk Factors, Smoking/adverse effects, Subarachnoid Hemorrhage/genetics",

author = "Bakker, {Mark K.} and {van der Spek}, {Rick A.A.} and {van Rheenen}, Wouter and Sandrine Morel and Romain Bourcier and Hostettler, {Isabel C.} and Alg, {Varinder S.} and {van Eijk}, {Kristel R.} and Masaru Koido and Masato Akiyama and Chikashi Terao and Koichi Matsuda and Robin Walters and Kuang Lin and Liming Li and Millwood, {Iona Y.} and Zhengming Chen and Rouleau, {Guy A.} and Sirui Zhou and Kristiina Rannikm{\"a}e and Sudlow, {Cathie L.M.} and Henry Houlden and {van den Berg}, {Leonard H.} and Christian Dina and Olivier Naggara and Gentric, {Jean Christophe} and Eimad Shotar and Fran{\c c}ois Eug{\`e}ne and Hubert Desal and Winsvold, {Bendik S.} and Sigrid B{\o}rte and Johnsen, {Marianne Bakke} and Brumpton, {Ben M.} and Sandvei, {Marie S{\o}fteland} and Willer, {Cristen J.} and Kristian Hveem and Zwart, {John Anker} and Verschuren, {W. M.Monique} and Friedrich, {Christoph M.} and Sven Hirsch and Sabine Schilling and J{\'e}r{\^o}me Dauvillier and Olivier Martin and Zheng Bian and Junshi Chen and Klijn, {Catharina J.M.} and Rinkel, {Gabriel J.E.} and Antti Lindgren and Veldink, {Jan H.} and Ruigrok, {Ynte M.}",

note = "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{\textquoteright}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. D{\'o}czi, J. Byrne, P. Summers, R. Risselada, M. Sturkenboom, U. Patel, S. Coley, A. Waterworth, D. R{\"u}fenacht, 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{\textquoteright}s Horizon 2020 research and innovation program (grant no. 852173). This project has received funding from the ERC under the European Union{\textquoteright}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 R{\'e}gion Nord-Pas-de-Calais in the framework of Contrat de Projets Etat-Region 2007–2013 R{\'e}gion Nord-Pas-de-Calais (grant no. 09120030), Centre National de G{\'e}notypage, the Emil Aaltonen Foundation, the Paavo Ilmari Ahvenainen Foundation, the Helsinki University Central Hospital Research Fund, the Helsinki University Medical Foundation, the P{\"a}ivikki 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 R{\'e}gional, Fondation de France, G{\'e}nop{\^o}le de Lille, Adrinord, the Basel Stroke Funds, and the K{\"a}the-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{\textquoteright}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{\textquoteright}s Horizon 2020 research and innovation program (no. 666881), SVDs@target (to M.D.) and CoSTREAM (Common Mechanisms and Pathways in Stroke and Alzheimer{\textquoteright}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-Tr{\o}ndelag 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-Tr{\o}ndelag 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: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2020",

month = dec,

doi = "10.1038/s41588-020-00725-7",

language = "English",

volume = "52",

pages = "1303--1313",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "12",

}

TY - JOUR

T1 - Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors

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

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 - Klijn, Catharina J.M.

AU - Rinkel, Gabriel J.E.

AU - Lindgren, Antti

AU - Veldink, Jan H.

AU - Ruigrok, Ynte M.

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. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

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.

KW - Asian Continental Ancestry Group/genetics

KW - Blood Pressure/genetics

KW - Case-Control Studies

KW - Endothelial Cells/pathology

KW - European Continental Ancestry Group/genetics

KW - Genetic Predisposition to Disease/genetics

KW - Genome-Wide Association Study

KW - Humans

KW - Hypertension/genetics

KW - Intracranial Aneurysm/genetics

KW - Polymorphism, Single Nucleotide/genetics

KW - Risk Factors

KW - Smoking/adverse effects

KW - Subarachnoid Hemorrhage/genetics

UR - http://www.scopus.com/inward/record.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

SN - 1061-4036

VL - 52

SP - 1303

EP - 1313

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

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

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Keywords

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