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; The ICAN Study Group; CADISP Group; Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study Investigators; International Stroke Genetics Consortium (ISGC)

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

HUNT All-In Stroke
, China Kadoorie Biobank Collaborative Group
, BioBank Japan Project Consortium
, The ICAN Study Group
, CADISP Group
, Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study Investigators
, International Stroke Genetics Consortium (ISGC)

Neurology

University at Buffalo

Utrecht University
University of Geneva
L'institut du Thorax
Nantes University Hospital
University College London
Technical University of Munich
RIKEN
The University of Tokyo
Kyushu University
University of Oxford
Peking University
McGill University
Jewish General Hospital
University of Edinburgh
UK Biobank
University College London Hospitals NHS Foundation Trust
Université Paris Cité
Centre Hospitalier Sainte-Anne
CHU de Brest
Sorbonne Université
CHU de Rennes
University of Oslo
Norwegian University of Science and Technology
University of Michigan, Ann Arbor
National Institute of Public Health and the Environment
Dortmund University of Applied Sciences and Arts
University of Duisburg-Essen
Zurich University of Applied Sciences
Swiss Institute of Bioinformatics
Chinese Academy of Medical Sciences
China National Center for Food Safety Risk Assessment

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

248 Scopus citations

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
State	Published - Dec 2020

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10.1038/s41588-020-00725-7

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HUNT All-In Stroke, China Kadoorie Biobank Collaborative Group, BioBank Japan Project Consortium, The ICAN Study Group, CADISP Group, Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study Investigators, & International Stroke Genetics Consortium (ISGC) (2020). Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors. Nature Genetics, 52(12), 1303-1313. https://doi.org/10.1038/s41588-020-00725-7

@article{7a9e2733e08b4a53bc0916ce8c8c710f,

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.",

author = "\{HUNT All-In Stroke\} and \{China Kadoorie Biobank Collaborative Group\} and \{BioBank Japan Project Consortium\} and \{The ICAN Study Group\} and \{CADISP Group\} and \{Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study Investigators\} and \{International Stroke Genetics Consortium (ISGC)\} and 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 Walters, \{Robin G.\} 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 Yiping Chen and Robert Clarke and Rory Collins and Yu Guo and Daniel Woo",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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",

}

HUNT All-In Stroke, China Kadoorie Biobank Collaborative Group, BioBank Japan Project Consortium, The ICAN Study Group, CADISP Group, Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study Investigators & International Stroke Genetics Consortium (ISGC) 2020, 'Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors', Nature Genetics, vol. 52, no. 12, pp. 1303-1313. https://doi.org/10.1038/s41588-020-00725-7

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 - Woo, Daniel

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 - https://www.scopus.com/pages/publications/85096147340

U2 - 10.1038/s41588-020-00725-7

DO - 10.1038/s41588-020-00725-7

M3 - Article

C2 - 33199917

SN - 1061-4036

VL - 52

SP - 1303

EP - 1313

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

HUNT All-In Stroke, China Kadoorie Biobank Collaborative Group, BioBank Japan Project Consortium, The ICAN Study Group, CADISP Group, Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study Investigators et al. Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors. Nature Genetics. 2020 Dec;52(12):1303-1313. 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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