Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

doi:10.1038/s41588-018-0058-3

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

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College of Public Health

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

1363 Scopus citations

Abstract

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

Original language	English
Pages (from-to)	524-537
Number of pages	14
Journal	Nature Genetics
Volume	50
Issue number	4
DOIs	https://doi.org/10.1038/s41588-018-0058-3
State	Published - Apr 1 2018

Bibliographical note

Publisher Copyright:
© 2018 The Author(s).

Funding

S.\u00A0Gretarsdottir, G.T., U.T., and K.S. are all employees of deCODE Genetics/ Amgen,\u00A0Inc. M.A.N. is an employee of Data Tecnica International. P.T.E. is the PI on a grant from Bayer HealthCare to the Broad Institute, focused on the genetics and therapeutics of atrial fibrillation. S.A.L. receives sponsored research support from Bayer HealthCare, Biotronik, and Boehringer Ingelheim, and has consulted for St. Jude Medical and Quest Diagnostics. E.I. is a scientific advisor for Precision Wellness, Cellink and Olink Proteomics for work unrelated to the present project. B.M.P. serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. The remaining authors have no disclosures.

Funders	Funder number
Johnson and Johnson Pharmaceutical Research and Development
St. Jude Medical Center
Boehringer-Ingelheim
Bayer HealthCare Pharmaceuticals Inc.
Biotronik Incorporated
Yale University
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	R01NS017950, R01NS087541
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council
Japan Society for the Promotion of Science	17H04143, 15K08539, 18K11545, 16K00385, 15K09464, 16H06277
Japan Society for the Promotion of Science
Medical Research Council	MR/L003120/1, MC_PC_13048, MR/P013880/1, MR/P02811X/1
Medical Research Council
Horizon 2020 Framework Programme	667375, 666881, 640643, 643417
Horizon 2020 Framework Programme
National Institute on Aging	ZIAAG007420, ZIAAG007270, P30AG010129, R01AG054076
National Institute on Aging
National Institute of Diabetes and Digestive and Kidney Diseases	P30DK063491
National Institute of Diabetes and Digestive and Kidney Diseases
National Heart, Lung, and Blood Institute (NHLBI)	R01HL138423, K24HL105780, R01HL092577, K23HL114724, ZIAHL006170, U01HL130114, R01HL088521
National Heart, Lung, and Blood Institute (NHLBI)
NIH Office of the Director	S10OD020069
NIH Office of the Director
National Institute of General Medical Sciences	U54GM115428
National Institute of General Medical Sciences
National Center for Advancing Translational Sciences (NCATS)	UL1TR001881
National Center for Advancing Translational Sciences (NCATS)

ASJC Scopus subject areas

Genetics

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10.1038/s41588-018-0058-3

Cite this

@article{3fb600b7bda1468db732321b2a1a72f3,

title = "Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes",

abstract = "Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.",

author = "Rainer Malik and Ganesh Chauhan and Matthew Traylor and Muralidharan Sargurupremraj and Yukinori Okada and Aniket Mishra and Loes Rutten-Jacobs and Giese, \{Anne Katrin\} and \{Van Der Laan\}, \{Sander W.\} and Solveig Gretarsdottir and Anderson, \{Christopher D.\} and Michael Chong and Adams, \{Hieab H.H.\} and Tetsuro Ago and Peter Almgren and Philippe Amouyel and Hakan Ay and Bartz, \{Traci M.\} and Benavente, \{Oscar R.\} and Steve Bevan and Boncoraglio, \{Giorgio B.\} and Brown, \{Robert D.\} and Butterworth, \{Adam S.\} and Caty Carrera and Carty, \{Cara L.\} and Chasman, \{Daniel I.\} and Chen, \{Wei Min\} and Cole, \{John W.\} and Adolfo Correa and Ioana Cotlarciuc and Carlos Cruchaga and John Danesh and \{De Bakker\}, \{Paul I.W.\} and Destefano, \{Anita L.\} and \{Den Hoed\}, Marcel and Qing Duan and Engelter, \{Stefan T.\} and Falcone, \{Guido J.\} and Gottesman, \{Rebecca F.\} and Grewal, \{Raji P.\} and Vilmundur Gudnason and Stefan Gustafsson and Jeffrey Haessler and Harris, \{Tamara B.\} and Ahamad Hassan and Havulinna, \{Aki S.\} and Heckbert, \{Susan R.\} and Holliday, \{Elizabeth G.\} and George Howard and Arnett, \{Donna K.\}",

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = apr,

day = "1",

doi = "10.1038/s41588-018-0058-3",

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T1 - Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

AU - Malik, Rainer

AU - Chauhan, Ganesh

AU - Traylor, Matthew

AU - Sargurupremraj, Muralidharan

AU - Okada, Yukinori

AU - Mishra, Aniket

AU - Rutten-Jacobs, Loes

AU - Giese, Anne Katrin

AU - Van Der Laan, Sander W.

AU - Gretarsdottir, Solveig

AU - Anderson, Christopher D.

AU - Chong, Michael

AU - Adams, Hieab H.H.

AU - Ago, Tetsuro

AU - Almgren, Peter

AU - Amouyel, Philippe

AU - Ay, Hakan

AU - Bartz, Traci M.

AU - Benavente, Oscar R.

AU - Bevan, Steve

AU - Boncoraglio, Giorgio B.

AU - Brown, Robert D.

AU - Butterworth, Adam S.

AU - Carrera, Caty

AU - Carty, Cara L.

AU - Chasman, Daniel I.

AU - Chen, Wei Min

AU - Cole, John W.

AU - Correa, Adolfo

AU - Cotlarciuc, Ioana

AU - Cruchaga, Carlos

AU - Danesh, John

AU - De Bakker, Paul I.W.

AU - Destefano, Anita L.

AU - Den Hoed, Marcel

AU - Duan, Qing

AU - Engelter, Stefan T.

AU - Falcone, Guido J.

AU - Gottesman, Rebecca F.

AU - Grewal, Raji P.

AU - Gudnason, Vilmundur

AU - Gustafsson, Stefan

AU - Haessler, Jeffrey

AU - Harris, Tamara B.

AU - Hassan, Ahamad

AU - Havulinna, Aki S.

AU - Heckbert, Susan R.

AU - Holliday, Elizabeth G.

AU - Howard, George

AU - Arnett, Donna K.

PY - 2018/4/1

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N2 - Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

AB - Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

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U2 - 10.1038/s41588-018-0058-3

DO - 10.1038/s41588-018-0058-3

M3 - Article

C2 - 29531354

AN - SCOPUS:85043463446

SN - 1061-4036

VL - 50

SP - 524

EP - 537

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

Access to Document

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