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

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

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

Rainer Malik, Ganesh Chauhan, Matthew Traylor, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten-Jacobs, Anne-Katrin Giese, Sander W van der Laan, Solveig Gretarsdottir, Christopher D Anderson, Michael Chong, Hieab H H Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, Traci M Bartz, Oscar R Benavente, Steve BevanGiorgio B Boncoraglio, Robert D Brown, Adam S Butterworth, Caty Carrera, Cara L Carty, Daniel I Chasman, Wei-Min Chen, John W Cole, Adolfo Correa, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, Paul I W de Bakker, Anita L DeStefano, Marcel den Hoed, Qing Duan, Stefan T Engelter, Guido J Falcone, Rebecca F Gottesman, Raji P Grewal, Vilmundur Gudnason, Stefan Gustafsson, Jeffrey Haessler, Tamara B Harris, Ahamad Hassan, Aki S Havulinna, Susan R Heckbert, Elizabeth G Holliday, Sara L Pulit, Paul I W de Bakker,

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

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
Early online date	2018
DOIs	https://doi.org/10.1038/s41588-018-0058-3
Publication status	Published - Apr 2018

Keywords

Journal Article
Genetic Predisposition to Disease
Genome-Wide Association Study
Epigenesis, Genetic
Humans
Risk Factors
Computational Biology
Databases, Genetic
Male
Genetic Loci
Gene Regulatory Networks
INDEL Mutation
Linkage Disequilibrium
Stroke/classification
Female
Models, Genetic
Polymorphism, Single Nucleotide

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10.1038/s41588-018-0058-3

s41588-018-0058-3Final published version, 2.07 MBLicence: Taverne

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Malik, R., Chauhan, G., Traylor, M., Sargurupremraj, M., Okada, Y., Mishra, A., Rutten-Jacobs, L., Giese, A.-K., van der Laan, S. W., Gretarsdottir, S., Anderson, C. D., Chong, M., Adams, H. H. H., Ago, T., Almgren, P., Amouyel, P., Ay, H., Bartz, T. M., Benavente, O. R. (2018). Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nature Genetics, 50(4), 524-537. https://doi.org/10.1038/s41588-018-0058-3

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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.",

keywords = "Journal Article, Genetic Predisposition to Disease, Genome-Wide Association Study, Epigenesis, Genetic, Humans, Risk Factors, Computational Biology, Databases, Genetic, Male, Genetic Loci, Gene Regulatory Networks, INDEL Mutation, Linkage Disequilibrium, Stroke/classification, Female, Models, Genetic, Polymorphism, Single Nucleotide",

author = "Rainer Malik and Ganesh Chauhan and Matthew Traylor and Muralidharan Sargurupremraj and Yukinori Okada and Aniket Mishra and Loes Rutten-Jacobs and Anne-Katrin Giese 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 Wei-Min Chen 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 Hoed, {Marcel den} 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 Pulit, {Sara L} and {de Bakker}, {Paul I W}",

year = "2018",

month = apr,

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

language = "English",

volume = "50",

pages = "524--537",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "4",

}

Malik, R, Chauhan, G, Traylor, M, Sargurupremraj, M, Okada, Y, Mishra, A, Rutten-Jacobs, L, Giese, A-K, van der Laan, SW, Gretarsdottir, S, Anderson, CD, Chong, M, Adams, HHH, Ago, T, Almgren, P, Amouyel, P, Ay, H, Bartz, TM, Benavente, OR, Bevan, S, Boncoraglio, GB, Brown, RD, Butterworth, AS, Carrera, C, Carty, CL, Chasman, DI, Chen, W-M, Cole, JW, Correa, A, Cotlarciuc, I, Cruchaga, C, Danesh, J, de Bakker, PIW, DeStefano, AL, Hoed, MD, Duan, Q, Engelter, ST, Falcone, GJ, Gottesman, RF, Grewal, RP, Gudnason, V, Gustafsson, S, Haessler, J, Harris, TB, Hassan, A, Havulinna, AS, Heckbert, SR, Holliday, EG, Pulit, SL, de Bakker, PIW 2018, 'Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes', Nature Genetics, vol. 50, no. 4, pp. 524-537. https://doi.org/10.1038/s41588-018-0058-3

TY - JOUR

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 - Hoed, Marcel den

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 - Pulit, Sara L

AU - de Bakker, Paul I W

PY - 2018/4

Y1 - 2018/4

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.

KW - Journal Article

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Epigenesis, Genetic

KW - Humans

KW - Risk Factors

KW - Computational Biology

KW - Databases, Genetic

KW - Male

KW - Genetic Loci

KW - Gene Regulatory Networks

KW - INDEL Mutation

KW - Linkage Disequilibrium

KW - Stroke/classification

KW - Female

KW - Models, Genetic

KW - Polymorphism, Single Nucleotide

UR - http://www.scopus.com/inward/record.url?scp=85043463446&partnerID=8YFLogxK

U2 - 10.1038/s41588-018-0058-3

DO - 10.1038/s41588-018-0058-3

M3 - Article

C2 - 29531354

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

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Keywords

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Publisher Correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes (Nature Genetics, (2018), 50, 4, (524-537), 10.1038/s41588-018-0058-3)

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