Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies: A meta-analysis of genome-wide association studies

Matthew Traylor; Martin Farrall; Elizabeth G Holliday; Cathie Sudlow; Jemma C Hopewell; Yu-Ching Cheng; Myriam Fornage; M Arfan Ikram; Rainer Malik; Steve Bevan; Unnur Thorsteinsdottir; Mike A Nalls; W. T. Longstreth; Kerri L Wiggins; Sunaina Yadav; Eugenio A Parati; Anita L Destefano; Bradford B Worrall; Steven J Kittner; Muhammad Saleem Khan; Alex P Reiner; Anna Helgadottir; Sefanja Achterberg; Israel Fernandez-Cadenas; Sherine Abboud; Reinhold Schmidt; Matthew Walters; Wei-Min Chen; E Bernd Ringelstein; Martin Ó Donnell; Weang Kee Ho; Joanna Pera; Robin Lemmens; Bo Norrving; Peter Higgins; Marianne Benn; Michele Sale; Gregor Kuhlenbäumer; Alexander S F Doney; Astrid M Vicente; Hossein Delavaran; Ale Algra; Gail Davies; Sofia A Oliveira; Colin N A Palmer; Ian Deary; Helena Schmidt; Massimo Pandolfo; Joan Montaner; Cara Carty; Paul I W De Bakker; Konstantinos Kostulas; Jose M Ferro; Natalie R Van Zuydam; Einar Valdimarsson; Børge G Nordestgaard; Arne Lindgren; Vincent Thijs; Agnieszka Slowik; Danish Saleheen; Guillaume Paré; Klaus Berger; Gudmar Thorleifsson; Albert Hofman; Thomas H Mosley; Braxton D Mitchell; Karen Furie; Robert Clarke; Christopher Levi; Sudha Seshadri; Andreas Gschwendtner; Giorgio B Boncoraglio; Pankaj Sharma; Joshua C Bis; Solveig Gretarsdottir; Bruce M Psaty; Peter M Rothwell; Jonathan Rosand; James F Meschia; Kari Stefansson; Martin Dichgans; Hugh S Markus

doi:10.13025/25720

Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies: A meta-analysis of genome-wide association studies

Matthew Traylor
, Martin Farrall
, Elizabeth G Holliday
, Cathie Sudlow
, Jemma C Hopewell
, Yu-Ching Cheng
, Myriam Fornage
, M Arfan Ikram
, Rainer Malik
, Steve Bevan
, Unnur Thorsteinsdottir
, Mike A Nalls
, W. T. Longstreth
, Kerri L Wiggins
, Sunaina Yadav
, Eugenio A Parati
, Anita L Destefano
, Bradford B Worrall
, Steven J Kittner
, Muhammad Saleem Khan

Alex P Reiner, Anna Helgadottir, Sefanja Achterberg, Israel Fernandez-Cadenas, Sherine Abboud, Reinhold Schmidt, Matthew Walters, Wei-Min Chen, E Bernd Ringelstein, Martin Ó Donnell, Weang Kee Ho, Joanna Pera, Robin Lemmens, Bo Norrving, Peter Higgins, Marianne Benn, Michele Sale, Gregor Kuhlenbäumer, Alexander S F Doney, Astrid M Vicente, Hossein Delavaran, Ale Algra, Gail Davies, Sofia A Oliveira, Colin N A Palmer, Ian Deary, Helena Schmidt, Massimo Pandolfo, Joan Montaner, Cara Carty, Paul I W De Bakker, Konstantinos Kostulas, Jose M Ferro, Natalie R Van Zuydam, Einar Valdimarsson, Børge G Nordestgaard, Arne Lindgren, Vincent Thijs, Agnieszka Slowik, Danish Saleheen, Guillaume Paré, Klaus Berger, Gudmar Thorleifsson, Albert Hofman, Thomas H Mosley, Braxton D Mitchell, Karen Furie, Robert Clarke, Christopher Levi, Sudha Seshadri, Andreas Gschwendtner, Giorgio B Boncoraglio, Pankaj Sharma, Joshua C Bis, Solveig Gretarsdottir, Bruce M Psaty, Peter M Rothwell, Jonathan Rosand, James F Meschia, Kari Stefansson, Martin Dichgans, Hugh S Markus

Medicine

St. George’s University of London
Wellcome Trust Centre for Human Genetics
University of Oxford
School of Medicine and Public Health
University of Edinburgh
University of Maryland School of Medicine
The University of Texas Health Science Center at Houston
Erasmus MC
Netherlands Consortium for Healthy Ageing
Ludwig-Maximilians-University
deCODE genetics
University of Iceland
National Institute on Aging (NIA)
University of Washington
University of Washington School of Medicine
Imperial College London
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan
Boston University School of Public Health
University of Virginia School of Medicine
University of Virginia
Baltimore VA Medical Center
Fred Hutchinson Cancer Center
Rudolf Magnus Institute of Neuroscience
Autonomous University of Barcelona (UAB)
Laboratory of Experimental Neurology
Medical University of Graz
University of Glasgow
University of Münster
University of Cambridge
Uniwersytet Jagielloński
VIB Center for the Biology of Disease
KU Leuven
KU Leuven– University Hospital Leuven
Lund University
University of Copenhagen
University of Kiel
University of Dundee School of Medicine
National Institute of Health Dr. Ricardo Jorge
University Medical Centre Utrecht
University of Lisbon
Broad Institute
Brigham and Women's Hospital
Karolinska University Hospital
Centro de Estudos Egas Moniz
Landspitali - The National University Hospital of Iceland
Copenhagen Wound Healing Center Bispebjerg Hospital
Centre for Non-Communicable Diseases
University of Pennsylvania
McMaster University
University of Mississippi Medical Center
Massachusetts General Hospital
University of Newcastle
Boston University School of Medicine
US Department of Health and Human Services
University of Oxford Medical Sciences Division
Mayo Clinic in Jacksonville, Florida

Research output: Contribution to a Journal (Peer & Non Peer) › Article › peer-review

424 Citations (Scopus)

Abstract

Background Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.Methods We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nudeotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.Findings We verified previous associations for cardioembolic stroke near PITX2 (p=2.8x10(-16)) and ZFHX3 (p=2.28x10(-8)), and for large-vessel stroke at a 9p21 locus (p=3.32x10(-5)) and HDAC9 (p=2.03x10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p5x10(-6). However, we were unable to replicate any of these novel associations in the replication cohort.Interpretation Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.

Original language	English (Ireland)
Pages (from-to)	951-962
Number of pages	12
Journal	LANCET NEUROLOGY
Volume	11
Issue number	11
DOIs	https://doi.org/10.13025/25720 https://doi.org/10.1016/s1474-4422(12)70234-x
Publication status	Published - 1 Nov 2012

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10.13025/25720Licence: CC BY-NC-ND
10.1016/s1474-4422(12)70234-x

Cite this

Traylor, M., Farrall, M., Holliday, E. G., Sudlow, C., Hopewell, J. C., Cheng, Y.-C., Fornage, M., Ikram, M. A., Malik, R., Bevan, S., Thorsteinsdottir, U., Nalls, M. A., Longstreth, W. T., Wiggins, K. L., Yadav, S., Parati, E. A., Destefano, A. L., Worrall, B. B., Kittner, S. J., ... Markus, H. S. (2012). Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies: A meta-analysis of genome-wide association studies. LANCET NEUROLOGY, 11(11), 951-962. https://doi.org/10.13025/25720, https://doi.org/10.1016/s1474-4422(12)70234-x

@article{b69c2fdf8ea54bf8874812f090964f06,

title = "Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies: A meta-analysis of genome-wide association studies",

abstract = "Background Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.Methods We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nudeotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.Findings We verified previous associations for cardioembolic stroke near PITX2 (p=2.8x10(-16)) and ZFHX3 (p=2.28x10(-8)), and for large-vessel stroke at a 9p21 locus (p=3.32x10(-5)) and HDAC9 (p=2.03x10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p5x10(-6). However, we were unable to replicate any of these novel associations in the replication cohort.Interpretation Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.",

author = "Matthew Traylor and Martin Farrall and Holliday, \{Elizabeth G\} and Cathie Sudlow and Hopewell, \{Jemma C\} and Yu-Ching Cheng and Myriam Fornage and Ikram, \{M Arfan\} and Rainer Malik and Steve Bevan and Unnur Thorsteinsdottir and Nalls, \{Mike A\} and Longstreth, \{W. T.\} and Wiggins, \{Kerri L\} and Sunaina Yadav and Parati, \{Eugenio A\} and Destefano, \{Anita L\} and Worrall, \{Bradford B\} and Kittner, \{Steven J\} and Khan, \{Muhammad Saleem\} and Reiner, \{Alex P\} and Anna Helgadottir and Sefanja Achterberg and Israel Fernandez-Cadenas and Sherine Abboud and Reinhold Schmidt and Matthew Walters and Wei-Min Chen and Ringelstein, \{E Bernd\} and \{{\'O} Donnell\}, Martin and Ho, \{Weang Kee\} and Joanna Pera and Robin Lemmens and Bo Norrving and Peter Higgins and Marianne Benn and Michele Sale and Gregor Kuhlenb{\"a}umer and Doney, \{Alexander S F\} and Vicente, \{Astrid M\} and Hossein Delavaran and Ale Algra and Gail Davies and Oliveira, \{Sofia A\} and Palmer, \{Colin N A\} and Ian Deary and Helena Schmidt and Massimo Pandolfo and Joan Montaner and Cara Carty and \{De Bakker\}, \{Paul I W\} and Konstantinos Kostulas and Ferro, \{Jose M\} and \{Van Zuydam\}, \{Natalie R\} and Einar Valdimarsson and Nordestgaard, \{B{\o}rge G\} and Arne Lindgren and Vincent Thijs and Agnieszka Slowik and Danish Saleheen and Guillaume Par{\'e} and Klaus Berger and Gudmar Thorleifsson and Albert Hofman and Mosley, \{Thomas H\} and Mitchell, \{Braxton D\} and Karen Furie and Robert Clarke and Christopher Levi and Sudha Seshadri and Andreas Gschwendtner and Boncoraglio, \{Giorgio B\} and Pankaj Sharma and Bis, \{Joshua C\} and Solveig Gretarsdottir and Psaty, \{Bruce M\} and Rothwell, \{Peter M\} and Jonathan Rosand and Meschia, \{James F\} and Kari Stefansson and Martin Dichgans and Markus, \{Hugh S\}",

year = "2012",

month = nov,

day = "1",

doi = "10.13025/25720",

language = "English (Ireland)",

volume = "11",

pages = "951--962",

journal = "LANCET NEUROLOGY",

number = "11",

}

Traylor, M, Farrall, M, Holliday, EG, Sudlow, C, Hopewell, JC, Cheng, Y-C, Fornage, M, Ikram, MA, Malik, R, Bevan, S, Thorsteinsdottir, U, Nalls, MA, Longstreth, WT, Wiggins, KL, Yadav, S, Parati, EA, Destefano, AL, Worrall, BB, Kittner, SJ, Khan, MS, Reiner, AP, Helgadottir, A, Achterberg, S, Fernandez-Cadenas, I, Abboud, S, Schmidt, R, Walters, M, Chen, W-M, Ringelstein, EB, Ó Donnell, M, Ho, WK, Pera, J, Lemmens, R, Norrving, B, Higgins, P, Benn, M, Sale, M, Kuhlenbäumer, G, Doney, ASF, Vicente, AM, Delavaran, H, Algra, A, Davies, G, Oliveira, SA, Palmer, CNA, Deary, I, Schmidt, H, Pandolfo, M, Montaner, J, Carty, C, De Bakker, PIW, Kostulas, K, Ferro, JM, Van Zuydam, NR, Valdimarsson, E, Nordestgaard, BG, Lindgren, A, Thijs, V, Slowik, A, Saleheen, D, Paré, G, Berger, K, Thorleifsson, G, Hofman, A, Mosley, TH, Mitchell, BD, Furie, K, Clarke, R, Levi, C, Seshadri, S, Gschwendtner, A, Boncoraglio, GB, Sharma, P, Bis, JC, Gretarsdottir, S, Psaty, BM, Rothwell, PM, Rosand, J, Meschia, JF, Stefansson, K, Dichgans, M & Markus, HS 2012, 'Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies: A meta-analysis of genome-wide association studies', LANCET NEUROLOGY, vol. 11, no. 11, pp. 951-962. https://doi.org/10.13025/25720, https://doi.org/10.1016/s1474-4422(12)70234-x

Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies: A meta-analysis of genome-wide association studies. / Traylor, Matthew; Farrall, Martin; Holliday, Elizabeth G et al.
In: LANCET NEUROLOGY, Vol. 11, No. 11, 01.11.2012, p. 951-962.

Research output: Contribution to a Journal (Peer & Non Peer) › Article › peer-review

TY - JOUR

T1 - Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies

T2 - A meta-analysis of genome-wide association studies

AU - Traylor, Matthew

AU - Farrall, Martin

AU - Holliday, Elizabeth G

AU - Sudlow, Cathie

AU - Hopewell, Jemma C

AU - Cheng, Yu-Ching

AU - Fornage, Myriam

AU - Ikram, M Arfan

AU - Malik, Rainer

AU - Bevan, Steve

AU - Thorsteinsdottir, Unnur

AU - Nalls, Mike A

AU - Longstreth, W. T.

AU - Wiggins, Kerri L

AU - Yadav, Sunaina

AU - Parati, Eugenio A

AU - Destefano, Anita L

AU - Worrall, Bradford B

AU - Kittner, Steven J

AU - Khan, Muhammad Saleem

AU - Reiner, Alex P

AU - Helgadottir, Anna

AU - Achterberg, Sefanja

AU - Fernandez-Cadenas, Israel

AU - Abboud, Sherine

AU - Schmidt, Reinhold

AU - Walters, Matthew

AU - Chen, Wei-Min

AU - Ringelstein, E Bernd

AU - Ó Donnell, Martin

AU - Ho, Weang Kee

AU - Pera, Joanna

AU - Lemmens, Robin

AU - Norrving, Bo

AU - Higgins, Peter

AU - Benn, Marianne

AU - Sale, Michele

AU - Kuhlenbäumer, Gregor

AU - Doney, Alexander S F

AU - Vicente, Astrid M

AU - Delavaran, Hossein

AU - Algra, Ale

AU - Davies, Gail

AU - Oliveira, Sofia A

AU - Palmer, Colin N A

AU - Deary, Ian

AU - Schmidt, Helena

AU - Pandolfo, Massimo

AU - Montaner, Joan

AU - Carty, Cara

AU - De Bakker, Paul I W

AU - Kostulas, Konstantinos

AU - Ferro, Jose M

AU - Van Zuydam, Natalie R

AU - Valdimarsson, Einar

AU - Nordestgaard, Børge G

AU - Lindgren, Arne

AU - Thijs, Vincent

AU - Slowik, Agnieszka

AU - Saleheen, Danish

AU - Paré, Guillaume

AU - Berger, Klaus

AU - Thorleifsson, Gudmar

AU - Hofman, Albert

AU - Mosley, Thomas H

AU - Mitchell, Braxton D

AU - Furie, Karen

AU - Clarke, Robert

AU - Levi, Christopher

AU - Seshadri, Sudha

AU - Gschwendtner, Andreas

AU - Boncoraglio, Giorgio B

AU - Sharma, Pankaj

AU - Bis, Joshua C

AU - Gretarsdottir, Solveig

AU - Psaty, Bruce M

AU - Rothwell, Peter M

AU - Rosand, Jonathan

AU - Meschia, James F

AU - Stefansson, Kari

AU - Dichgans, Martin

AU - Markus, Hugh S

PY - 2012/11/1

Y1 - 2012/11/1

N2 - Background Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.Methods We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nudeotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.Findings We verified previous associations for cardioembolic stroke near PITX2 (p=2.8x10(-16)) and ZFHX3 (p=2.28x10(-8)), and for large-vessel stroke at a 9p21 locus (p=3.32x10(-5)) and HDAC9 (p=2.03x10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p5x10(-6). However, we were unable to replicate any of these novel associations in the replication cohort.Interpretation Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.

AB - Background Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.Methods We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nudeotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.Findings We verified previous associations for cardioembolic stroke near PITX2 (p=2.8x10(-16)) and ZFHX3 (p=2.28x10(-8)), and for large-vessel stroke at a 9p21 locus (p=3.32x10(-5)) and HDAC9 (p=2.03x10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p5x10(-6). However, we were unable to replicate any of these novel associations in the replication cohort.Interpretation Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.

UR - http://hdl.handle.net/10379/14194

UR - https://www.scopus.com/pages/publications/84867645825

U2 - 10.13025/25720

DO - 10.13025/25720

M3 - Article

VL - 11

SP - 951

EP - 962

JO - LANCET NEUROLOGY

JF - LANCET NEUROLOGY

IS - 11

ER -

Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies: A meta-analysis of genome-wide association studies

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