Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): 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 O'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:10.1016/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

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 KhanAlex P. Reiner, Anna Helgadottir, Sefanja Achterberg, Israel Fernandez-Cadenas, Sherine Abboud, Reinhold Schmidt, Matthew Walters, Wei Min Chen, E. Bernd Ringelstein, Martin O'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

Neurology

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

326 Scopus citations

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 nucleotide 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=2·8×10^-16) and ZFHX3 (p=2·28×10^-8), and for large-vessel stroke at a 9p21 locus (p=3·32×10^-5) and HDAC9 (p=2·03×10^-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 p<5×10^-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. Funding: Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).

Original language	English (US)
Pages (from-to)	951-962
Number of pages	12
Journal	The Lancet Neurology
Volume	11
Issue number	11
DOIs	https://doi.org/10.1016/S1474-4422(12)70234-X
State	Published - Nov 2012

ASJC Scopus subject areas

Clinical Neurology

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10.1016/S1474-4422(12)70234-X

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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. The Lancet Neurology, 11(11), 951-962. https://doi.org/10.1016/S1474-4422(12)70234-X

Traylor, M, Farrall, M, Holliday, EG, Sudlow, C, Hopewell, JC, Cheng, YC, 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, WM, Ringelstein, EB, O'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', The Lancet Neurology, vol. 11, no. 11, pp. 951-962. https://doi.org/10.1016/S1474-4422(12)70234-X

@article{3ccdb40b3803437597e0070a26a5878a,

title = "Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): 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 nucleotide 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=2·8×10-16) and ZFHX3 (p=2·28×10-8), and for large-vessel stroke at a 9p21 locus (p=3·32×10-5) and HDAC9 (p=2·03×10-12). 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 p<5×10-6. 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. Funding: Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).",

author = "Matthew Traylor and Martin Farrall and Holliday, {Elizabeth G.} and Cathie Sudlow and Hopewell, {Jemma C.} and Cheng, {Yu Ching} 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 Chen, {Wei Min} and Ringelstein, {E. Bernd} and Martin O'Donnell 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,

doi = "10.1016/S1474-4422(12)70234-X",

language = "English (US)",

volume = "11",

pages = "951--962",

journal = "The Lancet Neurology",

issn = "1474-4422",

publisher = "Lancet Publishing Group",

number = "11",

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TY - JOUR

T1 - Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration)

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 - O'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

Y1 - 2012/11

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 nucleotide 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=2·8×10-16) and ZFHX3 (p=2·28×10-8), and for large-vessel stroke at a 9p21 locus (p=3·32×10-5) and HDAC9 (p=2·03×10-12). 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 p<5×10-6. 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. Funding: Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).

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 nucleotide 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=2·8×10-16) and ZFHX3 (p=2·28×10-8), and for large-vessel stroke at a 9p21 locus (p=3·32×10-5) and HDAC9 (p=2·03×10-12). 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 p<5×10-6. 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. Funding: Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).

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UR - http://www.scopus.com/inward/citedby.url?scp=84867645825&partnerID=8YFLogxK

U2 - 10.1016/S1474-4422(12)70234-X

DO - 10.1016/S1474-4422(12)70234-X

M3 - Article

C2 - 23041239

AN - SCOPUS:84867645825

SN - 1474-4422

VL - 11

SP - 951

EP - 962

JO - The Lancet Neurology

JF - The 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

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