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; Wt 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; Børge G Nordestgaard; Australian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2 (WTCCC2)

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, Wt 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, Børge G Nordestgaard, Australian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2 (WTCCC2)

326 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 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
Journal	Lancet Neurology
Volume	11
Issue number	11
Pages (from-to)	951-62
Number of pages	12
ISSN	1474-4422
DOIs	https://doi.org/10.1016/S1474-4422(12)70234-X
Publication status	Published - Nov 2012

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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., Wiggins, K. L., Yadav, S., Parati, E. A., Destefano, A. L., Worrall, B. B., Kittner, S. J., ... Australian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2 (WTCCC2) (2012). Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. Lancet Neurology, 11(11), 951-62. https://doi.org/10.1016/S1474-4422(12)70234-X

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, W, 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, 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, Nordestgaard, BG & Australian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2 (WTCCC2) 2012, 'Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies', Lancet Neurology, vol. 11, no. 11, pp. 951-62. https://doi.org/10.1016/S1474-4422(12)70234-X

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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 Yu-Ching Cheng and Myriam Fornage and Ikram, {M Arfan} and Rainer Malik and Steve Bevan and Unnur Thorsteinsdottir and Nalls, {Mike A} and Wt Longstreth 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 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 Nordestgaard, {B{\o}rge G} and B{\o}rge Nordestgaard",

year = "2012",

month = nov,

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

language = "English",

volume = "11",

pages = "951--62",

journal = "The Lancet Neurology",

issn = "1474-4422",

publisher = "TheLancet 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, Wt

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 - Nordestgaard, Børge G

AU - Australian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2 (WTCCC2)

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).

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

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

M3 - Journal article

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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