Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Céline Bellenguez; Steve Bevan; Andreas Gschwendtner; Chris C.A. Spencer; Annette I. Burgess; Matti Pirinen; Caroline A. Jackson; Matthew Traylor; Amy Strange; Zhan Su; Gavin Band; Paul D. Syme; Rainer Malik; Joanna Pera; Norrving Bo; Robin Lemmens; Colin Freeman; Renata Schanz; Tom James; Deborah Poole; Lee Murphy; Helen Segal; Lynelle Cortellini; Yu Ching Cheng; Daniel Woo; Michael A. Nalls; Bertram Müller-Myhsok; Christa Meisinger; Udo Seedorf; Helen Ross-Adams; Steven Boonen; Dorota Wloch-Kopec; Valerie Valant; Julia Slark; Karen Furie; Hossein Delavaran; Cordelia Langford; Panos Deloukas; Sarah Edkins; Sarah Hunt; Emma Gray; Serge Dronov; Leena Peltonen; Solveig Gretarsdottir; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Kari Stefansson; Giorgio B. Boncoraglio; Eugenio A. Parati; John Attia; Elizabeth Holliday; Chris Levi; Maria Grazia Franzosi; Anuj Goel; Anna Helgadottir; Jenefer M. Blackwell; Elvira Bramon; Matthew A. Brown; Juan P. Casas; Aiden Corvin; Audrey Duncanson; Janusz Jankowski; Christopher G. Mathew; Colin N.A. Palmer; Robert Plomin; Anna Rautanen; Stephen J. Sawcer; Richard C. Trembath; Ananth C. Viswanathan; Nicholas W. Wood; Bradford B. Worrall; Steven J. Kittner; Braxton D. Mitchell; Brett Kissela; James F. Meschia; Vincent Thijs; Arne Lindgren; Mary Joan MacLeod; Agnieszka Slowik; Matthew Walters; Jonathan Rosand; Pankaj Sharma; Martin Farrall; Cathie L.M. Sudlow; Peter M. Rothwell; Martin Dichgans; Peter Donnelly; Hugh S. Markus

doi:10.1038/ng.1081

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Céline Bellenguez, Steve Bevan, Andreas Gschwendtner, Chris C.A. Spencer, Annette I. Burgess, Matti Pirinen, Caroline A. Jackson, Matthew Traylor, Amy Strange, Zhan Su, Gavin Band, Paul D. Syme, Rainer Malik, Joanna Pera, Norrving Bo, Robin Lemmens, Colin Freeman, Renata Schanz, Tom James, Deborah PooleLee Murphy, Helen Segal, Lynelle Cortellini, Yu Ching Cheng, Daniel Woo, Michael A. Nalls, Bertram Müller-Myhsok, Christa Meisinger, Udo Seedorf, Helen Ross-Adams, Steven Boonen, Dorota Wloch-Kopec, Valerie Valant, Julia Slark, Karen Furie, Hossein Delavaran, Cordelia Langford, Panos Deloukas, Sarah Edkins, Sarah Hunt, Emma Gray, Serge Dronov, Leena Peltonen, Solveig Gretarsdottir, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Kari Stefansson, Giorgio B. Boncoraglio, Eugenio A. Parati, John Attia, Elizabeth Holliday, Chris Levi, Maria Grazia Franzosi, Anuj Goel, Anna Helgadottir, Jenefer M. Blackwell, Elvira Bramon, Matthew A. Brown, Juan P. Casas, Aiden Corvin, Audrey Duncanson, Janusz Jankowski, Christopher G. Mathew, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Stephen J. Sawcer, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Bradford B. Worrall, Steven J. Kittner, Braxton D. Mitchell, Brett Kissela, James F. Meschia, Vincent Thijs, Arne Lindgren, Mary Joan MacLeod, Agnieszka Slowik, Matthew Walters, Jonathan Rosand, Pankaj Sharma, Martin Farrall, Cathie L.M. Sudlow, Peter M. Rothwell, Martin Dichgans, Peter Donnelly^*, Hugh S. Markus

^*Corresponding author for this work

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

333 Citations (Scopus)

Abstract

Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10 ^-11; odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.

Original language	English
Pages (from-to)	328-333
Number of pages	6
Journal	Nature Genetics
Volume	44
Issue number	3
DOIs	https://doi.org/10.1038/ng.1081
Publication status	Published - Mar 2012

Bibliographical note

Funding Information:
We thank S. Bertrand, J. Bryant, S.L. Clark, J.S. Conquer, T. Dibling, J.C. Eldred, S. Gamble, C. Hind, M.L. Perez, C.R. Stribling, S. Taylor and A. Wilk of the Wellcome Trust Sanger Institute’s Sample and Genotyping Facilities for technical assistance. We acknowledge use of the British 1958 Birth Cohort DNA collection, which is funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02), and of the UK National Blood Service controls funded by the Wellcome Trust. We thank W. Bodmer and B. Winney for use of the People of the British Isles DNA collection, which was funded by the Wellcome Trust. We thank the following individuals who contributed to collection, phenotyping, sample processing and data management for the different cohorts: A. Burgess, A. Syed and N. Paul (Oxford Vascular Study); M. Dennis, P. Sandercock, C. Warlow, S. Hart, S. Keir, J. Wardlaw, A. Farrall, G. Potter, A. Hutchison and M. McDowall (Edinburgh Stroke Study); A. Pasdar and H. Clinkscale (Aberdeen); P. Higgins (Glasgow); T.G. Brott, R.D. Brown, S. Silliman, M. Frankel, D. Case, S. Rich, J. Hardy, A. Singleton (ISGS); M.J. Sparks, K. Ryan, J. Cole, M. Wozniak, B. Stern, R. Wityk, C. Johnson and D. Buchholz (GEOS); and J. Maguire, S. Koblar, J. Golledge, J. Surm, G. Hankey, J. Jannes, M. Lewis, R. Scott, L. Lincz; P. Moscato and R. Baker (Australian Stroke Genetics Collaborative membership). The principal funding for this study was provided by the Wellcome Trust as part of the WTCCC2 project (085475/B/08/Z, 085475/Z/08/Z and WT084724MA). For details of other funding support, see the Supplementary Note.

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Bellenguez, C., Bevan, S., Gschwendtner, A., Spencer, C. C. A., Burgess, A. I., Pirinen, M., Jackson, C. A., Traylor, M., Strange, A., Su, Z., Band, G., Syme, P. D., Malik, R., Pera, J., Bo, N., Lemmens, R., Freeman, C., Schanz, R., James, T., ... Markus, H. S. (2012). Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nature Genetics, 44(3), 328-333. https://doi.org/10.1038/ng.1081

@article{ebf206f60f79405c9970c1d6c8a0b76e,

title = "Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke",

abstract = "Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10 -11; odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.",

author = "C{\'e}line Bellenguez and Steve Bevan and Andreas Gschwendtner and Spencer, {Chris C.A.} and Burgess, {Annette I.} and Matti Pirinen and Jackson, {Caroline A.} and Matthew Traylor and Amy Strange and Zhan Su and Gavin Band and Syme, {Paul D.} and Rainer Malik and Joanna Pera and Norrving Bo and Robin Lemmens and Colin Freeman and Renata Schanz and Tom James and Deborah Poole and Lee Murphy and Helen Segal and Lynelle Cortellini and Cheng, {Yu Ching} and Daniel Woo and Nalls, {Michael A.} and Bertram M{\"u}ller-Myhsok and Christa Meisinger and Udo Seedorf and Helen Ross-Adams and Steven Boonen and Dorota Wloch-Kopec and Valerie Valant and Julia Slark and Karen Furie and Hossein Delavaran and Cordelia Langford and Panos Deloukas and Sarah Edkins and Sarah Hunt and Emma Gray and Serge Dronov and Leena Peltonen and Solveig Gretarsdottir and Gudmar Thorleifsson and Unnur Thorsteinsdottir and Kari Stefansson and Boncoraglio, {Giorgio B.} and Parati, {Eugenio A.} and John Attia and Elizabeth Holliday and Chris Levi and Franzosi, {Maria Grazia} and Anuj Goel and Anna Helgadottir and Blackwell, {Jenefer M.} and Elvira Bramon and Brown, {Matthew A.} and Casas, {Juan P.} and Aiden Corvin and Audrey Duncanson and Janusz Jankowski and Mathew, {Christopher G.} and Palmer, {Colin N.A.} and Robert Plomin and Anna Rautanen and Sawcer, {Stephen J.} and Trembath, {Richard C.} and Viswanathan, {Ananth C.} and Wood, {Nicholas W.} and Worrall, {Bradford B.} and Kittner, {Steven J.} and Mitchell, {Braxton D.} and Brett Kissela and Meschia, {James F.} and Vincent Thijs and Arne Lindgren and MacLeod, {Mary Joan} and Agnieszka Slowik and Matthew Walters and Jonathan Rosand and Pankaj Sharma and Martin Farrall and Sudlow, {Cathie L.M.} and Rothwell, {Peter M.} and Martin Dichgans and Peter Donnelly and Markus, {Hugh S.}",

note = "Funding Information: We thank S. Bertrand, J. Bryant, S.L. Clark, J.S. Conquer, T. Dibling, J.C. Eldred, S. Gamble, C. Hind, M.L. Perez, C.R. Stribling, S. Taylor and A. Wilk of the Wellcome Trust Sanger Institute{\textquoteright}s Sample and Genotyping Facilities for technical assistance. We acknowledge use of the British 1958 Birth Cohort DNA collection, which is funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02), and of the UK National Blood Service controls funded by the Wellcome Trust. We thank W. Bodmer and B. Winney for use of the People of the British Isles DNA collection, which was funded by the Wellcome Trust. We thank the following individuals who contributed to collection, phenotyping, sample processing and data management for the different cohorts: A. Burgess, A. Syed and N. Paul (Oxford Vascular Study); M. Dennis, P. Sandercock, C. Warlow, S. Hart, S. Keir, J. Wardlaw, A. Farrall, G. Potter, A. Hutchison and M. McDowall (Edinburgh Stroke Study); A. Pasdar and H. Clinkscale (Aberdeen); P. Higgins (Glasgow); T.G. Brott, R.D. Brown, S. Silliman, M. Frankel, D. Case, S. Rich, J. Hardy, A. Singleton (ISGS); M.J. Sparks, K. Ryan, J. Cole, M. Wozniak, B. Stern, R. Wityk, C. Johnson and D. Buchholz (GEOS); and J. Maguire, S. Koblar, J. Golledge, J. Surm, G. Hankey, J. Jannes, M. Lewis, R. Scott, L. Lincz; P. Moscato and R. Baker (Australian Stroke Genetics Collaborative membership). The principal funding for this study was provided by the Wellcome Trust as part of the WTCCC2 project (085475/B/08/Z, 085475/Z/08/Z and WT084724MA). For details of other funding support, see the Supplementary Note.",

year = "2012",

month = mar,

doi = "10.1038/ng.1081",

language = "English",

volume = "44",

pages = "328--333",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "3",

}

Bellenguez, C, Bevan, S, Gschwendtner, A, Spencer, CCA, Burgess, AI, Pirinen, M, Jackson, CA, Traylor, M, Strange, A, Su, Z, Band, G, Syme, PD, Malik, R, Pera, J, Bo, N, Lemmens, R, Freeman, C, Schanz, R, James, T, Poole, D, Murphy, L, Segal, H, Cortellini, L, Cheng, YC, Woo, D, Nalls, MA, Müller-Myhsok, B, Meisinger, C, Seedorf, U, Ross-Adams, H, Boonen, S, Wloch-Kopec, D, Valant, V, Slark, J, Furie, K, Delavaran, H, Langford, C, Deloukas, P, Edkins, S, Hunt, S, Gray, E, Dronov, S, Peltonen, L, Gretarsdottir, S, Thorleifsson, G, Thorsteinsdottir, U , Stefansson, K, Boncoraglio, GB, Parati, EA, Attia, J, Holliday, E, Levi, C, Franzosi, MG, Goel, A, Helgadottir, A, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Duncanson, A, Jankowski, J, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Worrall, BB, Kittner, SJ, Mitchell, BD, Kissela, B, Meschia, JF, Thijs, V, Lindgren, A, MacLeod, MJ, Slowik, A, Walters, M, Rosand, J, Sharma, P, Farrall, M, Sudlow, CLM, Rothwell, PM, Dichgans, M, Donnelly, P & Markus, HS 2012, 'Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke', Nature Genetics, vol. 44, no. 3, pp. 328-333. https://doi.org/10.1038/ng.1081

TY - JOUR

T1 - Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

AU - Bellenguez, Céline

AU - Bevan, Steve

AU - Gschwendtner, Andreas

AU - Spencer, Chris C.A.

AU - Burgess, Annette I.

AU - Pirinen, Matti

AU - Jackson, Caroline A.

AU - Traylor, Matthew

AU - Strange, Amy

AU - Su, Zhan

AU - Band, Gavin

AU - Syme, Paul D.

AU - Malik, Rainer

AU - Pera, Joanna

AU - Bo, Norrving

AU - Lemmens, Robin

AU - Freeman, Colin

AU - Schanz, Renata

AU - James, Tom

AU - Poole, Deborah

AU - Murphy, Lee

AU - Segal, Helen

AU - Cortellini, Lynelle

AU - Cheng, Yu Ching

AU - Woo, Daniel

AU - Nalls, Michael A.

AU - Müller-Myhsok, Bertram

AU - Meisinger, Christa

AU - Seedorf, Udo

AU - Ross-Adams, Helen

AU - Boonen, Steven

AU - Wloch-Kopec, Dorota

AU - Valant, Valerie

AU - Slark, Julia

AU - Furie, Karen

AU - Delavaran, Hossein

AU - Langford, Cordelia

AU - Deloukas, Panos

AU - Edkins, Sarah

AU - Hunt, Sarah

AU - Gray, Emma

AU - Dronov, Serge

AU - Peltonen, Leena

AU - Gretarsdottir, Solveig

AU - Thorleifsson, Gudmar

AU - Thorsteinsdottir, Unnur

AU - Stefansson, Kari

AU - Boncoraglio, Giorgio B.

AU - Parati, Eugenio A.

AU - Attia, John

AU - Holliday, Elizabeth

AU - Levi, Chris

AU - Franzosi, Maria Grazia

AU - Goel, Anuj

AU - Helgadottir, Anna

AU - Blackwell, Jenefer M.

AU - Bramon, Elvira

AU - Brown, Matthew A.

AU - Casas, Juan P.

AU - Corvin, Aiden

AU - Duncanson, Audrey

AU - Jankowski, Janusz

AU - Mathew, Christopher G.

AU - Palmer, Colin N.A.

AU - Plomin, Robert

AU - Rautanen, Anna

AU - Sawcer, Stephen J.

AU - Trembath, Richard C.

AU - Viswanathan, Ananth C.

AU - Wood, Nicholas W.

AU - Worrall, Bradford B.

AU - Kittner, Steven J.

AU - Mitchell, Braxton D.

AU - Kissela, Brett

AU - Meschia, James F.

AU - Thijs, Vincent

AU - Lindgren, Arne

AU - MacLeod, Mary Joan

AU - Slowik, Agnieszka

AU - Walters, Matthew

AU - Rosand, Jonathan

AU - Sharma, Pankaj

AU - Farrall, Martin

AU - Sudlow, Cathie L.M.

AU - Rothwell, Peter M.

AU - Dichgans, Martin

AU - Donnelly, Peter

AU - Markus, Hugh S.

N1 - Funding Information: We thank S. Bertrand, J. Bryant, S.L. Clark, J.S. Conquer, T. Dibling, J.C. Eldred, S. Gamble, C. Hind, M.L. Perez, C.R. Stribling, S. Taylor and A. Wilk of the Wellcome Trust Sanger Institute’s Sample and Genotyping Facilities for technical assistance. We acknowledge use of the British 1958 Birth Cohort DNA collection, which is funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02), and of the UK National Blood Service controls funded by the Wellcome Trust. We thank W. Bodmer and B. Winney for use of the People of the British Isles DNA collection, which was funded by the Wellcome Trust. We thank the following individuals who contributed to collection, phenotyping, sample processing and data management for the different cohorts: A. Burgess, A. Syed and N. Paul (Oxford Vascular Study); M. Dennis, P. Sandercock, C. Warlow, S. Hart, S. Keir, J. Wardlaw, A. Farrall, G. Potter, A. Hutchison and M. McDowall (Edinburgh Stroke Study); A. Pasdar and H. Clinkscale (Aberdeen); P. Higgins (Glasgow); T.G. Brott, R.D. Brown, S. Silliman, M. Frankel, D. Case, S. Rich, J. Hardy, A. Singleton (ISGS); M.J. Sparks, K. Ryan, J. Cole, M. Wozniak, B. Stern, R. Wityk, C. Johnson and D. Buchholz (GEOS); and J. Maguire, S. Koblar, J. Golledge, J. Surm, G. Hankey, J. Jannes, M. Lewis, R. Scott, L. Lincz; P. Moscato and R. Baker (Australian Stroke Genetics Collaborative membership). The principal funding for this study was provided by the Wellcome Trust as part of the WTCCC2 project (085475/B/08/Z, 085475/Z/08/Z and WT084724MA). For details of other funding support, see the Supplementary Note.

PY - 2012/3

Y1 - 2012/3

N2 - Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10 -11; odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.

AB - Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10 -11; odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.

UR - http://www.scopus.com/inward/record.url?scp=84863393715&partnerID=8YFLogxK

U2 - 10.1038/ng.1081

DO - 10.1038/ng.1081

M3 - Article

C2 - 22306652

AN - SCOPUS:84863393715

SN - 1061-4036

VL - 44

SP - 328

EP - 333

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Abstract

Bibliographical note

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