Common variants at 6p21.1 are associated with large artery atherosclerotic stroke

Elizabeth G. Holliday; Jane M. Maguire; Tiffany Jane Evans; Simon A. Koblar; Jim Jannes; Jonathan W. Sturm; Graeme J. Hankey; Ross Baker; Jonathan Golledge; Mark W. Parsons; Rainer Malik; Mark McEvoy; Erik Biros; Martin D. Lewis; Lisa F. Lincz; Roseanne Peel; Christopher Oldmeadow; Wayne Smith; Pablo Moscato; Simona Barlera; Steve Bevan; Joshua C. Bis; Eric Boerwinkle; Giorgio B. Boncoraglio; Thomas G. Brott; Robert D. Brown; Yu Ching Cheng; John W. Cole; Ioana Cotlarciuc; William J. Devan; Myriam Fornage; Karen L. Furie; Sólveig Grétarsdóttir; Andreas Gschwendtner; M. Arfan Ikram; W. T. Longstreth; James F. Meschia; Braxton D. Mitchell; Thomas H. Mosley; Michael A. Nalls; Eugenio A. Parati; Bruce M. Psaty; Pankaj Sharma; Kari Stefansson; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Matthew Traylor; Benjamin F.J. Verhaaren; Kerri L. Wiggins; Bradford B. Worrall; Cathie Sudlow; Peter M. Rothwell; Martin Farrall; Martin Dichgans; Jonathan Rosand; Hugh S. Markus; Rodney J. Scott; Christopher Levi; John Attia

doi:10.1038/ng.2397

Common variants at 6p21.1 are associated with large artery atherosclerotic stroke

Elizabeth G. Holliday, Jane M. Maguire, Tiffany Jane Evans, Simon A. Koblar, Jim Jannes, Jonathan W. Sturm, Graeme J. Hankey, Ross Baker, Jonathan Golledge, Mark W. Parsons, Rainer Malik, Mark McEvoy, Erik Biros, Martin D. Lewis, Lisa F. Lincz, Roseanne Peel, Christopher Oldmeadow, Wayne Smith, Pablo Moscato, Simona BarleraSteve Bevan, Joshua C. Bis, Eric Boerwinkle, Giorgio B. Boncoraglio, Thomas G. Brott, Robert D. Brown, Yu Ching Cheng, John W. Cole, Ioana Cotlarciuc, William J. Devan, Myriam Fornage, Karen L. Furie, Sólveig Grétarsdóttir, Andreas Gschwendtner, M. Arfan Ikram, W. T. Longstreth, James F. Meschia, Braxton D. Mitchell, Thomas H. Mosley, Michael A. Nalls, Eugenio A. Parati, Bruce M. Psaty, Pankaj Sharma, Kari Stefansson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Matthew Traylor, Benjamin F.J. Verhaaren, Kerri L. Wiggins, Bradford B. Worrall, Cathie Sudlow, Peter M. Rothwell, Martin Farrall, Martin Dichgans, Jonathan Rosand, Hugh S. Markus, Rodney J. Scott, Christopher Levi, John Attia

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Abstract

Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR) = 1.62, P = 3.9 × 10^-8) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR = 1.15, P = 3.9 × 10^-4; discovery and replication combined OR = 1.21, P = 4.7 × 10^-8). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.

Original language	English (US)
Pages (from-to)	1147-1151
Number of pages	5
Journal	Nature Genetics
Volume	44
Issue number	10
DOIs	https://doi.org/10.1038/ng.2397
State	Published - Oct 2012

ASJC Scopus subject areas

Genetics

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Holliday, E. G., Maguire, J. M., Evans, T. J., Koblar, S. A., Jannes, J., Sturm, J. W., Hankey, G. J., Baker, R., Golledge, J., Parsons, M. W., Malik, R., McEvoy, M., Biros, E., Lewis, M. D., Lincz, L. F., Peel, R., Oldmeadow, C., Smith, W., Moscato, P., ... Attia, J. (2012). Common variants at 6p21.1 are associated with large artery atherosclerotic stroke. Nature Genetics, 44(10), 1147-1151. https://doi.org/10.1038/ng.2397

Holliday, EG, Maguire, JM, Evans, TJ, Koblar, SA, Jannes, J, Sturm, JW, Hankey, GJ, Baker, R, Golledge, J, Parsons, MW, Malik, R, McEvoy, M, Biros, E, Lewis, MD, Lincz, LF, Peel, R, Oldmeadow, C, Smith, W, Moscato, P, Barlera, S, Bevan, S, Bis, JC, Boerwinkle, E, Boncoraglio, GB, Brott, TG , Brown, RD, Cheng, YC, Cole, JW, Cotlarciuc, I, Devan, WJ, Fornage, M, Furie, KL, Grétarsdóttir, S, Gschwendtner, A, Ikram, MA, Longstreth, WT, Meschia, JF, Mitchell, BD, Mosley, TH, Nalls, MA, Parati, EA, Psaty, BM, Sharma, P, Stefansson, K, Thorleifsson, G, Thorsteinsdottir, U, Traylor, M, Verhaaren, BFJ, Wiggins, KL, Worrall, BB, Sudlow, C, Rothwell, PM, Farrall, M, Dichgans, M, Rosand, J, Markus, HS, Scott, RJ, Levi, C & Attia, J 2012, 'Common variants at 6p21.1 are associated with large artery atherosclerotic stroke', Nature Genetics, vol. 44, no. 10, pp. 1147-1151. https://doi.org/10.1038/ng.2397

@article{6eedbea366404cc5a4ef2d39700344d2,

title = "Common variants at 6p21.1 are associated with large artery atherosclerotic stroke",

abstract = "Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR) = 1.62, P = 3.9 × 10-8) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR = 1.15, P = 3.9 × 10-4; discovery and replication combined OR = 1.21, P = 4.7 × 10-8). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.",

author = "Holliday, {Elizabeth G.} and Maguire, {Jane M.} and Evans, {Tiffany Jane} and Koblar, {Simon A.} and Jim Jannes and Sturm, {Jonathan W.} and Hankey, {Graeme J.} and Ross Baker and Jonathan Golledge and Parsons, {Mark W.} and Rainer Malik and Mark McEvoy and Erik Biros and Lewis, {Martin D.} and Lincz, {Lisa F.} and Roseanne Peel and Christopher Oldmeadow and Wayne Smith and Pablo Moscato and Simona Barlera and Steve Bevan and Bis, {Joshua C.} and Eric Boerwinkle and Boncoraglio, {Giorgio B.} and Brott, {Thomas G.} and Brown, {Robert D.} and Cheng, {Yu Ching} and Cole, {John W.} and Ioana Cotlarciuc and Devan, {William J.} and Myriam Fornage and Furie, {Karen L.} and S{\'o}lveig Gr{\'e}tarsd{\'o}ttir and Andreas Gschwendtner and Ikram, {M. Arfan} and Longstreth, {W. T.} and Meschia, {James F.} and Mitchell, {Braxton D.} and Mosley, {Thomas H.} and Nalls, {Michael A.} and Parati, {Eugenio A.} and Psaty, {Bruce M.} and Pankaj Sharma and Kari Stefansson and Gudmar Thorleifsson and Unnur Thorsteinsdottir and Matthew Traylor and Verhaaren, {Benjamin F.J.} and Wiggins, {Kerri L.} and Worrall, {Bradford B.} and Cathie Sudlow and Rothwell, {Peter M.} and Martin Farrall and Martin Dichgans and Jonathan Rosand and Markus, {Hugh S.} and Scott, {Rodney J.} and Christopher Levi and John Attia",

note = "Funding Information: A complete list of funding acknowledgments is included in the Supplementary Note. We are grateful to the participants with ischemic stroke and also to their families for participating in this study. Australian population control data were derived from the Hunter Community Study. We also thank the University of Newcastle for funding and the men and women of the Hunter region who participated in this study. This research was funded by grants from the Australian National Health and Medical Research Council (NHMRC; project grant 569257), the Australian National Heart Foundation (NHF; project grant G 04S 1623), the University of Newcastle, the Gladys M Brawn Fellowship scheme and the Vincent Fairfax Family Foundation in Australia. E.G.H. is supported by the Australian NHMRC Fellowship scheme. J.G. is supported by a Practitioner Fellowship from the NHMRC and a Senior Clinical Research Fellowship from the Australian Office of Health and Medical Research. The principal funding for the Wellcome Trust Case Control Consortium 2 (WTCCC2) ischemic stroke study was provided by the Wellcome Trust, as part of the WTCCC2 project (085475/B/ 08/Z, 085475/Z/08/Z and WT084724MA). This work was also supported by the European Community{\textquoteright}s Sixth Framework Programme (LSHM-CT-2007-037273), the Wellcome Trust core award (090532/Z/09/Z) and AstraZeneca. M. Farrall is a member of the Oxford British Heart Foundation (BHF) Centre of Research Excellence. The Siblings with Ischemic Stroke Study (SWISS) and the Ischemic Stroke Genetics Study (ISGS) were funded by grants from the US National Institute of Neurological Disorders and Stroke. Additional funding was provided by the US National Institute of Neurological Disorders and Stroke (U01NS069208). The Rotterdam Study received principal funding for this report from the Netherlands Heart Foundation (grant 2009B102).",

year = "2012",

month = oct,

doi = "10.1038/ng.2397",

language = "English (US)",

volume = "44",

pages = "1147--1151",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "10",

}

TY - JOUR

T1 - Common variants at 6p21.1 are associated with large artery atherosclerotic stroke

AU - Holliday, Elizabeth G.

AU - Maguire, Jane M.

AU - Evans, Tiffany Jane

AU - Koblar, Simon A.

AU - Jannes, Jim

AU - Sturm, Jonathan W.

AU - Hankey, Graeme J.

AU - Baker, Ross

AU - Golledge, Jonathan

AU - Parsons, Mark W.

AU - Malik, Rainer

AU - McEvoy, Mark

AU - Biros, Erik

AU - Lewis, Martin D.

AU - Lincz, Lisa F.

AU - Peel, Roseanne

AU - Oldmeadow, Christopher

AU - Smith, Wayne

AU - Moscato, Pablo

AU - Barlera, Simona

AU - Bevan, Steve

AU - Bis, Joshua C.

AU - Boerwinkle, Eric

AU - Boncoraglio, Giorgio B.

AU - Brott, Thomas G.

AU - Brown, Robert D.

AU - Cheng, Yu Ching

AU - Cole, John W.

AU - Cotlarciuc, Ioana

AU - Devan, William J.

AU - Fornage, Myriam

AU - Furie, Karen L.

AU - Grétarsdóttir, Sólveig

AU - Gschwendtner, Andreas

AU - Ikram, M. Arfan

AU - Longstreth, W. T.

AU - Meschia, James F.

AU - Mitchell, Braxton D.

AU - Mosley, Thomas H.

AU - Nalls, Michael A.

AU - Parati, Eugenio A.

AU - Psaty, Bruce M.

AU - Sharma, Pankaj

AU - Stefansson, Kari

AU - Thorleifsson, Gudmar

AU - Thorsteinsdottir, Unnur

AU - Traylor, Matthew

AU - Verhaaren, Benjamin F.J.

AU - Wiggins, Kerri L.

AU - Worrall, Bradford B.

AU - Sudlow, Cathie

AU - Rothwell, Peter M.

AU - Farrall, Martin

AU - Dichgans, Martin

AU - Rosand, Jonathan

AU - Markus, Hugh S.

AU - Scott, Rodney J.

AU - Levi, Christopher

AU - Attia, John

N1 - Funding Information: A complete list of funding acknowledgments is included in the Supplementary Note. We are grateful to the participants with ischemic stroke and also to their families for participating in this study. Australian population control data were derived from the Hunter Community Study. We also thank the University of Newcastle for funding and the men and women of the Hunter region who participated in this study. This research was funded by grants from the Australian National Health and Medical Research Council (NHMRC; project grant 569257), the Australian National Heart Foundation (NHF; project grant G 04S 1623), the University of Newcastle, the Gladys M Brawn Fellowship scheme and the Vincent Fairfax Family Foundation in Australia. E.G.H. is supported by the Australian NHMRC Fellowship scheme. J.G. is supported by a Practitioner Fellowship from the NHMRC and a Senior Clinical Research Fellowship from the Australian Office of Health and Medical Research. The principal funding for the Wellcome Trust Case Control Consortium 2 (WTCCC2) ischemic stroke study was provided by the Wellcome Trust, as part of the WTCCC2 project (085475/B/ 08/Z, 085475/Z/08/Z and WT084724MA). This work was also supported by the European Community’s Sixth Framework Programme (LSHM-CT-2007-037273), the Wellcome Trust core award (090532/Z/09/Z) and AstraZeneca. M. Farrall is a member of the Oxford British Heart Foundation (BHF) Centre of Research Excellence. The Siblings with Ischemic Stroke Study (SWISS) and the Ischemic Stroke Genetics Study (ISGS) were funded by grants from the US National Institute of Neurological Disorders and Stroke. Additional funding was provided by the US National Institute of Neurological Disorders and Stroke (U01NS069208). The Rotterdam Study received principal funding for this report from the Netherlands Heart Foundation (grant 2009B102).

PY - 2012/10

Y1 - 2012/10

N2 - Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR) = 1.62, P = 3.9 × 10-8) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR = 1.15, P = 3.9 × 10-4; discovery and replication combined OR = 1.21, P = 4.7 × 10-8). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.

AB - Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR) = 1.62, P = 3.9 × 10-8) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR = 1.15, P = 3.9 × 10-4; discovery and replication combined OR = 1.21, P = 4.7 × 10-8). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.

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JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

Common variants at 6p21.1 are associated with large artery atherosclerotic stroke

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