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

被引：168

作者：

Holliday, Elizabeth G. ^{[1
,2
]}

Maguire, Jane M. ^{[3
,4
,5
]}

Evans, Tiffany-Jane ^{[2
,6
]}

Koblar, Simon A. ^{[7
,8
]}

Jannes, Jim ^{[7
,8
]}

Sturm, Jonathan W. ^{[5
]}

Hankey, Graeme J. ^{[9
,10
]}

Baker, Ross ^{[11
,12
]}

Golledge, Jonathan ^{[13
,14
]}

Parsons, Mark W. ^{[4
]}

Malik, Rainer ^{[15
]}

McEvoy, Mark ^{[1
,16
]}

Biros, Erik ^{[13
]}

Lewis, Martin D. ^{[7
,17
]}

Lincz, Lisa F. ^{[4
,6
,18
]}

Peel, Roseanne ^{[1
,16
]}

Oldmeadow, Christopher ^{[19
]}

Smith, Wayne ^{[16
]}

Moscato, Pablo ^{[2
,20
]}

Barlera, Simona ^{[21
]}

Bevan, Steve ^{[22
]}

Bis, Joshua C. ^{[23
]}

Boerwinkle, Eric ^{[24
,25
]}

Boncoraglio, Giorgio B. ^{[26
]}

Brott, Thomas G. ^{[27
]}

Brown, Robert D., Jr. ^{[28
]}

Cheng, Yu-Ching ^{[29
]}

Cole, John W. ^{[30
,31
]}

Cotlarciuc, Ioana ^{[32
]}

Devan, William J. ^{[33
,34
,35
]}

Fornage, Myriam ^{[24
,25
]}

Furie, Karen L. ^{[34
,35
]}

Gretarsdottir, Solveig ^{[36
]}

Gschwendtner, Andreas ^{[15
]}

Ikram, M. Arfan ^{[37
,38
,39
]}

Longstreth, W. T., Jr. ^{[40
,41
,42
]}

Meschia, James F. ^{[27
]}

Mitchell, Braxton D. ^{[29
]}

Mosley, Thomas H. ^{[43
]}

Nalls, Michael A. ^{[44
]}

Parati, Eugenio A. ^{[26
]}

Psaty, Bruce M. ^{[23
,40
,45
,46
]}

Sharma, Pankaj ^{[32
]}

Stefansson, Kari ^{[36
,47
]}

Thorleifsson, Gudmar ^{[36
]}

Thorsteinsdottir, Unnur ^{[36
,47
]}

Traylor, Matthew ^{[22
]}

Verhaaren, Benjamin F. J. ^{[37
,39
]}

Wiggins, Kerri L. ^{[23
]}

Worrall, Bradford B. ^{[48
]}

机构：

[1] Univ Newcastle, Sch Med & Publ Hlth, Ctr Clin Epidemiol & Biostat, Newcastle, NSW 2300, Australia

[2] Hunter Med Res Inst, Ctr Bioinformat Biomarker Discovery & Informat Ba, Newcastle, NSW, Australia

[3] Univ Newcastle, Sch Nursing & Midwifery, Newcastle, NSW 2300, Australia

[4] Univ Newcastle, Ctr Brain & Mental Hlth Res, Newcastle, NSW 2300, Australia

[5] Gosford Hosp, Cent Coast Area Hlth, Dept Neurosci, Gosford, NSW, Australia

[6] Univ Newcastle, Sch Biomed Sci & Pharm, Newcastle, NSW 2300, Australia

[7] Univ Adelaide, Sch Med, Stroke Res Program, Adelaide, SA, Australia

[8] Queen Elizabeth Hosp, Dept Neurol, Stroke Unit, Adelaide, SA, Australia

[9] Royal Perth Hosp, Dept Neurol, Perth, WA, Australia

[10] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia

[11] Royal Perth Hosp, Dept Haematol, Perth, WA, Australia

[12] Murdoch Univ, Ctr Thrombosis & Haemophilia, Perth, WA, Australia

[13] James Cook Univ, Sch Med & Dent, Vasc Biol Unit, Townsville, Qld, Australia

[14] Townsville Hosp, Dept Vasc Surg, Townsville, Qld, Australia

[15] Univ Munich, Inst Stroke & Dementia Res ISD, Med Ctr, Klinikum Univ Munchen, Munich, Germany

[16] Hunter Med Res Inst, Publ Hlth Res Program, Newcastle, NSW, Australia

[17] Univ Adelaide, Discipline Genet, Sch Mol & Biomed Sci, Adelaide, SA, Australia

[18] Calvary Mater Newcastle Hosp, Hunter Haematol Res Grp, Newcastle, NSW, Australia

[19] Hunter Med Res Inst, Clin Res Design IT & Stat Support Unit, Newcastle, NSW, Australia

[20] Univ Newcastle, Sch Elect Engn & Comp Sci, Newcastle, NSW 2300, Australia

[21] Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy

[22] St Georges Univ London, Stroke & Dementia Res Ctr, London, England

[23] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[24] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA

[25] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX USA

[26] Ist Neurol Carlo Besta, Dept Cerebrovasc Dis, Fdn Ist Ricovero & Cura Carattere Sci IRCCS, Milan, Italy

[27] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA

[28] Mayo Clin, Dept Neurol, Rochester, MN USA

[29] Univ Maryland, Dept Med, Baltimore, MD 21201 USA

[30] Baltimore Vet Affairs Med Ctr, Baltimore, MD USA

[31] Univ Maryland, Sch Med, Baltimore, MD 21201 USA

[32] Univ London Imperial Coll Sci Technol & Med, ICCRU, London, England

[33] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[34] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[35] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA

[36] deCODE Genet, Reykjavik, Iceland

[37] Univ Med Ctr, Erasmus Med Ctr MC, Dept Epidemiol, Rotterdam, Netherlands

[38] Erasmus MC Univ Med Ctr, Dept Neurol, Rotterdam, Netherlands

[39] Erasmus MC Univ Med Ctr, Dept Radiol, Rotterdam, Netherlands

[40] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[41] Univ Washington, Dept Med, Seattle, WA USA

[42] Univ Washington, Dept Neurol, Seattle, WA 98195 USA

[43] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA

[44] NIA, Lab Neurogenet, US Natl Inst Hlth, Bethesda, MD 20892 USA

[45] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA

[46] Grp Hlth Res Inst, Grp Hlth, Seattle, WA USA

[47] Univ Iceland, Fac Med, Reykjavik, Iceland

[48] Univ Virginia, Dept Neurol, Charlottesville, VA USA

[49] Univ Edinburgh, Div Clin Neurosci, Edinburgh, Midlothian, Scotland

[50] Univ Edinburgh, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

来源：

NATURE GENETICS | 2012年 / 44卷 / 10期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; L GENE-CLUSTER; ISCHEMIC-STROKE; HERITABILITY; RISK; CLASSIFICATION; VISUALIZATION; METAANALYSIS; PHENOTYPES; LESIONS;

D O I：

10.1038/ng.2397

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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 x 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 x 10(-4); discovery and replication combined OR = 1.21, P = 4.7 x 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.

引用

页码：1147 / +

页数：7

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