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

被引：347

作者：

Bellenguez, Celine ^{[1
]}

Bevan, Steve ^{[2
]}

Gschwendtner, Andreas ^{[3
]}

Spencer, Chris C. A. ^{[1
]}

Burgess, Annette I. ^{[4
]}

Pirinen, Matti ^{[1
]}

Jackson, Caroline A. ^{[5
]}

Traylor, Matthew ^{[2
]}

Strange, Amy ^{[1
]}

Su, Zhan ^{[1
]}

Band, Gavin ^{[1
]}

Syme, Paul D. ^{[6
]}

Malik, Rainer ^{[3
]}

Pera, Joanna ^{[7
]}

Norrving, Bo ^{[8
,9
]}

Lemmens, Robin ^{[10
,11
]}

Freeman, Colin ^{[1
]}

Schanz, Renata ^{[12
]}

James, Tom ^{[2
]}

Poole, Deborah ^{[4
]}

Murphy, Lee ^{[13
]}

Segal, Helen ^{[4
]}

Cortellini, Lynelle ^{[14
,15
]}

Cheng, Yu-Ching ^{[16
,17
]}

Woo, Daniel ^{[18
]}

Nalls, Michael A. ^{[19
]}

Mueller-Myhsok, Bertram ^{[20
]}

Meisinger, Christa ^{[21
]}

Seedorf, Udo ^{[22
]}

Ross-Adams, Helen ^{[7
]}

Boonen, Steven ^{[23
]}

Wloch-Kopec, Dorota ^{[7
]}

Valant, Valerie ^{[14
,15
]}

Slark, Julia ^{[12
]}

Furie, Karen ^{[14
]}

Delavaran, Hossein ^{[8
,9
]}

Langford, Cordelia ^{[24
]}

Deloukas, Panos ^{[24
]}

Edkins, Sarah ^{[24
]}

Hunt, Sarah ^{[24
]}

Gray, Emma ^{[24
]}

Dronov, Serge ^{[24
]}

Peltonen, Leena ^{[24
]}

Gretarsdottir, Solveig ^{[25
]}

Thorleifsson, Gudmar ^{[25
]}

Thorsteinsdottir, Unnur ^{[25
,26
]}

Stefansson, Kari ^{[25
,26
]}

Boncoraglio, Giorgio B. ^{[27
]}

Parati, Eugenio A. ^{[27
]}

Attia, John ^{[28
]}

机构：

[1] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[2] St Georges Univ London, Stroke & Dementia Res Grp, London, England

[3] Univ Munich, Univ Munchen Klinikum, Inst Stroke & Dementia Res, Munich, Germany

[4] Univ Oxford, Nuffield Dept Clin Neurosci, Stroke Prevent Res Unit, Oxford, England

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

[6] Univ Aberdeen, Div Appl Med, Aberdeen, Scotland

[7] Jagiellonian Univ, Coll Med, Dept Neurol, Krakow, Poland

[8] Lund Univ, Dept Clin Sci, Lund, Sweden

[9] Skane Univ Hosp, Dept Neurol, Lund, Sweden

[10] Univ Hosp Leuven, Dept Neurol, Louvain, Belgium

[11] VIB, Vesalius Res Ctr, Louvain, Belgium

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

[13] Univ Edinburgh, Western Gen Hosp, Wellcome Trust Clin Res Facil Genet Core Lab, Edinburgh, Midlothian, Scotland

[14] Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, Boston, MA 02114 USA

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

[16] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA

[17] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA

[18] Univ Cincinnati, Coll Med, Dept Neurol, Cincinnati, OH USA

[19] NIA, Neurogenet Lab, Intramural Res Program, Bethesda, MD 20892 USA

[20] Max Planck Inst Psychiat, D-80804 Munich, Germany

[21] German Res Ctr Environm Hlth, Inst Epidemiol 2, Helmholtz Zentrum Munchen, Neuherberg, Germany

[22] Univ Munster, Leibniz Inst Arterioskleroseforsch, Munster, Germany

[23] Univ Hosp Leuven, Div Geriatr Med, Louvain, Belgium

[24] Wellcome Trust Sanger Inst, Cambridge, England

[25] deCODE Genet, Reykjavik, Iceland

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

[27] Fdn Ist Ricovero & Cura Carattere Sci IRCCS, Ist Neurol Carlo Besta, Milan, Italy

[28] Univ Newcastle, Hunter Med Res Inst, Ctr Brain & Mental Hlth Res, Newcastle, NSW 2300, Australia

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

[30] Univ Oxford, Dept Cardiovasc Med, Oxford, England

[31] Univ Western Australia, Ctr Child Hlth Res, Perth, WA, Australia

[32] Univ Cambridge, Sch Clin Med, Cambridge Inst Med Res, Cambridge, England

[33] Kings Coll London, Inst Psychiat, Biomed Res Ctr Mental Hlth, Div Psychol Med & Psychiat, London WC2R 2LS, England

[34] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld, Australia

[35] London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1, England

[36] UCL, Dept Epidemiol & Publ Hlth, London, England

[37] Trinity Coll Dublin, Inst Mol Med, Neuropsychiat Genet Res Grp, Dublin, Ireland

[38] Wellcome Trust Res Labs, London, England

[39] Barts & London Queen Marys Sch Med & Dent, Ctr Gastroenterol, London, England

[40] Univ Oxford, Div Clin Pharmacol, Oxford, England

[41] Kings Coll London, Guys Hosp, Sch Med, Dept Med & Mol Genet, London WC2R 2LS, England

[42] Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Ctr, Dundee DD1 9SY, Scotland

[43] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England

[44] Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Cambridge CB2 2QQ, England

[45] Natl Hlth Serv NHS Fdn Trust, Moorfields Eye Hosp, Biomed Res Ctr Ophthalmol, Natl Inst Hlth Res NIHR, London, England

[46] UCL, Inst Ophthalmol, London, England

[47] UCL, Inst Neurol, Dept Mol Neuroscience, London, England

[48] Univ Virginia, Sch Med, Dept Neurol, Charlottesville, VA 22908 USA

[49] Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA

[50] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA

来源：

NATURE GENETICS | 2012年 / 44卷 / 03期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

ATRIAL-FIBRILLATION; HISTONE DEACETYLASES; SUSCEPTIBILITY LOCI; ALGORITHM; GENETICS; DISEASE; SIGNALS; ROLES; RISK;

D O I：

10.1038/ng.1081

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 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.

引用

页码：328 / U141

页数：8

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