Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies

被引：93

作者：

Traylor, Matthew ^{[1
]}

Farrall, Martin ^{[2
,3
]}

Holliday, Elizabeth G. ^{[4
,5
]}

Sudlow, Cathie ^{[6
,7
]}

Hopewell, Jemma C. ^{[8
,9
]}

Cheng, Yu-Ching ^{[10
]}

Fomage, Myriam ^{[11
]}

Ikram, M. Arfan ^{[12
,13
,14
,15
]}

Malik, Rainer ^{[16
,17
]}

Bevan, Steve ^{[1
]}

Thorsteinsdottir, Unnur ^{[18
,19
]}

Nalls, Mike A. ^{[20
]}

Longstreth, W. T. ^{[21
,22
]}

Wiggins, Kerri L. ^{[23
]}

Yadav, Sunaina ^{[24
]}

Parati, Eugenio A. ^{[25
]}

DeStefano, Anita L. ^{[26
]}

Worrall, Bradford B. ^{[27
,28
]}

Kittner, Steven ^{[29
,30
]}

Khan, Muhammad Saleem ^{[24
]}

Reiner, Alex P. ^{[31
]}

Helgadottir, Anna ^{[3
,18
,19
]}

Achterberg, Sefanja ^{[32
]}

Fernandez-Cadenas, Israel ^{[33
,34
,35
]}

Abboud, Sherine ^{[36
]}

Schmidt, Reinhold ^{[37
]}

Walters, Matthew

Chen, Wei-Min ^{[28
,39
]}

Ringelstein, E. Bernd ^{[40
]}

O'Donnell, Martin ^{[41
]}

Ho, Weang Kee ^{[42
]}

Pera, Joanna ^{[43
]}

Lemmens, Robin ^{[44
,45
,46
]}

Norrving, Bo ^{[47
,48
]}

Higgins, Peter ^{[38
]}

Benn, Marianne ^{[49
,50
,51
]}

Sale, Michele ^{[39
,52
]}

Kuhlenbaeumer, Gregor ^{[53
]}

Doney, Alexander S. F. ^{[54
]}

Vicente, Astrid M. ^{[55
]}

Delavaran, Hossein ^{[47
,48
]}

Algra, Ale ^{[32
,56
]}

Davies, Gail ^{[57
,58
]}

Oliveira, Sofia A. ^{[59
]}

Palmer, Colin N. A. ^{[54
]}

Deary, Ian ^{[57
,58
]}

Schmidt, Helena ^{[60
]}

Pandolfo, Massimo ^{[36
]}

Montaner, Joan ^{[33
,34
,35
]}

Carty, Cara ^{[31
]}

机构：

[1] St Georges Univ London, Stroke & Dementia Res Ctr, London SW17 0RE, England

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

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

[4] Univ Newcastle, Sch Med & Publ Hlth, Ctr Clin Epidemiol & Biostat, Callaghan, NSW 2308, Australia

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

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

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

[8] Univ Oxford, Clin Trial Serv Unit, Oxford, England

[9] Univ Oxford, Epidemiol Studies Unit, Oxford, England

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

[11] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA

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

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

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

[15] Consortium Healthy Ageing, Leiden, Netherlands

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

[17] Munich Cluster Syst Neurol SyNergy, Munich, Germany

[18] DeCODE Genet, Reykjavik, Iceland

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

[20] NIA, Neurogenet Lab, Bethesda, MD 20892 USA

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

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

[23] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[24] Univ London Imperial Coll Sci Technol & Med, Cerebrovasc Res Unit ICCRU, London, England

[25] Ist Neurol Carlo Besta, Fdn Ist Ricovero Cura Carattere Sci IRCCS, Dept Cereberovasc Dis, Milan, Italy

[26] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

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

[28] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA

[29] Vet Affairs Med Ctr, Dept Neurol, Baltimore, MA USA

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

[31] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA

[32] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Utrecht Stroke Ctr, Dept Neurol & Neurosurg, Utrecht, Netherlands

[33] Univ Autonoma Barcelona, Neurovasc Res Lab, Dept Neurol, E-08193 Barcelona, Spain

[34] Univ Autonoma Barcelona, Dept Med, E-08193 Barcelona, Spain

[35] Vall dHebron Hosp, Inst Res, Barcelona, Spain

[36] Lab Expt Neurol, Brussels, Belgium

[37] Med Univ Graz, Dept Neurol, Div Neurogeriatr, Graz, Austria

[38] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland

[39] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA

[40] Univ Munster, Dept Neurol, D-4400 Munster, Germany

[41] Natl Univ Ireland Galway, Galway, Ireland

[42] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England

[43] Jagiellonian Univ, Dept Neurol, Krakow, Poland

[44] VIB, Vesalius Res Ctr, Neurobiol Lab, Louvain, Belgium

[45] Univ Leuven KU Leuven, Expt Neurol & Leuven Res Inst Neurodegenerat Dis, Louvain, Belgium

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

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

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

[49] Univ Copenhagen, Fac Hlth Sci, Copenhagen, Denmark

[50] Copenhagen Univ Hosp, Dept Clin Biochem, Copenhagen, Denmark

来源：

LANCET NEUROLOGY | 2012年 / 11卷 / 11期

基金：

美国国家卫生研究院; 英国医学研究理事会; 英国生物技术与生命科学研究理事会; 英国惠康基金; 澳大利亚国家健康与医学研究理事会;

关键词：

ATRIAL-FIBRILLATION; SEQUENCE VARIANT; PRKCH;

D O I：

暂无

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

100204 [神经病学];

摘要：

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 nudeotide 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=2.8x10(-16)) and ZFHX3 (p=2.28x10(-8)), and for large-vessel stroke at a 9p21 locus (p=3.32x10(-5)) and HDAC9 (p=2.03x10(-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<5x10(-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.

引用

页码：951 / 962

页数：12

共 31 条

[1]

CLASSIFICATION OF SUBTYPE OF ACUTE ISCHEMIC STROKE - DEFINITIONS FOR USE IN A MULTICENTER CLINICAL-TRIAL [J].

ADAMS, HP ;

BENDIXEN, BH ;

KAPPELLE, LJ ;

BILLER, J ;

LOVE, BB ;

GORDON, DL ;

MARSH, EE ;

KASE, CS ;

WOLF, PA ;

BABIKIAN, VL ;

LICATAGEHR, EE ;

ALLEN, N ;

BRASS, LM ;

FAYAD, PB ;

PAVALKIS, FJ ;

WEINBERGER, JM ;

TUHRIM, S ;

RUDOLPH, SH ;

HOROWITZ, DR ;

BITTON, A ;

MOHR, JP ;

SACCO, RL ;

CLAVIJO, M ;

ROSENBAUM, DM ;

SPARR, SA ;

KATZ, P ;

KLONOWSKI, E ;

CULEBRAS, A ;

CAREY, G ;

MARTIR, NI ;

FICARRA, C ;

HOGAN, EL ;

CARTER, T ;

GURECKI, P ;

MUNTZ, BK ;

RAMIREZLASSEPAS, M ;

TULLOCH, JW ;

QUINONES, MR ;

MENDEZ, M ;

ZHANG, SM ;

ALA, T ;

JOHNSTON, KC ;

ANDERSON, DC ;

TARREL, RM ;

NANCE, MA ;

BUDLIE, SR ;

DIERICH, M ;

HELGASON, CM ;

HIER, DB ;

SHAPIRO, RA .

STROKE, 1993, 24 (01) :35-41

[2]

A map of human genome variation from population-scale sequencing [J].

Altshuler, David ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Collins, Francis S. ;

De la Vega, Francisco M. ;

Donnelly, Peter ;

Egholm, Michael ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Knoppers, Bartha M. ;

Lander, Eric S. ;

Lehrach, Hans ;

Mardis, Elaine R. ;

McVean, Gil A. ;

Nickerson, DebbieA. ;

Peltonen, Leena ;

Schafer, Alan J. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Deiros, David ;

Metzker, Mike ;

Muzny, Donna ;

Reid, Jeff ;

Wheeler, David ;

Wang, Jun ;

Li, Jingxiang ;

Jian, Min ;

Li, Guoqing ;

Li, Ruiqiang ;

Liang, Huiqing ;

Tian, Geng ;

Wang, Bo ;

Wang, Jian ;

Wang, Wei ;

Yang, Huanming ;

Zhang, Xiuqing ;

Zheng, Huisong ;

Lander, Eric S. ;

Altshuler, David L. ;

Ambrogio, Lauren ;

Bloom, Toby ;

Cibulskis, Kristian ;

Fennell, Tim J. ;

Gabriel, Stacey B. .

NATURE, 2010, 467 (7319) :1061-1073

[3]

Integrating common and rare genetic variation in diverse human populations [J].

Altshuler, David M. ;

Gibbs, Richard A. ;

Peltonen, Leena ;

Dermitzakis, Emmanouil ;

Schaffner, Stephen F. ;

Yu, Fuli ;

Bonnen, Penelope E. ;

de Bakker, Paul I. W. ;

Deloukas, Panos ;

Gabriel, Stacey B. ;

Gwilliam, Rhian ;

Hunt, Sarah ;

Inouye, Michael ;

Jia, Xiaoming ;

Palotie, Aarno ;

Parkin, Melissa ;

Whittaker, Pamela ;

Chang, Kyle ;

Hawes, Alicia ;

Lewis, Lora R. ;

Ren, Yanru ;

Wheeler, David ;

Muzny, Donna Marie ;

Barnes, Chris ;

Darvishi, Katayoon ;

Hurles, Matthew ;

Korn, Joshua M. ;

Kristiansson, Kati ;

Lee, Charles ;

McCarroll, Steven A. ;

Nemesh, James ;

Keinan, Alon ;

Montgomery, Stephen B. ;

Pollack, Samuela ;

Price, Alkes L. ;

Soranzo, Nicole ;

Gonzaga-Jauregui, Claudia ;

Anttila, Verneri ;

Brodeur, Wendy ;

Daly, Mark J. ;

Leslie, Stephen ;

McVean, Gil ;

Moutsianas, Loukas ;

Nguyen, Huy ;

Zhang, Qingrun ;

Ghori, Mohammed J. R. ;

McGinnis, Ralph ;

McLaren, William ;

Takeuchi, Fumihiko ;

Grossman, Sharon R. .

NATURE, 2010, 467 (7311) :52-58

[4]

Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes [J].

Barrett, Jeffrey C. ;

Clayton, David G. ;

Concannon, Patrick ;

Akolkar, Beena ;

Cooper, Jason D. ;

Erlich, Henry A. ;

Julier, Cecile ;

Morahan, Grant ;

Nerup, Jorn ;

Nierras, Concepcion ;

Plagnol, Vincent ;

Pociot, Flemming ;

Schuilenburg, Helen ;

Smyth, Deborah J. ;

Stevens, Helen ;

Todd, John A. ;

Walker, Neil M. ;

Rich, Stephen S. .

NATURE GENETICS, 2009, 41 (06) :703-707

[5]

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

Bellenguez, Celine ;

Bevan, Steve ;

Gschwendtner, Andreas ;

Spencer, Chris C. A. ;

Burgess, Annette I. ;

Pirinen, Matti ;

Jackson, Caroline A. ;

Traylor, Matthew ;

Strange, Amy ;

Su, Zhan ;

Band, Gavin ;

Syme, Paul D. ;

Malik, Rainer ;

Pera, Joanna ;

Norrving, Bo ;

Lemmens, Robin ;

Freeman, Colin ;

Schanz, Renata ;

James, Tom ;

Poole, Deborah ;

Murphy, Lee ;

Segal, Helen ;

Cortellini, Lynelle ;

Cheng, Yu-Ching ;

Woo, Daniel ;

Nalls, Michael A. ;

Mueller-Myhsok, Bertram ;

Meisinger, Christa ;

Seedorf, Udo ;

Ross-Adams, Helen ;

Boonen, Steven ;

Wloch-Kopec, Dorota ;

Valant, Valerie ;

Slark, Julia ;

Furie, Karen ;

Delavaran, Hossein ;

Langford, Cordelia ;

Deloukas, Panos ;

Edkins, Sarah ;

Hunt, Sarah ;

Gray, Emma ;

Dronov, Serge ;

Peltonen, Leena ;

Gretarsdottir, Solveig ;

Thorleifsson, Gudmar ;

Thorsteinsdottir, Unnur ;

Stefansson, Kari ;

Boncoraglio, Giorgio B. ;

Parati, Eugenio A. ;

Attia, John .

NATURE GENETICS, 2012, 44 (03) :328-U141

[6]

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].

Burton, Paul R. ;

Clayton, David G. ;

Cardon, Lon R. ;

Craddock, Nick ;

Deloukas, Panos ;

Duncanson, Audrey ;

Kwiatkowski, Dominic P. ;

McCarthy, Mark I. ;

Ouwehand, Willem H. ;

Samani, Nilesh J. ;

Todd, John A. ;

Donnelly, Peter ;

Barrett, Jeffrey C. ;

Davison, Dan ;

Easton, Doug ;

Evans, David ;

Leung, Hin-Tak ;

Marchini, Jonathan L. ;

Morris, Andrew P. ;

Spencer, Chris C. A. ;

Tobin, Martin D. ;

Attwood, Antony P. ;

Boorman, James P. ;

Cant, Barbara ;

Everson, Ursula ;

Hussey, Judith M. ;

Jolley, Jennifer D. ;

Knight, Alexandra S. ;

Koch, Kerstin ;

Meech, Elizabeth ;

Nutland, Sarah ;

Prowse, Christopher V. ;

Stevens, Helen E. ;

Taylor, Niall C. ;

Walters, Graham R. ;

Walker, Neil M. ;

Watkins, Nicholas A. ;

Winzer, Thilo ;

Jones, Richard W. ;

McArdle, Wendy L. ;

Ring, Susan M. ;

Strachan, David P. ;

Pembrey, Marcus ;

Breen, Gerome ;

St Clair, David ;

Caesar, Sian ;

Gordon-Smith, Katherine ;

Jones, Lisa ;

Fraser, Christine ;

Green, Elain K. .

NATURE, 2007, 447 (7145) :661-678

[7]

Department of Health, 2005, RED BRAIN DAM FAST A

[8]

Genetic association studies in stroke methodological issues and proposed standard criteria [J].

Dichgans, M ;

Markus, HS .

STROKE, 2005, 36 (09) :2027-2031

[9]

Genetics of ischaemic stroke [J].

Dichgans, Martin .

LANCET NEUROLOGY, 2007, 6 (02) :149-161

[10]

Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci [J].

Franke, Andre ;

McGovern, Dermot P. B. ;

Barrett, Jeffrey C. ;

Wang, Kai ;

Radford-Smith, Graham L. ;

Ahmad, Tariq ;

Lees, Charlie W. ;

Balschun, Tobias ;

Lee, James ;

Roberts, Rebecca ;

Anderson, Carl A. ;

Bis, Joshua C. ;

Bumpstead, Suzanne ;

Ellinghaus, David ;

Festen, Eleonora M. ;

Georges, Michel ;

Green, Todd ;

Haritunians, Talin ;

Jostins, Luke ;

Latiano, Anna ;

Mathew, Christopher G. ;

Montgomery, Grant W. ;

Prescott, Natalie J. ;

Raychaudhuri, Soumya ;

Rotter, Jerome I. ;

Schumm, Philip ;

Sharma, Yashoda ;

Simms, Lisa A. ;

Taylor, Kent D. ;

Whiteman, David ;

Wijmenga, Cisca ;

Baldassano, Robert N. ;

Barclay, Murray ;

Bayless, Theodore M. ;

Brand, Stephan ;

Buening, Carsten ;

Cohen, Albert ;

Colombel, Jean-Frederick ;

Cottone, Mario ;

Stronati, Laura ;

Denson, Ted ;

De Vos, Martine ;

D'Inca, Renata ;

Dubinsky, Marla ;

Edwards, Cathryn ;

Florin, Tim ;

Franchimont, Denis ;

Gearry, Richard ;

Glas, Juergen ;

Van Gossum, Andre .

NATURE GENETICS, 2010, 42 (12) :1118-+

← 1 2 3 4 →