Shared Genetic Susceptibility to Ischemic Stroke and Coronary Artery Disease A Genome-Wide Analysis of Common Variants

被引：266

作者：

Dichgans, Martin ^{[1
,2
]}

Malik, Rainer ^{[1
]}

Koenig, Inke R. ^{[3
,5
]}

Rosand, Jonathan ^{[6
,7
,9
,10
]}

Clarke, Robert ^{[12
,13
]}

Gretarsdottir, Solveig ^{[17
]}

Thorleifsson, Gudmar ^{[17
]}

Mitchell, Braxton D. ^{[18
]}

Assimes, Themistocles L. ^{[19
]}

Levi, Christopher ^{[20
,21
]}

O'Donnell, Christopher J. ^{[8
,22
,23
]}

Fornage, Myriam ^{[24
]}

Thorsteinsdottir, Unnur ^{[17
]}

Psaty, Bruce M. ^{[25
,26
,27
,29
]}

Hengstenberg, Christian ^{[30
]}

Seshadri, Sudha ^{[22
,23
,31
]}

Erdmann, Jeanette ^{[4
,32
]}

Bis, Joshua C. ^{[28
]}

Peters, Annette ^{[33
]}

Boncoraglio, Giorgio B. ^{[34
]}

Maerz, Winfried ^{[35
]}

Meschia, James F. ^{[36
]}

Kathiresan, Sekar ^{[11
,37
,38
,39
]}

Ikram, M. Arfan ^{[40
,41
,42
,43
]}

McPherson, Ruth

Stefansson, Kari ^{[17
,45
]}

Sudlow, Cathie ^{[46
,47
]}

Reilly, Muredach P. ^{[48
]}

Thompson, John R. ^{[49
]}

Sharma, Pankaj ^{[52
]}

Hopewell, Jemma C. ^{[12
,13
]}

Chambers, John C. ^{[53
]}

Watkins, Hugh ^{[14
]}

Rothwell, Peter M. ^{[16
]}

Roberts, Robert ^{[44
]}

Markus, Hugh S. ^{[54
]}

Samani, Nilesh J. ^{[50
,51
]}

Farrall, Martin ^{[14
,15
]}

Schunkert, Heribert ^{[55
,56
]}

机构：

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

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

[3] Med Univ Lubeck, Inst Med Biometrie & Stat, D-23538 Lubeck, Germany

[4] Med Univ Lubeck, Inst Integrat & Expt Genom, D-23538 Lubeck, Germany

[5] Univ Klinikum Schleswig Holstein, Lubeck, Germany

[6] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

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

[8] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA

[9] Harvard Univ, Sch Med, Boston, MA USA

[10] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA

[11] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA

[12] Univ Oxford, John Radcliffe Hosp, Clin Trial Serv Unit, Oxford OX3 9DU, England

[13] Univ Oxford, John Radcliffe Hosp, Epidemiol Studies Unit, Oxford OX3 9DU, England

[14] Univ Oxford, John Radcliffe Hosp, Wellcome Trust Ctr Human Genet, Oxford OX3 9DU, England

[15] Univ Oxford, John Radcliffe Hosp, Dept Cardiovasc Med, Oxford OX3 9DU, England

[16] Univ Oxford, John Radcliffe Hosp, Stroke Prevent Res Unit, Nuffield Dept Clin Neurosci, Oxford OX3 9DU, England

[17] DeCODE Genet, Reykjavik, Iceland

[18] Univ Maryland Sch Med, Dept Med, Baltimore, MD USA

[19] Stanford Univ Sch Med, Dept Med, Stanford, CA USA

[20] Univ Newcastle, Ctr Translat Neurosci & Mental Hlth Res, Callaghan, NSW 2308, Australia

[21] Hunter Med Res Inst, New Lambton, NSW, Australia

[22] NHLBI, Bethesda, MA USA

[23] NHLBI, Framingham Heart Study, Bethesda, MA USA

[24] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA

[25] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

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

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

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

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

[30] Klin & Poliklin Innere Med II, Regensburg, Germany

[31] Boston Univ Sch Med, Dept Neurol, Boston, MA USA

[32] DZHK German Ctr Cardiovasc Res, Lubeck, Germany

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

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

[35] Synlab Acad, Mannheim, Germany

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

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

[38] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA

[39] Harvard Univ, Sch Med, Boston, MA USA

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

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

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

[43] Netherlands Consortium Hlth Aging, Leiden, Netherlands

[44] Univ Ottawa Heart Inst, John & Jennifer Ruddy Canadian Cardiovasc Genet C, Ottawa, ON, Canada

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

[46] Univ Edinburgh, Div Clin Neurosci, Edinburgh EH8 9YL, Midlothian, Scotland

[47] Univ Edinburgh, Inst Genet & Mol Med, Edinburgh EH8 9YL, Midlothian, Scotland

[48] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA

[49] Univ Leicester, Glenfield Hosp, Dept Hlth Sci, Leicester, Leics, England

[50] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England

来源：

STROKE | 2014年 / 45卷 / 01期

基金：

加拿大健康研究院; 英国惠康基金; 英国医学研究理事会; 美国国家卫生研究院; 加拿大创新基金会; 瑞典研究理事会;

关键词：

coronary artery disease; genetics; meta-analysis; polymorphism; single nucleotide; stroke; ASSOCIATION; METAANALYSIS; RISK; LOCI; PRESSURE; DESIGN;

D O I：

10.1161/STROKEAHA.113.002707

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Background and Purpose Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. Methods Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype. Results Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5x10(-8)) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (P-IS=1.62x10(-7)) and ABO (P-IS=2.6x10(-4)), as well as at HDAC9 (P-LAS=2.32x10(-12)), 9p21 (P-LAS=3.70x10(-6)), RAI1-PEMT-RASD1 (P-LAS=2.69x10(-5)), EDNRA (P-LAS=7.29x10(-4)), and CYP17A1-CNNM2-NT5C2 (P-LAS=4.9x10(-4)). Conclusions Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.

引用

页码：24 / 36

页数：13

共 31 条

[1] Familial History of Stroke Is Associated With Acute Coronary Syndromes in Women [J].

Banerjee, Amitava ;

Lim, Chris C. S. ;

Silver, Louise E. ;

Welch, Sarah J. V. ;

Banning, Adrian P. ;

Rothwell, Peter M. .

CIRCULATION-CARDIOVASCULAR GENETICS, 2011, 4 (01) :9-15

[2] 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

[3] Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque [J].

Bis, Joshua C. ;

Kavousi, Maryam ;

Franceschini, Nora ;

Isaacs, Aaron ;

Abecasis, Goncalo R. ;

Schminke, Ulf ;

Post, Wendy S. ;

Smith, Albert V. ;

Cupples, L. Adrienne ;

Markus, Hugh S. ;

Schmidt, Reinhold ;

Huffman, Jennifer E. ;

Lehtimaki, Terho ;

Baumert, Jens ;

Muenzel, Thomas ;

Heckbert, Susan R. ;

Dehghan, Abbas ;

North, Kari ;

Oostra, Ben ;

Bevan, Steve ;

Stoegerer, Eva-Maria ;

Hayward, Caroline ;

Raitakari, Olli ;

Meisinger, Christa ;

Schillert, Arne ;

Sanna, Serena ;

Voelzke, Henry ;

Cheng, Yu-Ching ;

Thorsson, Bolli ;

Fox, Caroline S. ;

Rice, Kenneth ;

Rivadeneira, Fernando ;

Nambi, Vijay ;

Halperin, Eran ;

Petrovic, Katja E. ;

Peltonen, Leena ;

Wichmann, H. Erich ;

Schnabel, Renate B. ;

Doerr, Marcus ;

Parsa, Afshin ;

Aspelund, Thor ;

Demissie, Serkalem ;

Kathiresan, Sekar ;

Reilly, Muredach P. ;

Taylor, Kent ;

Uitterlinden, Andre ;

Couper, David J. ;

Sitzer, Matthias ;

Kahonen, Mika ;

Illig, Thomas .

NATURE GENETICS, 2011, 43 (10) :940-U40

[4] EPIDEMIOLOGY OF STROKE [J].

BONITA, R .

LANCET, 1992, 339 (8789) :342-344

[5] Large-scale association analysis identifies new risk loci for coronary artery disease [J].

Deloukas, Panos ;

Kanoni, Stavroula ;

Willenborg, Christina ;

Farrall, Martin ;

Assimes, Themistocles L. ;

Thompson, John R. ;

Ingelsson, Erik ;

Saleheen, Danish ;

Erdmann, Jeanette ;

Goldstein, Benjamin A. ;

Stirrups, Kathleen ;

Koenig, Inke R. ;

Cazier, Jean-Baptiste ;

Johansson, Asa ;

Hall, Alistair S. ;

Lee, Jong-Young ;

Willer, Cristen J. ;

Chambers, John C. ;

Esko, Tonu ;

Folkersen, Lasse ;

Goel, Anuj ;

Grundberg, Elin ;

Havulinna, Aki S. ;

Ho, Weang K. ;

Hopewell, Jemma C. ;

Eriksson, Niclas ;

Kleber, Marcus E. ;

Kristiansson, Kati ;

Lundmark, Per ;

Lyytikainen, Leo-Pekka ;

Rafelt, Suzanne ;

Shungin, Dmitry ;

Strawbridge, Rona J. ;

Thorleifsson, Gudmar ;

Tikkanen, Emmi ;

Van Zuydam, Natalie ;

Voight, Benjamin F. ;

Waite, Lindsay L. ;

Zhang, Weihua ;

Ziegler, Andreas ;

Absher, Devin ;

Altshuler, David ;

Balmforth, Anthony J. ;

Barroso, Ines ;

Braund, Peter S. ;

Burgdorf, Christof ;

Claudi-Boehm, Simone ;

Cox, David ;

Dimitriou, Maria ;

Do, Ron .

NATURE GENETICS, 2013, 45 (01) :25-U52

[6] Genetics of ischaemic stroke [J].

Dichgans, Martin .

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

[7] Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk [J].

Ehret, Georg B. ;

Munroe, Patricia B. ;

Rice, Kenneth M. ;

Bochud, Murielle ;

Johnson, Andrew D. ;

Chasman, Daniel I. ;

Smith, Albert V. ;

Tobin, Martin D. ;

Verwoert, Germaine C. ;

Hwang, Shih-Jen ;

Pihur, Vasyl ;

Vollenweider, Peter ;

O'Reilly, Paul F. ;

Amin, Najaf ;

Bragg-Gresham, Jennifer L. ;

Teumer, Alexander ;

Glazer, Nicole L. ;

Launer, Lenore ;

Zhao, Jing Hua ;

Aulchenko, Yurii ;

Heath, Simon ;

Sober, Siim ;

Parsa, Afshin ;

Luan, Jian'an ;

Arora, Pankaj ;

Dehghan, Abbas ;

Zhang, Feng ;

Lucas, Gavin ;

Hicks, Andrew A. ;

Jackson, Anne U. ;

Peden, John F. ;

Tanaka, Toshiko ;

Wild, Sarah H. ;

Rudan, Igor ;

Igl, Wilmar ;

Milaneschi, Yuri ;

Parker, Alex N. ;

Fava, Cristiano ;

Chambers, John C. ;

Fox, Ervin R. ;

Kumari, Meena ;

Go, Min Jin ;

van der Harst, Pim ;

Kao, Wen Hong Linda ;

Sjogren, Marketa ;

Vinay, D. G. ;

Alexander, Myriam ;

Tabara, Yasuharu ;

Shaw-Hawkins, Sue ;

Whincup, Peter H. .

NATURE, 2011, 478 (7367) :103-109

[8] Sequence Variants on Chromosome 9p21.3 Confer Risk for Atherosclerotic Stroke [J].

Gschwendtner, Andreas ;

Bevan, Steve ;

Cole, John W. ;

Plourde, Anna ;

Matarin, Mar ;

Ross-Adams, Helen ;

Meitinger, Thomas ;

Wichmann, Erich ;

Mitchell, Braxton D. ;

Furie, Karen ;

Slowik, Agnieszka ;

Rich, Stephen S. ;

Syme, Paul D. ;

MacLeod, Mary J. ;

Meschia, James F. ;

Rosand, Jonathan ;

Kittner, Steve J. ;

Markus, Hugh S. ;

Mueller-Myhsok, Bertram ;

Dichgans, Martin .

ANNALS OF NEUROLOGY, 2009, 65 (05) :531-539

[9] Common variants at 6p21.1 are associated with large artery atherosclerotic stroke [J].

Holliday, Elizabeth G. ;

Maguire, Jane M. ;

Evans, Tiffany-Jane ;

Koblar, Simon A. ;

Jannes, Jim ;

Sturm, Jonathan W. ;

Hankey, Graeme J. ;

Baker, Ross ;

Golledge, Jonathan ;

Parsons, Mark W. ;

Malik, Rainer ;

McEvoy, Mark ;

Biros, Erik ;

Lewis, Martin D. ;

Lincz, Lisa F. ;

Peel, Roseanne ;

Oldmeadow, Christopher ;

Smith, Wayne ;

Moscato, Pablo ;

Barlera, Simona ;

Bevan, Steve ;

Bis, Joshua C. ;

Boerwinkle, Eric ;

Boncoraglio, Giorgio B. ;

Brott, Thomas G. ;

Brown, Robert D., Jr. ;

Cheng, Yu-Ching ;

Cole, John W. ;

Cotlarciuc, Ioana ;

Devan, William J. ;

Fornage, Myriam ;

Furie, Karen L. ;

Gretarsdottir, Solveig ;

Gschwendtner, Andreas ;

Ikram, M. Arfan ;

Longstreth, W. T., Jr. ;

Meschia, James F. ;

Mitchell, Braxton D. ;

Mosley, Thomas H. ;

Nalls, Michael A. ;

Parati, Eugenio A. ;

Psaty, Bruce M. ;

Sharma, Pankaj ;

Stefansson, Kari ;

Thorleifsson, Gudmar ;

Thorsteinsdottir, Unnur ;

Traylor, Matthew ;

Verhaaren, Benjamin F. J. ;

Wiggins, Kerri L. ;

Worrall, Bradford B. .

NATURE GENETICS, 2012, 44 (10) :1147-+

[10] Genomewide Association Studies of Stroke [J].

Ikram, M. Arfan ;

Seshadri, Sudha ;

Bis, Joshua C. ;

Fornage, Myriam ;

DeStefano, Anita L. ;

Aulchenko, Yurii S. ;

Debette, Stephanie ;

Lumley, Thomas ;

Folsom, Aaron R. ;

van den Herik, Evita G. ;

Bos, Michiel J. ;

Beiser, Alexa ;

Cushman, Mary ;

Launer, Lenore J. ;

Shahar, Eyal ;

Struchalin, Maksim ;

Du, Yangchun ;

Glazer, Nicole L. ;

Rosamond, Wayne D. ;

Rivadeneira, Fernando ;

Kelly-Hayes, Margaret ;

Lopez, Oscar L. ;

Coresh, Josef ;

Hofman, Albert ;

DeCarli, Charles ;

Heckbert, Susan R. ;

Koudstaal, Peter J. ;

Yang, Qiong ;

Smith, Nicholas L. ;

Kase, Carlos S. ;

Rice, Kenneth ;

Haritunians, Talin ;

Roks, Gerwin ;

de Kort, Paul L. M. ;

Taylor, Kent D. ;

de Lau, Lonneke M. ;

Oostra, Ben A. ;

Uitterlinden, Andre G. ;

Rotter, Jerome I. ;

Boerwinkle, Eric ;

Psaty, Bruce M. ;

Mosley, Thomas H. ;

van Duijn, Cornelia M. ;

Breteler, Monique M. B. ;

Longstreth, W. T., Jr. ;

Wolf, Philip A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2009, 360 (17) :1718-1728

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