Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants

被引：872

作者：

Kathiresan, Sekar ^{[1
]}

Altschuler, David

Anand, Sonia

Ardissino, Diego

Asselta, Rosanna

Ball, Stephen G.

Balmforth, Anthony J.

Berger, Klaus

Berglund, Goran

Bernardi, Francesco

Bernardinelli, Luisa

Berzuini, Carlo

Braund, Peter S.

Burnett, Mary-Susan

Burtt, Noel

Cambien, Francois

Casari, Giorgio

Celli, Patrizia

Chen, Zhen

Corrocher, Roberto

Daly, Mark J.

Deloukas, Panos

Devaney, Joe

Do, Ron

Duga, Stefano

Elosua, Roberto

Engert, James C.

Epstein, Stephen E.

Erdmann, Jeanette

Ferrario, Maurizio

Fetiveau, Raffaela

Fischer, Marcus

Friedlander, Yechiel

Gabriel, Stacey B.

Galli, Michele

Gianniny, Lauren

Girelli, Domenico

Grosshennig, Anika

Guiducci, Candace

Hakonarson, Hakon H.

Hall, Alistair S.

Havulinna, Aki S.

Hengstenberg, Christian

Hirschhorn, Joel N.

Holm, Hilma

Huge, Andreas

Kent, Kenneth M.

Konig, Inke R.

Korn, Joshua M.

Li, Mingyao

机构：

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

[2] Massachusetts Gen Hosp, Ctr Hum Genet Res, Boston, MA 02114 USA

[3] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA

[4] Massachusetts Gen Hosp, Diabet Ctr, Boston, MA 02114 USA

[5] Massachusetts Gen Hosp, Dept Med, Gen Med Div, Boston, MA 02114 USA

[6] Broad Inst MIT & Harvard, Prgm Med Populat Genet, Cambridge, MA 02142 USA

[7] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[8] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA

[9] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA

[10] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[11] Univ Parma, Azienda Osped, I-43100 Parma, Italy

[12] Univ Milan, Dept Intern Med & Med Specialities, Fdn Ist Ricov & Cura Carattere Sci, Osped Maggiore Mangiagalle & Regina Elena, I-20122 Milan, Italy

[13] Univ Milan, Dept Biol Genet Med Sci, I-20133 Milan, Italy

[14] McMaster Univ, Populat Hlth Res Inst, Hamilton Hlth Sci, Hamilton, ON L8L 2X2, Canada

[15] McMaster Univ, Hamilton Hlth Sci, Dept Med, Hamilton, ON L8L 2X2, Canada

[16] McMaster Univ, Hamilton Hlth Sci, Dept Clin Epidemiol, Hamilton, ON L8L 2X2, Canada

[17] McMaster Univ, Hamilton Hlth Sci, Dept Biostatist, Hamilton, ON L8L 2X2, Canada

[18] McGill Univ, Dept Med, Quebec City, PQ H3A 1A1, Canada

[19] McGill Univ, Dept Human Genet, Quebec City, PQ H3A 1A1, Canada

[20] Azienda Osped Niguarda Ca Granda, Div Cardiol, I-20162 Milan, Italy

[21] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Cardiovasc Endocrinol Sect, Boston, MA 02115 USA

[22] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA

[23] Univ Kiel, Inst Klin Molekularbiol, D-24105 Kiel, Germany

[24] CIBER Epidemiol & Salud Publ, Barcelona 08003, Spain

[25] Ctr Mathemat Sci, Stat Lab, Cambridge CB3 0WA, England

[26] deCODE Genet Inc, IS-101 Reykjavik, Iceland

[27] Framingham Heart Study &, Natl Heart Lung Blood Inst, Framingham, MA 01702 USA

[28] Hebrew Univ Hadassah Sch Publ Hlth, Epidemiol, IL-91120 Jerusalem, Israel

[29] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol, D-85764 Neuherberg, Germany

[30] Hosp Girona Josep Trueta, Cardiol, Coronar, Girona 17007, Spain

[31] Inst Catala Salut, IDIAP Jordi Gol, Barcelona 08007, Spain

[32] Inst Invest Biomed Girona, Girona 17007, Spain

[33] Inst Municip Invest Med, Cardiovasc Epidemiol & Genet, Barcelona 08003, Spain

[34] Ist Clin Humanitas, Fdn Ist Ricov & Cura Carrattere Sci, Div Cardiol, I-20089 Milan, Italy

[35] Ludwig Maximilians Univ Munchen, Inst Med Inform Sci Biometr & Epidemiol, D-81377 Munich, Germany

[36] Lund Univ, Univ Hosp Malmo, Dept Clin Sci Hypertens & Cardiovasc Dis, S-20502 Malmo, Sweden

[37] Lund Univ, Univ Hosp Malmo, Dept Clin Sci, Int Med, S-20502 Malmo, Sweden

[38] MRC, Biostat Unit, Cambridge, England

[39] Mid America Heart Inst & Univ Missouri, Kansas City, MO 64111 USA

[40] Natl Publ Hlth Inst, Dept Hlth Promot & Chron Dis Prevent, Helsinki 00300, Finland

[41] Osped Livorno, Div Cardiol, I-57100 Livorno, Italy

[42] Osped San Camillo, Div Cardiol, I-00151 Rome, Italy

[43] Osped San Filippo Neri, Div Cardiol, I-00135 Rome, Italy

[44] Policlin San Matteo, Fdn Ist Ricov & Cura Carrattere Sci, I-27100 Pavia, Italy

[45] Queens Univ Belfast, Ctr Publ Hlth, Inst Clin Sci, Belfast BT12 6BJ, North Ireland

[46] Ist Sci San Raffaele, Milan, Italy

[47] San Raffaele Univ, Vita Salute, I-20132 Milan, Italy

[48] Trium Anal Online GmbH, D-81677 Munich, Germany

[49] Univ Cambridge, Dept Hematol, Cambridge CB2 2PT, England

[50] Univ Ferrara, Dept Biochem & Mol Biol, I-44100 Ferrara, Italy

来源：

NATURE GENETICS | 2009年 / 41卷 / 03期

基金：

芬兰科学院; 英国医学研究理事会; 美国国家卫生研究院; 英国惠康基金;

关键词：

CORONARY-ARTERY-DISEASE; LDL-RECEPTOR GENE; HEART-DISEASE; CARDIOVASCULAR-DISEASE; COMMON VARIANTS; RISK; CHOLESTEROL; LOCI; PCSK9; HYPERCHOLESTEROLEMIA;

D O I：

10.1038/ng.327

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases ad 3,075 controls. We carried out replication in an independent sample with an effective sample size of up to 19,492. SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations(1-4) (9p21, 1p13 near CERSL2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9). We tested 554 common copy number polymorphisms (> 1% allele frequency) and none met the pre-specified threshold for replication (P < 10(-3)). We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus. SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk.

引用

页码：334 / 341

页数：8

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