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

Sekar Kathiresan, Benjamin F. Voight, Shaun Purcell, Kiran Musunuru, Diego Ardissino, Pier M. Mannucci, Sonia Anand, James C. Engert, Nilesh J. Samani, Heribert Schunkert, Jeanette Erdmann, Muredach P. Reilly, Daniel J. Rader, Thomas Morgan, John A. Spertus, Monika Stoll, Domenico Girelli, Pascal P. McKeown, Chris C. Patterson, David S. SiscovickChristopher J. O'Donnell, Roberto Elosua, Leena Peltonen, Veikko Salomaa, Stephen M. Schwartz, Olle Melander, David Altshuler, Pier Angelica Merlini, Carlo Berzuini, Luisa Bernardinelli, Flora Peyvandi, Marco Tubaro, Patrizia Celli, Maurizio Ferrario, Raffaela Fetiveau, Nicola Marziliano, Giorgio Casari, Michele Galli, Flavio Ribichini, Marco Rossi, Francesco Bernardi, Pietro Zonzin, Alberto Piazza, Jean Yee, Yechiel Friedlander, Jaume Marrugat, Gavin Lucas, Isaac Subirana, Joan Sala, Rafael Ramos, James B. Meigs, Gordon Williams, David M. Nathan, Calum A. MacRae, Aki S. Havulinna, Goran Berglund, Joel N. Hirschhorn, Rosanna Asselta, Stefano Duga, Marta Spreafico, Mark J. Daly, James Nemesh, Joshua M. Korn, Steven A. McCarroll, Aarti Surti, Candace Guiducci, Lauren Gianniny, Daniel Mirel, Melissa Parkin, Noel Burtt, Stacey B. Gabriel, John R. Thompson, Peter S. Braund, Benjamin J. Wright, Anthony J. Balmforth, Stephen G. Ball, Alistair S. Hall, Patrick Linsel-Nitschke, Wolfgang Lieb, Andreas Ziegler, Inke R. König, Christian Hengstenberg, Marcus Fischer, Klaus Stark, Anika Grosshennig, Michael Preuss, H. Erich Wichmann, Stefan Schreiber, Willem Ouwehand, Panos Deloukas, Michael Scholz, Francois Cambien, [No Value] Cardiogenics, Mingyao Li, Zhen Chen, Robert Wilensky, William Matthai, Atif Qasim, Hakon H. Hakonarson, Joe Devaney, Mary Susan Burnett, Augusto D. Pichard, Kenneth M. Kent, Lowell Satler, Joseph M. Lindsay, Ron Waksman, Stephen E. Epstein, Thomas Scheffold, Klaus Berger, Andreas Huge, Nicola Martinelli, Oliviero Olivieri, Roberto Corrocher, Hilma Hólm, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Kari Stefansson, Ron Do, Changchun Xie, David Siscovick

Research output: Contribution to journalArticle

788 Citations (Scopus)

Abstract

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 and 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 observations1-4 (9p21, 1p13 near CELSR2-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.

Original languageEnglish
Pages (from-to)334-341
Number of pages8
JournalNature Genetics
Volume41
Issue number3
DOIs
Publication statusPublished - 2009

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Single Nucleotide Polymorphism
Myocardial Infarction
Genome
DNA Copy Number Variations
Genome-Wide Association Study
Gene Frequency
Sample Size
Genes

ASJC Scopus subject areas

  • Genetics
  • Medicine(all)

Cite this

Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. / Kathiresan, Sekar; Voight, Benjamin F.; Purcell, Shaun; Musunuru, Kiran; Ardissino, Diego; Mannucci, Pier M.; Anand, Sonia; Engert, James C.; Samani, Nilesh J.; Schunkert, Heribert; Erdmann, Jeanette; Reilly, Muredach P.; Rader, Daniel J.; Morgan, Thomas; Spertus, John A.; Stoll, Monika; Girelli, Domenico; McKeown, Pascal P.; Patterson, Chris C.; Siscovick, David S.; O'Donnell, Christopher J.; Elosua, Roberto; Peltonen, Leena; Salomaa, Veikko; Schwartz, Stephen M.; Melander, Olle; Altshuler, David; Merlini, Pier Angelica; Berzuini, Carlo; Bernardinelli, Luisa; Peyvandi, Flora; Tubaro, Marco; Celli, Patrizia; Ferrario, Maurizio; Fetiveau, Raffaela; Marziliano, Nicola; Casari, Giorgio; Galli, Michele; Ribichini, Flavio; Rossi, Marco; Bernardi, Francesco; Zonzin, Pietro; Piazza, Alberto; Yee, Jean; Friedlander, Yechiel; Marrugat, Jaume; Lucas, Gavin; Subirana, Isaac; Sala, Joan; Ramos, Rafael; Meigs, James B.; Williams, Gordon; Nathan, David M.; MacRae, Calum A.; Havulinna, Aki S.; Berglund, Goran; Hirschhorn, Joel N.; Asselta, Rosanna; Duga, Stefano; Spreafico, Marta; Daly, Mark J.; Nemesh, James; Korn, Joshua M.; McCarroll, Steven A.; Surti, Aarti; Guiducci, Candace; Gianniny, Lauren; Mirel, Daniel; Parkin, Melissa; Burtt, Noel; Gabriel, Stacey B.; Thompson, John R.; Braund, Peter S.; Wright, Benjamin J.; Balmforth, Anthony J.; Ball, Stephen G.; Hall, Alistair S.; Linsel-Nitschke, Patrick; Lieb, Wolfgang; Ziegler, Andreas; König, Inke R.; Hengstenberg, Christian; Fischer, Marcus; Stark, Klaus; Grosshennig, Anika; Preuss, Michael; Wichmann, H. Erich; Schreiber, Stefan; Ouwehand, Willem; Deloukas, Panos; Scholz, Michael; Cambien, Francois; Cardiogenics, [No Value]; Li, Mingyao; Chen, Zhen; Wilensky, Robert; Matthai, William; Qasim, Atif; Hakonarson, Hakon H.; Devaney, Joe; Burnett, Mary Susan; Pichard, Augusto D.; Kent, Kenneth M.; Satler, Lowell; Lindsay, Joseph M.; Waksman, Ron; Epstein, Stephen E.; Scheffold, Thomas; Berger, Klaus; Huge, Andreas; Martinelli, Nicola; Olivieri, Oliviero; Corrocher, Roberto; Hólm, Hilma; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Stefansson, Kari; Do, Ron; Xie, Changchun; Siscovick, David.

In: Nature Genetics, Vol. 41, No. 3, 2009, p. 334-341.

Research output: Contribution to journalArticle

Kathiresan, S, Voight, BF, Purcell, S, Musunuru, K, Ardissino, D, Mannucci, PM, Anand, S, Engert, JC, Samani, NJ, Schunkert, H, Erdmann, J, Reilly, MP, Rader, DJ, Morgan, T, Spertus, JA, Stoll, M, Girelli, D, McKeown, PP, Patterson, CC, Siscovick, DS, O'Donnell, CJ, Elosua, R, Peltonen, L, Salomaa, V, Schwartz, SM, Melander, O, Altshuler, D, Merlini, PA, Berzuini, C, Bernardinelli, L, Peyvandi, F, Tubaro, M, Celli, P, Ferrario, M, Fetiveau, R, Marziliano, N, Casari, G, Galli, M, Ribichini, F, Rossi, M, Bernardi, F, Zonzin, P, Piazza, A, Yee, J, Friedlander, Y, Marrugat, J, Lucas, G, Subirana, I, Sala, J, Ramos, R, Meigs, JB, Williams, G, Nathan, DM, MacRae, CA, Havulinna, AS, Berglund, G, Hirschhorn, JN, Asselta, R, Duga, S, Spreafico, M, Daly, MJ, Nemesh, J, Korn, JM, McCarroll, SA, Surti, A, Guiducci, C, Gianniny, L, Mirel, D, Parkin, M, Burtt, N, Gabriel, SB, Thompson, JR, Braund, PS, Wright, BJ, Balmforth, AJ, Ball, SG, Hall, AS, Linsel-Nitschke, P, Lieb, W, Ziegler, A, König, IR, Hengstenberg, C, Fischer, M, Stark, K, Grosshennig, A, Preuss, M, Wichmann, HE, Schreiber, S, Ouwehand, W, Deloukas, P, Scholz, M, Cambien, F, Cardiogenics, NV, Li, M, Chen, Z, Wilensky, R, Matthai, W, Qasim, A, Hakonarson, HH, Devaney, J, Burnett, MS, Pichard, AD, Kent, KM, Satler, L, Lindsay, JM, Waksman, R, Epstein, SE, Scheffold, T, Berger, K, Huge, A, Martinelli, N, Olivieri, O, Corrocher, R, Hólm, H, Thorleifsson, G, Thorsteinsdottir, U, Stefansson, K, Do, R, Xie, C & Siscovick, D 2009, 'Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants', Nature Genetics, vol. 41, no. 3, pp. 334-341. https://doi.org/10.1038/ng.327
Kathiresan, Sekar ; Voight, Benjamin F. ; Purcell, Shaun ; Musunuru, Kiran ; Ardissino, Diego ; Mannucci, Pier M. ; Anand, Sonia ; Engert, James C. ; Samani, Nilesh J. ; Schunkert, Heribert ; Erdmann, Jeanette ; Reilly, Muredach P. ; Rader, Daniel J. ; Morgan, Thomas ; Spertus, John A. ; Stoll, Monika ; Girelli, Domenico ; McKeown, Pascal P. ; Patterson, Chris C. ; Siscovick, David S. ; O'Donnell, Christopher J. ; Elosua, Roberto ; Peltonen, Leena ; Salomaa, Veikko ; Schwartz, Stephen M. ; Melander, Olle ; Altshuler, David ; Merlini, Pier Angelica ; Berzuini, Carlo ; Bernardinelli, Luisa ; Peyvandi, Flora ; Tubaro, Marco ; Celli, Patrizia ; Ferrario, Maurizio ; Fetiveau, Raffaela ; Marziliano, Nicola ; Casari, Giorgio ; Galli, Michele ; Ribichini, Flavio ; Rossi, Marco ; Bernardi, Francesco ; Zonzin, Pietro ; Piazza, Alberto ; Yee, Jean ; Friedlander, Yechiel ; Marrugat, Jaume ; Lucas, Gavin ; Subirana, Isaac ; Sala, Joan ; Ramos, Rafael ; Meigs, James B. ; Williams, Gordon ; Nathan, David M. ; MacRae, Calum A. ; Havulinna, Aki S. ; Berglund, Goran ; Hirschhorn, Joel N. ; Asselta, Rosanna ; Duga, Stefano ; Spreafico, Marta ; Daly, Mark J. ; Nemesh, James ; Korn, Joshua M. ; McCarroll, Steven A. ; Surti, Aarti ; Guiducci, Candace ; Gianniny, Lauren ; Mirel, Daniel ; Parkin, Melissa ; Burtt, Noel ; Gabriel, Stacey B. ; Thompson, John R. ; Braund, Peter S. ; Wright, Benjamin J. ; Balmforth, Anthony J. ; Ball, Stephen G. ; Hall, Alistair S. ; Linsel-Nitschke, Patrick ; Lieb, Wolfgang ; Ziegler, Andreas ; König, Inke R. ; Hengstenberg, Christian ; Fischer, Marcus ; Stark, Klaus ; Grosshennig, Anika ; Preuss, Michael ; Wichmann, H. Erich ; Schreiber, Stefan ; Ouwehand, Willem ; Deloukas, Panos ; Scholz, Michael ; Cambien, Francois ; Cardiogenics, [No Value] ; Li, Mingyao ; Chen, Zhen ; Wilensky, Robert ; Matthai, William ; Qasim, Atif ; Hakonarson, Hakon H. ; Devaney, Joe ; Burnett, Mary Susan ; Pichard, Augusto D. ; Kent, Kenneth M. ; Satler, Lowell ; Lindsay, Joseph M. ; Waksman, Ron ; Epstein, Stephen E. ; Scheffold, Thomas ; Berger, Klaus ; Huge, Andreas ; Martinelli, Nicola ; Olivieri, Oliviero ; Corrocher, Roberto ; Hólm, Hilma ; Thorleifsson, Gudmar ; Thorsteinsdottir, Unnur ; Stefansson, Kari ; Do, Ron ; Xie, Changchun ; Siscovick, David. / Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. In: Nature Genetics. 2009 ; Vol. 41, No. 3. pp. 334-341.
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T1 - Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants

AU - Kathiresan, Sekar

AU - Voight, Benjamin F.

AU - Purcell, Shaun

AU - Musunuru, Kiran

AU - Ardissino, Diego

AU - Mannucci, Pier M.

AU - Anand, Sonia

AU - Engert, James C.

AU - Samani, Nilesh J.

AU - Schunkert, Heribert

AU - Erdmann, Jeanette

AU - Reilly, Muredach P.

AU - Rader, Daniel J.

AU - Morgan, Thomas

AU - Spertus, John A.

AU - Stoll, Monika

AU - Girelli, Domenico

AU - McKeown, Pascal P.

AU - Patterson, Chris C.

AU - Siscovick, David S.

AU - O'Donnell, Christopher J.

AU - Elosua, Roberto

AU - Peltonen, Leena

AU - Salomaa, Veikko

AU - Schwartz, Stephen M.

AU - Melander, Olle

AU - Altshuler, David

AU - Merlini, Pier Angelica

AU - Berzuini, Carlo

AU - Bernardinelli, Luisa

AU - Peyvandi, Flora

AU - Tubaro, Marco

AU - Celli, Patrizia

AU - Ferrario, Maurizio

AU - Fetiveau, Raffaela

AU - Marziliano, Nicola

AU - Casari, Giorgio

AU - Galli, Michele

AU - Ribichini, Flavio

AU - Rossi, Marco

AU - Bernardi, Francesco

AU - Zonzin, Pietro

AU - Piazza, Alberto

AU - Yee, Jean

AU - Friedlander, Yechiel

AU - Marrugat, Jaume

AU - Lucas, Gavin

AU - Subirana, Isaac

AU - Sala, Joan

AU - Ramos, Rafael

AU - Meigs, James B.

AU - Williams, Gordon

AU - Nathan, David M.

AU - MacRae, Calum A.

AU - Havulinna, Aki S.

AU - Berglund, Goran

AU - Hirschhorn, Joel N.

AU - Asselta, Rosanna

AU - Duga, Stefano

AU - Spreafico, Marta

AU - Daly, Mark J.

AU - Nemesh, James

AU - Korn, Joshua M.

AU - McCarroll, Steven A.

AU - Surti, Aarti

AU - Guiducci, Candace

AU - Gianniny, Lauren

AU - Mirel, Daniel

AU - Parkin, Melissa

AU - Burtt, Noel

AU - Gabriel, Stacey B.

AU - Thompson, John R.

AU - Braund, Peter S.

AU - Wright, Benjamin J.

AU - Balmforth, Anthony J.

AU - Ball, Stephen G.

AU - Hall, Alistair S.

AU - Linsel-Nitschke, Patrick

AU - Lieb, Wolfgang

AU - Ziegler, Andreas

AU - König, Inke R.

AU - Hengstenberg, Christian

AU - Fischer, Marcus

AU - Stark, Klaus

AU - Grosshennig, Anika

AU - Preuss, Michael

AU - Wichmann, H. Erich

AU - Schreiber, Stefan

AU - Ouwehand, Willem

AU - Deloukas, Panos

AU - Scholz, Michael

AU - Cambien, Francois

AU - Cardiogenics, [No Value]

AU - Li, Mingyao

AU - Chen, Zhen

AU - Wilensky, Robert

AU - Matthai, William

AU - Qasim, Atif

AU - Hakonarson, Hakon H.

AU - Devaney, Joe

AU - Burnett, Mary Susan

AU - Pichard, Augusto D.

AU - Kent, Kenneth M.

AU - Satler, Lowell

AU - Lindsay, Joseph M.

AU - Waksman, Ron

AU - Epstein, Stephen E.

AU - Scheffold, Thomas

AU - Berger, Klaus

AU - Huge, Andreas

AU - Martinelli, Nicola

AU - Olivieri, Oliviero

AU - Corrocher, Roberto

AU - Hólm, Hilma

AU - Thorleifsson, Gudmar

AU - Thorsteinsdottir, Unnur

AU - Stefansson, Kari

AU - Do, Ron

AU - Xie, Changchun

AU - Siscovick, David

PY - 2009

Y1 - 2009

N2 - 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 and 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 observations1-4 (9p21, 1p13 near CELSR2-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.

AB - 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 and 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 observations1-4 (9p21, 1p13 near CELSR2-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.

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