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. Siscovick; Christopher 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; 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

doi:10.1038/ng.327

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. Siscovick

Christopher 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, 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

Massachusetts General Hospital
The Broad Institute of MIT and Harvard
Harvard Medical School
Università Degli Studi di Parma
University of Milan
Population Health Research Institute, Ontario
McGill University
University of Leicester
University of Lübeck
University of Pennsylvania
Vanderbilt School of Medicine
University of Missouri-Kansas City
University of Münster
University of Verona
Queen's University Belfast
University of Washington School of Medicine
Framingham Heart Study
Institut Municipal d'Investigacio Medica
Wellcome Sanger Institute
University of Helsinki
National Institute for Health and Welfare
University of Washington School of Public Health and Community Medicine
Lunds University Hospital
Ospedale Niguarda Ca' Granda
Medical Research Council
University of Cambridge
University of Pavia
San Filippo Neri Hospital
Ospedale S. Camillo-Forlanini
IRCCS Fondazione Mondino
University Vita-Salute San Raffaele
Ospedale di Livorno
Humanitas Clinical and Research Center
University of Ferrara
Ospedale di Rovigo
University of Torino
The Hebrew University of Jerusalem
IDIBGi
Unitat de Recerca I Unitat Docent de Medicina de Familia de Girona, IDIAP Jordi Gol, Institut Català de la Salut
Brigham and Women's Hospital
University of Leicester
University of Leeds
Klinikum der Universität Regensburg und Medizinische Fakultät
Helmholtz Zentrum München German Research Center for Environmental Health
Ludwig-Maximilians-Universität München
Christian-Albrechts-Universitat zu Kiel
Trium Analysis Online GmbH
INSERM U70
Children's Hospital of Philadelphia
Washington Hospital Center
University Witten-Herdecke
deCODE genetics
University of Iceland

Research output: Contribution to journal › Article › peer-review

991 Scopus citations

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 observations^1-4 (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 language	English
Pages (from-to)	334-341
Number of pages	8
Journal	Nature Genetics
Volume	41
Issue number	3
DOIs	https://doi.org/10.1038/ng.327
State	Published - Mar 2009
Externally published	Yes

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10.1038/ng.327

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Kathiresan, S., Voight, B. F., Purcell, S., Musunuru, K., Ardissino, D., Mannucci, P. M., Anand, S., Engert, J. C., Samani, N. J., Schunkert, H., Erdmann, J., Reilly, M. P., Rader, D. J., Morgan, T., Spertus, J. A., Stoll, M., Girelli, D., McKeown, P. P., Patterson, C. C., ... Siscovick, D. (2009). Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nature Genetics, 41(3), 334-341. https://doi.org/10.1038/ng.327

@article{c97c54d2f76e4c478bcfcd1a454490b9,

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

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.",

author = "Sekar Kathiresan and Voight, \{Benjamin F.\} and Shaun Purcell and Kiran Musunuru and Diego Ardissino and Mannucci, \{Pier M.\} and Sonia Anand and Engert, \{James C.\} and Samani, \{Nilesh J.\} and Heribert Schunkert and Jeanette Erdmann and Reilly, \{Muredach P.\} and Rader, \{Daniel J.\} and Thomas Morgan and Spertus, \{John A.\} and Monika Stoll and Domenico Girelli and McKeown, \{Pascal P.\} and Patterson, \{Chris C.\} and Siscovick, \{David S.\} and O'Donnell, \{Christopher J.\} and Roberto Elosua and Leena Peltonen and Veikko Salomaa and Schwartz, \{Stephen M.\} and Olle Melander and David Altshuler and Merlini, \{Pier Angelica\} and Carlo Berzuini and Luisa Bernardinelli and Flora Peyvandi and Marco Tubaro and Patrizia Celli and Maurizio Ferrario and Raffaela Fetiveau and Nicola Marziliano and Giorgio Casari and Michele Galli and Flavio Ribichini and Marco Rossi and Francesco Bernardi and Pietro Zonzin and Alberto Piazza and Jean Yee and Yechiel Friedlander and Jaume Marrugat and Gavin Lucas and Isaac Subirana and Joan Sala and Rafael Ramos and Meigs, \{James B.\} and Gordon Williams and Nathan, \{David M.\} and MacRae, \{Calum A.\} and Havulinna, \{Aki S.\} and Goran Berglund and Hirschhorn, \{Joel N.\} and Rosanna Asselta and Stefano Duga and Marta Spreafico and Daly, \{Mark J.\} and James Nemesh and Korn, \{Joshua M.\} and McCarroll, \{Steven A.\} and Aarti Surti and Candace Guiducci and Lauren Gianniny and Daniel Mirel and Melissa Parkin and Noel Burtt and Gabriel, \{Stacey B.\} and Thompson, \{John R.\} and Braund, \{Peter S.\} and Wright, \{Benjamin J.\} and Balmforth, \{Anthony J.\} and Ball, \{Stephen G.\} and Hall, \{Alistair S.\} and Patrick Linsel-Nitschke and Wolfgang Lieb and Andreas Ziegler and K{\"o}nig, \{Inke R.\} and Christian Hengstenberg and Marcus Fischer and Klaus Stark and Anika Grosshennig and Michael Preuss and Wichmann, \{H. Erich\} and Stefan Schreiber and Willem Ouwehand and Panos Deloukas and Michael Scholz and Francois Cambien and Cardiogenics and Mingyao Li and Zhen Chen and Robert Wilensky and William Matthai and Atif Qasim and Hakonarson, \{Hakon H.\} and Joe Devaney and Burnett, \{Mary Susan\} and Pichard, \{Augusto D.\} and Kent, \{Kenneth M.\} and Lowell Satler and Lindsay, \{Joseph M.\} and Ron Waksman and Epstein, \{Stephen E.\} and Thomas Scheffold and Klaus Berger and Andreas Huge and Nicola Martinelli and Oliviero Olivieri and Roberto Corrocher and Hilma H{\'o}lm and Gudmar Thorleifsson and Unnur Thorsteinsdottir and Kari Stefansson and Ron Do and Changchun Xie and David Siscovick",

note = "Funding Information: ACKNOWLEDGMENTS HARPS. The HARPS study was supported by the grants (R01HL056931, P30ES007033) and a contract (N01HD013107) from US National Institutes of Health. REGICOR. The REGICOR study was partially funded by the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (Red HERACLES RD06/0009), the CIBER Epidemiolog{\'i}a y Salud P{\'u}blica, the FIS and AGAUR Generalitat de Catalunya. Massachusetts General Hospital. The MIGen study was funded by the US National Institutes of Health (NIH) and National Heart, Lung, and Blood Institute{\textquoteright}s STAMPEED genomics research program through a grant to D.A. S.K. is supported by a Doris Duke Charitable Foundation Clinical Scientist Development Award, a charitable gift from the Fannie E. Rippel Foundation, the Donovan Family Foundation, a career development award from the NIH and the Department of Medicine and Cardiovascular Research Center at Massachusetts General Hospital. J.B.M. is supported by grant K24 DK080140 from the NIH. Broad Institute. Genotyping was partially funded by The Broad Institute Center for Genotyping and Analysis, which is supported by grant U54 RR020278 from the National Center for Research Resources. FINRISK. V.S. was supported by the Sigrid Juselius Foundation. L.P. was supported by the Center of Excellence in Complex Disease Genetics of the Academy of Finland, the Nordic Center of Excellence in Disease Genetics and the Finnish Foundation for Cardiovascular Research. WTCCC Study. The study was funded by the Wellcome Trust. Recruitment of cases for the WTCCC Study was carried out by the British Heart Foundation (BHF) Family Heart Study Research Group and supported by the BHF and the UK Medical Research Council. N.J.S. and S.G.B. hold chairs funded by the BHF. PennCATH/MedStar. Recruitment of the PennCATH cohort was supported by the Cardiovascular Institute of the University of Pennsylvania. Recruitment of the MedStar cohort was supported by a research grant from GlaxoSmithKline and from the MedStar Research Institute. Genotyping was done at the Center for Applied Genomics at the Children{\textquoteright}s Hospital of Philadelphia and supported by GlaxoSmithKline through an Alternate Drug Discovery Initiative research alliance award (to M.P.R. and D.J.R.) with the University of Pennsylvania School of Medicine. D.J.R. was supported by a Doris Duke Charitable Foundation Distinguished Clinical Scientist Award.",

year = "2009",

month = mar,

doi = "10.1038/ng.327",

language = "English",

volume = "41",

pages = "334--341",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "3",

}

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, 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

TY - JOUR

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,

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

N1 - Funding Information: ACKNOWLEDGMENTS HARPS. The HARPS study was supported by the grants (R01HL056931, P30ES007033) and a contract (N01HD013107) from US National Institutes of Health. REGICOR. The REGICOR study was partially funded by the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (Red HERACLES RD06/0009), the CIBER Epidemiología y Salud Pública, the FIS and AGAUR Generalitat de Catalunya. Massachusetts General Hospital. The MIGen study was funded by the US National Institutes of Health (NIH) and National Heart, Lung, and Blood Institute’s STAMPEED genomics research program through a grant to D.A. S.K. is supported by a Doris Duke Charitable Foundation Clinical Scientist Development Award, a charitable gift from the Fannie E. Rippel Foundation, the Donovan Family Foundation, a career development award from the NIH and the Department of Medicine and Cardiovascular Research Center at Massachusetts General Hospital. J.B.M. is supported by grant K24 DK080140 from the NIH. Broad Institute. Genotyping was partially funded by The Broad Institute Center for Genotyping and Analysis, which is supported by grant U54 RR020278 from the National Center for Research Resources. FINRISK. V.S. was supported by the Sigrid Juselius Foundation. L.P. was supported by the Center of Excellence in Complex Disease Genetics of the Academy of Finland, the Nordic Center of Excellence in Disease Genetics and the Finnish Foundation for Cardiovascular Research. WTCCC Study. The study was funded by the Wellcome Trust. Recruitment of cases for the WTCCC Study was carried out by the British Heart Foundation (BHF) Family Heart Study Research Group and supported by the BHF and the UK Medical Research Council. N.J.S. and S.G.B. hold chairs funded by the BHF. PennCATH/MedStar. Recruitment of the PennCATH cohort was supported by the Cardiovascular Institute of the University of Pennsylvania. Recruitment of the MedStar cohort was supported by a research grant from GlaxoSmithKline and from the MedStar Research Institute. Genotyping was done at the Center for Applied Genomics at the Children’s Hospital of Philadelphia and supported by GlaxoSmithKline through an Alternate Drug Discovery Initiative research alliance award (to M.P.R. and D.J.R.) with the University of Pennsylvania School of Medicine. D.J.R. was supported by a Doris Duke Charitable Foundation Distinguished Clinical Scientist Award.

PY - 2009/3

Y1 - 2009/3

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.

UR - https://www.scopus.com/pages/publications/70749096913

U2 - 10.1038/ng.327

DO - 10.1038/ng.327

M3 - Article

C2 - 19198609

AN - SCOPUS:70749096913

SN - 1061-4036

VL - 41

SP - 334

EP - 341

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

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

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