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. 2009 Mar;41(3):334-41.
doi: 10.1038/ng.327. Epub 2009 Feb 8.

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

Myocardial Infarction Genetics Consortium  1 ; 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, Diego Ardissino, 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, Pier M Mannucci, Stephen M Schwartz, David S Siscovick, Jean Yee, Yechiel Friedlander, Roberto Elosua, Jaume Marrugat, Gavin Lucas, Isaac Subirana, Joan Sala, Rafael Ramos, Sekar Kathiresan, James B Meigs, Gordon Williams, David M Nathan, Calum A MacRae, Christopher J O'Donnell, Veikko Salomaa, Aki S Havulinna, Leena Peltonen, Olle Melander, Goran Berglund, Benjamin F Voight, Sekar Kathiresan, Joel N Hirschhorn, Rosanna Asselta, Stefano Duga, Marta Spreafico, Kiran Musunuru, Mark J Daly, Shaun Purcell, Benjamin F Voight, Shaun Purcell, James Nemesh, Joshua M Korn, Steven A McCarroll, Stephen M Schwartz, Jean Yee, Sekar Kathiresan, Gavin Lucas, Isaac Subirana, Roberto Elosua, Aarti Surti, Candace Guiducci, Lauren Gianniny, Daniel Mirel, Melissa Parkin, Noel Burtt, Stacey B Gabriel, Nilesh J Samani, John R Thompson, Peter S Braund, Benjamin J Wright, Anthony J Balmforth, Stephen G Ball, Alistair S Hall; Wellcome Trust Case Control Consortium; Heribert Schunkert, Jeanette Erdmann, Patrick Linsel-Nitschke, Wolfgang Lieb, Andreas Ziegler, Inke König, Christian Hengstenberg, Marcus Fischer, Klaus Stark, Anika Grosshennig, Michael Preuss, H-Erich Wichmann, Stefan Schreiber, Heribert Schunkert, Nilesh J Samani, Jeanette Erdmann, Willem Ouwehand, Christian Hengstenberg, Panos Deloukas, Michael Scholz, Francois Cambien, Muredach P Reilly, 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, Christopher W Knouff, Dawn M Waterworth, Max C Walker, Vincent Mooser, Stephen E Epstein, Daniel J Rader, Thomas Scheffold, Klaus Berger, Monika Stoll, Andreas Huge, Domenico Girelli, Nicola Martinelli, Oliviero Olivieri, Roberto Corrocher, Thomas Morgan, John A Spertus, Pascal McKeown, Chris C Patterson, Heribert Schunkert, Erdmann Erdmann, 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, Hilma Hólm, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Kari Stefansson, James C Engert, Ron Do, Changchun Xie, Sonia Anand, Sekar Kathiresan, Diego Ardissino, Pier M Mannucci, David Siscovick, Christopher J O'Donnell, Nilesh J Samani, Olle Melander, Roberto Elosua, Leena Peltonen, Veikko Salomaa, Stephen M Schwartz, David Altshuler
Affiliations

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

Myocardial Infarction Genetics Consortium et al. Nat Genet. 2009 Mar.

Erratum in

  • Nat Genet. 2009 Jun;41(6):762. Knouff, Christopher W [added]; Waterworth, Dawn M [added]; Walker, Max C [added]; Mooser, Vincent [added]

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 (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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Figures

Figure 1
Figure 1. Study Design
The genome-wide association study consisted of three stages with an evaluation of common single nucleotide polymorphisms, common copy number variants, and rare copy number variants in Stage 1. The design called for all variants with a P < 0.001 to be taken forward to Stage 2. As only SNPs met this criterion, 1441 SNPs were taken forward to Stage 2. A total of 33 SNPs were tested in Stage 3. Statistical evidence for association was combined across Stages 1, 2, and 3 using meta-analysis.
Figure 2
Figure 2. CDKN2B messenger RNA expression in subcutaneous fat tissue stratified by rs4977574 genotyped on 9p21.3
The CDKN2B transcript level in each of 848 subcutaneous fat samples was compared with the mean level in a control mRNA pool of 100 randomly-selected samples. A ratio of the sample transcript level over that in control pool was first calculated and then log-transformed. This percent change is shown on the y-axis with the genotype at rs4977574 shown on the x-axis. Note that the G allele represents the risk allele for MI with each copy of the G allele increasing risk for MI by 28%.
Figure 3
Figure 3. Plot of observed versus expected P value distribution for association of 554 common copy number variants with early-onset myocardial infarction
The CANARY algorithm was used to test 554 commonly segregating CNVs (> 1% frequency) for association with early-onset MI in 2,783 cases and 2,865 controls that passed sample quality control for CNV analysis (Methods). The estimated genomic control lambda for the entire set of CNVs was ~1.23; for 316 CNVs with allele frequency greater than 5%, lambda was ~1.05. We did not observe any CNV with evidence for association surpassing our pre-specified threshold for replication of P < 0.001. The observed versus expected P value distribution did not show deviation from the null distribution.
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