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

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  • A Corrigendum to this article was published on 01 June 2009

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 observations1,2,3,4 (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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Figure 1: Study design.

Change history

  • 27 May 2009

    NOTE: In the version of this article initially published, the names of four co-authors (Christopher W Knouff, Dawn M Waterworth, Max C Walker, Vincent Mooser) were omitted from the author list. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

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.

Verona Heart Study. The study was supported by a grant from the Italian Ministry of University and Research and grants from the Veneto Region and the Cariverona Foundation, Verona, Italy.

Mid-America Heart Institute. T.M. is supported by a career development grant from the NIH.

Irish Family Study. We thank the clinical staff members for their valuable contribution to the collection of families for this study. The research was supported by the Northern Ireland Research and Development Office, a Royal Victoria Hospital Research Fellowship, the Northern Ireland Chest, Heart and Stroke Association, and the Heart Trust Fund (Royal Victoria Hospital).

GerMIFS I and II. The German Study was supported by the Deutsche Forschungsgemeinschaft and the German Federal Ministry of Education and Research in the context of the German National Genome Research Network.

Cardiogenics. Cardiogenics is an EU-funded integrated project (LSHM-CT-2006-037593).

INTERHEART. S.A. holds the Michael G. DeGroote and Heart and Stroke Foundation of Ontario Chair in Population Health and the May Cohen Eli Lilly Endowed Chair in Women's Health Research, McMaster University. We acknowledge the contribution of S. Yusuf who initiated and, together with the Steering Committee, supervised the conduct of the INTERHEART study. We thank members of the Project Office, S. Rangarajan (study coordinator) and K. Hall (laboratory manager), for their assistance in coordinating the genetics component of the INTERHEART project. R.D. is a recipient of a Canada Graduate Scholarship Doctoral Award from the Canadian Institutes for Health Research.

Disclosures. The collection of clinical and sociodemographic data in the Dortmund Health Study was supported by the German Migraine & Headache Society (DMKG) and by unrestricted grants of equal share from Astra Zeneca, Berlin Chemie, Boots Healthcare, Glaxo-Smith-Kline, McNeil Pharma (former Woelm Pharma), MSD Sharp & Dohme and Pfizer to the University of Muenster.

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Correspondence to (leader) Sekar Kathiresan.

Additional information

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Note, Supplementary Figures 1 and 2, Supplementary Tables 1–3 (PDF 845 kb)

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