Abstract

We identify the SLC22A3-LPAL2-LPA gene cluster as a strong susceptibility locus for coronary artery disease (CAD) through a genome-wide haplotype association (GWHA) study. This locus was not identified from previous genome-wide association (GWA) studies focused on univariate analyses of SNPs. The proposed approach may have wide utility for analyzing GWA data for other complex traits.

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Acknowledgements

The WTCCC 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. We also acknowledge support of the Wellcome Trust Functional Genomics Initiative in Cardiovascular Genetics. The German Study was supported by the Deutsche Forschungsgemeinschaft, the German Federal Ministry of Education and Research in the context of the German National Genome Research Network (NGFN-2 and NGFN-plus). The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the GSF-National Research Centre for Environment and Health, which is funded by the German Federal Ministry of Education and Research and of the State of Bavaria. This work has also been partially supported by the EGEE-II project funded by the European Union INFSO-RI-031688. N.J.S. is supported by a Chair funded by the BHF. The main sponsor of the current analysis is the EU funded integrated project 'Cardiogenics' (LSHM-CT-2006-037593).

Author information

Affiliations

  1. Institut National de la Santé Et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR_S) 525, Université Pierre et Marie Curie (UPMC). Paris 06, Paris 75013, France.

    • David-Alexandre Trégouët
    • , Alexandru Munteanu
    • , Claire Perret
    • , Maylis DeSuremain
    • , Laurence Tiret
    •  & Francois Cambien
  2. Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, D-23538 Lübeck, Germany.

    • Inke R König
    • , Anika Großhennig
    • , Michael Preuss
    •  & Andreas Ziegler
  3. Medizinische Klinik II, Universität zu Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany.

    • Jeanette Erdmann
    • , Anika Großhennig
    • , Patrick Linsel-Nitschke
    •  & Heribert Schunkert
  4. Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK.

    • Peter S Braund
    • , Pim van der Harst
    •  & Nilesh J Samani
  5. Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds, LS1 3EX, UK.

    • Alistair S Hall
    • , Anthony J Balmforth
    •  & Stephen G Ball
  6. Institut für Humangenetik, Helmholtz Zentrum München, Deutsches Forschungszentrum für Umwelt und Gesundheit, D-85764 Neuherberg, Germany.

    • Thomas Meitinger
    • , Christa Meisinger
    •  & H-Erich Wichmann
  7. Department of Health Sciences and Genetics, University of Leicester, LE1 7RH Leicester, UK.

    • Ben J Wright
    •  & John R Thompson
  8. Centre National de la Recherche Scientifique (CNRS), UMR_S 8623, Université Paris-Sud, Laboratoire de Recherche en Informatique, 91403 Orsay, France.

    • Cécile Germain
  9. Department of Epidemiology and Public Health, Queen's University of Belfast, BT7 1NN Belfast, UK.

    • Alun Evans
  10. EA1801-Laboratoire d'Epidémiologie et de Santé Publique, Faculté de Médecine, Multinational MONItoring of Trends and Determinants in CArdiovascular Disease (MONICA), Strasbourg, 67085 Strasbourg, France.

    • Dominique Arveiler
  11. INSERM U545, Pasteur Institute of Lille, University of Lille 2, 59019 Lille, France.

    • Gérald Luc
  12. INSERM U518, Faculté de Médecine, MONICA Toulouse, 31073 Toulouse, France.

    • Jean-Bernard Ruidavets
  13. The MONICA Project, Glasgow Royal Infirmary, Scotland, G4 0SF, UK.

    • Caroline Morrison
  14. Institut für Klinische Molekularbiologie, Christian-Albrechts Universität, D-24105 Kiel, Germany.

    • Stefan Schreiber
    • , Arne Schäfer
    •  & Nour E El Mokhtari
  15. Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, D-93042 Regensburg, Germany.

    • Katharina Neureuther
    • , Klaus Stark
    •  & Christian Hengstenberg
  16. Molecular Biology Laboratory, Institute of Transfusion Medicine and Immunology, University of Heidelberg, Medical Faculty of Mannheim Mannheim, D-69117 Germany.

    • Peter Bugert
  17. Bundesforschungsanstalt für Ernährung und Lebensmittel, Institut für Physiologie und Biochemie der Ernährung, D-24121 Kiel, Germany.

    • Jürgen Schrezenmeir
    •  & Diana Rubin
  18. Department of Haematology, University of Cambridge, Long Road, Cambridge, CB2 2PT, UK.

    • Willem Ouwehand

Consortia

  1. Wellcome Trust Case Control Consortium

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

  2. Cardiogenics Consortium

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

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Contributions

This work was designed by D.-A.T., L.T., F.C., H.S. and N.J.S. Statistical analyses were carried out by D.-A.T., I.R.K., A.G., M.P., P.H., A.Z. and J.R.T., J.E., P.S.B., C.P., M.D., P.B. and W.O. supervised and/or participated in the genetic laboratory analyses. A.M. developed the computing grid program under the supervision of D.-A.T. and C.G. Case collections were coordinated by P.S.B., A.S.H., B.J.W., A.J.B., S.G.B., W.O., J.R.T., N.J.S. (WTCCC), J.E., T.M., H.-E.W., C. Meisinger, C.H., K.N., K.S., J.S., D.R. (GerMIFS), S.S., A.S., N.E.E.-M. (PopGene), J.E., P.L.-N. (Angio-Luebeck), A.E., D.A., G.L., J.-B.R., and C. Morrison (ECTIM). D.A.T., L.T., F.C., H.S. and N.J.S. drafted the manuscript with substantial contributions from I.R.K., J.E., A.Z.

Corresponding author

Correspondence to David-Alexandre Trégouët.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Methods, Supplementary Tables 1–3, Supplementary Figures 1–3 and Supplementary Note

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DOI

https://doi.org/10.1038/ng.314

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