Article | Published:

A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium

Nature Genetics volume 41, pages 11821190 (2009) | Download Citation

Abstract

The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.

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Acknowledgements

The Wellcome Trust, EU (HEALTH-F2-2008-ENGAGE, QLG2-CT-2002-01254), National Institute for Health Research of England (NIHR) (TwinsUK); The Wellcome Trust (UKBS-CC1); Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany, the German Federal Ministry of Education and Research (BMBF), the German National Genome Research Network (NGFN), Munich Center of Health Sciences (MC Health) (KORA); Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103 and 01ZZ0403), Ministry of Cultural Affairs, Social Ministry of the Federal State of Mecklenburg-West Pomerania, Deutsche Forschungsgemeinschaft (grant SFB TR 19), the Federal Ministry of Education and Research (grant no. 03ZIK012); a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania (SHIP); NIHR, CBMRC, NHSBT, (CBR); Deutsche Forschungsgemeinschaft, the German Federal Ministry of Education and Research (BMBF) (NGFN-2 and NGFN-plus), EU (LSHM-CT-2006-037593) (GerMIFS I and II); BHF and the UK MRC, the Wellcome Trust, Leicester NIHR Biomedical Research Unit in Cardiovascular Disease and EU-FP6 (LSHM-CT-2004-503485) (WTCCC-CAD); Cardiovascular Institute (University of Pennsylvania), GlaxoSmithKline, MedSTAR Research Institute (PennCATH/MedSTAR); US National Institutes of Health (NIH) and National Heart, Lung, and Blood Institute (STAMPEED), National Center for Research Resource (U54 RR020278) (MIGen); Canadian Institutes of Health Research (MOP82810, NA6650 and MOP77682), Canada Foundation for Innovation and Ontario Research Foundation (#11966) (OHGS); Finnish Foundation for Cardiovascular Research, Sigrid Juselius Foundation (COROGENE); Juvenile Diabetes Research Foundation/Wellcome Trust (T1D).

Author information

Author notes

    • Nicole Soranzo
    • , Tim D Spector
    • , Massimo Mangino
    • , Panos Deloukas
    • , Willem H Ouwehand
    •  & Christian Gieger

    These authors contributed equally to this work.

Affiliations

  1. Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK.

    • Nicole Soranzo
    • , Yali Xue
    • , Suzannah Bumpstead
    • , Mohammed J R Ghori
    • , Rhian Gwilliam
    • , Naomi Hammond
    • , Simon C Potter
    • , Catherine M Rice
    • , Chris Tyler-Smith
    • , Panos Deloukas
    •  & Willem H Ouwehand
  2. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Nicole Soranzo
    • , Tim D Spector
    • , Massimo Mangino
    •  & Mario Falchi
  3. Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Brigitte Kühnel
    • , Angela Döring
    • , Thomas Illig
    • , H-Erich Wichmann
    • , Christa Meisinger
    •  & Christian Gieger
  4. Department of Haematology, University of Cambridge and National Health Service Blood and Transplant, Cambridge, UK.

    • Augusto Rendon
    • , Philippa Burns
    • , Stephen F Garner
    • , Jennifer Sambrook
    • , Jovana Serbanovic-Canic
    • , Jonathan Stephens
    • , Nicholas A Watkins
    •  & Willem H Ouwehand
  5. Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-Universität Greifswald, Greifswald, Germany.

    • Alexander Teumer
    •  & Uwe Völker
  6. Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany.

    • Christina Willenborg
    •  & Inke R König
  7. Medizinische Klinik II, Universität zu Lübeck, Lübeck, Germany.

    • Christina Willenborg
    • , Heribert Schunkert
    •  & Jeanette Erdmann
  8. Department of Health Sciences, University of Leicester, Leicester, UK.

    • Benjamin Wright
    •  & John R Thompson
  9. John & Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

    • Li Chen
    • , Ruth McPherson
    • , Robert Roberts
    • , George A Wells
    •  & Alexandre F R Stewart
  10. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Mingyao Li
  11. Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.

    • Perttu Salo
    • , Leena Peltonen
    • , Veikko Salomaa
    •  & Markus Perola
  12. The Institute of Molecular Medicine, University of Helsinki, Finland.

    • Perttu Salo
    • , Leena Peltonen
    • , Veikko Salomaa
    • , Ida Surakka
    •  & Markus Perola
  13. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Benjamin F Voight
    •  & David Altshuler
  14. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Benjamin F Voight
    •  & David Altshuler
  15. European Bioinformatics Institute, Genome Campus, Hinxton, UK.

    • Roman A Laskowski
  16. Department of Haematology, King's College London, London, UK.

    • Stephan Menzel
    •  & Swee Lay Thein
  17. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • David Altshuler
  18. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • David Altshuler
    • , Christopher J O'Donnell
    •  & Sekar Kathiresan
  19. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • David Altshuler
  20. Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK.

    • John R Bradley
  21. Cardiovascular Research Institute, MedStar Research Institute, Washington Hospital Center, Washington, DC, USA.

    • Mary-Susan Burnett
    • , Joseph Devaney
    •  & Stephen E Epstein
  22. Cardiovascular Epidemiology and Genetics, Institut Municipal D'investigacio Medica and CIBER Epidemiología y Salud Pública, Barcelona, Spain.

    • Roberto Elosua
  23. Haematology Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

    • Wendy Erber
  24. Section of Genomic Medicine, Imperial College London, South Kensington Campus, London, UK.

    • Mario Falchi
  25. Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK.

    • Alison H Goodall
    •  & Nilesh J Samani
  26. The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Hakon H Hakonarson
  27. BHF Heart Research Centre, Clinical Cardiology, Leeds General Infirmary, Leeds, UK.

    • Alistair S Hall
  28. Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, Regensburg, Germany.

    • Christian Hengstenberg
    •  & Klaus Stark
  29. Genetics Division, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.

    • Christopher W Knouff
    •  & Vincent Mooser
  30. Department of Clinical Sciences, Hypertension and Cardiovascular Diseases, University Hospital Malmö, Lund University, Malmö, Sweden.

    • Olle Melander
  31. Institut für Klinische Chemie und Laboratoriumsmedizin, Ernst-Moritz-Arndt Universität Greifswald, Greifswald, Germany.

    • Matthias Nauck
  32. Division of Cardiology, Department of Medicine, Helsinki University Central Hospital (HUCH), Helsinki, Finland.

    • Markku S Nieminen
    •  & Juha Sinisalo
  33. Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Christopher J O'Donnell
    •  & Sekar Kathiresan
  34. Department of Human Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.

    • Holger Prokisch
  35. Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Holger Prokisch
  36. The Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Daniel J Rader
    •  & Muredach P Reilly
  37. The Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Daniel J Rader
    •  & Muredach P Reilly
  38. Institut für Klinische Molekularbiologie, Christian-Albrechts Universität, Kiel, Germany.

    • Stefan Schreiber
  39. Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington, USA.

    • Stephen M Schwartz
    •  & David S Siscovick
  40. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Stephen M Schwartz
    •  & David S Siscovick
  41. Institute for Community Medicine, Ernst-Moritz-Arndt-Universität Greifswald, Greifswald, Germany.

    • Henry Völzke
  42. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität and Klinikum Grosshadern, Munich, Germany.

    • H-Erich Wichmann
  43. Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • David A Van Heel
  44. Institut für Immunologie und Transfusionsmedizin, Ernst-Moritz-Arndt-Universität Greifswald, Greifswald, Germany.

    • Andreas Greinacher

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Contributions

Manuscript preparation: N.S., M.M., A.R., W.H.O., T.D.S., P.D., N.J.S. and C.G.

Main data analysis: N.S., C.G., B.K., A.R., A.T., R.A.L., Y.X. and C.T.-S. Intermediate trait analysis cohorts. Study design and biobanking: T.D.S. (TwinsUK), J.R.B., W.E., S.F.G., J.S.-C., J. Sambrook, N.A.W., W.H.O. (UKBS-CC1 and CBR), C.G., T.I., H.-E.W. (KORA F3 and F4), M.N., U.V. and H.V. (SHIP). Phenotype assessment: S.M., M.F., S.L.T., T.D.S. (TwinsUK), A.D., C.M. (KORA F3 and F4) and A.G. (SHIP). Genotyping: R.G., S.C.P., C.M.R., P.D. (TwinsUK), S.B., M.J.R.G., R.G., N.H., J. Stephens (CBR), H.P. and T.I. (KORA F3 and F4). Statistical analysis: N.S. (TwinsUK, CBR and UKBS-CC1), C.G, B.K. (KORA F3 and F4), A.T. (SHIP), A.R. and P.B. (Transcriptomics). CAD/MI cohorts. GerMIFS I and GerMIFS II: C.H., I.R.K., S.S., K.S., C.W., H.-E.W., C.W., J.E., H.S. WTCCC-CAD: N.J.S., A.H.G., A.S.H., B.W. and J.R.T. Ottawa Heart Study: L.C., R.M., R.R., G.A.W. and A.F.R.S. PennCATH/MedSTAR: M.L., M.S.B., J.D., S.E.E., H.H.H., D.J.R., M.P.R., V.M. and C.W.K. MIGEN: S.K., B.F.V., S.M.S., V.S., R.E., O.M., C.J.O., L.P., D.S.S. and D.A. COROGENE: M.P., P.S., V.S., L.P., I.S., J. Sinisalo and M.S.N. Celiac disease. D.A.v.H.

Corresponding author

Correspondence to Nicole Soranzo.

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DOI

https://doi.org/10.1038/ng.467

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