Article | Published:

Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium

Nature Genetics volume 41, pages 11911198 (2009) | Download Citation

Abstract

Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 × 10−8 to 7 × 10−86). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.

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Acknowledgements

Complete study acknowledgments are listed in the Supplementary Note. The authors thank the studies' participants and staff and the funding agencies for their support.

Author information

Author notes

    • Santhi K Ganesh
    • , Neil A Zakai
    • , Frank J A van Rooij
    • , Nicole Soranzo
    • , Albert V Smith
    • , Michael A Nalls
    • , Andreas Greinacher
    • , Christopher J O'Donnell
    • , Jacqueline C M Witteman
    • , Susan Furth
    • , Mary Cushman
    • , Tamara B Harris
    •  & Jing-Ping Lin

    These authors contributed equally to this work.

Affiliations

  1. National Human Genome Research Institute, Division of Intramural Research, Bethesda, Maryland, USA.

    • Santhi K Ganesh
  2. National Heart, Lung, and Blood Institute (NHLBI), Division of Intramural Research, Bethesda, Maryland, USA.

    • Santhi K Ganesh
    • , Caroline S Fox
    • , Daniel Levy
    •  & Christopher J O'Donnell
  3. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

    • Santhi K Ganesh
    • , Georg B Ehret
    •  & Aravinda Chakravarti
  4. Departments of Medicine and Pathology, University of Vermont, Burlington, Vermont, USA.

    • Neil A Zakai
    •  & Mary Cushman
  5. Department of Epidemiology, Erasmus Medical Center (MC), Rotterdam, The Netherlands.

    • Frank J A van Rooij
    • , Abbas Dehghan
    • , Germaine C Verwoert
    • , Janine F Felix
    • , Albert Hofman
    • , André G Uitterlinden
    • , Ben A Oostra
    • , Cornelia M van Duijn
    •  & Jacqueline C M Witteman
  6. The Netherlands Genomics Initiative–sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden, The Netherlands.

    • Frank J A van Rooij
    • , Abbas Dehghan
    • , Germaine C Verwoert
    • , Janine F Felix
    • , Albert Hofman
    • , André G Uitterlinden
    • , Ben A Oostra
    • , Cornelia M van Duijn
    •  & Jacqueline C M Witteman
  7. Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK.

    • Nicole Soranzo
    • , Willem H Ouwehand
    •  & Panos Deloukas
  8. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Nicole Soranzo
    • , L Adrienne Cupples
    •  & Tim D Spector
  9. Icelandic Heart Association, Kopavogur, Iceland.

    • Albert V Smith
    • , Thor Aspelund
    • , Gudny Eiriksdottir
    •  & Vilmundur Gudnason
  10. Laboratory of Neurogenetics, National Institute of Aging (NIA), National Institutes of Health (NIH), Bethesda, Maryland, USA.

    • Michael A Nalls
    •  & Andrew B Singleton
  11. NHLBI's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Ming-Huei Chen
    • , Qiong Yang
    • , Caroline S Fox
    • , Daniel Levy
    • , L Adrienne Cupples
    •  & Christopher J O'Donnell
  12. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Ming-Huei Chen
  13. Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, USA.

    • Anna Kottgen
    • , Andrew Jaffe
    •  & Josef Coresh
  14. Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Nicole L Glazer
    •  & Bruce M Psaty
  15. Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA.

    • Nicole L Glazer
    • , Joshua C M Bis
    •  & Bruce M Psaty
  16. Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Brigitte Kuhnel
    • , Christa Meisinger
    •  & Christian Gieger
  17. University of Iceland, Reykjavik, Iceland.

    • Thor Aspelund
    •  & Vilmundur Gudnason
  18. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Qiong Yang
  19. Longitudinal Studies Section–Clinical Research Branch, NIA, NIH, Baltimore, Maryland, USA.

    • Toshiko Tanaka
    •  & Luigi Ferrucci
  20. MedStar Research Institute, Hyattsville, Maryland, USA.

    • Toshiko Tanaka
  21. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Germaine C Verwoert
    •  & André G Uitterlinden
  22. Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-Universität Greifswald, Greifswald, Germany.

    • Alexander Teumer
  23. Laboratory for Epidemiology, Demography, and Biometry, NIA, NIH, Bethesda, Maryland, USA.

    • Jack M Guralnik
    • , Kushang V Patel
    • , Lenore J Launer
    •  & Tamara B Harris
  24. Cardiology Center, Geneva University Hospital, Geneva, Switzerland.

    • Georg B Ehret
  25. Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • Kenneth Rice
    •  & Thomas Lumley
  26. Department of Haematology, University of Cambridge and National Health Service Blood and Transplant, Long Road, Cambridge, UK.

    • Augusto Rendon
    • , Jennifer G Sambrook
    •  & Willem H Ouwehand
  27. Human Genetics Center, University of Texas Health Science Center, Houston, Texas, USA.

    • Eric Boerwinkle
  28. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Jerome I Rotter
  29. Intramural Research Program, Laboratory of Neurogenetics, NIA, NIH, Bethesda, Maryland, USA.

    • Dena G Hernandez
  30. Office of Biostatistical Research, Division of Cardiovascular Sciences, NHLBI, NIH, Bethesda, Maryland, USA.

    • Gang Zheng
    •  & Jing-Ping Lin
  31. Geriatric Unit ASF, Firenze, Italy.

    • Stefania Bandinelli
  32. Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, The Netherlands.

    • André G Uitterlinden
  33. Leiden University Medical Center, Leiden, The Netherlands.

    • Janine M vanGils
  34. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Ben A Oostra
  35. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.

    • Jaap-Jan Zwaginga
  36. Department of Experimental Immunohematology, Sanquin Research, Amsterdam, The Netherlands.

    • Jaap-Jan Zwaginga
  37. Department of Haematology, King's College London, London, UK.

    • Swee-Lay Thein
  38. Institut für Klinische Chemie und Laboratoriumsmedizin, Ernst-Moritz-Arndt Universität Greifswald, Greifswald, Germany.

    • Matthias Nauck
  39. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  40. Department of Health Services, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  41. Group Health Research Institute, Group Health, Seattle, Washington, USA.

    • Bruce M Psaty
  42. Institut für Immunologie und Transfusionsmedizin, Ernst-Moritz-Arndt-Universität Greifswald, Greifswald, Germany.

    • Andreas Greinacher
  43. Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Christopher J O'Donnell
  44. Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

    • Susan Furth

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Contributions

AGES: Study design and phenotype collection, T.B.H.,V.G., L.J.L., G.E.; data analysis, A.V.S., M.A.N., T.A.; manuscript preparation, M.A.N., N.S.; manuscript revisions, T.B.H.,V.G., L.J.L., A.V.S., A.B.S., D.G.H., M.A.N. ARIC: Study design and phenotype collection, E.B., J.C., S.F., A.C.; genotyping, E.B., A.C.; data analysis, S.K.G., A.K., A.C., A.G., G.B.E., A.J.; manuscript preparation, S.K.G., S.F.; manuscript revisions, S.K.G., A.C., E.B., J.C., A.K., S.F. CHS: Study design and phenotype collection, B.M.P., J.I.R., M.C., N.A.Z., N.L.G.; genotyping, J.I.R.; data analysis, N.L.G, T.L.; manuscript preparation, N.A.Z.; manuscript revisions, B.M.P., J.C.M.B., K.R., J.I.R., M.C., N.A.Z., N.L.G., T.L. FHS: Study design and phenotype collection, M.-H.C., Q.Y., C.S.F., D.L., L.A.C., C.J.O., J.-P.L.; data analysis, M.-H.C., Q.Y., J.-P.L., G.Z.; manuscript preparation, M.-H.C., C.J.O., J.-P.L.; manuscript revisions, M.-H.C., Q.Y., C.S.F., D.L., L.A.C., C.J.O., J.-P.L. Rotterdam: Study design and phenotype collection, F.J.A.v.R., A.H., A.G.U., B.A.O., C.M.v.D., J.C.M.W.; genotyping, A.G.U.; data analysis, F.J.A.v.R., J.F.F., A.D., G.C.V.; manuscript preparation, F.J.A.v.R., J.F.F., C.M.v.D.; manuscript revisions, F.J.A.v.R., J.F.F., A.D., G.C.V., A.H., A.G.U., B.A.O., C.M.v.D., J.C.M.W. InCHIANTI: Study design and phenotype collection, L.F., J.M.G., S.B.; data analysis, M.A.N., T.T.; manuscript preparation, M.A.N.; manuscript revisions, L.F., J.M.G., S.B., K.V.P., A.B.S., D.G.H., M.A.N., T.T. HaemGen: A.R., J.-J.Z., J.M.vG. Twins UK: Study design and phenotype collection, T.D.S., S.-L.T., P.D.; data analysis and manuscript preparation and revisions, N.S. UKBS1: Study design and phenotype collection, W.H.O., J.G.S.; data analysis, N.S.; manuscript preparation and revisions, N.S., A.R. KORA: Study design and phenotype collection, C.M., C.G.; data analysis, C.G., B.K.; manuscript preparation and revisions, C.G. SHIP: Study design and phenotype collection, M.N., A.G.; data analysis, A.T.; gene expression, A.R., J.-J.Z., J.M.vG.

Competing interests

A. Chakravarti is a paid member of the Scientific Advisory Boards of Affymetrix and Pyxis Genomics. These potential conflicts of interest are managed by the policies of Johns Hopkins University School of Medicine.

Corresponding authors

Correspondence to Santhi K Ganesh or Christopher J O'Donnell.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Tables 1, 2, 4 and 5, Supplementary Figures 1 and 2, and Supplementary Note

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    Supplementary Table 3

    All CHARGE meta analysis results.

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DOI

https://doi.org/10.1038/ng.466

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