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Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium

Nature Genetics volume 41, pages 1191–1198 (2009)Cite this article

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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Figure 1: Overview of CHARGE meta-analysis results for six erythrocyte traits: hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV) and erythrocyte count (RBC).
Figure 2
Figure 3: Gene expression in blood and endothelial cells for genes in the chromosome 6q23.3 region.

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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

  1. 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 and Jing-Ping Lin: These authors contributed equally to this work.

Authors and Affiliations

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

    Santhi K Ganesh

  2. Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI), 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. Division of Cardiovascular Sciences, Office of Biostatistical Research, 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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  1. Santhi K Ganesh
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  2. Neil A Zakai
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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.

Corresponding authors

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

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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.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1, 2, 4 and 5, Supplementary Figures 1 and 2, and Supplementary Note (PDF 3493 kb)

Supplementary Table 3

All CHARGE meta analysis results. (XLS 288 kb)

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Ganesh, S., Zakai, N., van Rooij, F. et al. Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. Nat Genet 41, 1191–1198 (2009). https://doi.org/10.1038/ng.466

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